Aesthetic reconstruction of retroauricular keloid: Creating a keystone flap from the mastoid-helix area

Abstract

Advances in aesthetic rhinoplasty using conchal cartilage grafts have led to a high occurrence of retroauricular keloids. The purpose of this study is to introduce our surgical experiences using a keystone flap in retroauricular keloids following conchal cartilage grafts. The present study is a retrospective review of patients with pathologically confirmed retroauricular keloids following conchal cartilage grafts. These cases were surgically excised and we covered the defect with a keystone flap followed by one-time steroid injection at postoperative day 14 and silicone gel sheeting application for 3 months. Treatment outcome was recorded as recurrence or non-recurrence. In all patients, a follow-up period of minimum 12 months was required. Of these patients, 90.0% had successful treatment of their auricular keloids, whereas 10.0% had recurrences. The postoperative course was uneventful. In conclusion, our aesthetic reconstruction using a keystone flap created from the mastoid-helix area is a useful treatment strategy in terms of retroauricular keloids following conchal cartilage grafts.

http://ift.tt/2n3VphI

Computerbasierte Testung neurokognitiver Aspekte im Rahmen der audiologischen Diagnostik

Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-124972

Hintergrund Im Hinblick auf den demographischen Wandel der Gesellschaft gewinnen in der Hörrehabilitation neurokognitive Fähigkeiten immer mehr an Bedeutung. Fragestellung Ziel der Studie war es zu untersuchen, inwiefern eine neurokognitive Testung mittels PC-gestützter Aufgaben zur Evaluation der unterschiedlichen Bereiche der Kognition auch für ältere Patienten mit und ohne Hörstörung geeignet ist und wie sich diese in den klinischen Alltag des HNO-Arztes integrieren lässt. Patientenbeschreibung 171 Patienten ≥ 50 Jahren mit und ohne eine beidseitige Hörbeeinträchtigung wurden eingeschlossen: n = 90 im Alter zwischen 50 und 64 Jahren (57,0 ± 4,5) und 81 Ältere ab 65 (72,5 ± 5,4). Methode Eine computerbasierte Testung mit rein visuellen Instruktionen beinhaltete neben der Aufmerksamkeit, der Verarbeitungsgeschwindigkeit, dem Kurz- und Langzeitgedächtnis auch exekutive Funktionen. Zuvor erfolgte ein Probedurchgang unter Anleitung einer geschulten Mitarbeiterin. Ergebnisse Auch wenn die Testung unabhängig von Alter oder Hörstatus in allen Fällen eigenständig möglich war, benötigten Hörgeschädigte 15 Minuten länger zur Durchführung und beurteilten diese als anstrengender als Hörgesunde (71 % versus 63 %). Patienten mittleren Alters sahen die Durchführbarkeit für Menschen des höheren Lebensalters mit 30 % signifikant (p = 0,02) kritischer als die betroffene Altersgruppe selbst (10 %). Schlussfolgerung Eine umfassende kognitive Testung älterer Schwerhöriger mit computerbasierten Aufgaben lässt sich problemlos in den klinischen HNO Alltag integrieren und könnte eine wertvolle Ergänzung der audiologischen Diagnostik im Hinblick auf eine bestmögliche Hörrehabilitation darstellen.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Inherited thrombotic thrombocytopenic purpura mimicking immune thrombocytopenic purpura during pregnancy: a case report

Thrombotic thrombocytopenic purpura is a very rare hereditary blood deficiency disorder of ADAMTS13 (von Willebrand factor-cleaving protease) and a life-threatening thrombotic microangiopathy characterized by ...

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Histological Changes in the Rat Femoral Artery Following the Use of the Empty-and-Refill Test

J reconstr Microsurg
DOI: 10.1055/s-0037-1621727

Background This study examines the effects of the empty-and-refill patency test on rat femoral arteries in the longer postoperative time period. Methods A simple arterial anastomosis was performed bilaterally on 20 rats. The empty-and-refill test was performed unilaterally in all rats, leaving the contralateral artery as an internal control. Rats were divided into two cohorts of 10 rats and survived for 48 hours and 2 weeks. Vessel patency was assessed prior to closing and immediately prior to sacrifice. The femoral arteries were harvested bilaterally and hematoxylin and eosin stains were performed. The femoral artery distal to the anastomosis in the region of the empty-and-refill test was histologically evaluated. Results All vessels were patent at the time of sacrifice. There was no statistical difference in the numeric scoring between the experimental and control vessels in the 48-hour cohort. Almost all vessels harvested at 48 hours showed endothelial cell loss distal to the anastomosis regardless of whether they underwent the empty-and-refill test. The only statistically significant difference in the 2-week cohort was an increase in adventitial smooth muscle proliferation in the experimental group. There were no other statistically significant results between the experimental and control groups at 2 weeks. An overall comparison of both cohorts revealed a statistically significant increase in endothelial cell number and intimal proliferation by 2 weeks postsurgery. Conclusion The empty-and-refill test does not compromise rat femoral artery anastomotic patency, nor does it produce histological damage either 48 hours or 2 weeks postsurgery.
[...]

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

Article in Thieme eJournals:
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Impact of Duration of Perioperative Ischemia on Outcomes of Microsurgical Reconstructions

J reconstr Microsurg
DOI: 10.1055/s-0037-1621729

Background Free tissue transfers have become routine for a variety of reconstructive purposes. During the time of transfer, some period of ischemia time is unavoidable, causing structural and metabolic changes. This study aimed to evaluate whether length of intraoperative ischemia affects the outcomes of microsurgical reconstructions. Methods Within a 7-year period, 638 patients having undergone 690 microvascular free flap reconstructions fulfilled inclusion criteria for this study. The data were retrospectively screened for patients' demographics, intra- and perioperative details, flap survival, surgical complications, and outcomes. The cases were divided into two groups according to the length of intraoperative ischemia time, "< 60" versus "≥ 60 minutes." Results Both groups were comparable regarding the patient constellation, comorbidities, smoking status, and perioperative characteristics. Operative times were significantly longer in patients which had ischemia times of ≥ 60 minutes (p < 0.05). Also, during our 3-month follow-up period, a significantly higher rate of major and minor surgical complications, including total and partial flap losses, as well as higher revision rates occurred in the ≥ 60 minutes ischemia time group (p < 0.05). Conclusion In this study, prolonged ischemia time during free flap reconstructions was associated with higher rates of revision surgeries and complications rates.
[...]

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

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

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Reassessment of Differentiated Thyroid Cancer Patients Using the Eighth TNM/AJCC Classification System: A Comparative Study

Thyroid , Vol. 0, No. 0.


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Clinical study to evaluate the performance of a noninvasive focused ultrasound device for thigh fat and circumference reduction compared to control

Summary

Background and objectives

An FDA-cleared focused ultrasound device (UltraShape, Syneron Candela^®, Yokneam, Israel) for noninvasive abdominal fat reduction produces localized mechanical cellular membrane disruption in adipocytes. This study seeks to determine the safety and efficacy of this device for use on the thighs.

Study designs/Materials and methods

Fourteen women aged 33-60 were selected to receive 3 biweekly treatments to one thigh with the other thigh serving as an internal control. The subjects had a BMI range of 18-30 kg/m² and a weight range of 54-83 kg. After the third treatment, patients were followed at 4, 8, and 16 weeks. Fat thickness was measured by both caliper and ultrasound. In addition, thigh circumference and the patient's weight were measured. Pain, edema, erythema, and adverse events as well as investigator and patient overall satisfaction were recorded at all visits.

Results

In comparison with the control, there was a statistically significant average reduction in fat thickness measured by calipers at all time points with a 22.20% (P = .0165) improvement in 16 weeks. By ultrasound, there was a 19.23% (4.03 mm P = .0051) reduction in fat thickness at 16 weeks with statistically significant improvement at the other follow-up visits. At 16 weeks, thigh circumference improved, on average, 2.8 cm (P = .0059) at the midline. 90.0% of the subjects were satisfied with the results at 16 weeks, and the investigator was 100% satisfied. No adverse events were reported; no edema was observed in any subject. All subjects experienced mild erythema. All reported zero pain on a 0-10 scale.

Conclusion

Focused ultrasound is safe, effective, and well tolerated to improve the circumference and fat thickness of the thighs without significant side effects. There were no significant adverse events. Investigators and subjects were highly satisfied with the results.

http://ift.tt/2n2e6U1

Effect of Diabetes Sleep Education for T2DM Who Sleep After Midnight: A Pilot Study from China

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


http://ift.tt/2n1nbwi

The Association Between Sleeping Time and Metabolic Syndrome Features, Among Older Adults Living in Mediterranean Region: The MEDIS Study

Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.


http://ift.tt/2BkQ76G

Clinical study to evaluate the performance of a noninvasive focused ultrasound device for thigh fat and circumference reduction compared to control

Summary

Background and objectives

An FDA-cleared focused ultrasound device (UltraShape, Syneron Candela^®, Yokneam, Israel) for noninvasive abdominal fat reduction produces localized mechanical cellular membrane disruption in adipocytes. This study seeks to determine the safety and efficacy of this device for use on the thighs.

Study designs/Materials and methods

Fourteen women aged 33-60 were selected to receive 3 biweekly treatments to one thigh with the other thigh serving as an internal control. The subjects had a BMI range of 18-30 kg/m² and a weight range of 54-83 kg. After the third treatment, patients were followed at 4, 8, and 16 weeks. Fat thickness was measured by both caliper and ultrasound. In addition, thigh circumference and the patient's weight were measured. Pain, edema, erythema, and adverse events as well as investigator and patient overall satisfaction were recorded at all visits.

Results

In comparison with the control, there was a statistically significant average reduction in fat thickness measured by calipers at all time points with a 22.20% (P = .0165) improvement in 16 weeks. By ultrasound, there was a 19.23% (4.03 mm P = .0051) reduction in fat thickness at 16 weeks with statistically significant improvement at the other follow-up visits. At 16 weeks, thigh circumference improved, on average, 2.8 cm (P = .0059) at the midline. 90.0% of the subjects were satisfied with the results at 16 weeks, and the investigator was 100% satisfied. No adverse events were reported; no edema was observed in any subject. All subjects experienced mild erythema. All reported zero pain on a 0-10 scale.

Conclusion

Focused ultrasound is safe, effective, and well tolerated to improve the circumference and fat thickness of the thighs without significant side effects. There were no significant adverse events. Investigators and subjects were highly satisfied with the results.

http://ift.tt/2n2e6U1

Antibody Immunodominance: The Key to Understanding Influenza Virus Antigenic Drift

Viral Immunology , Vol. 0, No. 0.


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Correction to: Rejuvenation Res 2015;18(5):422-436; DOI: 10.1089/rej.2014.1656

Rejuvenation Research , Vol. 0, No. 0.


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A Screening Tool Using Five Risk Factors Was Developed for Fall-Risk Prediction in Chinese Community-Dwelling Elderly Individuals

Rejuvenation Research , Vol. 0, No. 0.


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Preventing Peanut Allergy

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


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Routine Oxygen Supplementation in Acute Cardiovascular Disease: The End of a Paradigm?.

Author: Hofmann, Robin MD, PhD; James, Stefan K. MD, PhD

Page: 320-322

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Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study).

Author: Mahaffey, Kenneth W. MD; Neal, Bruce MB, ChB, PhD; Perkovic, Vlado MBBS, PhD; de Zeeuw, Dick MD, PhD; Fulcher, Greg MD; Erondu, Ngozi MD, PhD; Shaw, Wayne DSL; Fabbrini, Elisa MD, PhD; Sun, Tao PhD; Li, Qiang MBiostat, BPH, AStat; Desai, Mehul MD; Matthews, David R. DPhil, BM, BCh; On behalf of the CANVAS Program Collaborative Group

Page: 323-334

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Canagliflozin: Cui Bono?.

Author: Cavender, Matthew A. MD, MPH; Kosiborod, Mikhail MD

Page: 335-337

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Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).

Author: Bonaca, Marc P. MD, MPH; Nault, Patrice MD; Giugliano, Robert P. MD, SM; Keech, Anthony C. MD; Pineda, Armando Lira MD; Kanevsky, Estella MS; Kuder, Julia MA; Murphy, Sabina A. MPH; Jukema, J. Wouter MD, PhD; Lewis, Basil S. MD; Tokgozoglu, Lale MD; Somaratne, Ransi MD; Sever, Peter S. PhD; Pedersen, Terje R. MD; Sabatine, Marc S. MD, MPH

Page: 338-350

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Protecting Life and Limb in Peripheral Artery Disease.

Author: Creager, Mark A. MD

Page: 351-353

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ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway.

Author: Than, Martin P. MBBS; Pickering, John W. PhD; Dryden, Jeremy M. MBChB; Lord, Sally J. MBBS; Aitken, S. Andrew MBChB; Aldous, Sally J. MBBS; Allan, Kate E. MBChB; Ardagh, Michael W. MBChB; Bonning, John W.N. MBChB; Callender, Rosie MBChB; Chapman, Laura R.E. MBBS; Christiansen, Jonathan P. MBChB; Cromhout, Andre P.J. MBChB; Cullen, Louise MBBS; Deely, Joanne M. PhD; Devlin, Gerard P. MBChB; Ferrier, Katherine A. MBChB; Florkowski, Christopher M. MBBS; Frampton, Christopher M.A. PhD; George, Peter M. MBBS; Hamilton, Gregory J. PhD; Jaffe, Allan S. MD; Kerr, Andrew J. MBChB; Larkin, G. Luke MD; Makower, Richard M. MBBS; Matthews, Timothy J.E. MBChB; Parsonage, William A. MBBS; Peacock, W. Frank MD; Peckler, Bradley F. MD; van Pelt, Niels C. MBChB; Poynton, Louise MBChB; Richards, A. Mark MBChB, PhD, DSc; Scott, Anthony G. MBChB; Simmonds, Mark B. MBChB; Smyth, David MBBS; Thomas, Oliver P. MBBS; To, Andrew C.Y. MBChB; Du Toit, Stephen A. MBChB; Troughton, Richard W. MBChB, PhD; Yates, Kim M. MBChB; On behalf of the ICare-ACS Implementation Group

Page: 354-363

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Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial.

Author: Feldman, Ted MD *,; Mauri, Laura MD, MSc *,; Kahwash, Rami MD; Litwin, Sheldon MD; Ricciardi, Mark J. MD; van der Harst, Pim MD, PhD; Penicka, Martin MD, PhD; Fail, Peter S. MD; Kaye, David M. MD, PhD; Petrie, Mark C. MB ChB; Basuray, Anupam MD; Hummel, Scott L. MD, MS; Forde-McLean, Rhondalyn MD, MHS; Nielsen, Christopher D. MD; Lilly, Scott MD, PhD; Massaro, Joseph M. PhD; Burkhoff, Daniel MD, PhD; Shah, Sanjiv J. MD; On behalf of the REDUCE LAP-HF I Investigators and Study Coordinators

Page: 364-375

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Impact of Regionalization of ST-Segment-Elevation Myocardial Infarction Care on Treatment Times and Outcomes for Emergency Medical Services-Transported Patients Presenting to Hospitals With Percutaneous Coronary Intervention: Mission: Lifeline Accelerator-2.

Author: Jollis, James G. MD; Al-Khalidi, Hussein R. PhD; Roettig, Mayme L. RN, MSN; Berger, Peter B. MD; Corbett, Claire C. MMS; Doerfler, Shannon M. PhD; Fordyce, Christopher B. MD, MHS, MSc; Henry, Timothy D. MD; Hollowell, Lori BSN; Magdon-Ismail, Zainab DrPH; Kochar, Ajar MD; McCarthy, James J. MD; Monk, Lisa RN, MSN; O'Brien, Peter MD; Rea, Thomas D. MD; Shavadia, Jay MD; Tamis-Holland, Jacqueline MD; Wilson, B. Hadley MD; Ziada, Khaled M. MD; Granger, Christopher B. MD

Page: 376-387

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Standardized Definition of Structural Valve Degeneration for Surgical and Transcatheter Bioprosthetic Aortic Valves.

Author: Dvir, Danny MD *,; Bourguignon, Thierry MD *,; Otto, Catherine M. MD; Hahn, Rebecca T. MD; Rosenhek, Raphael MD; Webb, John G. MD; Treede, Hendrik MD; Sarano, Maurice E. MD; Feldman, Ted MD; Wijeysundera, Harindra C. MD; Topilsky, Yan MD; Aupart, Michel MD; Reardon, Michael J. MD; Mackensen, G. Burkhard MD; Szeto, Wilson Y. MD; Kornowski, Ran MD; Gammie, James S. MD; Yoganathan, Ajit P. PhD; Arbel, Yaron MD; Borger, Michael A. MD; Simonato, Matheus; Reisman, Mark MD; Makkar, Raj R. MD; Abizaid, Alexandre MD; McCabe, James M. MD; Dahle, Gry MD; Aldea, Gabriel S. MD; Leipsic, Jonathon MD; Pibarot, Philippe PhD; Moat, Neil E. MD; Mack, Michael J. MD; Kappetein, A. Pieter MD; Leon, Martin B. MD; On behalf of VIVID (Valve in Valve International Data) Investigators

Page: 388-399

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From the Literature.

Author: Hampton, Tracy PhD

Page: 400-401

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Asymptomatic ST-Segment-Elevation ECG in Patient With Kidney Failure.

Author: Sotananusak, Thanyaluck MD; Meemook, Krissada MD

Page: 402-404

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Burden of Catastrophic Health Expenditures for Acute Myocardial Infarction and Stroke Among Uninsured in the United States.

Author: Khera, Rohan MD *,; Hong, Jonathan C. MD, MHS *,; Saxena, Anshul PhD; Arrieta, Alejandro PhD; Virani, Salim S. MD, PhD; Blankstein, Ron MD; de Lemos, James A. MD; Krumholz, Harlan M. MD, SM; Nasir, Khurram MD, MPH

Page: 408-410

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Letter by Koutsampasopoulos et al Regarding Article, "Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction".

Author: Koutsampasopoulos, Konstantinos MD, MSc, PhD(c); Ouzouni, Christina PhD; Vogiatzis, Ioannis MD, MSc, PhD

Page: 411-412

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Letter by Jin-shan and Xue-bin Regarding Article, "Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction".

Author: Jin-shan, He MD; Xue-bin, Li MD

Page: 413

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Letter by Carbone et al Regarding Article, "Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction".

Author: Carbone, Salvatore MS; Canada, Justin M. MS, RCEP; Abbate, Antonio MD, PhD

Page: 414-415

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Response by Obokata and Borlaug to Letters Regarding Article, "Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction".

Author: Obokata, Masaru MD, PhD; Borlaug, Barry A. MD

Page: 416-417

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Editorial Board

Publication date: January 2018
Source:Cortex, Volume 98





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Cover Figure

Publication date: January 2018
Source:Cortex, Volume 98





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Reachability judgement in optic ataxia: Effect of peripheral vision on hand and target perception in depth

Publication date: January 2018
Source:Cortex, Volume 98
Author(s): Angela Bartolo, Yves Rossetti, Patrice Revol, Christian Urquizar, Laure Pisella, Yann Coello
The concept of peripersonal space was first proposed by Rizzolatti, Scandolara, Matelli, and Gentilucci (1981), who introduced the term to highlight the close links between somatosensory and visual processing for stimuli close to the body and suggested that this near-body space could in fact be characterized as an action space (Rizzolatti, Fadiga, Fogassi, & Gallese, 1997). Supporting this idea, patients with right hemisphere lesions have been described as impaired in performing actions towards objects and in perceiving their location − but only when the objects were presented within arm's reach (Bartolo, Carlier, Hassaini, Martin, & Coello, 2014; Brain, 1941). Whether the deficit of optic ataxia patients in processing target locations for action has an effect on the representation of peripersonal space has never been explored. The present study highlights optic ataxia patients' specific difficulties in processing hand-to-target distances in a motor task and in a perceptual task requiring identification of what is reachable in the visual environment. The difficulties are especially evident when both the target and the hand are perceived in the visual periphery. Indeed, when patient I.G. was able to fixate the target, her reaching accuracy and her perception of reachable space both largely improved. Furthermore, the difficulties were enhanced when the hand and the target were both in the lower visual field (in a fixed-far condition vs a fixed-near condition). This novel up-down dimension of optic ataxia fits with the larger representation of the lower visual field in the posterior parietal cortex (Pitzalis et al., 2013; Previc, 1990).



http://ift.tt/2E0n37A

Multi-perspective comparisons and mitigation implications of SO 2 and NO x discharges from the industrial sector of China: a decomposition analysis

Abstract

This study is the first attempt to investigate the drivers of Chinese industrial SO₂ and NO_x emissions from both periodic and structural perspectives through a decomposition analysis using the logarithmic mean Divisia index (LMDI). The two pollutants' emissions were decomposed into output effects, structural effects, clean production effects, and pollution abatement effects. The results showed that China's industrial SO₂ discharge increased by 1.14 Mt during 2003–2014, and the contributions from the four effects were 23.17, − 1.88, − 3.80, and − 16.36 Mt, respectively. Likewise, NO_x discharge changed by − 3.44 Mt over 2011–2014, and the corresponding contributions from the four effects were 2.97, − 0.62, − 1.84, and − 3.95 Mt. Thus, the output effect was mainly responsible for the growth of the two discharges. The average annual contribution rates of SO₂ and NO_x from output were 14.33 and 5.97%, respectively, but pollution abatement technology presented the most obvious mitigating effects (− 10.11 and − 7.92%), followed by the mitigating effects of clean production technology (− 2.35 and − 3.7%), and the mitigation from the structural effect was the weakest (− 1.16 and − 1.25%, respectively), which meant pollutant reduction policies related to industrial structure adjustment should be a long-term measure for the two discharges. In addition, the sub-sectors of I20 (manufacture of raw chemical materials and chemical products), I24 (manufacture of non-metallic mineral products), and I26 (smelting and pressing of non-ferrous metals) were the major contributors to both discharges. Thus, these sub-sectors should be given priority consideration when designing mitigation-related measures. Last, some particular policy implications were recommended for reducing the two discharges, including that the government should seek a technological discharge reduction route.

http://ift.tt/2F1xtmD

Phytoremediation of a petroleum-polluted soil by native plant species in Lorestan Province, Iran

Abstract

Petroleum hydrocarbons are potentially toxic for organisms due to the inherent properties, such as solubility, volatility, and biodegradability. The petroleum materials released from corroded old pipelines would pollute soils, shallow groundwater and air as a consequence, and threat the health of human and environment. Therefore, the removal of these compounds from environment is vital. The stability of these pollutants at the soil and their gradual accumulation over time would disrupt the normal function of the soil, such as reduced agricultural capability. In this research, the influence of two plant species (Bromus tectorum L. and Festuca arundinacea) with different amendments including arbuscular mycorrhizal fungi, alfalfa residues, and nutrient solution on the degradation rate of petroleum hydrocarbons in soil was studied. The results showed that the most effective treatment for petroleum remediation was related to B. tectorum L. plant when treated with mycorrhizal fungi and nutrient solution. The degradation rate during 40 days was about 83.27% when compared to the control. Arbuscular mycorrhizal associations are important in the restoration of degraded ecosystems because of the benefits to their symbiotic partners. This fungal phytotechnological mechanism is still in its infancy and there has been little research on aged-contaminated soils.

http://ift.tt/2DxvOIz

Hippocampal GABAA antagonism reverses the novel object recognition deficit in sub-chronic phencyclidine-treated rats

Publication date: 16 April 2018
Source:Behavioural Brain Research, Volume 342
Author(s): Nichole M. Neugebauer, Masanori Miyauchi, Tatsuya Sato, Jun Tadano, Hanife Akal, Hossein Ardehali, Herbert Y. Meltzer
BackgroundAbnormalities in prefrontal cortical and hippocampal GABAergic function are postulated to be major causes of the cognitive impairment associated with schizophrenia (CIAS). There are conflicting views on whether diminished or enhanced GABAergic activity contributes to the deficit in short-term novel object recognition (NOR) in the sub-chronic phencyclidine (scPCP) rodent model of CIAS. This study assessed the role of GABAA signaling in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) in NOR in saline (scSAL)- and scPCP-treated rats.MethodsThe effects of local administration of a GABAA agonist (muscimol) into the vHPC or mPFC and an antagonist (bicuculline) or a GABAA/benzodiazepine partial agonist (bretazenil) into the vHPC on NOR in scSAL and scPCP-treated rats were determined.ResultsIn scSAL-treated rats, injection of muscimol into the vHPC, but not mPFC, induced a deficit in NOR. The scPCP-induced NOR deficit was significantly reversed by intra-vHPC bicuculline, while intra-vHPC bretazenil produced a non-significant trend for reversal (p = .06). scPCP treatment increased mRNA expression of GABAA γ2 in PFC and GABAA α5 and GABAA β1 in the HPC. However, GABA concentration in the PFC or HPC was not altered.ConclusionsThese findings indicate that the scPCP-induced NOR deficit can be rescued by reducing GABAA receptor stimulation in vHPC, indicating that increased vHPC GABAA inhibition may contribute to the scPCP-induced NOR deficit in rats. These results also indicate that excessive GABAA receptor signalling in the vHPC has a deleterious effect on NOR in normal rats.



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Cognitive decline and increased hippocampal p-tau expression in mice with hearing loss

Publication date: 16 April 2018
Source:Behavioural Brain Research, Volume 342
Author(s): So Young Park, Min Jung Kim, Hong Lim Kim, Dong Kee Kim, Sang Won Yeo, Shi Nae Park
Hearing and cognition are commonly involved in both normal and pathological aging. Current clinical interest lies in whether peripheral hearing loss promotes cognitive decline. In our previous publication, the authors have shown a causal relationship between hearing and cognitive impairments in C57BL/6 mice. Here we extended the follow-up to 12 months to determine the long-term effects of hearing loss on cognition and to observe hippocampal p-tau and lipofuscin. One month old male mice were randomly allocated into two groups, the control (n = 12) and noise-induced hearing loss (NIHL) (n = 12). After baseline hearing and cognitive measurements, the mice in the NIHL group were exposed to 110 dB SPL white noise for 1 h every day for 20 consecutive days. Cognitive function was assessed by radial arm maze and novel object recognition tests. p-Tau was observed by the western blot, immunofluorescence, and immunogold staining. The mice in the NIHL group showed elevated auditory brainstem response thresholds and poorer performances in spatial working and recognition memories than the controls. They exhibited more p-tau and lipofuscin in the hippocampus. The cognitive impact of hearing loss varied with the types of memory. Working memory impairment was reversible, whereas recognition memory impairment was permanent. Our results provide behavioral and histopathological evidence for hearing-related cognitive decline. Early hearing loss is suggested to be one of the important determinants between normal and pathological cognitive aging.



http://ift.tt/2rus7P3

The monoamine-oxidase B inhibitor deprenyl increases selection of high-effort activity in rats tested on a progressive ratio/chow feeding choice procedure: Implications for treating motivational dysfunctions

Publication date: 16 April 2018
Source:Behavioural Brain Research, Volume 342
Author(s): Samantha E. Yohn, Shanika Reynolds, Giuseppe Tripodi, Merce Correa, John D. Salamone
Motivated behaviors often are characterized by a high degree of behavioral activation and work output, and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with depression and other disorders frequently show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Tasks measuring effort-related choice are being used as animal models of these motivational symptoms. The present studies characterized the ability of the monoamine oxidase –B (MAO-B) inhibitor deprenyl (selegiline) to enhance selection of high-effort lever pressing in rats tested on a concurrent progressive ratio (PROG)/chow feeding choice task. Deprenyl is widely used as an antiparkinsonian drug, but it also has been shown to have antidepressant effects in humans, and to induce antidepressant-like effects in traditional rodent models of depression. Systemic administration of deprenyl (1.5–12.0 mg/kg IP) shifted choice behavior, significantly increasing markers of PROG lever pressing at a moderate dose (6.0 mg/kg), and decreasing chow intake at 6.0 and 12.0 mg/kg. Intracranial injections of deprenyl into nucleus accumbens (2.0 and 4.0 μg) also increased PROG lever pressing and decreased chow intake. Microdialysis studies showed that the dose of deprenyl that was effective at increasing PROG lever pressing (6.0 mg/kg) also significantly elevated extracellular dopamine in nucleus accumbens. Thus, similar to the well-known antidepressant bupropion, deprenyl is capable of increasing selection of high-effort PROG lever pressing at doses that increase extracellular dopamine in nucleus accumbens. These studies have implications for the potential use of MAO-B inhibitors as treatments for the motivational symptoms of depression and Parkinsonism.



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Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson’s disease

Publication date: 16 April 2018
Source:Behavioural Brain Research, Volume 342
Author(s): Débora Dalla Vecchia, Luiz Kae Sales Kanazawa, Etiéli Wendler, Palloma de Almeida Soares Hocayen, Estevan Bruginski, Francinete Ramos Campos, Cristina Aparecida Jark Stern, Maria Aparecida Barbato Frazão Vital, Edmar Miyoshi, Markus Wöhr, Rainer K.W. Schwarting, Roberto Andreatini
Parkinson's disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia, but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50-kHz ultrasonic vocalizations, gait impairment (catwalk test), and depressive-like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50-kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion-induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6-hydroxydopamine induced subtle motor and non-motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinson's disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson's disease.

Graphical abstract

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Water treatment by new-generation graphene materials: hope for bright future

Abstract

Water is the most important and essential component of earth's ecosystem playing a vital role in the proper functioning of flora and fauna. But, our water resources are contaminating continuously. The whole world may be in great water scarcity after few decades. Graphene, a single-atom thick carbon nanosheet, and graphene nanomaterials have bright future in water treatment technologies due to their extraordinary properties. Only few papers describe the use of these materials in water treatment by adsorption, filtration, and photodegradation methods. This article presents a critical evaluation of the contribution of graphene nanomaterials in water treatment. Attempts have been made to discuss the future perspectives of these materials in water treatment. Besides, the efforts are made to discuss the nanotoxicity and hazards of graphene-based materials. The suggestions are given to explore the full potential of these materials along with precautions of nanotoxicity and its hazards. It was concluded that the future of graphene-based materials is quite bright.

http://ift.tt/2DznTdA

The p38-MK2/3 Module Is Critical for IL-33-Induced Signaling and Cytokine Production in Dendritic Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-B signaling and activation of MAPKs. In bone marrow–derived dendritic cells, IL-33 induces the production of IL-6, IL-13, and TNF-α. However, the signaling pathways resulting in IL-33–induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33–induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38–Mapk-activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow–derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3–dependent IL-13 production. Furthermore, we found that effective TNF-α production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33–induced cytokine production in dendritic cells.

http://ift.tt/2DvE1xw

Intestinal Inflammation-Mediated Clearance of Amebic Parasites Is Dependent on IFN-{gamma} [INFECTIOUS DISEASE AND HOST RESPONSE]

Intestinal amebiasis is a major cause of diarrhea. However, research on host–amebae interactions has been hampered owing to a lack of appropriate animal models. Recently, a mouse model of intestinal amebiasis was established, and using it, we reported that Entamoeba moshkovskii colonized the intestine in a manner similar to that of the pathogenic Entamoeba histolytica. In this study, we evaluated the protective mechanisms present against amebae using this model. CBA/J mice infected with E. histolytica had a persistent infection without apparent symptoms. In contrast, E. moshkovskii–infected mice rapidly expelled the ameba, which was associated with weight loss, diarrhea, and intestinal damage characterized by apoptosis of intestinal epithelial cells (IECs). Expression of NKG2D on intestinal intraepithelial lymphocytes (IELs) and IFN-–producing cells in Peyer's patches were significantly induced after infection with E. moshkovskii but not with E. histolytica. IFN-–deficient mice infected with E. moshkovskii showed no obvious symptoms. Notably, none of these mice expelled E. moshkovskii, indicating that IFN- is responsible not only for intestinal symptoms but also for the expulsion of amebae. Furthermore, apoptosis of IECs and expression of NKG2D on IELs observed in E. moshkovskii–infected mice did not occur in the absence of IFN-. In vivo blocking of NKG2D in mice infected with E. moshkovskii enabled ameba to survive longer and remarkably reduced apoptotic IECs. Our results clearly demonstrate a novel protective mechanism exerted by IFN- against intestinal amebae, including induction of cytotoxicity of IELs toward IECs.

http://ift.tt/2DvQGR8

Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage [INNATE IMMUNITY AND INFLAMMATION]

The extent of NK cell activity during the innate immune response affects downstream immune functions and, ultimately, the outcome of infectious or malignant disease. However, the mechanisms that terminate human NK cell responses have yet to be defined. When activation receptors expressed on NK cell surfaces bind to ligands on diseased cells, they initiate a signal that is propagated by a number of intracellular kinases, including Zap70 and Syk, eventually leading to NK cell activation. We assayed Zap70 and Syk content in NK cells from healthy human donors and identified a subset of NK cells with unusually low levels of these two kinases. We found that this Zap70^lowSyk^low subset consisted of NK cells expressing a range of surface markers, including CD56^hi and CD56^low NK cells. Upon in vitro stimulation with target cells, Zap70^lowSyk^low NK cells failed to produce IFN- and lysed target cells at one third the capacity of Zap70^hiSyk^hi NK cells. We determined two independent in vitro conditions that induce the Zap70^lowSyk^low phenotype in NK cells: continuous stimulation with activation beads and DNA damage. The expression of inhibitory receptors, including NKG2A and inhibitory killer Ig-like receptors (KIRs), was negatively correlated with the Zap70^lowSyk^low phenotype. Moreover, expression of multiple KIRs reduced the likelihood of Zap70 downregulation during continuous activation, regardless of whether NK cells had been educated through KIR–HLA interactions in vivo. Our findings show that human NK cells are able to terminate their functional activity without the aid of other immune cells through the downregulation of activation kinases.

http://ift.tt/2DvK8lr

Identification of a Multipotent Progenitor Population in the Spleen That Is Regulated by NR4A1 [IMMUNE SYSTEM DEVELOPMENT]

The developmental fate of hematopoietic stem and progenitor cells is influenced by their physiological context. Although most hematopoietic stem and progenitor cells are found in the bone marrow of the adult, some are found in other tissues, including the spleen. The extent to which the fate of stem cells is determined by the tissue in which they reside is not clear. In this study, we identify a new progenitor population, which is enriched in the mouse spleen, defined by cKit⁺CD71^lowCD24^high expression. This previously uncharacterized population generates exclusively myeloid lineage cells, including erythrocytes, platelets, monocytes, and neutrophils. These multipotent progenitors of the spleen (MPPS) develop from MPP2, a myeloid-biased subset of hematopoietic progenitors. We find that NR4A1, a transcription factor expressed by myeloid-biased long term-hematopoietic stem cells, guides the lineage specification of MPPS. In vitro, NR4A1 expression regulates the potential of MPPS to differentiate into erythroid cells. MPPS that express NR4A1 differentiate into a variety of myeloid lineages, whereas those that do not express NR4A1 primarily develop into erythroid cells. Similarly, in vivo, after adoptive transfer, Nr4a1-deficient MPPS contribute more to erythrocyte and platelet populations than do wild-type MPPS. Finally, unmanipulated Nr4a1^–/– mice harbor significantly higher numbers of erythroid progenitors in the spleen compared with wild-type mice. Together, our data show that NR4A1 expression by MPPS limits erythropoiesis and megakaryopoeisis, permitting development to other myeloid lineages. This effect is specific to the spleen, revealing a unique molecular pathway that regulates myeloid bias in an extramedullary niche.

http://ift.tt/2DwCOWP

Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success [INFECTIOUS DISEASE AND HOST RESPONSE]

The contribution of the host immune system to the efficacy of new anti-hepatitis C virus (HCV) drugs is unclear. We undertook a longitudinal prospective study of 33 individuals with chronic HCV treated with combination pegylated IFN-α, ribavirin, and telaprevir/boceprevir. We characterized innate and adaptive immune cells to determine whether kinetics of the host response could predict sustained virologic response (SVR). We show that characteristics of the host immune system present before treatment were correlated with successful therapy. Augmentation of adaptive immune responses during therapy was more impressive among those achieving SVR. Most importantly, active memory T cell proliferation before therapy predicted SVR and was associated with the magnitude of the HCV-specific responses at week 12 after treatment start. After therapy initiation, the most important correlate of success was minimal monocyte activation, as predicted by previous in vitro work. In addition, subjects achieving SVR had increasing expression of the transcription factor T-bet, a driver of Th1 differentiation and cytotoxic effector cell maturation. These results show that host immune features present before treatment initiation predict SVR and eventual development of a higher frequency of functional virus-specific cells in blood. Such host characteristics may also be required for successful vaccine-mediated protection.

http://ift.tt/2DytJgf

The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury [INNATE IMMUNITY AND INFLAMMATION]

The disposal of apoptotic bodies by professional phagocytes is crucial to effective inflammation resolution. Our ability to improve the disposal of apoptotic bodies by professional phagocytes is impaired by a limited understanding of the molecular mechanisms that regulate the engulfment and digestion of the efferocytic cargo. Macrophages are professional phagocytes necessary for liver inflammation, fibrosis, and resolution, switching their phenotype from proinflammatory to restorative. Using sterile liver injury models, we show that the STAT3–IL-10–IL-6 axis is a positive regulator of macrophage efferocytosis, survival, and phenotypic conversion, directly linking debris engulfment to tissue repair.

http://ift.tt/2DvQFwy

Extracellular Lactate: A Novel Measure of T Cell Proliferation [NOVEL IMMUNOLOGICAL METHODS]

Following activation, T cells rapidly divide and acquire effector functions. This energetically demanding process depends upon the ability of T cells to undergo metabolic remodeling from oxidative phosphorylation to aerobic glycolysis, during which glucose is converted into lactate and released extracellularly. In this article, we demonstrate that extracellular lactate can be used to dynamically assess human T cell responses in vitro. Extracellular lactate levels strongly correlated with T cell proliferation, and measuring lactate compared favorably with traditional methods for determining T cell responses (i.e., [³H]thymidine incorporation and the use of cell proliferation dyes). Furthermore, we demonstrate the usefulness of measuring lactate as a read-out in conventional suppression assays and high-throughput peptide-screening assays. Extracellular lactate was stably produced over 7 d, and results were reproducibly performed over several freeze–thaw cycles. We conclude that the use of extracellular lactate measurements can be a sensitive, safe, stable, and easy-to-implement research tool for measuring T cell responses and cellular metabolic changes in vitro.

http://ift.tt/2DArWY0

The Hypoxia-Adenosine Link during Intestinal Inflammation [BRIEF REVIEWS]

Intestinal inflammation is a key element in inflammatory bowel disease and is related to a combination of factors, including genetics, mucosal barrier dysfunction, bacteria translocation, deleterious host–microbe interactions, and dysregulated immune responses. Over the past decade, it has been appreciated that these inflammatory lesions are associated with profound tissue hypoxia. Interestingly, an endogenous adaptive response under the control of hypoxia signaling is enhancement in adenosine signaling, which impacts these different endpoints, including promoting barrier function and encouraging anti-inflammatory activity. In this review, we discuss the hypoxia–adenosine link in inflammatory bowel disease, intestinal ischemia/reperfusion injury, and colon cancer. In addition, we provide a summary of clinical implications of hypoxia and adenosine signaling in intestinal inflammation and disease.

http://ift.tt/2n1B9NW

Cutting Edge: Low-Affinity TCRs Support Regulatory T Cell Function in Autoimmunity [CUTTING EDGE]

Regulatory T cells (Tregs) use a distinct TCR repertoire and are more self-reactive compared with conventional T cells. However, the extent to which TCR affinity regulates the function of self-reactive Tregs is largely unknown. In this study, we used a two-TCR model to assess the role of TCR affinity in Treg function during autoimmunity. We observed that high- and low-affinity Tregs were recruited to the pancreas and contributed to protection from autoimmune diabetes. Interestingly, high-affinity cells preferentially upregulated the TCR-dependent Treg functional mediators IL-10, TIGIT, GITR, and CTLA4, whereas low-affinity cells displayed increased transcripts for Areg and Ebi3, suggesting distinct functional profiles. The results of this study suggest mechanistically distinct and potentially nonredundant roles for high- and low-affinity Tregs in controlling autoimmunity.

http://ift.tt/2DArY24

Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity [ALLERGY AND OTHER HYPERSENSITIVITIES]

Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT₂R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease–like Ptges^–/– mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C₄ synthase (Ltc4s). Administrations of either LTC₄ (the parent cysLT) or the selective CysLT₂R agonist N-methyl LTC₄ to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT₂R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT₂R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC₄-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT₂R prior to inhalation challenge of Ptges^–/– mice with aspirin blocked IL-33–dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT₂R signaling, IL-33–dependent ILC2 expansion, and IL-33–driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT₂R-targeted drugs may interrupt these processes.

http://ift.tt/2n4D9ES

B Cell-Intrinsic MyD88 Signaling Promotes Initial Cell Proliferation and Differentiation To Enhance the Germinal Center Response to a Virus-like Particle [ANTIGEN RECOGNITION AND RESPONSES]

Although TLR signaling in B cells has been implicated in the germinal center (GC) responses during viral infections and autoimmune diseases, the underlying mechanism is unclear. Bacterial phage Qβ-derived virus-like particle (Qβ-VLP) contains TLR ligands, which can enhance Qβ-VLP-induced Ab response, including GC response, through TLR/MyD88 signaling in B cells. In this study, by examining Ag-specific B cell response to Qβ-VLP, we found that lack of B cell MyD88 from the beginning of the immune response led to a more severe defect in the GC scale than abolishing MyD88 at later time points of the immune response. Consistently, B cell–intrinsic MyD88 signaling significantly enhanced the initial proliferation of Ag-specific B cells, which was accompanied with a dramatic increase of plasma cell generation and induction of Bcl-6⁺ GC B cell precursors. In addition, B cell–intrinsic MyD88 signaling promoted strong T-bet expression independent of IFN- and led to the preferential isotype switching to IgG2a/c. Thus, by promoting the initial Ag-specific B cell proliferation and differentiation, B cell–intrinsic MyD88 signaling enhanced both T-independent and T-dependent Ab responses elicited by Qβ-VLP. This finding will provide additional insight into the role of TLR signaling in antiviral immunity, autoimmune diseases, and vaccine design.

http://ift.tt/2n2DRTj

Murine Red Blood Cells Lack Ligands for B Cell Siglecs, Allowing Strong Activation by Erythrocyte Surface Antigens [ANTIGEN RECOGNITION AND RESPONSES]

CD22 and sialic acid–binding Ig-like lectin (Siglec)-G are members of the Siglec family of inhibitory coreceptors expressed on B cells that participate in enforcement of peripheral B cell tolerance. We have shown previously that when a BCR engages its cognate Ag on a cell surface that also expresses Siglec ligands, B cell Siglecs are recruited to the immunological synapse, resulting in suppression of BCR signaling and B cell apoptosis. Because all cells display sialic acids, and CD22 and Siglec-G have distinct, yet overlapping, specificities for sialic acid–containing glycan ligands, any cell could, in principle, invoke this tolerogenic mechanism for cell surface Ags. However, we show in this article that C57BL/6J mouse RBCs are essentially devoid of CD22 and Siglec-G ligands. As a consequence, RBCs that display a cell surface Ag, membrane-bound hen egg lysozyme, strongly activate Ag-specific B cells. We reasoned that de novo introduction of CD22 ligands in RBCs should abolish B cell activation toward its cognate Ag on the surface of RBCs. Accordingly, we used a glyco-engineering approach wherein synthetic CD22 ligands linked to lipids are inserted into the membrane of RBCs. Indeed, insertion of CD22 ligands into the RBC cell surface strongly inhibited B cell activation, cytokine secretion, and proliferation. These results demonstrate that the lack of Siglec ligands on the surface of murine RBCs permits B cell responses to erythrocyte Ags and show that Siglec-mediated B cell tolerance is restricted to cell types that express glycan ligands for the B cell Siglecs.

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Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models [AUTOIMMUNITY]

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

http://ift.tt/2n0t100

GM-CSF Promotes Chronic Disability in Experimental Autoimmune Encephalomyelitis by Altering the Composition of Central Nervous System-Infiltrating Cells, but Is Dispensable for Disease Induction [AUTOIMMUNITY]

GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)_35–55. The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG_35–55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG_35–55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG_35–55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits.

http://ift.tt/2DxTTQj

Production of IL-17 by MAIT Cells Is Increased in Multiple Sclerosis and Is Associated with IL-7 Receptor Expression [AUTOIMMUNITY]

Multiple sclerosis (MS) is a T cell–driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4⁺ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism. In this study, we characterized MAIT cells from the peripheral blood of MS patients in comparison with healthy individuals with respect to their type-17 differentiation. We found a specific increase of IL-17⁺ MAIT cells as well as an increased expression of retinoic acid–related orphan receptor (ROR)t and CCR6 in MAIT cells from MS patients, whereas the expression of T cell activation markers HLA-DR and CD38 was not different. IL-17 production by MAIT cells furthermore correlated with the surface expression level of the IL-7 receptor α-chain (CD127), which was significantly increased on MAIT cells from MS patients in comparison with healthy individuals. In summary, our findings indicate an augmented type-17 differentiation of MAIT cells in MS patients associated with their IL-7 receptor surface expression, implicating a proinflammatory role of these unconventional T cells in MS immunopathology.

http://ift.tt/2n2NuRM

Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor [IMMUNE REGULATION]

Natural killer gene complex–encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell–mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti–Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8α⁺ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g-expressing activated DCs during immune responses.

http://ift.tt/2Dp1vQR

Novel TCR-Mediated Mechanisms of Notch Activation and Signaling [IMMUNE REGULATION]

The Notch receptor is an evolutionarily highly conserved transmembrane protein that is essential to a wide spectrum of cellular systems. Notch signaling is especially important to T cell development, and its deregulation leads to leukemia. Although not well characterized, it continues to play an integral role in peripheral T cells, in which a unique mode of Notch activation can occur. In contrast to canonical Notch activation initiated by adjacent ligand-expressing cells, TCR stimulation is sufficient to induce Notch signaling. However, the interactions between these two pathways have not been defined. In this article, we show that Notch activation occurs in peripheral T cells within a few hours post–TCR stimulation and is required for optimal T cell activation. Using a panel of inhibitors against components of the TCR signaling cascade, we demonstrate that Notch activation is facilitated through initiation of protein kinase C–induced ADAM activity. Moreover, our data suggest that internalization of Notch via endocytosis plays a role in this process. Although ligand-mediated Notch stimulation relies on mechanical pulling forces that disrupt the autoinhibitory domain of Notch, we hypothesized that, in T cells in the absence of ligands, these conformational changes are induced through chemical adjustments in the endosome, causing alleviation of autoinhibition and receptor activation. Thus, T cells may have evolved a unique method of Notch receptor activation, which is described for the first time, to our knowledge, in this article.

http://ift.tt/2DwN5lH

Human M2 Macrophages Limit NK Cell Effector Functions through Secretion of TGF-{beta} and Engagement of CD85j [IMMUNE REGULATION]

NK cells play important roles during immunosurveillance against tumors and viruses as they trigger cytotoxicity against susceptible cells and secrete proinflammatory cytokines such as IFN-. In addition, upon activation, macrophages can become proinflammatory (M1) or anti-inflammatory (M2) cells. Although the consequences of the cross-talk between M1 and NK cells are known, the outcome of the cross-talk between M2 and NK cells remains ill-defined. Therefore, in the current work, we investigated the outcome and the underlying mechanisms of the interaction between resting or stimulated human NK cells with M1 or M2. We observed a lower percentage of activated NK cells that produced less IFN- upon coculture with M2. Also, CD56^dim NK cells cocultured with M2 displayed lower degranulation and cytotoxic activity than NK cells cocultured with M1. Soluble TGF-β and M2-driven upregulation of CD85j (ILT-2) on NK cells accounted for the diminished IFN- production by CD56^bright NK cells, whereas M2-driven upregulation of CD85j on NK cells accounted for the generation of hyporesponsive CD56^dim NK cells with limited degranulation and cytotoxic capacity. Accordingly, M2 expressed higher amounts of HLA-G, the main ligand for CD85j, than M1. Hyporesponsiveness to degranulation in NK cells was not restored at least for several hours upon removal of M2. Therefore, alternatively activated macrophages restrain NK cell activation and effector functions through different mechanisms, leading to NK cells that display diminished IFN- production and at least a transiently impaired degranulation ability. These results unravel an inhibitory circuit of possible relevance in pathological situations.

http://ift.tt/2n0qP8M

Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-{gamma} Immunity in Mycobacterial Infection [IMMUNE REGULATION]

The nucleic acids of Mycobacterium tuberculosis can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL-1β. However, whether cross-talk occurs between AIM2–IL-1β and cyclic GMP-AMP synthase–type I IFN signaling upon M. tuberculosis infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2^–/– mice reciprocally induces overreactive IFN-β and depressive IFN- responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck-like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow–derived macrophages and bone marrow–derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis-associated speck-like protein expression is inversely correlated with IFN-β levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2–IL-1β signaling pathway negatively regulates the STING–type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from M. tuberculosis infection. This finding has potential clinical significance.

http://ift.tt/2Dyv2Mg

IL-4-Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation [IMMUNE REGULATION]

Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4–induced gene-1 (IL4I1), a secreted l-phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology.

http://ift.tt/2n0OZQp

EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production [IMMUNE REGULATION]

Epigenetic remodeling is required during B cell differentiation. However, little is known about the direct functions of epigenetic enzymes in Ab-secreting cells (ASC) in vivo. In this study, we examined ASC differentiation independent of T cell help and germinal center reactions using mice with inducible or B cell–specific deletions of Ezh2. Following stimulation with influenza virus or LPS, Ezh2-deficient ASC poorly proliferated and inappropriately maintained expression of inflammatory pathways, B cell–lineage transcription factors, and Blimp-1–repressed genes, leading to fewer and less functional ASC. In the absence of EZH2, genes that normally gained histone H3 lysine 27 trimethylation were dysregulated and exhibited increased chromatin accessibility. Furthermore, EZH2 was also required for maximal Ab secretion by ASC, in part due to reduced mitochondrial respiration, impaired glucose metabolism, and poor expression of the unfolded-protein response pathway. Together, these data demonstrate that EZH2 is essential in facilitating epigenetic changes that regulate ASC fate, function, and metabolism.

http://ift.tt/2Dw0Zo7

A Cellular MicroRNA Facilitates Regulatory T Lymphocyte Development by Targeting the FOXP3 Promoter TATA-Box Motif [IMMUNE SYSTEM DEVELOPMENT]

The CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs) mediate immunological self-tolerance and suppress various immune responses. FOXP3 is a key transcriptional factor for the generation and development of Tregs. Its expression is regulated by various cytokines including TGF-β, IL-2, and IL-10. It is important to further identify the regulatory factors for Tregs. Given that many microRNAs (miRNAs) could specifically interact with the core promoter region and specifically enhance the transcription of many target genes, we searched for any possible miRNA(s) targeting the core promoter region of the FOXP3 gene. We found that miR-4281, an miRNA specifically expressed in hominids, can potently and specifically upregulate FOXP3 expression by directly interacting with the TATA-box motif in the human FOXP3 promoter. Consequently, miR-4281 significantly accelerated the differentiation of human naive cells to induced Tregs (iTregs) that possess immune suppressor functions and weaken the development of graft-versus-host disease in a humanized mouse model. Interestingly, iTregs induced by the combination of TGF-β, IL-2, and chemically synthesized miR-4281 were more stable and functional than those induced by TGF-β and IL-2 alone. Moreover, we found that the IL-2/STAT5 signal transduction upregulates FOXP3 expression not only through the classical pathway, but also by enhancing the expression of the miR-4281 precursor gene (SNCB) and, correspondingly, miR-4281. This study reveals a novel mechanism regulating FOXP3 expression and human iTreg development and, therefore, offers a new therapeutic target to manipulate immunosuppressive system.

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Newly Generated CD4+ T Cells Acquire Metabolic Quiescence after Thymic Egress [IMMUNE SYSTEM DEVELOPMENT]

Mature naive T cells circulate through the secondary lymphoid organs in an actively enforced quiescent state. Impaired cell survival and cell functions could be found when T cells have defects in quiescence. One of the key features of T cell quiescence is low basal metabolic activity. It remains unclear at which developmental stage T cells acquire this metabolic quiescence. We compared mitochondria among CD4 single-positive (SP) T cells in the thymus, CD4⁺ recent thymic emigrants (RTEs), and mature naive T cells in the periphery. The results demonstrate that RTEs and naive T cells had reduced mitochondrial content and mitochondrial reactive oxygen species when compared with SP thymocytes. This downregulation of mitochondria requires T cell egress from the thymus and occurs early after young T cells enter the circulation. Autophagic clearance of mitochondria, but not mitochondria biogenesis or fission/fusion, contributes to mitochondrial downregulation in RTEs. The enhanced apoptosis signal-regulating kinase 1/MAPKs and reduced mechanistic target of rapamycin activities in RTEs relative to SP thymocytes may be involved in this mitochondrial reduction. These results indicate that the gain of metabolic quiescence is one of the important maturation processes during SP–RTE transition. Together with functional maturation, it promotes the survival and full responsiveness to activating stimuli in young T cells.

http://ift.tt/2DyqIMM

Neonicotinoids thiamethoxam and clothianidin adversely affect the colonisation of invertebrate populations in aquatic microcosms

Abstract

Surface waters are sometimes contaminated with neonicotinoids: a widespread, persistent, systemic class of insecticide with leaching potential. Previous ecotoxicological investigations of this chemical class in aquatic ecosystems have largely focused on the impacts of the neonicotinoid imidacloprid; few empirical, manipulative studies have investigated the effect on invertebrate abundances of two other neonicotinoids which are now more widely used: clothianidin and thiamethoxam. In this study, we employ a simple microcosm semi-field design, incorporating a one-off contamination event, to investigate the effect of these pesticides at field-realistic levels (ranging from 0 to 15 ppb) on invertebrate colonisation and survival in small ephemeral ponds. In line with previous research on neonicotinoid impacts on aquatic invertebrates, significant negative effects of both neonicotinoids were found. There were clear differences between the two chemicals, with thiamethoxam generally producing stronger negative effects than clothianidin. Populations of Chironomids (Diptera) and Ostracoda were negatively affected by both chemicals, while Culicidae appeared to be unaffected by clothianidin at the doses used. Our data demonstrate that field-realistic concentrations of neonicotinoids are likely to reduce populations of invertebrates found in ephemeral ponds, which may have knock on effects up the food chain. We highlight the importance of developing pesticide monitoring schemes for European surface waters.

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Altered HDL Remodeling and Functionality in Familial Hypercholesterolemia

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1-Year Outcomes of Patients Undergoing Primary Angioplasty for Myocardial Infarction Treated With Prasugrel Versus Ticagrelor

AbstractBackground

Early outcomes of patients in the PRAGUE-18 (Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction) study did not find any significant differences between 2 potent P2Y₁₂ inhibitors.

Objectives

The 1-year follow-up of the PRAGUE-18 study focused on: 1) a comparison of efficacy and safety between prasugrel and ticagrelor; and 2) the risk of major ischemic events related to an economically motivated post-discharge switch to clopidogrel.

Methods

A total of 1,230 patients with acute myocardial infarction (MI) treated with primary percutaneous coronary intervention were randomized to prasugrel or ticagrelor with an intended treatment duration of 12 months. The combined endpoint was cardiovascular death, MI, or stroke at 1 year. Because patients had to cover the costs of study medication after hospital discharge, some patients decided to switch to clopidogrel.

Results

The endpoint occurred in 6.6% of prasugrel patients and in 5.7% of ticagrelor patients (hazard ratio: 1.167; 95% confidence interval: 0.742 to 1.835; p = 0.503). No significant differences were found in: cardiovascular death (3.3% vs. 3.0%; p = 0.769), MI (3.0% vs. 2.5%; p = 0.611), stroke (1.1% vs. 0.7%; p = 0.423), all-cause death (4.7% vs. 4.2%; p = 0.654), definite stent thrombosis (1.1% vs. 1.5%; p = 0.535), all bleeding (10.9% vs. 11.1%; p = 0.999), and TIMI (Thrombolysis In Myocardial Infarction) major bleeding (0.9% vs. 0.7%; p = 0.754). The percentage of patients who switched to clopidogrel for economic reasons was 34.1% (n = 216) for prasugrel and 44.4% (n = 265) for ticagrelor (p = 0.003). Patients who were economically motivated to switch to clopidogrel had (compared with patients who continued the study medications) a lower risk of major cardiovascular events; however, they also had lower ischemic risk.

Conclusions

Prasugrel and ticagrelor are similarly effective during the first year after MI. Economically motivated early post-discharge switches to clopidogrel were not associated with an increased risk of ischemic events. (Comparison of Prasugrel and Ticagrelor in the Treatment of Acute Myocardial Infarction [PRAGUE-18]; NCT02808767)

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Reply: Pregnancy-Associated Coronary Artery Dissection: A Therapeutic Dilemma

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Prevalence of Cardiac Amyloidosis in Patients Referred for Transcatheter Aortic Valve Replacement

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Can Biomarker Panels Predict Response to Pharmacotherapy in Heart Failure?

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The Difficulty in Identifying Pregnancy-Associated Coronary Artery Dissection Using Nationwide Inpatient Databases

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Trends in Survival After In-Hospital Cardiac Arrest During Nights and Weekends

AbstractBackground

Survival after in-hospital cardiac arrest (IHCA) is lower during nights and weekends (off-hours) compared with daytime during weekdays (on-hours). As overall IHCA survival has improved over time, it remains unknown whether survival differences between on-hours and off-hours have changed.

Objectives

This study sought to examine temporal trends in survival differences between on-hours and off-hours IHCA.

Methods

We identified 151,071 adults at 470 U.S. hospitals in the Get with the Guidelines–Resuscitation registry during 2000 to 2014. Using multivariable logistic regression with generalized estimating equations, we examined whether survival trends in IHCA differed during on-hours (Monday to Friday 7:00 am to 10:59 pm) versus off-hours (Monday to Friday 11:00 pm to 6:59 am, and Saturday to Sunday, all day).

Results

Among 151,071 participants, 79,091 (52.4%) had an IHCA during off-hours. Risk-adjusted survival improved over time in both groups (on-hours: 16.0% in 2000, 25.2% in 2014; off-hours: 11.9% in 2000, 21.9% in 2014; p for trend <0.001 for both). However, there was no significant change in the survival difference over time between on-hours and off-hours, either on an absolute (p = 0.75) or a relative scale (p = 0.059). Acute resuscitation survival improved significantly in both groups (on-hours: 56.1% in 2000, 71% in 2014; off-hours: 46.9% in 2000, 68.2% in 2014; p for trend <0.001 for both) and the difference between on-hours and off-hours narrowed over time (p = 0.02 absolute scale, p < 0.001 relative scale). In contrast, although post-resuscitation survival also improved over time in both groups (p for trend < 0.001 for both), the absolute and relative difference persisted.

Conclusions

Despite an overall improvement in survival, lower survival in IHCA during off-hours compared with on-hours persists.

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Should We Recommend Cardiac Rehabilitation in Patients With Spontaneous Coronary Artery Dissection?

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Is it Like Night and Day, or Weekend?

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A New Educational Framework to Improve Lifelong Learning for Cardiologists

Abstract

Lifelong learning is essential for the practicing cardiologist. Present lifelong learning mechanisms are stagnant and at risk for not meeting the needs of currently practicing cardiologists. With the increasing burden of cardiovascular disease, growing complexity of patient care, and ongoing pressures of nonclinical responsibilities, educational programming must evolve to meet the demands of the contemporary cardiovascular professional. A paradigm shift, replete with modern and practical educational tools, is needed in the lifelong learning armamentarium. Emerging evidence of novel educational strategies in graduate medical education supports the promise of broader application of these tools to different stages of professional life. In this commentary from the Fellows-in-Training Section Leadership Council, the authors propose 3 novel educational tools—personalized learning, adaptive learning, and the flipped classroom—to improve lifelong learning to meet the educational needs of fellows-in-training to practicing cardiologists alike.

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Coronary Adventitial and Perivascular Adipose Tissue Inflammation in Patients With Vasospastic Angina

AbstractBackground

Recent studies suggested that perivascular components, such as perivascular adipose tissue (PVAT) and adventitial vasa vasorum (VV), play an important role as a source of various inflammatory mediators in cardiovascular disease.

Objectives

The authors tested their hypothesis that coronary artery spasm is associated with perivascular inflammation in patients with vasospastic angina (VSA) using ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT).

Methods

This study prospectively examined 27 consecutive VSA patients with acetylcholine-induced diffuse spasm in the left anterior descending artery (LAD) and 13 subjects with suspected angina but without organic coronary lesions or coronary spasm. Using CT coronary angiography and electrocardiogram-gated ¹⁸F-FDG PET/CT, coronary PVAT volume and coronary perivascular FDG uptake in the LAD were examined. In addition, adventitial VV formation in the LAD was examined with optical coherence tomography, and Rho-kinase activity was measured in circulating leukocytes.

Results

Patient characteristics were comparable between the 2 groups. CT coronary angiography and ECG-gated ¹⁸F-FDG PET/CT showed that coronary PVAT volume and coronary perivascular FDG uptake significantly increased in the VSA group compared with the non-VSA group. Furthermore, optical coherence tomography showed that adventitial VV formation significantly increased in the VSA group compared with the non-VSA group, as did Rho-kinase activity. Importantly, during the follow-up period with medical treatment, both coronary perivascular FDG uptake and Rho-kinase activity significantly decreased in the VSA group.

Conclusions

These results provide the first evidence that coronary spasm is associated with inflammation of coronary adventitia and PVAT, where ¹⁸F-FDG PET/CT could be useful for disease activity assessment. (Morphological and Functional Change of Coronary Perivascular Adipose Tissue in Vasospastic Angina [ADIPO-VSA Trial]; UMIN000016675)

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Cardiac Resynchronization Therapy for End-Stage Hypertrophic Cardiomyopathy: The Need for Disease-Specific Criteria

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The Forgotten Vascular Layer in the Forgotten Coronary Disorder

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Pregnancy-Associated Spontaneous Coronary Artery Dissection: A Different Presentation Although Perhaps Not Such a Distinct Condition

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Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction

AbstractBackground

In addition to scalability, human embryonic stem cells (hESCs) have the unique advantage of allowing their directed differentiation toward lineage-specific cells.

Objectives

This study tested the feasibility of leveraging the properties of hESCs to generate clinical-grade cardiovascular progenitor cells and assessed their safety in patients with severe ischemic left ventricular dysfunction.

Methods

Six patients (median age 66.5 years [interquartile range (IQR): 60.5 to 74.7 years]; median left ventricular ejection fraction 26% [IQR: 22% to 32%]) received a median dose of 8.2 million (IQR: 5 to 10 million) hESC-derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure. The primary endpoint was safety at 1 year and focused on: 1) cardiac or off-target tumor, assessed by imaging (computed tomography and fluorine-18 fluorodeoxyglucose positron emission tomography scans); 2) arrhythmias, detected by serial interrogations of the cardioverter-defibrillators implanted in all patients; and 3) alloimmunization, assessed by the presence of donor-specific antibodies. Patients were followed up for a median of 18 months.

Results

The protocol generated a highly purified (median 97.5% [IQR: 95.5% to 98.7%]) population of cardiovascular progenitors. One patient died early post-operatively from treatment-unrelated comorbidities. All others had uneventful recoveries. No tumor was detected during follow-up, and none of the patients presented with arrhythmias. Three patients developed clinically silent alloimmunization. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments. One patient died of heart failure after 22 months.

Conclusions

This trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900)

http://ift.tt/2Bj01WF

Pregnancy-Associated Coronary Artery Dissection: A Therapeutic Dilemma

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Trial of Embryonic Stem Cell-Derived Cardiac Progenitor Cells: An Encouraging Start

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Comparative study on the incision healing of the palatal mucosa by using Er:YAG laser or traditional scalpel in the SD rats

Abstract

The aim of this study was to compare the histology of wound healing following incisions with the scalpel or the Er:YAG laser in the palatal mucosa of SD rats. Two types of wounds were performed with the stainless steel scalpel or the Er:YAG laser in the palatal mucosa of SD rats, while the adjacent untreated palatal mucosa was chosen as control. Rats were sacrificed on day 1, day 3, day 7, and day 30 post-surgery. Biopsy samples from each wound were examined and the expression of IL-1ß and TGF-ß1 was determined by enzyme-linked immunosorbent assay (ELISA). The early postoperative incision of the scalpel group had obvious bleeding and swelling, while the laser wound mainly covered the surface of white pseudomembrane. The infiltration of neutrophils and lymphocytes in the stroma of the scalpel incision was more than that of the laser group. Compared to the laser group, 1 and 3 days after operation, the TGF-β1 content of the scalpel group were significantly increased (P = 0.032 and 0.019). Seven days after operation, the TGF-β1 content of two groups was decreased. TGF-β1 expression of control group was obviously increased (P > 0.05); 1, 3, and 7 days after operation, the traditional scalpel amount of IL-1β expression was significantly higher than that of control group (P = 0.000, 0.000, and 0.001). Postoperative day 1, IL-1β expression of laser group and control group had no significant difference (P = 0.572). Three days after operation, IL-1β expression of laser incision was increased and was significantly higher than that in control group (P = 0.032), however lower than the scalpel group (P = 0.03). Seven days after operation, the IL-1β expression of two groups had no significant difference (P = 0.333); however, the IL-1β expression of two groups were significantly higher than that of the control group (P = 0.02 and 0.001). Compared to the traditional scalpel, the incision of Er:YAG laser has smaller inflammation reaction, more pseudomembrane coverage, and minimal damage of the mucoperiosteal tissue.

http://ift.tt/2G5joFX

A grey DEMATEL-based approach for modeling enablers of green innovation in manufacturing organizations

Abstract

Incorporating green practices into the manufacturing process has gained momentum over the past few years and is a matter of great concern for both manufacturers as well as researchers. Regulatory pressures in developed countries have forced the organizations to adopt green practices; however, this issue still lacks attention in developing economies like India. There is an urgent need to identify enablers of green innovation for manufacturing organizations and also to identify prominent enablers among those. This study is an attempt to first identify enablers of green innovation and then establish a causal relationship among them to identify the enablers that can drive others. Grey DEMATEL (Decision Making Trial and Evaluation Laboratory) methodology is used for establishing the causal relationship among enablers. The novelty of this study lies in the fact that no study has been done in the past to identify the enablers of green innovation and then establishing the causal relationship among them. A total of 21 enablers of green innovation have been identified; research indicates developing green manufacturing capabilities, resources for green innovation, ease of getting loans from financial institutions, and environmental regulations as the most influential enablers of green innovation. Managerial and practical implications of the research are also presented to assist managers of the case company in adopting green innovation practices at their end.

http://ift.tt/2F2Fc3O

Does finance affect environmental degradation: evidence from One Belt and One Road Initiative region?

Abstract

This paper explores the effects of finance on environmental degradation and investigates environmental Kuznets curve (EKC) of each country among 52 that participate in the One Belt and One Road Initiative (OBORI) using the latest long panel data span (1980–2016). We utilized panel long run econometric models (fully modified ordinary least square and dynamic ordinary least square) to explore the long-run estimates in full panel and country level. Moreover, the Dumitrescu and Hurlin (2012) causality test is applied to examine the short-run causalities among our considered variables. The empirical findings validate the EKC hypothesis; the long-run estimates point out that finance significantly enhances the environmental degradation (negatively in few cases). The short-run heterogeneous causality confirms the bi-directional causality between finance and environmental degradation. The empirical outcomes suggest that policymakers should consider the environmental degradation issue caused by financial development in the One Belt and One Road region.

http://ift.tt/2DAlq2w

Stevens–Johnson syndrome/toxic epidermal necrolysis and erythema multiforme drug-related hospitalisations in a national administrative database

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and erythema multiforme (EM) are immunologically-mediated dermatological disorders commonly triggered by drug exposure and/or other external agents...

http://ift.tt/2BkpmiN

Does hyperthyroidism worsen prognosis of thyroid carcinoma? A retrospective analysis on 2820 consecutive thyroidectomies

Hyperthyroidism is associated with high incidence of thyroid carcinoma; furthermore, tumors arisen in hyperthyroid tissue show an aggressive behavior. Thyroid Stimulating Hormone (TSH) and Thyroid-stimulating ...

http://ift.tt/2n52lwb

An automated A-value measurement tool for accurate cochlear duct length estimation

There has been renewed interest in the cochlear duct length (CDL) for preoperative cochlear implant electrode selection and postoperative generation of patient-specific frequency maps. The CDL can be estimated...

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Seltene Ursache einer supraklavikulären Schwellung

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Retinoic acid signalling is a candidate regulator of the expression of pituitary-specific transcription factor Prop1 in the developing rodent pituitary

Abstract

Development of the anterior pituitary proceeds via spatiotemporal patterning of transcription factors and signalling molecules. Among them, retinoic acid (RA) functions as an important signalling molecule for vertebrate organogenesis in many tissues. However, little is known regarding target genes in the developing pituitary. The present study aimed to clarify the relationship between endogenous RA signalling and mRNA expression of the pituitary-specific transcription factor Prop1 in the pituitary primordium of Rathke's pouch. Gene expression analysis and in situ hybridisation demonstrated that retinaldehyde dehydrogenases (Raldhs) and all types of RA receptors (Rars) are expressed at the level of transcription in the rat Rathke's pouch. Ex vivo organ culture using Rathke's pouch and in vitro reporter assay demonstrated that RA signalling increases the expression level of Prop1 via RARα. Moreover, a reporter assay using serial truncated constructs of the 5′-upstream region of mouse Prop1 revealed a predicted cis-regulatory element of RARα. This is the first report exhibiting a relationship between RA signalling and Prop1-expression during early pituitary development.

This article is protected by copyright. All rights reserved.

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3D accuracy of implant positions in template-guided implant placement as a function of the remaining teeth and the surgical procedure: a retrospective study

Abstract

Objective

The aim of this study was to investigate differences between the virtually planned and clinically achieved implant positions in completely template-guided implantations as a function of the type of edentulous space, the residual natural dentition, and the surgical implementation.

Materials and methods

Fifty-six patient cases with a total of 122 implants were evaluated retrospectively. The implantations were completely template-based. The data of the planned implant positions were overlaid with the actual clinical implant positions, followed by measurements of the 3D deviations in terms of coronal (x_c) and apical distance, height (x_h), and angulation (ang) and statistical analysis.

Results

The mean x_c was 1.2 mm (SD 0.7 mm); the mean x_a was 1.8 mm (SD 0.9 mm), the mean x_h was 0.8 mm (SD 0.7 mm); and the mean ang was 4.8° (SD 3.1). The type of edentulous space and the jaw (maxilla/mandible) had no significant effect on the results in terms of implant positions. The presence of an adjacent natural tooth at the time of implantation had a significant influence on x_h (p = 0.04) and ang (p = 0.05). No significant differences were found regarding the surgical approach for any of the parameters examined.

Conclusion

The results of our study are in the same range as those of other studies. Template-guided implantation offers a high degree of accuracy even in the presence of different configurations of the residual dentition or different surgical approaches. A clinical benefit is therefore present, especially from a prosthetic point of view.

Clinical relevance

The clinically achievable accuracy can be described as sufficient for further prosthetic treatment, given the intrinsic and methodological tolerances, making prosthetic rehabilitation safe and predictable.

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In response to socioeconomic disparities and comorbidities, not race, affect salivary gland malignancy survival outcomes

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Early-injection laryngoplasty may lower risk of thyroplasty: A systematic review and meta-analysis

Objective

To determine whether injection laryngoplasty within 6 months following the onset of unilateral vocal fold paralysis (UVFP) decreases the rate of permanent thyroplasty in adults.

Data Sources

Search strategies created by a medical librarian were implemented in multiple online research databases.

Review Methods

Inclusion and exclusion criteria were designed to capture randomized clinical trials and cohort studies examining adults with UVFP who received injection laryngoplasty early in the course of treatment, within 6 months of onset, or who were observed. The primary outcome was the rate of thyroplasty. The Newcastle-Ottawa scale was used to assess quality of included cohort studies. Random effects meta-analysis was used to calculate an overall relative risk (RR). Heterogeneity was evaluated with the I² statistic.

Results

The search strategy resulted in 1,177 studies, of which four cohort studies remained for meta-analysis after applying inclusion and exclusion criteria. All studies were rated as 9 of 9 on the Newcastle-Ottawa scale. Meta-analysis of 275 patients with UVFP revealed that the overall pooled RR of undergoing thyroplasty in those receiving an early injection was 0.25 (95% confidence interval 0.14–0.45) compared to conservative management (late or no injection). The I² overall was 62.4%.

Conclusion

Otolaryngologists should offer injection laryngoplasty to patients with a diagnosis of UVFP within 6 months of diagnosis (recommendation based on grade C evidence with a preponderance of benefit over harm). Laryngoscope, 2018

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Innervation status in chronic vocal fold paralysis and implications for laryngeal reinnervation

Objective

Treatment options for symptomatic unilateral vocal fold paralysis (VFP) include vocal fold augmentation, laryngeal framework surgery, and laryngeal reinnervation. Laryngeal reinnervation (LR) has been suggested to provide "tone" to the paralyzed VF. This implies a loss of tone as a result of denervation without reinnervation. We performed laryngeal electromyography (LEMG) in patients with chronic VFP to understand the innervation status associated with a chronically paralyzed vocal fold.

Study Design

Retrospective review of LEMG data in adult patients with chronic VFP from January 2009 to December 2014.

Methods

LEMG was performed at least 6 months after-onset of VFP. Qualitative LEMG, quantitative LEMG, and adductory synkinesis testing were performed, and the parameters were collected.

Results

Twenty-seven vocal folds were studied (23 unilateral VFP and 2 bilateral VFP). Average age was 59 ± 17 years. The median duration from recurrent laryngeal nerve injury to LEMG was 8.5 months (range 6–90 months). The majority of patients, 24 of 27 (89%), had motor unit potentials during phonation tasks on LEMG, and only 3 of 27 (11%) patients were electrically silent. Quantitative LEMG showed 287.8 mean turns per second (normal ≥ 400). Motor unit configuration was normal in 12 of 27 (44%), polyphasic in 12 of 27 (44%), and absent in the electrically silent patients. Adductory synkinesis was found in 6 of 20 (30%) patients.

Conclusion

Chronic vocal fold paralysis is infrequently associated with absent motor-unit recruitment, indicating some degree of preserved innervation and/or reinnervation in these patients. LEMG should be part of the routine workup for chronic VFP prior to consideration of LR.

Level of Evidence

4. Laryngoscope, 2018

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Perception and duration of pain after office-based vocal fold injection augmentation

Objectives/Hypothesis

In-office laryngology procedures are important in the treatment of voice and swallowing disorders. Patient tolerance determines which procedures can be performed without sedation or formal anesthesia. This study examines pain perception during and after in-office vocal fold injection augmentation.

Study Design

Prospective cohort study.

Methods

Patients scheduled for office-based vocal fold injection augmentation were prospectively enrolled at an academic voice center. The short-form McGill Pain Questionnaire was administered before, during, and after the procedure and on postprocedure days 1, 3, and 7. Pre- and postprocedure vital signs were recorded and heart rate was continuously monitored. Telephone questionnaires were completed on postprocedure days 1 and 3.

Results

Forty-five patients consented to participate in our study (24 males, mean age 61 years). Most patients experienced mild to moderate pain with increasing heart rate during the procedure. Pain remained or increased 20 minutes after the procedure and improved but persisted for 1 day. Sensory and affective discomfort was endorsed by the majority. A minority of patients experienced bruising and changes in swallowing with diet modification for 3 days after the procedure. Sixteen percent had discomfort after 1 week.

Conclusions

This is the first prospective study examining patient perception of pain during and after in-office injection augmentation using a validated scale and pain descriptors with extended follow-up. The results may offer guidance for patient counseling, consent, and treatment to improve tolerance and success.

Level of Evidence

4. Laryngoscope, 2018

http://ift.tt/2DX4z7Q

Programmed death ligand-1 expression as immunotherapeutic target in sinonasal cancer

Abstract

Background

Sinonasal cancer carries a poor prognosis, especially in recurrent stages, and it is a disease with very limited treatment options.

Methods

The expression of programmed death ligand-1 (PD-L1) as a marker for immunotherapy was evaluated in 53 sinonasal squamous cell carcinoma (SCC) and 126 intestinal-type adenocarcinoma (ITAC) samples. Results were correlated to clinicopathological characteristics and follow-up data.

Results

Membranous PD-L1 staining of tumor cells was observed in 34% (18/53) of the sinonasal SCC samples and in 17% (22/126) of the ITAC samples. The PD-L1 positivity on infiltrating immune cells occurred in 45% (24/53) of the sinonasal SCC samples and in 33% (41/126) of the ITAC samples. Expression of PD-L1 showed no correlation to clinicopathological parameters and was not an independent risk factor for survival.

Conclusion

The PD-L1 positivity does not seem to have prognostic value. However, a proportion of patients with sinonasal SCC and ITAC may benefit from therapy with immune checkpoint inhibitors that recently have been approved for clinical application in head and neck cancer.

http://ift.tt/2Dr40ly

Targeting of miR-31/96/182 to the Numb gene during head and neck oncogenesis

Abstract

Background

MicroRNAs (miRNAs) play crucial roles in head and neck squamous cell carcinoma (HNSCC). This study investigates whether miR-31, miR-96, and miR-182 are involved in targeting Numb during HNSCC.

Methods

The expression of miR-31/96/182 in tumor tissues was analyzed. Reporter assay, knockdown, expression, and oncogenic analysis were carried out in cell lines.

Results

Upregulation of miR-31/96/182 was detected in tumor tissues. In addition, advanced tumors showed higher expression levels of these miRNAs. The expression of these miRNAs was upregulated after treatment with areca ingredients (P < .01 or P < .001). These miRNAs directly targeted the 3′ untranslated region (UTR) sequence of the Numb gene. An increased migration and invasion of HNSCC cells was associated with the exogenous expression of miR-31/96/182 (P < .01 or P < .001), and this was reverted by expression of Numb.

Conclusion

This study provides new evidence demonstrating that there is frequent and concordant upregulation of miR-31, miR-96, and miR-182 during HNSCC and these miRNAs co-target Numb.

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Multicenter assessment of exclusive endoscopic endonasal approach for the treatment of 53 olfactory neuroblastomas

Abstract

Background

Given the particularities of olfactory neuroblastoma (ONB) and the lack of studies on the subject, a multicenter collaborative study was conducted to assess treatment strategy.

Methods

Fifty-three patients with ONB were included from the French Rare Head and Neck Cancer Expert Network (REFCOR) database: 16T1, 8T2, 19T3, and 10T4. All cases were treated endoscopically with skull base removal and repair in 26 cases (49%) and without external craniotomy.

Results

The overall survival (OS) and disease-free survival (DFS) rates at 5 years were 87% and 71%, respectively, with mean follow-up of 45.4 ± 26.5 months. The complication rate was 18.8% with 4 cases of meningitis. Pathological analysis showed positive margins in 26.8%, notably on the dura-mater and periorbita, without impairment of OS or DFS. Forty-eight patients received adjuvant radiotherapy on T ± N. Ten patients had a recurrence (18.9%). Six patients died of their disease. Prophylactic neck irradiation seemed to reduce the recurrence rate.

Conclusion

Exclusively endoscopic treatment proved efficient and reliable in a large controlled series.

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