Orthopaedic implant materials drive M1 macrophage polarization in a Spleen Tyrosine Kinase- and Mitogen-Activated Protein Kinase-dependent manner.

Publication date: Available online 2 November 2017
Source:Acta Biomaterialia
Author(s): Olwyn R. Mahon, Sarah O'Hanlon, Clare Cunningham, Geraldine M McCarthy, Christopher Hobbs, Valeria Nicolosi, Daniel J. Kelly, Aisling Dunne
Total joint replacements (TJR) are costly procedures required to relieve pain and restore function in patients suffering from end-stage arthritis. Despite great progress in the development and durability of TJRs, the generation of prosthesis-associated wear particles over time leads to an inflammatory cascade which culminates in periprosthetic osteolysis. Studies suggest that wear particles drive the polarization/differentiation of immature macrophages towards a pro-inflammatory M1 phenotype rather than an anti-inflammatory M2 phenotype associated with normal bone and wound healing. This, in turn, contributes to the initiation of peri-implant inflammation. As a result, modulating M1 macrophage cytokine production has been recognised as a viable therapeutic option. The aim of this study was to examine the impact of hydroxyapatite (HA) and poly(methyl methacrylate) (PMMA) particles on human macrophage polarization by comparing their effect on M1/M2-associated gene expression using real-time PCR. Furthermore, using immunoblotting to assess kinase activation, we sought to identify the intracellular signalling molecules activated by PMMA/HA particles and to determine whether pharmacological blockade of these molecules impacts on macrophage phenotype and cytokine production as measured by ELISA. We report that wear particles preferentially polarize macrophages towards an M1 phenotype, an effect that is dependent on activation of the membrane proximal kinase, Syk and members of the mitogen-activated protein kinase (MAPK) family of signalling molecules. Pre-treatment of macrophages with Syk inhibitors (R788/piceatannol) or MAPK inhibitors (SB203580 and PD98059), not only prevents M1 polarization, but also attenuates production of key pro-inflammatory mediators that have been specifically implicated in periprosthetic osteolysis and osteoclast differentiation.Statement of SignificanceIt is now well established that wear-debris particles from implanted materials drive deleterious inflammatory responses which can eventually lead to implant loosening. In this study, we provide further insight into the specific cellular pathways activated by wear particles in primary human immune cells. We demonstrate that PMMA bone cement and hydroxyapatite, a commonly used biomaterial, drive the polarization of macrophages towards an inflammatory phenotype and identify the specific signalling molecules that are activated in this process. Pre-treatment of macrophages with pharmacological inhibitors of these molecules in turn prevents macrophage polarization and dampens inflammatory cytokine production. Hence these signalling molecules represent potential therapeutic targets to treat or possibly prevent particulate induced osteolysis.

Graphical abstract

http://ift.tt/2iXnAQY

Regarding complications following completion lymphadenectomy

Publication date: Available online 2 November 2017
Source:European Journal of Surgical Oncology
Author(s): Mark B. Faries, Alistair J. Cochran, John F. Thompson




http://ift.tt/2z9lDYn

Performance and microbial characteristics of biomass in a full-scale aerobic granular sludge wastewater treatment plant

Abstract

By modification of the operational conditions of batch reactors, a municipal wastewater treatment plant was upgraded from activated sludge to aerobic granular sludge (AGS) technology. After upgrading, the volume of the biological reactors was reduced by 30%, but the quality of the effluent substantially improved. The concentration of biomass in the reactors increased twofold; the average biomass yield was 0.6 g MLVSS/g COD, and excess granular sludge was efficiently stabilized in aerobic conditions. Canonical correspondence analysis based on the results of next-generation sequencing showed that the time of adaptation significantly influenced the microbial composition of the granules. In mature granules, the abundance of ammonium-oxidizing bacteria was very low, while the abundance of the nitrite-oxidizing bacteria Nitrospira sp. was 0.5 ± 0.1%. The core genera were Tetrasphaera, Sphingopyxis, Dechloromonas, Flavobacterium, and Ohtaekwangia. Bacteria belonging to these genera produce extracellular polymeric substances, which stabilize granule structure and accumulate phosphorus. The results of this study will be useful for designers of AGS wastewater treatment plants, and molecular data given here provide insight into the ecology of mature aerobic granules from a full-scale facility.

http://ift.tt/2lKhHI6

Advanced scoring method of eco-efficiency in European cities

Abstract

This paper analyzes a set of selected German and French cities' performance in terms of the relative behavior of their eco-efficiencies, computed as the ratio of their gross domestic product (GDP) over their CO₂ emissions. For this analysis, eco-efficiency scores of the selected cities are computed using the data envelopment analysis (DEA) technique, taking the eco-efficiencies as outputs, and the inputs being the energy consumption, the population density, the labor productivity, the resource productivity, and the patents per inhabitant. Once DEA results are analyzed, the Malmquist productivity indexes (MPI) are used to assess the time evolution of the technical efficiency, technological efficiency, and productivity of the cities over the window periods 2000 to 2005 and 2005 to 2008. Some of the main conclusions are that (1) most of the analyzed cities seem to have suboptimal scales, being one of the causes of their inefficiency; (2) there is evidence that high GDP over CO₂ emissions does not imply high eco-efficiency scores, meaning that DEA like approaches are useful to complement more simplistic ranking procedures, pointing out potential inefficiencies at the input levels; (3) efficiencies performed worse during the period 2000–2005 than during the period 2005–2008, suggesting the possibility of corrective actions taken during or at the end of the first period but impacting only on the second period, probably due to an increasing environmental awareness of policymakers and governors; and (4) MPI analysis shows a positive technological evolution of all cities, according to the general technological evolution of the reference cities, reflecting a generalized convergence of most cities to their technological frontier and therefore an evolution in the right direction.

http://ift.tt/2A4RAxL

Low-level laser therapy prevents endothelial cells from TNF-α/cycloheximide-induced apoptosis

Abstract

Low-level laser therapy (LLLT), widely used in physiotherapy, has been known to enhance wound healing and stimulate cell proliferation, including fibroblast and endothelial cells. Applying LLLT can increase cell proliferation in many kinds of cells including fibroblasts and endothelial cells. However, the protective mechanisms of LLLT on endothelial apoptosis remain unclear. We hypothesized LLLT can protect endothelial cells from inflammation-induced apoptosis. Human endothelial cell line, EA.hy926 cells, and TNF-α/cycloheximide (TNF/CHX) were used to explore the protective effects of LLLT (660 nm) on inflammation-induced endothelial apoptosis. Cell viability, apoptosis, caspase-3/7/8/9 activity, MAPKs signaling, NF-κB activity, and inducible/endothelial nitric oxide synthase (iNOS/eNOS) expression were measured. Our results showed that LLLT increased EA.hy926 cell proliferation, attenuated the TNF/CHX-induced apoptosis, and reduced the TNF/CHX-mediated caspase-3/7/8/9 activation. In addition, LLLT increased ERK MAPK phosphorylation and suppressed the TNF/CHX-increased p38 MAPK, JNK, IKK phosphorylation, NF-κB translocation, and iNOS expression. The caspases-3 cleavage and cell death were not increased in cells treating with ERK inhibitor U0126, which implicated that ERK is not to be responsible for the protective effects of LLLT. After treating with p38 mitogen-activated protein kinase (MAPK) activator, the protection of LLLT in cell apoptosis was no longer existed, showing that LLLT protected the endothelial cells by suppressing p38 MAPK signaling. Our results provide a new insight into the possible molecular mechanisms in which LLLT protects against inflammatory-induced endothelial dysfunction.

http://ift.tt/2gWgVCC

A study on diffusion and kurtosis features of cervical cancer based on non-Gaussian diffusion weighted model

Publication date: Available online 2 November 2017
Source:Magnetic Resonance Imaging
Author(s): Panying Wang, Deepa Thapa, Guangyao Wu, Qunqi Sun, Hongbing Cai, Fei Tuo
ObjectiveTo explore the diffusion and kurtosis features of cervical cancer (CC) and study the feasibility of diffusion kurtosis imaging (DKI) based on the non-Gaussian diffusion-weighted model to differentiate the stage and grade of CC.MethodsA total of 50 patients with pathologically confirmed CC were enrolled. MRI examinations including DKI (with 5b values 200, 500, 1000, 1500, and 2000smm⁻² were performed before any treatment. The apparent coefficient (Dapp) and the apparent kurtosis value (Kapp) were derived from the non-gaussian diffusion model, and the apparent diffusion coefficient (ADC) was derived from the Gaussian model. The parameters of CC and normal tissue (myometrium) were obtained, analyzed statistically, and evaluated with respect to differentiating stage and grade between the tissue and the CC.ResultsADC and Dapp values of CC were significantly lower than that of the normal myometrium (P=0.024 and P<0.001, respectively), while the Kapp value was not found to exhibit a significant difference. Compared to the well/moderately differentiated CC, poorly differentiated CC had a significantly decreased mean ADC and Dapp (P=0.018 and P=0.026, respectively); however, the mean Kapp (P=0.035) increased significantly. In the clinical staging, the DKI sequence was advantageous over conventional MRI sequences (degree of accuracy: 90% vs. 74%), Although in the quantitative analysis, these parameters did not show a significant difference.ConclusionsThe pilot study demonstrated that these diffusion and kurtosis indices from DKI based on the non-Gaussian diffusion-weighted model putatively differentiated the grade and stage of CC.



http://ift.tt/2gYhL1x

Synthesis, nature and utility of universal iron chelator − siderophore: a review

Publication date: Available online 1 November 2017
Source:Microbiological Research
Author(s): Azmi Khan, Pratika Singh, Amrita Srivastava
Siderophores, the secondary metabolite of various microorganisms are ferric ion specific chelators secreted under iron stressed condition. These non-ribosomal peptides have been classified as catecholate, hydroxamate, carboxylate and mixed types. Recent studies focus on discovery of possible mammalian siderophores. The biosynthesis pathway including non-ribosomal dependent as well as non-ribosomal independent pathways are of great interest now a days. Many significant roles of siderophores such as virulence in pathogens, oxidative stress tolerance, classification of organisms etc. are being discovered. Studies on siderophore utilization in bioremediation and other heavy metal chelation have increased in past decade. The iron chelation ability of siderophores is being recently studied with regards to malignant cancerous cells. Not only this, it has been found that they possess antimicrobial properties which can be utilized against number of microbes. This review covers all recent aspects of siderophore and its applications.



http://ift.tt/2A1va0k

CO2: Editorial Board/Subscription info.

Publication date: November 2017
Source:Progress in Neurobiology, Volume 158





http://ift.tt/2A1Dygd

And yet it moves: Recovery of volitional control after spinal cord injury

Publication date: Available online 1 November 2017
Source:Progress in Neurobiology
Author(s): G. Taccola, D. Sayenko, P. Gad, Y.P. Gerasimenko, V.R. Edgerton
Preclinical and clinical neurophysiological and neurorehabilitation research has generated rather surprising levels of recovery of volitional sensory-motor function in persons with chronic motor paralysis following a spinal cord injury. The key factor in this recovery is largely activity-dependent plasticity of spinal and supraspinal networks. This key factor can be triggered by neuromodulation of these networks with electrical and pharmacological interventions. This review addresses some of the systems-level physiological mechanisms that might explain the effects of electrical modulation and how repetitive training facilitates the recovery of volitional motor control. In particular, we substantiate the hypotheses that: (1) in the majority of spinal lesions, a critical number and type of neurons in the region of the injury survive, but cannot conduct action potentials, and thus are electrically non-responsive; (2) these neuronal networks within the lesioned area can be neuromodulated to a transformed state of electrical competency; (3) these two factors enable the potential for extensive activity-dependent reorganization of neuronal networks in the spinal cord and brain, and (4) propriospinal networks play a critical role in driving this activity-dependent reorganization after injury. Real-time proprioceptive input to spinal networks provides the template for reorganization of spinal networks that play a leading role in the level of coordination of motor pools required to perform a given functional task. Repetitive exposure of multi-segmental sensory-motor networks to the dynamics of task-specific sensory input as occurs with repetitive training can functionally reshape spinal and supraspinal connectivity thus re-enabling one to perform complex motor tasks, even years post injury.

Graphical abstract

http://ift.tt/2hBfsCx

Genotoxicity of carbon tetrachloride and the protective role of essential oil of Salvia officinalis L. in mice using chromosomal aberration, micronuclei formation, and comet assay

Abstract

The present work was conducted to evaluate the genotoxic effect of carbon tetrachloride (CCl₄) in mouse bone marrow and male germ cells. The safety and the modulating activity of sage (Salvia officinalis L.) essential oil (SEO) against the possible genotoxic effect of CCl₄ were also evaluated. A combination of in vivo mutagenic endpoints was included: micronucleus (MN), apoptosis using dual acridine orange/ethidium bromide (AO/EB) staining, comet assay, chromosomal aberrations (CAs), and sperm abnormalities. Histological examination of testis tissues was also studied. The extracted SEO was subjected to gas chromatography-mass spectrometry (GC-MS) for identifying its chemical constituents. Safety/genotoxicity of SEO was determined after two consecutive weeks (5 days/week) from oral treatment with different concentrations (0.1, 0.2, and 0.4 mL/kg). For assessing genotoxicity of CCl₄, both acute (once) and subacute i.p. treatment for 2 weeks (3 days/week) with the concentrations 1.2 mL/kg (for acute) and 0.8 mL/kg (for subacute) were performed. For evaluating the protective role of SEO, simultaneous treatment with SEO plus CCl₄ was examined. In sperm abnormalities, mice were treated with the subject materials for five successive days and the samples were collected after 35 days from the beginning of treatment. Based on GC-MS findings, 22 components were identified in the chromatogram of SEO. The results demonstrated that the three concentrations of SEO were safe and non-genotoxic in all the tested endpoints. Negative results were also observed in bone marrow after acute and subacute treatment with CCl_4. In contrast, CCl₄ induced testicular DNA damage as evidenced by a significant increase of CAs in primary spermatocytes, sperm abnormalities, and histological distortion of testis. A remarkable reduction in these cells was observed in groups treated with SEO plus CCl₄ especially with the two higher concentrations of SEO. In conclusion, SEO is safe and non-genotoxic under the tested conditions and can modulate genetic damage and histological alteration induced by CCl₄ in the testes.

http://ift.tt/2iposKq

Identification and characterization of key circadian clock genes of tobacco hairy roots: putative regulatory role in xenobiotic metabolism

Abstract

The circadian clock is an endogenous system that allows organisms to daily adapt and optimize their physiology and metabolism. We studied the key circadian clock gene (CCG) orthologs in Nicotiana tabacum seedlings and in hairy root cultures (HRC). Putative genes involved in the metabolism of xenobiotic compounds (MXC) were selected and their expression profiles were also analyzed. Seedlings and HRC displayed similar diurnal variations in the expression profiles for the CCG examined under control conditions (CC). MXC-related genes also showed daily fluctuations with specific peaks of expression. However, when HRC were under phenol treatment (PT), the expression patterns of the clock and MXC-related genes were significantly affected. In 2-week-old HRC, PT downregulated the expression of NtLHY, NtTOC1, and NtPRR9 while NtFKF1 and NtGI genes were upregulated by phenol. In 3-week-old HRC, PT also downregulated the expression of all CCG analyzed and NtTOC1 was the most affected. Following PT, the expression of the MXC-related genes was upregulated or displayed an anti-phasic expression profile compared to the expression under CC. Our studies thus provide a glimpse of the circadian expression of clock genes in tobacco and the use of HRC as a convenient system to study plant responses to xenobiotic stresses.

http://ift.tt/2gYvvt7

Electric arc furnace (EAF) dust: Application of air classification for improved zinc enrichment in in-plant recycling

Publication date: 10 February 2018
Source:Journal of Cleaner Production, Volume 174
Author(s): C. Lanzerstorfer
Currently, more than half of the electric arc furnace (EAF) dust produced worldwide is still sent to landfill. This dust contains approximately 7.0% of the world Zn production. The other half of the EAF dust is processed pyrometallurgically or hydrometallurgically to recover Zn. The processing costs for EAF dust strongly depend on the Zn concentration. Therefore, several steel mills apply in-plant enrichment of Zn by recycling part of the dust back into the furnace to reduce the specific processing cost for the EAF dust and at the same time decrease the amount of dust that has to be discharged. Separation of EAF dust into size fractions by air classification showed a distinct dependence of the Zn concentration on the particle size with an enrichment of Zn in the fine size fractions and depletion in the coarse fractions. Therefore, in in-plant dust recycling, air classification of the dust could be used to reduce the amount of recycled Zn and dust but still reaching the same Zn concentration in the discharged dust. This would reduce the energy demand for Zn volatilization in the furnace and the required capacity of the dust recycling system.

Graphical abstract

http://ift.tt/2z9tOBA

Copyright

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4





http://ift.tt/2zfuJlV

Contributors

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4





http://ift.tt/2zuJSk8

Contents

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4





http://ift.tt/2zdElh3

Anesthesia Outside of the Operating Room: The Wild West or the New Frontier?

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Lee A. Fleisher




http://ift.tt/2ze45di

Anesthesia Outside the Operating Room

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Mark S. Weiss, Wendy L. Gross




http://ift.tt/2zstLUl

Demands of Integrated Care Delivery in Interventional Medicine and Anesthesiology

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Wendy L. Gross, Lebron Cooper, Steven Boggs

Teaser

Evolving financial and medical constraints fueled by the increasing repertoire of nonoperating room cases and widening scope of patient comorbidities are discussed. The need to integrate finances and care approaches is detailed, and strategic suggestions for broader collaborative practice are suggested.


http://ift.tt/2ztuvIT

Implementation and Use of Anesthesia Information Management Systems for Non–operating Room Locations

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Jason T. Bouhenguel, David A. Preiss, Richard D. Urman

Teaser

Non–operating room anesthesia (NORA) encounters comprise a significant fraction of contemporary anesthesia practice. With the implemention of an aneshtesia information management system (AIMS), anesthesia practitioners can better streamline preoperative assessment, intraoperative automated documentation, real-time decision support, and remote surveillance. Despite the large personal and financial commitments involved in adoption and implementation of AIMS and other electronic health records in these settings, the benefits to safety, efficacy, and efficiency are far too great to be ignored. Continued future innovation of AIMS technology only promises to further improve on our NORA experience and improve care quality and safety.


http://ift.tt/2zdE1il

An Anesthesiologist’s View of Tumor Ablation in the Radiology Suite

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Annie Amin, Jason Lane, Thomas Cutter

Teaser

The advent of radiology image–guided tumor ablation procedures has opened up a new era in minimally invasive procedures. Using CT, MRI, ultrasound, and other modalities, radiologists and surgeons can now ablate a tumor through percutaneous entry sites. What traditionally was done in an operating room via large open incisions, with multiple days in the hospital recovering, is now becoming an outpatient procedure via these new techniques. Anesthesiologists play a critical role in optimizing outcome in these patients. Knowledge by anesthesiologists of procedural goals, technology used, and inherit safety concerns of anesthetizing patients in the radiology suite are all critical to patients and proceduralists.


http://ift.tt/2ztue8P

A Radiologist’s View of Tumor Ablation in the Radiology Suite

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Sharath K. Bhagavatula, Jason Lane, Paul Shyn

Teaser

Image-guided percutaneous, minimally invasive ablation techniques offer a wide variety of new modalities to treat tumors in some of the most medically complicated patients coming to our hospitals. The use of computed tomography, PET, ultrasound imaging, and MRI to guide radiofrequency ablation, microwave ablation, and cryoablation techniques now makes it possible to treat patients on a short stay or outpatient basis with very good immediate outcomes. This rapid expansion of new tumor ablation techniques often presents challenges for the non–operating room anesthesia team. Collaboration and communication between the radiologist and anesthesiologist are key to safety and excellent patient outcomes.


http://ift.tt/2zdVbMW

Catheterization Laboratory

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Paul N. Fiorilli, Saif Anwaruddin, Elizabeth Zhou, Ronak Shah

Teaser

The cardiac catheterization laboratory is advancing medicine by performing procedures on patients who would usually require sternotomy and cardiopulmonary bypass. These procedures are done percutaneously, allowing them to be performed on patients considered inoperable. Patients have compromised cardiovascular function or advanced age. An anesthesiologist is essential for these procedures in case of hemodynamic compromise. Interventionalists are becoming more familiar with transcatheter aortic valve replacement and the device has become smaller, both contributing to less complications. Left atrial occlusion and the endovascular edge-to-edge mitral valve repair devices were approved. Although these devices require general anesthesia, an invasive surgery and cardiopulmonary bypass machine are not necessary for deployment.


http://ift.tt/2zstkJH

Anesthesia in the Electrophysiology Laboratory

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Jeff E. Mandel, William G. Stevenson, David S. Frankel

Teaser

The electrophysiology suite is a foreign location to many anesthesiologists. The initial experience was with shorter procedures under conscious sedation, and the value of greater tailoring of the sedation/anesthesia by anesthesiologists was not perceived until practice patterns had already been established. Although better control of ventilation with general anesthesia may be expected, suppression of arrhythmias, blunting of the hemodynamic adaptation to induced arrhythmias, and interference by muscle relaxants with identification of the phrenic nerve may be seen. We review a range of electrophysiology procedures and discuss anesthetic approaches that balance patient safety and favorable outcomes.


http://ift.tt/2zdV7Nc

Cardioversions and Transthoracic Echocardiography

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Ronak Shah, Elizabeth Zhou

Teaser

Patients with atrial fibrillation and flutter routinely require transesophageal echocardiography with cardioversion. It is not uncommon to encounter patients with reduced ejection fractions, coronary artery disease, prior cardiac surgery, or obstructive sleep apnea. The anesthesiologist must carefully evaluate the patient and any available laboratory and study findings to assess for potential complications after anesthesia. Appropriate anesthetics must be chosen based on the preoperative evaluation. Additionally, because most of these cases are done without a secured airway, emergency medications and airway equipment must be readily available.


http://ift.tt/2ztu15x

Anesthesia for Routine and Advanced Upper Gastrointestinal Endoscopic Procedures

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): Christopher D. Sharp, Ezekiel Tayler, Gregory G. Ginsberg

Teaser

This article aims to detail the breadth and depth of advanced upper gastrointestinal endoscopic procedures. It will focus on sedation and airway management concerns pertaining to this emerged and emerging class of minimally invasive interventions. The article will also cover endoscopic hemostasis, endoscopic resection, stenting and Barrett eradication therapy plus endoscopic ultrasound. It additionally will address the nuances of endoscopic retrograde cholangiopancreatography and new natural orifice transluminal endoscopic surgery procedures including endoscopic cystgastrostomy and the per-oral endoscopic myotomy procedure.


http://ift.tt/2zdV4B0

Anesthesia for Colonoscopy and Lower Endoscopic Procedures

Publication date: December 2017
Source:Anesthesiology Clinics, Volume 35, Issue 4
Author(s): John Michael Trummel, Vinay Chandrasekhara, Michael L. Kochman

Teaser

Demand for anesthesiologist-assisted sedation is expanding for gastrointestinal lower endoscopic procedures and may add to the cost of these procedures. Most lower endoscopy can be accomplished with either no, moderate, or deep sedation; general anesthesia and active airway management are rarely needed. Propofol-based sedation has advantages in terms of satisfaction and recovery over other modalities, but moderate sedation using benzodiazepines and opiates work well for low-risk patients and procedures. No sedation for routine colonoscopy works well for selected patients and eliminates sedation-related risks. There is no difference in outcome measures based on sedation received.


http://ift.tt/2ztwcWQ

Evidence for the formal development of trauma subspecialty within plastic surgery in the united kingdom.

The Royal College of Surgeons working group on trauma recently recommended the reorganization of Plastic surgery training to incorporate a trauma subspeciality as a means to provide a sustainable workforce for trauma care provision nationally. The aim of this work was to gauge trainee opinion and aspiration in order to advice and shape the future of trauma training to meet this potential need. An online survey was conducted of UK Plastic surgical trainees to assess their interest in subspecialisiing in trauma.

http://ift.tt/2z9zj3f

Targeted muscle reinnervation for pain control in an elective transradial amputation

Targeted muscle reinnervation (TMR) is primarily used to transfer residual nerves of the amputated upper limb to reinnervate alternate target muscle groups, for intuitive control of a myoelectric prosthesis. Furthermore, TMR can significantly reduce the incidence of neuropathic and neuroma-related pain compared with conventional amputation techniques, by providing each nerve 'somewhere to go and something to do'.We report the use of TMR in a case of elective transradial amputation for intractable severe chronic post-traumatic and end neuroma limb pain (constant VAS pain score 10/10), 2 years following a severe crush injury to his left hand.

http://ift.tt/2iVMLDM

The liquid facelift: first hands-on experience with facial water jet-assisted liposuction as an additive technique for rhytidectomy - a case series of 25 patients

Recently, water jet-assisted liposuction (WAL) was successfully applied by several other authors to remove fat and induce skin contraction in non-facial body areas. Extending the range of indications for this new method, the authors of this article report on their first experience with its use in facial contouring, fat harvesting, and hydrodissection of the facial skin flap in rhytidectomy in a case series of 25 patients.

http://ift.tt/2z9zeMZ

Rapidly growing mycobacteria infections among “cosmetic tourists” returning to the netherlands

Medical tourism for cosmetic surgery is becoming increasingly popular1. Most cosmetic tourists travel to developing parts of the world, such as Latin America and South Asia.2 Cosmetic surgery abroad has advantages such as shorter waiting lists, anonymity and lower costs, combined with a vacation.1-2 Although this seems appealing, it also carries risks.

http://ift.tt/2iWOUyQ

3D graphene-based nanostructured materials as sorbents for cleaning oil spills and for the removal of dyes and miscellaneous pollutants present in water

Abstract

Oil spills over seawater and dye pollutants in water cause economic and environmental damage every year. Among various methods to deal oil spill problems, the use of porous materials has been proven as an effective strategy. In recent years, graphene-based porous sorbents have been synthesized to address the shortcomings associated with conventional sorbents such as their low uptake capacity, slow sorption rate, and non-recyclability. This article reviews the research undertaken to control oil spillage using three-dimensional (3D) graphene-based materials. The use of these materials for removal of dyes and miscellaneous environmental pollutants from water is explored and the application of various multifunctional 3D oil sorbents synthesized by surface modification technique is presented. The future prospects and limitations of these materials as sorbents are also discussed.

http://ift.tt/2AcnOrR

The Gαq/11-provoked induction of Akr1c18 in murine luteal cells is mediated by phospholipase C

Publication date: Available online 2 November 2017
Source:Molecular and Cellular Endocrinology
Author(s): Joshua Kapfhamer, Courtney Waite, Mario Ascoli
Towards the end of gestation prostaglandin F2α (PGF2α) stimulates the expression of Akr1c18 in the murine corpus luteum. Akr1c18 codes for 20α-hydroxysteroid dehydrogenase, an enzyme that precipitates parturition by catabolizing progesterone.Previous results from our laboratory have shown that this effect of PGF2α is mediated by the activation of Gαq/11, but the downstream effector(s) of Gαq/11 that elicit the increase in Akr1c18 expression have not been identified. The physiological effects of Gαq/11 are mediated by its ability to interact with phospholipase Cβ, p63RhoGEF, and PKCζ. In the experiments described herein we used biochemical and pharmacological approaches, as well as adenoviral-mediated expression of a constitutively active form of Gαq and mutants thereof, to examine the role of each of these effectors as potential mediators of the increased expression of luteal Akr1c18.By measuring the effects of PGF2α on the activation of RhoA (activated by p63RhoGEF) and the effects of activators and inhibitors of RhoA on the PGF2α-induced expression of luteal Akr1c18, we determined that RhoA is neither activated by PGF2α or involved in the PGF2α-induced expression of luteal Akr1c18. The potential involvement of PKCζ was ruled out by the inability of a mutant of a constitutively active Gαq that prevents PKCζ binding to block the increased expression of Akr1c18. Furthermore, PGF2α does not increase the phosphorylation of ERK-5, the only known downstream target of PKCζ. On the other hand, three different mutants of a constitutively active Gαq that prevent phospholipase C activation blocked the induction of luteal Akr1c18. We conclude that the induction of luteal Akr1c18 by Gαq/11 is mediated by the activation of phospholipase C.



http://ift.tt/2xSrEEU

Gonadotropin regulation by pulsatile GnRH: Signaling and gene expression

Publication date: Available online 1 November 2017
Source:Molecular and Cellular Endocrinology
Author(s): George A. Stamatiades, Ursula B. Kaiser
The precise orchestration of hormonal regulation at all levels of the hypothalamic-pituitary-gonadal axis is essential for normal reproductive function and fertility. The pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by pituitary gonadotropes. GnRH acts by binding to its high affinity seven-transmembrane receptor (GnRHR) on the cell surface of anterior pituitary gonadotropes. Different signaling cascades and transcriptional mechanisms are activated, depending on the variation in GnRH pulse frequency, to stimulate the synthesis and release of FSH and LH. While changes in GnRH pulse frequency may explain some of the differential regulation of FSH and LH, other factors, such as activin, inhibin and sex steroids, also contribute to gonadotropin production. In this review, we focus on the transcriptional regulation of the gonadotropin subunit genes and the signaling pathways activated by pulsatile GnRH.



http://ift.tt/2h9pY6O

Optimization of Peptide-based Polyagonists for Treatment of Diabetes and Obesity

Publication date: Available online 2 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Patrick Knerr, Brian Finan, Vasily Gelfanov, Diego Perez-Tilve, Matthias H. Tschöp, Richard D. DiMarchi

Graphical abstract

http://ift.tt/2iqgPU6

Examining the bleeding incidences associated with targeted therapies used in metastatic renal cell carcinoma

Publication date: Available online 1 November 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): MacKenzie Crist, Elizabeth Hansen, Lipika Chablani, Elizabeth Guancial
A systematic review was conducted to illustrate the bleeding risks associated with targeted therapies used in the treatment of metastatic renal cell carcinoma (mRCC). Eligible studies included phase II, III, or IV clinical trials using pazopanib, sunitinib, cabozantinib, lenvatinib, everolimus, temsirolimus, bevacizumab, axitinib, and/or sorafenib in the setting of mRCC. Types of bleeding event(s), bleeding event frequency, and incidence of thrombocytopenia were collected from the relevant articles. ClinicalTrials.gov was also searched for incidence of "Serious bleeding adverse effects" reported in these trials. The incidences of bleeding events ranged from 1 to 36%, and incidences of thrombocytopenia ranged from 2 to 78%. Available serious bleeding adverse events ranged from 1 to 7%. The highest percentage of bleeding incidences were seen with bevacizumab, while the lowest percentage of bleeding incidences were seen with axitinib. All of the included trials were of high quality per Jadad scoring.



http://ift.tt/2ypXL34

Enzymatic dynamics into the Eisenia fetida (Savigny, 1826) gut during vermicomposting of coffee husk and market waste in a tropical environment

Abstract

Epigeic worms modify microbial communities through their digestive processes, thereby influencing the decomposition of organic matter in vermicomposting systems. Nevertheless, the enzyme dynamics within the gut of tropically adapted earthworms is unknown, and the enzymes involved have not been simultaneously studied. The activities of 19 hydrolytic enzymes within three different sections of the intestine of Eisenia fetida were determined over a fasting period and at 24 h and 30, 60, and 90 days of vermicomposting, and data were evaluated by multivariate analyses. There were found positive correlations between the maximal activity of glycosyl hydrolases and one esterase with the anterior intestine (coincident with the reduction of hemicellulose in the substrate) and the activity of the protease α-chymotrypsin with posterior intestine. The results suggest that activities of enzymes change in a coordinated manner within each gut section, probably influenced by selective microbial enzyme enrichment and by the availability of nutrients throughout vermicomposting.

http://ift.tt/2h7zGH2

Ovarian growth impairment after chronic exposure to Roundup Ultramax® in the estuarine crab Neohelice granulata

Abstract

Adult females of the estuarine crab Neohelice granulata were exposed to the glyphosate formulation Roundup Ultramax® during the entire 3-month pre-reproductive period. At the end of the assay, a significant higher increment of glycemia was noted at both glyphosate concentrations assayed (0.01 and 0.2 mg/L, acid equivalent). Although no differences were observed in the gonadosomatic index, a significantly higher proportion of reabsorbed vitellogenic oocyte was observed at the highest glyphosate concentration, together with a significant decrease of vitellogenin content in the ovary. In addition, some in vitro assays were carried out by co-incubating small pieces of ovary with or without the addition of Roundup; at both concentrations tested (same as those used in vivo), a decrease in the ovarian vitellogenin content was observed, whereas the ovarian protein synthesis was significantly inhibited by glyphosate at 0.2 mg/L in the Roundup formulation used.

http://ift.tt/2zaWhJq

Literature Commentary.

In this issue of Journal of Neuro-Ophthalmology, M. Tariq Bhatti, MD and Mark L. Moster, MD will discuss the following 6 articles: 1. Davoudi S, Ebrahimiadib N, Yasa C, Sevgi DD, Roohipoor R, Papavasilieou E, Comander J, Sobrin L. Outcomes in autoimmune retinopathy patients treated with rituximab. Am J Ophthalmol. 2017;180:124-132. 2. Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand'Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376:2122-2133. 3. Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Muller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I; Movement Disorder Society-Endorsed PSP Study Group. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. 2017;32:853-864. 4. Sodhi M, Sheldon CA, Carleton B, Etminan M. Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome: nested case-control study. Neurology. 2017;89:792-795. 5. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, Uhara H, Hasegawa Y, Inomata S, Otani Y, Yokota K, Hirose T, Tanaka R, Suzuki N, Matsui M. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89:1127-1134. 6. Hennes EM, Baumann M, Schanda K, Anlar B, Bajer-Kornek B, Blaschek A, Brantner-Inthaler S, Diepold K, Eisenkolbl A, Gotwald T, Kuchukhidze G, Gruber-Sedlmayr U, Hausler M, Hoftberger R, Karenfort M, Klein A, Koch J, Kraus V, Lechner C, Leiz S, Leypoldt F, Mader S, Marquard K, Poggenburg I, Pohl D, Pritsch M, Raucherzauner M, Schimmel M, Thiels C, Tibussek D, Vieker S, Zeches C, Berger T, Reindl M, Rostasy K; BIOMARKER Study Group. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017;89:900-908. (C) 2017 by North American Neuro-Ophthalmology Society

http://ift.tt/2zftcw7

EUNOS Meeting, September 10-13, 2017, Budapest, Hungary.

No abstract available

http://ift.tt/2zsuODY

The Optic Disc Drusen Studies Consortium Recommendations for Diagnosis of Optic Disc Drusen Using Optical Coherence Tomography.

Background: Making an accurate diagnosis of optic disc drusen (ODD) is important as part of the work-up for possible life-threatening optic disc edema. It also is important to follow the slowly progressive visual field defects many patients with ODD experience. The introduction of enhanced depth imaging optical coherence tomography (EDI-OCT) has improved the visualization of more deeply buried ODD. There is, however, no consensus regarding the diagnosis of ODD using OCT. The purpose of this study was to develop a consensus recommendation for diagnosing ODD using OCT. Methods: The members of the Optic Disc Drusen Studies (ODDS) Consortium are either fellowship trained neuro-ophthalmologists with an interest in ODD, or researchers with an interest in ODD. Four standardization steps were performed by the consortium members with a focus on both image acquisition and diagnosis of ODD. Results: Based on prior knowledge and experiences from the standardization steps, the ODDS Consortium reached a consensus regarding OCT acquisition and diagnosis of ODD. The recommendations from the ODDS Consortium include scanning protocol, data selection, data analysis, and nomenclature. Conclusions: The ODDS Consortium recommendations are important in the process of establishing a reliable and consistent diagnosis of ODD using OCT for both clinicians and researchers. (C) 2017 by North American Neuro-Ophthalmology Society

http://ift.tt/2zf6aWi

Predictive and prognostic potential of volume-based metabolic variables obtained by a baseline 18F-FDG PET/CT in breast cancer with neoadjuvant chemotherapy indication

Publication date: Available online 2 November 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): A.M. Garcia-Vicente, J. Pérez-Beteta, M. Amo-Salas, D. Molina, G.A. Jimenez-Londoño, A.M. Soriano-Castrejón, F.J. Pena Pardo, A. Martínez-González
AimTo investigate the usefulness of metabolic variables using ¹⁸F-FDG PET/CT in the prediction of neoadjuvant chemotherapy (NC) response and the prognosis in locally advanced breast cancer (LABC).Materials and methodsProspective study including 67 patients with LABC, NC indication and a baseline ¹⁸F-FDG PET/CT. After breast tumor segmentation, SUV variables (SUVmax, SUVmean and SUVpeak) and volume-based variables, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were obtained. Tumors were grouped into molecular phenotypes, and classified as responders or non-responders after completion of NC. Disease-free status (DFs), disease-free survival (DFS), and overall survival (OS) were assessed. A univariate and multivariate analysis was performed to study the potential of all variables to predict DFs, DFS, and OS.ResultsFourteen patients were classified as responders. Median±SD of DFS and OS was 43±15 and 46±13 months, respectively. SUV and TLG showed a significant correlation (p<0.005) with the histological response, with higher values in responders compared to non-responders. MTV and TLG showed a significant association with DFs (p=0.015 and p=0.038 respectively). Median, mean and SD of MTV and TLG for patients with DFs were: 8.90, 13.73, 15.10 and 33.78, and 90.54 and 144.64, respectively. Median, mean and SD of MTV and TLG for patients with non-DFs were: 16.72, 29.70 and 31.09 and 90.89, 210.98 and 382.80, respectively. No significant relationships were observed with SUV variables and DFs. Volume-based variables were significantly associated with OS and DFS, although in multivariate analysis only MTV was related to OS. No SUV variables showed an association with the prognosis.ConclusionVolume-based metabolic variables obtained with ¹⁸F-FDG PET/CT, unlike SUV based variables, were good predictors of both neoadjuvant chemotherapy response and prognosis.



http://ift.tt/2gXrncS

Structural basis for the recognition and processing of DNA containing bulky lesions by the mammalian nucleotide excision repair system

Publication date: Available online 2 November 2017
Source:DNA Repair
Author(s): Alexey N. Evdokimov, Alexandra Yu. Tsidulko, Alexander V. Popov, Yury N. Vorobiev, Alexander A. Lomzov, Lyudmila S. Koroleva, Vladimir N. Silnikov, Irina O. Petruseva, Olga I. Lavrik
Mammalian nucleotide excision repair (NER) eliminates the broadest diversity of bulky lesions from DNA with wide specificity. However, the double incision efficiency for structurally different adducts can vary over several orders of magnitude. Therefore, great attention is drawn to the question of the relationship among structural properties of bulky DNA lesions and the rate of damage elimination. This paper studies the properties of several structurally diverse synthetic (model) DNAs containing bulky modifications. Model DNAs have been designed using modified nucleosides (exo-N-{2-N-[N-(4-azido-2,5-difluoro-3-chloropyridin-6-yl)-3-aminopropionyl]aminoethyl}-2′-deoxycytidine (Fap-dC) and 5-{1-[6-(5[6]-fluoresceinylcarbomoyl)hexanoyl]-3-aminoallyl}-2′-deoxyuridine (Flu-dU)) and the nonnucleosidic reagent N-[6-(9-antracenylcarbomoyl)hexanoyl]-3-amino-1,2-propandiol (nAnt). The impact of these lesions on spatial organization and stability of the model DNA was evaluated. Their affinity for the damage sensor XPC was also studied. It was expected, that the values of melting temperature decrease, bending angles and KD values clearly define the row of model DNA substrate properties such as Flu-dU-DNA>>nAnt≈Fap-dC-DNA. Unexpectedly the experimentally estimated levels of the substrate properties were actually in the row: nAnt-DNA>>Flu-dU-DNA>>Fap-dC-DNA. Molecular dynamics simulations have revealed structural and energetic bases for the discrepancies observed. DNA destabilization patterns plotted explain these results on a structural basis in terms of differences in dynamic perturbations of stacking interactions.



http://ift.tt/2A25bWv

Cathelicidin-WA polarizes E. coli K88-induced M1 macrophage to M2-like macrophage in RAW264.7 cells

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Shan Chen, Zeqing Lu, Fengqin Wang, Yizhen Wang
Immune cells - macrophages induced by E. coli K88 will lead to a pro-inflammatory response, which is important in host defense. Cathelicidin-WA (CWA) is an efficient antimicrobial peptide (AMP) and can exert immunomodulatory properties. Many studies have demonstrated that AMP can modulate cellular subsets but whether CWA can regulate macrophage polarization by transferring E. coli K88-induced M1 macrophage towards M2 one that of anti-inflammation remains unclear. In this study, E. coli K88 increased the expression of pro-inflammatory cytokines interleukin-6, interleukin-1β, tumor necrosis factor-α and chemokine CCL3 in RAW264.7 cells with a time-dependent manner, as well as the expression of reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). On this basis, CWA significantly decreased the pro-inflammatory molecules but increased the anti-inflammatory mediators interleukin-4, interleukin-10 and other M2-related genes in E. coli K88-induced macrophages. Western blot analysis indicated that CWA suppressed the expression of TLR-4 and the phosphorylation of STAT1 and NF-κB which modulated M1 macrophage while induced the phosphorylation of STAT6 which activated M2 macrophage. Double staining of M1-specific CD86 and M2-specific CD206 also proved the hypothesis. These results suggested that CWA might dampen the inflammation by modulating M1 phenotype to M2 phenotype in E. coli K88-induced macrophages.



http://ift.tt/2ztlShs

Internal dosimetry of inhaled iodine-131

Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): Mitra Kiani Nasab, Laleh Rafat Motavalli, Hashem Miri Hakimabad
In this paper, the dose assessment for the iodine inhalation exposure in 19 aerosol sizes and three gas/vapor forms at three levels of thyroid uptake, was performed. Two different modes of work (light vs. heavy) and breathing (nose vs. mouth) for aerosol inhalation were investigated. In order to calculate the cumulated activities per unit of inhaled activity, a combined model which included the latest models of both human respiratory and alimentary tract was developed. The S values for ¹³¹I were computed based on the ICRP adult male and female reference voxel phantoms by the Monte Carlo method. Then, the committed equivalent and committed effective dose coefficients were obtained (The data are available at http://ift.tt/2zgPtKh). In general, for the nonzero thyroid uptakes, the maximum cumulated activity was found in the thyroid. When the thyroid is blocked, however, the maximum depends on the work and breathing mode and radioisotope form. Overall, the maximum CED coefficient was evaluated for the inhalation of elemental iodine at thyroid uptake of ∼27% (2.8 × 10⁻⁸ Sv/Bq). As for the particle inhalation per se, mouth breathing of 0.6 nm and 0.2 μm AMTD particles showed to have the maximum (2.8 × 10⁻⁸ Sv/Bq) and minimum (6.4 × 10⁻⁹ Sv/Bq) CED coefficients, respectively. Compared to the reference CED coefficients, the authors found an increase of about 58% for inhalation of the aerosols with AMAD of 1 μm and 70% for 5 μm.



http://ift.tt/2ztccn9

Assessment of the calibration of gamma spectrometry systems in forest environments

Publication date: January 2018
Source:Journal of Environmental Radioactivity, Volume 181
Author(s): Alan J. Cresswell, David C.W. Sanderson, Katsuhiko Yamaguchi
A Monte Carlo simulation was used to develop a model of the response of a portable gamma spectrometry system in forest environments. This model was used to evaluate any corrections needed to measurements of ¹³⁷Cs activity per unit area calibrated assuming an open field geometry. These were shown to be less than 20% for most forest environments. The model was also used to assess the impact of activity in the canopy on ground level measurements. For similar activity per unit area in the lower parts of the canopy as on the ground, 10-25% of the ground based measurement would be due to activity in the canopy, depending on the depth profile in the soil. The model verifies that an optional collimator cap can assess activity in the canopy by repeat survey.



http://ift.tt/2ztcaf1

The anti-tumor effect of RANKL inhibition in malignant solid tumors – a systematic review

Publication date: Available online 1 November 2017
Source:Cancer Treatment Reviews
Author(s): AF. de Groot, NM. Appelman-Dijkstra, SH. van der Burg, JR. Kroep
At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.



http://ift.tt/2hyABwW

BDNF Val66Met polymorphism modulates the effect of loneliness on white matter microstructure in young adults

Publication date: December 2017
Source:Biological Psychology, Volume 130
Author(s): Jie Meng, Lei Hao, Dongtao Wei, Jiangzhou Sun, Yu Li, Jiang Qiu
Loneliness is a common experience. Susceptibility to loneliness is a stable trait and is heritable. Previous studies have suggested that loneliness may impact regional gray matter density and brain activation to social stimuli, but its relation to white matter structure and how it may interact with genetic factors remains unclear. In this study, we investigated whether and how a common polymorphism (Val66Met) in the brain-derived neurotrophic factor gene modulated the association between loneliness and white matter microstructure in 162 young adults. The tract-based spatial statistics analyses revealed that the relationships between loneliness and white matter microstructures were significantly different between Val/Met heterozygotes and Val/Val homozygotes. Specifically, loneliness was significantly correlated with reduced fractional anisotropy and increased radial diffusivity in widespread white matter fibers within Val/Met heterozygotes. It was also significantly correlated with increased radial diffusivity in Met/Met genotypes but showed no significant association with white matter measures in Val/Val genotypes. Furthermore, the associations between loneliness and fractional anisotropy (or radial diffusivity) in Val/Met heterozygotes turned out to be global effects. These results provide evidence that loneliness may interact with the BDNF Val66Met polymorphism to shape the microstructures of white matter, and the Val/Met heterozygotes may be more susceptible to social environment.



http://ift.tt/2zdFqFA

Frontal alpha asymmetry and aerobic exercise: are changes due to cardiovascular demand or bilateral rhythmic movement?

Publication date: Available online 1 November 2017
Source:Biological Psychology
Author(s): Robert A. Hicks, Peter A. Hall, William R. Staines, William E. McIlroy
The left and right prefrontal cortices are linked to networks that control approach and withdrawal motivation, respectively. The relationship between activity in the left and right prefrontal activity is used to assess brain states and specifically their link to motivational behaviours and tendencies. The most common measure used in this context is called the frontal alpha asymmetry (FAA), which compares alpha (8–13Hz) power at each region. Interestingly, research shows that FAA is influenced by aerobic exercise by increasing relative left prefrontal cortex activity. In turn this effect may be beneficial for individuals with mood disorders that are associated with abnormal motivational tendencies. However, it is unknown whether changes in FAA after exercise are due to cardiovascular demands of activity or simply the movement required for the exercise. Therefore, this study aimed to investigate the influence of aerobic exercise and 'no intensity' bilateral movement cycling on FAA in young healthy adults. Results showed aerobic exercise caused a significant increase in FAA scores 22–38minutes after exercise. However, movement did not lead to a significant change in FAA. This suggests there is an intensity required for physical activity to evoke a change in FAA.



http://ift.tt/2zqQkbT

Neurophysiological differentiation between preattentive and attentive processing of emotional expressions on French vowels

Publication date: Available online 1 November 2017
Source:Biological Psychology
Author(s): Mathilde Carminati, Nicole Fiori-Duharcourt, Frédéric Isel
The present electrophysiological study investigated the processing of emotional prosody by minimizing as much as possible the effect of emotional information conveyed by the lexical-semantic context. Emotionally colored French vowels (i.e., happiness, sadness, fear, and neutral) were presented in a mismatch negativity (MMN) oddball paradigm. Both the MMN, i.e., an event-related potential (ERP) component thought to reflect preattentive change detection, and the P3a, i.e., an ERP marker of involuntary orientation of attention toward deviant stimuli, were significantly modulated by the emotional deviants compared to the neutral ones. Critically, the largest amplitude (MMN, P3a) and the shortest peak latency (MMN) were observed for fear deviants, all other things being equal. Taken together, the present findings lend support to a sequential neurocognitive model of emotion processing (Scherer, 2001) which postulates, among other checks, a first stage of automatic emotion detection (MMN) followed by a second stage of subjective evaluation of the stimulus or event (P3a). Consistently with previous studies, our data suggest that among the six universal emotions, fear could have a special status probably because of its adaptive role in the evolution of the human species.



http://ift.tt/2zdFmFQ

Determination of restless legs syndrome prevalence in children aged 13–16 years in the provincial center of Kayseri

Publication date: Available online 1 November 2017
Source:Brain and Development
Author(s): Hüseyin Per, Neslihan Günay, Sevda İsmailoğulları, Didem Behice Öztop, Osman Günay




http://ift.tt/2xSoKAd

Goal-directed behavior elevates gamma oscillations in nidopallium caudolaterale of pigeon

Publication date: Available online 2 November 2017
Source:Brain Research Bulletin
Author(s): Xinyu Liu, Kun Zhao, Wang Dongyun, Yanna Ping, Hong Wan
Avian nidopallium caudolaterale (NCL), a functional analogue of mammalian prefrontal cortex, is thought to be participated to goal-directed behavior. However, few studies so far investigated local field potential (LFP) properties within this area. In this study, we recorded the LFP activity from the NCL of six pigeons when they performed a goal-directed decision-making task in a plus-maze. Spectral analysis revealed a significant LFP-power increase in the gamma-band (40−60 Hz) during the decision-making process. Moreover, the LFP activity in the gamma-band was modulated by the behavioral outcomes of pigeons. It could decode effectively the motion directions of animals. These results indicate that the gamma rhythm of LFP recorded from the NCL correlates with the goal-directed behavior of pigeons.



http://ift.tt/2iWhFvu

The Anticonvulsant Activity and Cerebral Protection of Chronic Lithium Chloride via NMDA Receptor/Nitric Oxide and phospho-ERK

Publication date: Available online 2 November 2017
Source:Brain Research Bulletin
Author(s): Razieh Mohammad Jafari, Mohammad Hossein Ghahremani, Nastaran Rahimi, Amir Shadboorestan, Amir Rashidian, Jamileh Esmaeili, Shahram Ejtemaei Mehr, Ahmad Reza Dehpour
The underlying mechanisms for the neuroprotective effects of lithium chloride in neurodegenerative diseases such as seizures remain unknown. In present study the downstream signaling pathway of phospho-ERK/NMDA receptors/nitric oxide has been studied. For this purpose, acute and chronic effect of lithium in seizure animal model and the interaction of NMDA receptor antagonist (MK-801) and neuronal nitric oxide synthase (nNOS) inhibitor (7-NI) with these neuroprotection has been studied.Acute lithium administration showed pro-convulsive properties in pentylenetetrazole (PTZ)-induced seizure model while chronic treatment increased the seizure threshold significantly. The serum level of lithium in treated mice were 0.48 mEq/L corresponding the therapeutic range. Administration of 7-NI (30mg/kg, i.p.) and MK-801 (0.001mg/kg, i.p.) had no effect on seizure threshold, while co-administration of them before the sub-effective dose of lithium (4mg/kg, i.p.) increased the anticonvulsant effect of lithium significantly. Furthermore, acute injection of MK-801 (0.05mg/kg) or 7-NI (60mg/kg) and co-administration of them significantly suppressed the anticonvulsant effect of effective dose of lithium (10mg/kg). This data demonstrated involvement of NMDA receptors/nitric oxide pathway in anticonvulsant effect of lithium.In cerebellar granule neurons (CGNs) culture studies on glutamate excitotoxicity western blot analysis, nitrite assay by Griess reaction, cell viability and microscopic morphology evaluation has been carried out to find the role of NMDA receptor/nitric oxide and phospho-ERK signaling in lithium neuroprotection. Using MTT assay and morphologic examinations, chronic lithium treatment showed protective effects against glutamate toxicity in primary cerebellar culture neurons. The level of nitric oxide was significantly reduced in co-administration of lithium and glutamate while glutamate significantly increased levels of nitric oxide. The involvement of NMDA receptors/nitric oxide and phospho-ERK pathway in the effects of lithium on cerebellar neurons has been shown. Inhibition of ERK signaling may be reconsidered as a pharmacological approach for seizure control.



http://ift.tt/2z7XfDR

Leadership rounds to reduce health care–associated infections

Publication date: Available online 2 November 2017
Source:American Journal of Infection Control
Author(s): Mary Jo Knobloch, Betty Chewning, Jackson Musuuza, Susan Rees, Christopher Green, Erin Patterson, Nasia Safdar
BackgroundEvidence-based guidelines exist to reduce health care–associated infections (HAIs). Leadership rounds are one tool leaders can use to ensure compliance with guidelines, but have not been studied specifically for the reduction of HAIs. This study examines HAI leadership rounds at one facility.MethodsWe explored unit-based HAI leadership rounds led by 2 hospital leaders at a large academic hospital. Leadership rounds were observed on 19 units, recorded, and coded to identify themes. Themes were linked to the Consolidated Framework for Implementation Research and used to guide interviews with frontline staff members.ResultsStaff members disclosed unit-specific problems and readily engaged in problem-solving with top hospital leaders. These themes appeared over 350 times within 22 rounds. Findings revealed that leaders used words that demonstrated fallibility and modeled curiosity, 2 factors associated with learning climate and psychologic safety. These 2 themes appeared 115 and 142 times, respectively. The flexible nature of the rounds appeared to be conducive for reflection and evaluation, which was coded 161 times.ConclusionsEach interaction between leaders and frontline staff can foster psychologic safety, which can lead to open problem-solving to reduce barriers to implementation. Discovering specific communication and structural factors that contribute to psychologic safety may be powerful in reducing HAIs.



http://ift.tt/2z90zig

Surveillance-guided selective digestive decontamination of carbapenem-resistant Enterobacteriaceae in the intensive care unit: A cost-effectiveness analysis

Publication date: Available online 2 November 2017
Source:American Journal of Infection Control
Author(s): Joyce H.S. You, Hong-kiu Li, Margaret Ip
BackgroundClinical findings have shown effectiveness and safety of selective digestive decontamination (SDD) for eradication of carbapenem-resistant Enterobacteriaceae (CRE) in high-risk carriers. We aimed to evaluate the cost-effectiveness of SDD guided by CRE surveillance in the intensive care unit (ICU).MethodsOutcomes of surveillance-guided SDD (test-guided SDD) and no screening (control) in the ICU were compared by Markov model simulations. Model outcomes were CRE infection and mortality rates, direct costs, and quality-adjusted life year (QALY) loss. Model inputs were estimated from clinical literature. Sensitivity analyses were conducted to examine the robustness of base case results.ResultsTest-guided SDD reduced infection (4.8% vs 5.0%) and mortality (1.8% vs 2.1%) rates at a higher cost ($1,102 vs $1,074) than the control group in base case analysis, respectively. Incremental cost per QALY saved (incremental cost-effectiveness ratio [ICER]) by the test-guided SDD group was $557 per QALY. Probabilistic sensitivity analysis showed that test-guided SDD was effective in saving QALYs in 100% of 10,000 Monte Carlo simulations, and cost-saving 59.1% of time. The remaining 40.9% of simulations found SDD to be effective at an additional cost, with ICERs accepted as cost-effective per the willingness-to-pay threshold.ConclusionsSurveillance-guided SDD appears to be cost-effective in reducing CRE infection and mortality with QALYs saved.



http://ift.tt/2iWfkAM

Pilot study of digital tools to support multimodal hand hygiene in a clinical setting

Publication date: Available online 1 November 2017
Source:American Journal of Infection Control
Author(s): Gary Thirkell, Joanne Chambers, Wayne Gilbart, Kerrill Thornhill, James Arbogast, Gerard Lacey
BackgroundDigital tools for hand hygiene do not share data, limiting their potential to support multimodal programs. The Christie NHS Foundation Trust, United Kingdom, worked with GOJO (in the United States), MEG (in Ireland), and SureWash (in Ireland) to integrate their systems and pilot their combined use in a clinical setting.MethodsA 28-bed medical oncology unit piloted the system for 5 weeks. Live data from the tools were combined to create a novel combined risk status metric that was displayed publicly and via a management Web site.ResultsThe combined risk status reduced over the pilot period. However, larger and longer duration studies are required to reach statistical significance. Staff and especially patient reaction was positive in that 70% of the hand hygiene training events were by patients. The digital tools did not negatively impact clinical workflow and received positive engagement from staff and patients. The combined risk status did not change significantly over the short pilot period because there was also no specific hand hygiene improvement campaign underway at the time of the pilot study.ConclusionsThe results indicate that integrated digital tools can provide both rich data and novel tools that both measure impact and provide feedback to support the implementation of multimodal hand hygiene campaigns, reducing the need for significant additional personnel resources.



http://ift.tt/2z8DwE9

Risk factors for infection with multidrug-resistant organisms in Haryana, India

Publication date: Available online 1 November 2017
Source:American Journal of Infection Control
Author(s): Shilpa Kalluru, Shoshannah Eggers, Anna Barker, Daniel Shirley, Ajay K. Sethi, Sharmila Sengupta, Kajal Yeptho, Nasia Safdar
BackgroundThe objective of this study was to investigate risk factors for multidrug-resistant organism (MDRO) infection within patients from a tertiary care hospital in Northern India. This case-control study examined MDRO infection risk factors, including diet, health history, and medical device use. We administered a diet questionnaire to collect data on usual diet and collected data on other risk factors from chart review. All participants were inpatients identified through hospital microbiology reports. A total of 39 MDRO patient cases and 91 controls were included.MethodsDescriptive statistics, univariate analysis, and multivariate logistic regression were performed to evaluate the association between risk factors and MDRO infection.ResultsAll cases had gram-negative MDRO infections. Univariate analyses found length of hospital stay, connective tissue disease, hospitalization in the last 12 months, hospitalization of a family member, in-hospital antibiotic use, antibiotic use in the last 12 months, and feeding tube, central venous line, and urinary catheter use to be significantly different between cases and controls. Logistic regression showed a >3-fold increase in the odds of infection with antibiotic use in the last 12 months (odds ratio [OR], 3.30; 95% confidence interval [CI], 1.22-8.91) and urinary catheter use (OR, 3.63; 95% CI, 1.14-11.58). Differences in dietary preferences and fruit, vegetable, and fiber consumption were not significantly associated with infection.ConclusionsAntibiotic use is a major driver of MDRO infections. Our findings suggest that interventions optimizing antibiotic stewardship and reducing device use should be a priority to prevent MDRO infections.



http://ift.tt/2iVWCJF

The effects of lapatinib on CYP3A metabolism of midazolam in patients with advanced cancer

Abstract

Purpose

The potential inhibition of CYP3A4 by lapatinib was studied using midazolam as a probe substrate in patients with cancer.

Methods

This was a partially randomized, 4-period, 4-sequence, 4-treatment, cross-over study in 24 patients with advanced cancer. Single 1-mg IV and 3-mg oral doses of midazolam were given 2 days apart, in a partially random order, on study days 1, 3, 9, and 11. Lapatinib 1500-mg was administered orally once daily on study days 4 through 11. Midazolam plasma concentrations were measured up to 24-h post dosing, and lapatinib plasma concentrations measured prior to each midazolam dose.

Results

Lapatinib increased the geometric mean (95% CIs) midazolam AUC_(o−∞) by 45% (31–60%) after the oral dose and by 14% (0–29%) after the IV dose, and prolonged the midazolam elimination half-life by 48% (22–81%) after the oral dose and by 20% (2–40%) after the IV dose. Lapatinib decreased midazolam total clearance by 13% (1–23%), while total bioavailability was increased 23% (4–46%) without changes in apparent volume of distribution or hepatic bioavailability.

Conclusion

These data show that lapatinib caused weak inhibition of gastrointestinal CYP3A4 in vivo. This suggests that oral CYP3A4 drug substrates with a narrow therapeutic index may need dose reduction if lapatinib is to be co-prescribed.

http://ift.tt/2h7mj9Q

Location, Location, Location: Spatio-Temporal Cues That Define the Cell of Origin in Melanoma

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Maria S. Soengas, E. Elizabeth Patton
It is unclear whether melanoma initiates from mature melanocytes or stem cell precursors. In this issue of Cell Stem Cell, Moon et al. (2017) and Köhler et al. (2017) use in vivo lineage tracing to demonstrate that these two possibilities may occur downstream of the same pro-tumorigenic lesions, depending on environmental factors or the anatomical location.

Teaser

It is unclear whether melanoma initiates from mature melanocytes or stem cell precursors. In this issue of Cell Stem Cell, Moon et al. (2017) and Köhler et al. (2017) use in vivo lineage tracing to demonstrate that these two possibilities may occur downstream of the same pro-tumorigenic lesions, depending on environmental factors or the anatomical location.


http://ift.tt/2z7N58L

Vitamin C: C-ing a New Way to Fight Leukemia

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Katharina Schönberger, Nina Cabezas-Wallscheid
Metabolic cues and (epi-)genetic factors are emerging regulators of hematopoietic stem cell (HSC) potency. Two new studies in Nature and Cell, from Agathocleous et al. (2017) and Cimmino et al. (2017), respectively, show that vitamin C regulates HSC function and suppresses leukemogenesis by modulating Tet2 activity.

Teaser

Metabolic cues and (epi-)genetic factors are emerging regulators of hematopoietic stem cell (HSC) potency. Two new studies in Nature and Cell, from Agathocleous et al. (2017) and Cimmino et al. (2017), respectively, show that vitamin C regulates HSC function and suppresses leukemogenesis by modulating Tet2 activity.


http://ift.tt/2h5Qf65

At Last: Gene Editing in Human Embryos to Understand Human Development

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Albert Ruzo, Ali H. Brivanlou
Our understanding of early human development is typically based on inference from animal models, which may not fully recapitulate human embryonic features. As proof of concept, Fogarty et al. (2017) used CRISPR/Cas9 to genetically ablate the OCT4 gene in human preimplantation embryos and found key differences from its function in model systems.

Teaser

Our understanding of early human development is typically based on inference from animal models, which may not fully recapitulate human embryonic features. As proof of concept, Fogarty et al. (2017) used CRISPR/Cas9 to genetically ablate the OCT4 gene in human preimplantation embryos and found key differences from its function in model systems.


http://ift.tt/2z7N2d5

EMPhasis on Mutant Microglia: Dysregulation of Brain Sentinels Induces Neurodegeneration

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Bettina Schreiner, Melanie Greter
Reactive microglia are often implicated in the pathology of neurodegenerative disease. In a recent study in Nature, Mass et al. (2017) demonstrate that targeted mutation of Braf in early erythro-myeloid precursors (EMPs) causes histiocytosis-associated late onset neurodegeneration driven by activated microglia.

Teaser

Reactive microglia are often implicated in the pathology of neurodegenerative disease. In a recent study in Nature, Mass et al. (2017) demonstrate that targeted mutation of Braf in early erythro-myeloid precursors (EMPs) causes histiocytosis-associated late onset neurodegeneration driven by activated microglia.


http://ift.tt/2h6ggSK

Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson’s Disease: Dawn of a New Era

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Roger A. Barker, Malin Parmar, Lorenz Studer, Jun Takahashi
Stem cell-based therapies for Parkinson's disease are moving into a new and exciting era, with several groups pursuing clinical trials with pluripotent stem cell (PSC)-derived dopamine neurons. As many groups have ongoing or completed GMP-level cell manufacturing, we highlight key clinical translation considerations from our recent fourth GForce-PD meeting.

Teaser

Stem cell-based therapies for Parkinson's disease are moving into a new and exciting era, with several groups pursuing clinical trials with pluripotent stem cell (PSC)-derived dopamine neurons. As many groups have ongoing or completed GMP-level cell manufacturing, we highlight key clinical translation considerations from our recent fourth GForce-PD meeting.


http://ift.tt/2z6YLc1

Neural Circuits Serve as Periscopes for NSCs

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Nannan Guo, Amar Sahay
Neural stem cells (NSCs) within the hippocampal niche integrate local cues, such as activity of inhibitory interneurons, into their homeostatic fate choices. Now in Cell Stem Cell, Bao et al. (2017) describe how these local interneurons relay signals from distal brain regions to govern NSC quiescence and activation.

Teaser

Neural stem cells (NSCs) within the hippocampal niche integrate local cues, such as activity of inhibitory interneurons, into their homeostatic fate choices. Now in Cell Stem Cell, Bao et al. (2017) describe how these local interneurons relay signals from distal brain regions to govern NSC quiescence and activation.


http://ift.tt/2h5Q7U9

Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Richard A. Morgan, David Gray, Anastasia Lomova, Donald B. Kohn
The use of allogeneic hematopoietic stem cells (HSCs) to treat genetic blood cell diseases has become a clinical standard but is limited by the availability of suitable matched donors and potential immunologic complications. Gene therapy using autologous HSCs should avoid these limitations and thus may be safer. Progressive improvements in techniques for genetic correction of HSCs, by either vector gene addition or gene editing, are facilitating successful treatments for an increasing number of diseases. We highlight the progress, successes, and remaining challenges toward the development of HSC gene therapies and discuss lessons they provide for the development of future clinical stem cell therapies.

Teaser

Morgan et al. discuss the progress, successes, and remaining challenges toward the development of hematopoietic stem cell gene therapies and highlight lessons learned and how they can inform the development of future clinical stem cell therapies.


http://ift.tt/2z9i0S1

Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Wenchao Zhou, Cong Chen, Yu Shi, Qiulian Wu, Ryan C. Gimple, Xiaoguang Fang, Zhi Huang, Kui Zhai, Susan Q. Ke, Yi-Fang Ping, Hua Feng, Jeremy N. Rich, Jennifer S. Yu, Shideng Bao, Xiu-Wu Bian
The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting glioma stem cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.

Graphical abstract

Teaser

The blood-brain barrier (BBB) blocks entry of harmful materials into normal brains, but the blood-tumor barrier (BTB) prevents anti-cancer drugs from penetrating GBM tumors. Targeting GSC-derived neoplastic pericytes selectively disrupted the BTB, but not BBB, and potently enhanced drug delivery to effectively improve GBM treatment.


http://ift.tt/2h5Q4rr

Long-Range GABAergic Inputs Regulate Neural Stem Cell Quiescence and Control Adult Hippocampal Neurogenesis

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Hechen Bao, Brent Asrican, Weidong Li, Bin Gu, Zhexing Wen, Szu-Aun Lim, Issac Haniff, Charu Ramakrishnan, Karl Deisseroth, Benjamin Philpot, Juan Song
The quiescence of adult neural stem cells (NSCs) is regulated by local parvalbumin (PV) interneurons within the dentate gyrus (DG). Little is known about how local PV interneurons communicate with distal brain regions to regulate NSCs and hippocampal neurogenesis. Here, we identify GABAergic projection neurons from the medial septum (MS) as the major afferents to dentate PV interneurons. Surprisingly, dentate PV interneurons are depolarized by GABA signaling, which is in sharp contrast to most mature neurons hyperpolarized by GABA. Functionally, these long-range GABAergic inputs are necessary and sufficient to maintain adult NSC quiescence and ablating them leads to NSC activation and subsequent depletion of the NSC pool. Taken together, these findings delineate a GABAergic network involving long-range GABAergic projection neurons and local PV interneurons that couples dynamic brain activity to the neurogenic niche in controlling NSC quiescence and hippocampal neurogenesis.

Graphical abstract

Teaser

Bao et al. demonstrate that long-range GABAergic projections from the medial septum control adult hippocampal neurogenesis through depolarizing GABA signaling onto local PV interneurons. Functionally, these long-range inputs are required for maintaining NSC quiescence and ablating them depletes the NSC pool and impairs neurogenesis.


http://ift.tt/2haWPbn

TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Jessie A. Brown, Yoshiya Yonekubo, Nicole Hanson, Ana Sastre-Perona, Alice Basin, Julie A. Rytlewski, Igor Dolgalev, Shane Meehan, Aristotelis Tsirigos, Slobodan Beronja, Markus Schober
Squamous cell carcinomas (SCCs) are heterogeneous tumors sustained by tumor-propagating cancer cells (TPCs). SCCs frequently resist chemotherapy through still unknown mechanisms. Here, we combine H2B-GFP-based pulse-chasing with cell-surface markers to distinguish quiescent from proliferative TPCs within SCCs. We find that quiescent TPCs resist DNA damage and exhibit increased tumorigenic potential in response to chemotherapy, whereas proliferative TPCs undergo apoptosis. Quiescence is regulated by TGF-β/SMAD signaling, which directly regulates cell-cycle gene transcription to control a reversible G1 cell-cycle arrest, independent of p21^CIP function. Indeed, genetic or pharmacological TGF-β inhibition increases the susceptibility of TPCs to chemotherapy because it prevents entry into a quiescent state. These findings provide direct evidence that TPCs can reversibly enter a quiescent, chemoresistant state and thereby underscore the need for combinatorial approaches to improve treatment of chemotherapy-resistant SCCs.

Graphical abstract

Teaser

Heterogeneous tumors, such as squamous cell carcinomas, are often chemoresistant and comprise subpopulations of poorly characterized tumor-propagating cancer cells (TPCs). Brown et al. demonstrate that TPCs reversibly enter a quiescent, chemoresistant state and inhibiting TGF-β signaling can increase their susceptibility to chemotherapy by preventing cell-cycle withdrawal in tumors.


http://ift.tt/2h72gs4

An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Rebecca V. Berrens, Simon Andrews, Dominik Spensberger, Fátima Santos, Wendy Dean, Poppy Gould, Jafar Sharif, Nelly Olova, Tamir Chandra, Haruhiko Koseki, Ferdinand von Meyenn, Wolf Reik
Erasure of DNA methylation and repressive chromatin marks in the mammalian germline leads to risk of transcriptional activation of transposable elements (TEs). Here, we used mouse embryonic stem cells (ESCs) to identify an endosiRNA-based mechanism involved in suppression of TE transcription. In ESCs with DNA demethylation induced by acute deletion of Dnmt1, we saw an increase in sense transcription at TEs, resulting in an abundance of sense/antisense transcripts leading to high levels of ARGONAUTE2 (AGO2)-bound small RNAs. Inhibition of Dicer or Ago2 expression revealed that small RNAs are involved in an immediate response to demethylation-induced transposon activation, while the deposition of repressive histone marks follows as a chronic response. In vivo, we also found TE-specific endosiRNAs present during primordial germ cell development. Our results suggest that antisense TE transcription is a "trap" that elicits an endosiRNA response to restrain acute transposon activity during epigenetic reprogramming in the mammalian germline.

Graphical abstract

Teaser

In this issue of Cell Stem Cell, Berrens et al. report the control of transposable elements by endosiRNAs during global DNA demethylation induced in mouse embryonic stem cells. The study uncovered an "immediate" repression of transposons accomplished by endosiRNAs followed by their "chronic/long-term" silencing by repressive histone modifications.


http://ift.tt/2h5PWbr

A Morbidly Obese Man With an Enlarging Right Thigh Mass.

No abstract available

http://ift.tt/2z8X1MY

Melanocytic Matricoma With Consumption of the Epidermis: An Atypical Histologic Attribute or a Malignant Variant?.

Melanocytic matricoma is a recently described cutaneous adnexal tumor composed of matrical and supramatrical cells admixed with pigmented dendritic melanocytes, thought to recapitulate the anagen bulb of the hair follicle. We report a case of a 75-year-old white man, which demonstrates consumption of the epidermis that is defined as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of the normal rete architecture in areas of direct contact with neoplastic cells. It has been associated with aggressive histologic features in melanoma and likely represents an early phase of ulceration due to attenuation. Epidermal consumption has not been previously reported in nonmelanocytic tumors and it is uncertain whether this atypical histologic feature represents a sign of malignant behavior in this rare tumor. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2iWW9Hc

Eccrine-Centric Melanocytic Nevus.

Benign melanocytic neoplasms present with a diverse array of well-known histopathologic patterns. It is imperative to recognize the benign patterns to render accurate diagnoses. We describe here an interesting and hitherto not described low-power architectural pattern of a benign melanocytic lesion: eccrine-centric melanocytic nevus. The patient was a 50-year-old African American woman who noticed a new mole on her foot that began as a dark speck but quickly grew larger. The lesion was excised to exclude the possibility of melanoma. Upon review of the specimen, the lesion was noted to demonstrate a distinctive pattern consistent with a melanocytic nevus of possible congenital onset. Remarkably, the ducts of eccrine glands were increased in density and the nests of melanocytes were found solely in a peri-eccrine distribution without melanocytes in any other locations (ie, interstitial, perifollicular). Additionally, all melanocytes in the nevus were rather heavily pigmented. Although this pattern demonstrated no atypical features that would cause one to consider it malignant to the trained eye, this presentation could implicate a metastatic disease (well-delineated nests in the dermis without concomitant interstitial component) and it is important to recognize. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2z9cyMJ

Holocrine Poroma: A Distinctive Adnexal Tumor.

There are 36 cases of complex poroid tumors with folliculosebaceous and apocrine differentiation reported in the literature. The authors evaluated 111 poroid tumors including 63 typical eccrine poromas and 48 poroid tumors with folliculosebaceous elements. Folliculosebaceous poroid tumors (FSPT) had basaloid and squamous cells (100%), ducts with steatocystoma-like cuticles and holocrine secretions (89.6%), infundibular follicular structures (66.7%), and entrapped sebocytes (56.3%). No definite apocrine decapitation secretions in FSPT were found. Immunohistochemistry was strongly positive for CK903 and focally positive for CAM5.2, epithelial membrane antigen, and carcinoembryonic antigen. No loss of MLH-1, MSH-2, or MSH-6 mismatch repair proteins was found. FSPT had distinctive features that differentiate them from eccrine poromas including the frequent head and neck locations (62.5% vs. 20.6%, P

http://ift.tt/2iUXDSm

Cytotoxic CD8+ Granulomatous Cutaneous T-Cell Lymphoma Associated With Human Immunodeficiency Virus Infection: A Diagnostic Challenge.

No abstract available

http://ift.tt/2z7zoV5

Comparison of MRI sequences in ideal fiducial maker-based radiotherapy for prostate cancer

Publication date: November–December 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 6
Author(s): Osamu Tanaka, Hisao Komeda, Mitsuyoshi Hattori, Shigeki Hirose, Eiichi Yama, Masayuki Matsuo
AimProstate contouring using CT alone is difficult. To overcome the uncertainty, CT/MRI registration using a fiducial marker is generally performed. However, visualization of the marker itself can be difficult with MRI. This study aimed to determine the optimal MRI pulse sequence for defining the marker as well as the prostate outline among five sequences.Materials and methodsA total of 21 consecutive patients with prostate cancer were enrolled. Two gold fiducial markers were placed before CT/MRI examination. We used the following five sequences: T1-weighted spin-echo (T1WI; TR/TE, 400–650/8ms); T2-weighted fast spin-echo (T2WI; 4000/80); T2*-2D-weighted gradient echo (T2*2D; 700/18); T2*-3D-weighted gradient echo (T2*3D; TR/TE1/deltaTE, 37/14/7.3); and contrast-enhanced T1-weighted spin-echo (CE-T1WI; 400–650/8). Qualitative image analysis of the sequences was performed by three observers. These observers subjectively scored all images on a scale of 1–3 (1=unclear, 2=moderate, 3=well visualized). A higher score indicated better visualization.ResultsT2WI was significantly superior to the other sequences in terms of prostate definition. T2*2D and T2*3D were strongly superior to the other sequences and were significantly superior in terms of fiducial marker definition.ConclusionsT2*2D and T2*3D are superior to the other sequences for prostate contouring and marker identification. Therefore, we recommend initial T2*3D and T2*2D examinations.



http://ift.tt/2h6Nu4k

Clinical outcomes with MRI-guided image-based brachytherapy in cervical cancer: An institutional experience

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Vijai Simha, Bhavana Rai, Firuza D. Patel, Rakesh Kapoor, Suresh C. Sharma, Oinam A. Singh, Veenu Singla, Bhaswanth Dhanireddy, Sushmita Ghoshal
PurposeTo evaluate the long-term disease control and toxicity to the organs at risk after dose-escalated image-based adaptive brachytherapy (BT) in cervical cancer.Methods and MaterialsSixty patients of cervical cancer were treated with external radiotherapy 46 Gy in 23 fractions with weekly cisplatin and MRI-guided BT 7 Gy × 4 fractions with a minimum dose of 85.7 Gy (EQD2) to the high-risk clinical target volume (HRCTV). The BT dose was initially prescribed to point A and plans were optimized to ensure coverage of both point A and HRCTV while maintaining doses to the organs at risk within the recommended constraints. Patients were followed up clinically every three months for the first two years and six months thereafter. Toxicity scoring for urinary and bowel symptoms was done using CTCAE version 3.0.ResultsThe mean doses to the point A and D90 HRCTV were 85.5 (±2.75) Gy and 98.4 (±9.6) Gy EQD2 respectively. The mean 2 cc EQD2, the bladder, rectum, and sigmoid were 90.6 Gy, 70.2 Gy, and 74.2 Gy respectively. The overall survival at a median followup of 49.8 months was 91.66%. Six (10%) patients developed grade 3 gastrointestinal toxicity. One patient developed grade 3 bladder toxicity. The incidence of bladder, rectal, and sigmoid toxicity increased significantly with doses >85 Gy, 66 Gy, and >71 Gy EQD2 respectively.ConclusionsWhile the incidence of grade 3-4 toxicity was low (8.3% for gastrointestinal toxicity and 1.6% for bladder), the threshold for development of grade 1-2 bladder and rectal toxicity was lower than the doses recommended by the GEC-ESTRO group. By adhering to volume-based prescriptions, there is scope of further reduction in toxicity to organs at risk.



http://ift.tt/2z9rwCm

Physics aspects of the Papillon technique—Five decades later

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Li Heng Liang, Nada Tomic, Te Vuong, Saad Aldelaijan, Hamed Bekerat, Francois DeBlois, Jan Seuntjens, Slobodan Devic
PurposeThe Papillon technique using 50-kVp soft X-rays to treat rectal adenocarcinomas was developed and clinically implemented in the 1960s. We describe differences between accurate dosimetry and clinical implementation of this technique that is extending from its very inception to date.Methods and MaterialsA renaissance of the Papillon technique occurred with two recently introduced 50-kVp systems: Papillon+ by Ariane and a custom-made rectal applicator (consisting of a surface applicator inserted into a proctoscope) by iCAD's Xoft Axxent Electronic Brachytherapy (eBT) System (iCad, Inc., Sunnyvale, CA). In contrast to the initial design, we investigated the impact of introducing a plastic lid, which would provide more reproducible and more accurate dose delivery across the rectal adenocarcinoma patient population. We use both parallel-plate chamber and radiochromic film dosimeters to determine differences in basic dosimetry characteristics (beam half-value layers, outputs, percent depth doses, and profiles) between the Xoft Electronic Brachytherapy rectal applicator system with and without the plastic lid in place.ResultsCompared to the open-cone applicator, the proposed applicator with the plastic lid produces a slightly harder (more penetrating) beam quality (half-value layer of 1.4 vs. 1.3-mm Al), but with reduced output (by 33%), and a slightly broader beam with flatness not worse than 3% and symmetry not worse than 2%.ConclusionsIn addition to characterizing beam properties modified by the possible introduction of the plastic cap, we also pointed out and addressed misconceptions in the use of radiochromic films for dose measurements at low-energy photon beams.



http://ift.tt/2iVJeVS

Manual vs. automated implantation of seeds in prostate brachytherapy: Oncologic results from a single-center study

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Laurence Thomas, Antony Chemin, Nicolas Leduc, Sarah Belhomme, Emilie Rich, Olivier Lasbareilles, Antoine Giraud, Edouard Descat, Guilhem Roubaud, Paul Sargos
PurposeThe objective of this study was to study survival and tolerance of prostate cancer patients treated with ¹²⁵I permanent interstitial brachytherapy by automated vs. manual implantation of seeds.Methods and MaterialsBetween 2002 and 2010, 349 selected patients were treated with ¹²⁵I brachytherapy by the same team: from 2002 to April 2005, 65 patients with linked seeds and then 284 patients treated using Nucletron First System automated implantation. We analyzed biochemical recurrence-free survival (bRFS) rates and toxicities (univariate and multivariate analyses).ResultsTwo hundred seventy-seven (79.4%) and 69 patients (19.8%) with low- and intermediate-risk disease were treated, respectively (median follow-up: 64 months). The 5-year bRFS rate was 93.1% (95% confidence interval 89.3–95.6) for the entire cohort. The 5-year bRFS rates were 93.4% and 91.7% for patients with low- and intermediate-risk disease, respectively (p = 0.42). In univariate and multivariate analyses, there was no statistically significant difference in the 5-year bRFS rate depending on the implantation technique (93.1% vs. 91.8%, respectively, for automated and linked seeds; p = 0.53). In univariate analysis, only D90 prostate (dose delivered to 90% of the prostate) <140 Gy (p = 0.01), lack of prostate-specific antigen bounce (p = 0.008), and nadir prostate-specific antigen >0.11 (p = 0.01) were predictive factors for bRFS. We observed Grade 3 urethritis in 7 patients (2%), urinary incontinence in 2 patients (0.7%), and Grade 4 proctitis in 2 patients (0.7%).ConclusionsIn this large single-center series, brachytherapy for selected localized prostate cancer achieved excellent rates of biochemical control at 5 years (93.1%) with an acceptable toxicity profile, irrespective of the implantation technique used.



http://ift.tt/2z9xXFD

The role of 125I interstitial brachytherapy for inoperable parotid gland carcinoma

Publication date: Available online 1 November 2017
Source:Brachytherapy
Author(s): Ming-Wei Huang, Wen-Jie Wu, Xiao-Ming Lv, Guang-Yan Yu, Jian-Guo Zhang
PurposeThe treatment of inoperable parotid gland carcinoma is challenging and controversial. The purpose of this paper was to present our experience in treating this malignancy using ¹²⁵I interstitial brachytherapy.Methods and MaterialsThirteen patients with advanced carcinomas of the parotid gland were included and treated with ¹²⁵I interstitial brachytherapy in Peking University School and Hospital of Stomatology from January 2003 to December 2015. All patients were treated with ¹²⁵I interstitial brachytherapy as a sole modality for the primary tumor. Furthermore, all of them were treated with neck dissection with/without adjunctive external beam radiotherapy for the neck, simultaneously. The prescription dose of interstitial brachytherapy was 140–160 Gy.ResultsMedian followup was 56 months (range: 8–105 months). The 2-year and 5-year local control rates were 91.7% and 58.2%, respectively. The 2-year and 5-year overall survival rates were 100% and 61%, respectively. No cervical lymph node metastasis was observed during the followup. No interstitial brachytherapy-related severe complications occurred. Facial nerve function was preserved well.Conclusions¹²⁵I interstitial brachytherapy is a feasible and effective treatment for inoperable parotid gland carcinomas without severe complications. And neck dissection with/without external beam radiotherapy is necessary for patients with cervical metastasis or at high risk of cervical metastasis.



http://ift.tt/2iZahQo

Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Maria-Ioanna Stefanou, Debora Desideri, Justus Marquetand, Paolo Belardinelli, Christoph Zrenner, Holger Lerche, Ulf Ziemann
ObjectiveMutations in STX1B encoding the presynaptic protein syntaxin-1B are associated with febrile seizures with or without epilepsy. It is unclear to what extent these mutations are linked to abnormalities of cortical glutamatergic or GABAergic neurotransmission. We explored this question using single- and paired-pulse transcranial magnetic stimulation (TMS) excitability markers.MethodsWe studied nine currently asymptomatic adult STX1B mutation carriers with history of epilepsy and febrile seizures, who had been seizure-free for at least eight years without antiepileptic drug treatment, and ten healthy age-matched controls. Resting motor threshold (RMT), and input-output curves of motor evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI, marker of GABAAergic excitability) and intracortical facilitation (ICF, marker of glutamatergic excitability) were tested.ResultsRMT, and input-output curves of MEP amplitude, SICI and ICF revealed no significant differences between STX1B mutation carriers and healthy controls.ConclusionsFindings suggest normal motor cortical GABAAergic and glutamatergic excitability in currently asymptomatic STX1B mutation carriers.SignificanceTMS measures of motor cortical excitability show utility in demonstrating normal excitability in adult STX1B mutation carriers with history of seizures.



http://ift.tt/2zcU0NG

Early corticospinal tract damage in prodromal SCA2 revealed by EEG-EMG and EMG-EMG coherence

Publication date: December 2017
Source:Clinical Neurophysiology, Volume 128, Issue 12
Author(s): Luis Velázquez-Pérez, Johannes Tünnerhoff, Roberto Rodríguez-Labrada, Reidenis Torres-Vega, Yusely Ruiz-Gonzalez, Paolo Belardinelli, Jacqueline Medrano-Montero, Nalia Canales-Ochoa, Yanetza González-Zaldivar, Yaimeé Vazquez-Mojena, Georg Auburger, Ulf Ziemann
ObjectiveClinical data suggest early involvement of the corticospinal tract (CST) in spinocerebellar ataxia type 2 (SCA2). Here we tested if early CST degeneration can be detected in prodromal SCA2 mutation carriers by electrophysiological markers of CST integrity.MethodsCST integrity was tested in 15 prodromal SCA2 mutation carriers, 19 SCA2 patients and 25 age-matched healthy controls, using corticomuscular (EEG-EMG) and intermuscular (EMG-EMG) coherence measures in upper and lower limb muscles.ResultsSignificant reductions of EEG-EMG and EMG-EMG coherences were observed in the SCA2 patients, and to a similar extent in the prodromal SCA2 mutation carriers. In prodromal SCA2, EEG-EMG and EMG-EMG coherences correlated with the predicted time to ataxia onset.ConclusionsFindings indicate early CST neurodegeneration in SCA2. EEG-EMG and EMG-EMG coherence may serve as biomarkers of early CST neurodegeneration in prodromal SCA2 mutation carriers.SignificanceFindings are important for developing preclinical disease markers in the context of currently emerging disease-modifying therapies of neurodegenerative disorders.



http://ift.tt/2zsuapR