Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5 Άγιος Νικόλαος
Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com

Αρχειοθήκη ιστολογίου

! # Ola via Alexandros G.Sfakianakis on Inoreader

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Δευτέρα 23 Απριλίου 2018

Role of Adenoid-Nasopharyngeal Ratio in Assessing Adenoid Hypertrophy

Abstract

Most of the time, pediatrician is the first to see children with adenotonsillar hypertrophy (AH) and they mostly rely on clinical assessment with or without some investigation to refer these children to otorhinolaryngologist. Numerous methods have been described for evaluation of AH, but many of these methods are not possible to follow in busy pediatric outpatient unit either because of lack of cooperation from child or due to limited availability of test or due to cost constraints. This study has been conducted to determine the diagnostic accuracy of lateral neck X-ray (LNX) for assessing AH and to assess the correlation between adenoid size in LNX and clinical symptoms in a pediatric unit. Prospective study conducted in Department of ENT, Pathmavathy Medical Foundation, Kollam, Kerala, India from January 2015 to March 2016. 60 consecutive children of both genders, between the age group of 5 to 14 years, attending Department of Pediatrics with a provisional diagnosis of AH were included in the study. The symptom scores, radiographic ratio of adenoid to nasopharynx and endoscopic scorings were calculated. Lateral neck X-ray with calculation of adenoid-to-nasopharynx ratio is found to have significant correlation with patient reported symptoms and findings in nasal endoscopic examination (NE). LNX can be considered as a useful objective tool in evaluation of children with adenoid hypertrophy. Primary care physicians or pediatricians can confidently use lateral neck X-ray for making clinical decisions and can consider nasopharyngoscopy when clinical picture remains unclear or more evaluation is needed.



https://ift.tt/2Jm7WGW

Laryngectomy With or Without Partial Pharyngectomy: A Systematic Review

Abstract

Complications following the total laryngectomy with or without partial pharyngectomy with neck dissection for laryngeal and pyriform fossa malignancies like aspiration, pharyngocutaneous fistula wound infection, flap necrosis, haematoma, chyle fistula and carotid blowout can cause serious implication on the final outcome of the treatment, which leads to increased postoperative morbidity, hospital stay and hospital cost. A prospective study in the Department of Otolaryngology and Head–Neck Surgery, JSS Hospital, Mysore, from November 2014 to July 2016. 30 patients undergoing Total laryngectomy with or without partial pharyngectomy for laryngeal and pyriform fossa were included in this study. The presentation, diagnosis, and management of the complications that were occurred, were discussed. The age of the patients vary between 32 and 76. Also, male preponderance was seen with approximately M:F ratio 3:1. Out of these 30 patients, 6 patients developed complications. The most common complication was pharyngocutaneous fistula (2 patients, 6%), which was developed after the 7th day. It was managed conservatively in both patients, wound infection was a second complication (2, 6%). Other complications were drain failure (1, 3%) and chylous fistula (1, 3%). The Most common complications after total laryngectomy with or without partial pharyngectomy with neck dissection in our study were wound infection and pharyngocutaneous fistula. Assessment of risk factors, early recognition of complications per operative protocols with improvised techniques are necessary to reduce incidence of complication after total laryngectomy with or without partial pharyngectomy with neck dissection.



https://ift.tt/2HKFnWl

Barbed Reposition Pharyngoplasty in Indian Population: A New Palatal Surgery for OSAS

Abstract

Obstructive sleep apnoea (OSA) is a common problem affecting almost 4% of the population. Although continuous positive airway pressure (CPAP) is considered the standard of care, the patient compliance for long term use is poor. Clinicians have explored surgical options for cure with varying success. Uvulopalatopharyngoplasty was considered as a standard of surgical care but long-term results were not satisfactory. Surgical researchers have explored newer techniques to improve outcomes in the past decade with less morbidity and better quality of life outcomes. One of such development is Barbed Reposition Pharyngoplasty (BRP). We would like to discuss the technique of BRP for OSA patients step by step.



https://ift.tt/2Jk2CDR

Ecotoxicology in tropical regions



https://ift.tt/2qW6u6t

Role of Adenoid-Nasopharyngeal Ratio in Assessing Adenoid Hypertrophy

Abstract

Most of the time, pediatrician is the first to see children with adenotonsillar hypertrophy (AH) and they mostly rely on clinical assessment with or without some investigation to refer these children to otorhinolaryngologist. Numerous methods have been described for evaluation of AH, but many of these methods are not possible to follow in busy pediatric outpatient unit either because of lack of cooperation from child or due to limited availability of test or due to cost constraints. This study has been conducted to determine the diagnostic accuracy of lateral neck X-ray (LNX) for assessing AH and to assess the correlation between adenoid size in LNX and clinical symptoms in a pediatric unit. Prospective study conducted in Department of ENT, Pathmavathy Medical Foundation, Kollam, Kerala, India from January 2015 to March 2016. 60 consecutive children of both genders, between the age group of 5 to 14 years, attending Department of Pediatrics with a provisional diagnosis of AH were included in the study. The symptom scores, radiographic ratio of adenoid to nasopharynx and endoscopic scorings were calculated. Lateral neck X-ray with calculation of adenoid-to-nasopharynx ratio is found to have significant correlation with patient reported symptoms and findings in nasal endoscopic examination (NE). LNX can be considered as a useful objective tool in evaluation of children with adenoid hypertrophy. Primary care physicians or pediatricians can confidently use lateral neck X-ray for making clinical decisions and can consider nasopharyngoscopy when clinical picture remains unclear or more evaluation is needed.



https://ift.tt/2Jm7WGW

Laryngectomy With or Without Partial Pharyngectomy: A Systematic Review

Abstract

Complications following the total laryngectomy with or without partial pharyngectomy with neck dissection for laryngeal and pyriform fossa malignancies like aspiration, pharyngocutaneous fistula wound infection, flap necrosis, haematoma, chyle fistula and carotid blowout can cause serious implication on the final outcome of the treatment, which leads to increased postoperative morbidity, hospital stay and hospital cost. A prospective study in the Department of Otolaryngology and Head–Neck Surgery, JSS Hospital, Mysore, from November 2014 to July 2016. 30 patients undergoing Total laryngectomy with or without partial pharyngectomy for laryngeal and pyriform fossa were included in this study. The presentation, diagnosis, and management of the complications that were occurred, were discussed. The age of the patients vary between 32 and 76. Also, male preponderance was seen with approximately M:F ratio 3:1. Out of these 30 patients, 6 patients developed complications. The most common complication was pharyngocutaneous fistula (2 patients, 6%), which was developed after the 7th day. It was managed conservatively in both patients, wound infection was a second complication (2, 6%). Other complications were drain failure (1, 3%) and chylous fistula (1, 3%). The Most common complications after total laryngectomy with or without partial pharyngectomy with neck dissection in our study were wound infection and pharyngocutaneous fistula. Assessment of risk factors, early recognition of complications per operative protocols with improvised techniques are necessary to reduce incidence of complication after total laryngectomy with or without partial pharyngectomy with neck dissection.



https://ift.tt/2HKFnWl

Barbed Reposition Pharyngoplasty in Indian Population: A New Palatal Surgery for OSAS

Abstract

Obstructive sleep apnoea (OSA) is a common problem affecting almost 4% of the population. Although continuous positive airway pressure (CPAP) is considered the standard of care, the patient compliance for long term use is poor. Clinicians have explored surgical options for cure with varying success. Uvulopalatopharyngoplasty was considered as a standard of surgical care but long-term results were not satisfactory. Surgical researchers have explored newer techniques to improve outcomes in the past decade with less morbidity and better quality of life outcomes. One of such development is Barbed Reposition Pharyngoplasty (BRP). We would like to discuss the technique of BRP for OSA patients step by step.



https://ift.tt/2Jk2CDR

Feasibility of 3D UV-C treatment to reduce fungal growth and mycotoxin loads on maize and wheat kernels

Abstract

Fungal disease of grain crops is a concern for the agricultural industry, resulting in economic losses. Aside from severe yield losses, mycotoxigenic fungi such as Penicillium and Fusarium can produce harmful mycotoxins, including deoxynivalenol (DON), zearalenone (ZEN), and ochratoxin A (OTA). This proof-of-concept study explored the feasibility and effects of ultraviolet (UV) C light at 253.7 nm to reduce fungal and mycotoxin loads on model surfaces as well as on maize and wheat kernels using benchtop 2D and 3D illumination strategies. Reduction of Penicillium verrucosum (98.6%) and Fusarium graminearum (88.8%) on agar was achieved using a UV-C dose of 100 mJ cm−2. Naturally occurring fungal growth resembling P. verrucosum on maize was reduced by 79% after exposure to 5000 mJ cm−2. Similarly, fungal growth resembling F. graminearum on maize was reduced by 60% with 1000 mJ cm−2. On wheat, significant reduction of fungal growth was not observed. Maximal reduction of DON (97.3%), ZEN (75.4%), and OTA (91.2%) on filter paper was obtained using 15,000 mJ cm−2. The overall reduction of DON (30%; 14%), ZEN (52%; 42%), and OTA (17%; 6%) on maize and wheat, respectively, was lower than on filter paper. Moisture and crude protein content as well as percent germination of maize kernels were not affected by UV-C treatment up to 5000 mJ cm−2. This study has shown that 3D UV-C treatment is a feasible option for reducing Fusarium and Penicillium growth on maize kernels and, at higher doses, decreasing ZEN by ~ 50%.



https://ift.tt/2I0k7df

Editorial Board

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Publication date: June 2018
Source:Atmospheric Environment, Volume 182





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Transcriptome Network Analysis Reveals Aging-Related Mitochondrial and Proteasomal Dysfunction and Immune Activation in Human Thyroid

Thyroid, Ahead of Print.


https://ift.tt/2HpwL8s

Blimp-1 prolongs allograft survival without regimen via influencing T cell development in favor of regulatory T cells while suppressing Th1

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Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Aline Yen Ling Wang, Charles Yuen Yung Loh, Shyi-Jou Chen, Huang-Kai Kao, Cheng-Hung Lin, Sheng-Hao Chuang, Chin-Ming Lee, Huey-Kang Sytwu, Fu-Chan Wei
BackgroundB lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown.MethodsThis study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1.ResultsWithout any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation.DiscussionAs such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.



https://ift.tt/2HMqYZZ

Blimp-1 prolongs allograft survival without regimen via influencing T cell development in favor of regulatory T cells while suppressing Th1

S01615890.gif

Publication date: July 2018
Source:Molecular Immunology, Volume 99
Author(s): Aline Yen Ling Wang, Charles Yuen Yung Loh, Shyi-Jou Chen, Huang-Kai Kao, Cheng-Hung Lin, Sheng-Hao Chuang, Chin-Ming Lee, Huey-Kang Sytwu, Fu-Chan Wei
BackgroundB lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown.MethodsThis study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1.ResultsWithout any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation.DiscussionAs such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.



https://ift.tt/2HMqYZZ

Conductive textile for flexible lithium batteries

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Publication date: Available online 23 April 2018
Source:Materials Today
Author(s): Laurie Winkless




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Black is the new black

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Publication date: Available online 22 April 2018
Source:Materials Today
Author(s): David Bradley




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3D printing soft tissue scaffolds

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Publication date: Available online 22 April 2018
Source:Materials Today
Author(s): David Bradley




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EPMA powder metallurgy summer school 2018

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Publication date: Available online 23 April 2018
Source:Materials Today





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COVER

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Publication date: April 2018
Source:Materials Today, Volume 21, Issue 3





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Inner cover 1 - A. Scidà et al.

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Publication date: April 2018
Source:Materials Today, Volume 21, Issue 3





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CONTENTS 1

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Publication date: April 2018
Source:Materials Today, Volume 21, Issue 3





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CONTENTS 2

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Publication date: April 2018
Source:Materials Today, Volume 21, Issue 3





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Mortality Differences Associated With Treatment Responses in CANTOS and FOURIER: Insights and Implications.

Author: Ridker, Paul M MD, MPH
Page: 1763-1766


https://ift.tt/2HTN763

Dawn of a New Era for Stroke Treatment: Implications of the DAWN Study for Acute Stroke Care and Stroke Systems of Care.

Author: Alberts, Mark J. MD; Ollenschleger, Martin D. MD; Nouh, Amre MD
Page: 1767-1769


https://ift.tt/2HrMFv7

High-Target Versus Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients: A Randomized Controlled Trial.

Author: Vedel, Anne G. MD; Holmgaard, Frederik BMSc; Rasmussen, Lars S. DMSc, PhD, MD; Langkilde, Annika PhD, MD; Paulson, Olaf B. DMSc, MD; Lange, Theis PhD, MSc; Thomsen, Carsten DMSc, MD; Olsen, Peter Skov DMSc, MD; Ravn, Hanne Berg DMSc, PhD, MD; Nilsson, Jens C. PhD, MD
Page: 1770-1780


https://ift.tt/2HT6lsB

Preventing Brain Injury After Cardiopulmonary Bypass Will Require More Than Just Dialing Up the Pressure.

Author: Cheung, Albert T. MD; Messe, Steven R. MD
Page: 1781-1783


https://ift.tt/2FbqRSn

Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival.

Author: Berg, Robert A. MD; Sutton, Robert M. MD, MSCE; Reeder, Ron W. PhD; Berger, John T. MD; Newth, Christopher J. MD; Carcillo, Joseph A. MD; McQuillen, Patrick S. MD; Meert, Kathleen L. MD; Yates, Andrew R. MD; Harrison, Rick E. MD; Moler, Frank W. MD; Pollack, Murray M. MD; Carpenter, Todd C. MD; Wessel, David L. MD; Jenkins, Tammara L. MSN, RN; Notterman, Daniel A. MD; Holubkov, Richard PhD; Tamburro, Robert F. MD; Dean, J. Michael MD; Nadkarni, Vinay M. MD, MS; For the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) PICqCPR (Pediatric Intensive Care Quality of Cardio-Pulmonary Resuscitation) Investigators; Zuppa, Athena F. MD, MSCE; Graham, Katherine BS; Twelves, Carolann RN; Landis, William BSE; DiLiberto, Mary Ann RN; Tomanio, Elyse RN; Kwok, Jeni JD; Bell, Michael J. MD; Abraham, Alan MBA; Sapru, Anil MD; Alkhouli, Mustafa F. BA; Heidemann, Sabrina MD; Pawluszka, Ann RN; Hall, Mark W. MD; Steele, Lisa RN; Shanley, Thomas P. MD; Weber, Monica RN; Dalton, Heidi J. MD; Bell, Aimee La RN; Mourani, Peter M. MD; Malone, Kathryn RN; Telford, Russell MS; Coleman, Whitney RN; Peterson, Alecia MS; Thelen, Julie RN; Doctor, Allan MD; CPCCRN PICqCPR Investigators
Page: 1784-1795


https://ift.tt/2HVdNUb

Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction.

Author: Fayyaz, Ahmed U. MD; Edwards, William D. MD; Maleszewski, Joseph J. MD; Konik, Ewa A. MD; DuBrock, Hilary M. MD; Borlaug, Barry A. MD; Frantz, Robert P. MD; Jenkins, Sarah M. MS; Redfield, Margaret M. MD
Page: 1796-1810


https://ift.tt/2HpHkEr

Pulmonary Venous Remodeling in Pulmonary Hypertension: The Veins Take Center Stage.

Author: Leopold, Jane A. MD
Page: 1811-1813


https://ift.tt/2HUi8a9

Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.

Author: Pandey, Ambarish MD, MSCS; Omar, Wally MD; Ayers, Colby MS; LaMonte, Michael PhD, MPH; Klein, Liviu MD, MS; Allen, Norrina B. PhD; Kuller, Lewis H. MD, DrPH; Greenland, Philip MD; Eaton, Charles B. MD, MS; Gottdiener, John S. MD; Lloyd-Jones, Donald M. MD, SM; Berry, Jarett D. MD, MS
Page: 1814-1823


https://ift.tt/2Hm03k7

miR-22 Is a Novel Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation and Neointima Formation.

Author: Yang, Feng MD *,,; Chen, Qishan MD, PhD *,; He, Shiping MD; Yang, Mei MD; Maguire, Eithne Margaret MRes; An, Weiwei PhD; Afzal, Tayyab Adeel MSc; Luong, Le Anh PhD; Zhang, Li MD, PhD; Xiao, Qingzhong MD, PhD
Page: 1824-1841


https://ift.tt/2HXDZxe

miR-22 in Smooth Muscle Cells: A Potential Therapy for Cardiovascular Disease.

Author: Huang, Zhan-Peng PhD; Wang, Da-Zhi PhD
Page: 1842-1845


https://ift.tt/2Hr9oXR

Insights From the International Registry of Acute Aortic Dissection: A 20-Year Experience of Collaborative Clinical Research.

Author: Evangelista, Arturo MD; Isselbacher, Eric M. MD; Bossone, Eduardo MD; Gleason, Thomas G. MD; Eusanio, Marco Di MD; Sechtem, Udo MD; Ehrlich, Marek P. MD; Trimarchi, Santi MD; Braverman, Alan C. MD; Myrmel, Truls MD; Harris, Kevin M. MD; Hutchinson, Stuart MD; O'Gara, Patrick MD; Suzuki, Toru MD; Nienaber, Christoph A. MD; Eagle, Kim A. MD; on behalf of the IRAD Investigators
Page: 1846-1860


https://ift.tt/2HUSWjM

Barbershop-Based Care Dramatically Trims Blood Pressure.

Author: Kuehn, Bridget M.
Page: 1861-1862


https://ift.tt/2Hr9kaz

Unexplained Cardiac Arrest in an Apparently Healthy Young Woman: What Is the Underlying Substrate of the Arrhythmia?.

Author: Noti, Fabian MD; Asatryan, Babken MD; Seiler, Jens MD; Baldinger, Samuel H. MD; Servatius, Helge MD; de Marchi, Stefano F. MD; Martinelli, Michele Vittorio MD; Hunziker Munsch, Lukas Christoph MD; Lam, Anna MD; Fuhrer, Juerg MD; Tanner, Hildegard MD; Roten, Laurent MD; Medeiros-Domingo, Argelia MD, PhD
Page: 1863-1866


https://ift.tt/2HYN9da

Impact of the US Food and Drug Administration-Approved Sex-Specific Cutoff Values for High-Sensitivity Cardiac Troponin T to Diagnose Myocardial Infarction.

Author: Rubini Gimenez, Maria MD *,; Badertscher, Patrick MD *,; Twerenbold, Raphael MD; Boeddinghaus, Jasper MD; Nestelberger, Thomas MD; Wussler, Desiree MD; Miro, Oscar MD; Martin-Sanchez, F. Javier MD; Reichlin, Tobias MD; Mueller, Christian MD
Page: 1867-1869


https://ift.tt/2Fd35oS

Letter by Clerkin et al Regarding Article, "Importance of Routine Antihuman/Leukocyte Antibody Monitoring: De Novo Donor Specific Antibodies Are Associated With Rejection and Allograft Vasculopathy After Heart Transplantation".

Author: Clerkin, Kevin J. MD, MSc; Farr, Maryjane A. MD, MSc; Mancini, Donna M. MD
Page: 1870-1871


https://ift.tt/2HVdKrt

Response by Wong et al to Letter Regarding Article, "Importance of Routine Antihuman/Leukocyte Antibody Monitoring: De Novo Donor Specific Antibodies Are Associated With Rejection and Allograft Vasculopathy After Heart Transplantation".

Author: Wong, Ka L. MBBS; Smith, Byron H. PhD; Kremers, Walter K. PhD; Pereira, Naveen L. MD
Page: 1872-1873


https://ift.tt/2FaZFmQ

Letter by Jin-shan and Xue-bin Regarding Article, "Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus".

Author: Jin-shan, He MD; Xue-bin, Li MD
Page: 1874


https://ift.tt/2HUSgee

Letter by Gong et al Regarding Article, "Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus".

Author: Gong, Liying PhD; Li, Jingle MD; Yang, Guoping PhD
Page: 1875-1876


https://ift.tt/2FaP7E8

Response by Hu et al to Letters Regarding Article, "Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus".

Author: Hu, Liang PhD; Qi, Zhiyong MD; Zhang, Si MD, PhD; Luo, Xinping MD, PhD; Kunapuli, Satya P. PhD; Ye, Hongying MD, PhD; Ding, Zhongren MD, PhD
Page: 1877-1878


https://ift.tt/2HUSH8m

Letter by Thornton Regarding Article, "Wine and Cardiovascular Health: A Comprehensive Review".

Author: Thornton, Simon N. PhD
Page: 1879


https://ift.tt/2HmGzMs

The first step of patient-specific design calvarial implant: A quantitative analysis of fresh parietal bones

Abstract

Background

Accurate knowledge of the fracture of cranial bone can provide insight into the prevention of skull fracture injuries and help aid the design of energy-absorbing head protection systems and safety helmets. When cranial bone needs to be removed or is lost, subsequent reconstruction of the defect is necessary to protect the underlying brain, or correct esthetic deformities, or both. Ideal reconstruction of defected bone is possible utilizing a biocompatible implant with a bone-like design individualized for the specific patient. The purpose of this study is to investigate the anatomical and mechanical characteristics of fresh frozen human parietal bones and determine compliance of polylactic acid-based personalized three-dimensional implants in terms of mechanical properties in order to replace such defective bones.

Methods

Parietal bone specimens were extracted from 19 fresh frozen cadavers. Morphological parameters of individual bone specimens were measured using Image J software. Three-point bend tests were performed to extract Young's modulus and tensile strength of the specimens from the measured force and displacement data by modeling the bone specimens as curved linear elastic beams. Also, three-point bend tests were performed to polylactic acid-based three-dimensional replicas mimicking geometry of the bone specimens in order to determine whether the material's Young's modulus and tensile strength properties comply with parietal bones.

Results

Entire fresh parietal specimens were observed to be comprised of a three-layered structure: external layers consisting of compact, high-density cortical bone and the central layer consisting of low-density, irregularly porous bone structure. Mean thickness of three-layered structure was 6.25 ± 1.46 mm. Mean Young's modulus and tensile strength of the specimens were 1.40 ± 1.34 GPa and 44.56 ± 21.94 MPa, respectively where no statistically significant differences among genders were detected (p > 0.05). Mean Young's modulus and tensile strength of the polylactic acid-based three-dimensional implants mimicking geometry of the bone specimens were 1.8 ± 0.7 GPa and 72.8 ± 2.5 MPa, respectively.

Conclusions

Polylactic acid-based three-dimensional implants can be considered as acceptable candidates for temporary replacement of parietal defects in terms of mechanical properties.

Level of Evidence: Not ratable.



https://ift.tt/2HloW3D

Is single-stage implant-based breast reconstruction (SSBR) with an acellular matrix safe?

Abstract

Background

Acellular matrices (AM) might enable a direct single-stage breast reconstruction procedure resulting in an improved efficacy of the reconstruction phase for patients. Safety concerns are an important issue due to a recent study which shows that single-stage breast reconstruction with Strattice™ resulted in more complications versus a two-stage reconstruction. Therefore, the goal of this study is to compare the short- and long-term complications of a single-stage breast reconstruction with the use of two types of AM (Strattice™ and Meso Biomatrix®) versus two-stage breast reconstruction without the use of an AM.

Methods

Cohort study with single-stage breast reconstruction with Strattice™ (n = 28) or Meso BioMatrix® (n = 20) or two-stage breast reconstruction without an AM (n = 36) at the Maastricht Academic Hospital, the Netherlands. All complications, in particular major complications with the need for re-admission to the hospital, re-exploration, and implant explantation, were the primary outcome measures. A 1-year follow-up was achieved for all patients.

Results

Baseline characteristics of all 52 patients were similar between groups. There was a significantly higher complication rate in the single-stage AM groups with loss of the implant in 40.0% of the breasts from the Meso BioMatrix® group and in 10.7% of the Strattice™ group compared to no implant loss in the control group.

Conclusions

This cohort study clearly suggests that the use of a single-stage breast reconstruction is not safe with the use of these AMs. Well-designed prospective studies that guarantee the safety of those matrices should be published before these AMs are used in implant-based surgery.

Level of Evidence: Level III, risk / prognostic study.



https://ift.tt/2qVMMYN

Strategies of molecular imprinting-based fluorescence sensors for chemical and biological analysis

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Qian Yang, Jinhua Li, Xiaoyan Wang, Hailong Peng, Hua Xiong, Lingxin Chen
One pressing concern today is to construct sensors that can withstand various disturbances for highly selective and sensitive detecting trace analytes in complicated samples. Molecularly imprinted polymers (MIPs) with tailor-made binding sites are preferred to be recognition elements in sensors for effective targets detection, and fluorescence measurement assists in highly sensitive detection and user-friendly control. Accordingly, molecular imprinting-based fluorescence sensors (MI-FL sensors) have attracted great research interest in many fields such as chemical and biological analysis. Herein, we comprehensively review the recent advances in MI-FL sensors construction and applications, giving insights on sensing principles and signal transduction mechanisms, focusing on general construction strategies for intrinsically fluorescent or nonfluorescent analytes and improvement strategies in sensing performance, particularly in sensitivity. Construction strategies are well overviewed, mainly including the traditional indirect methods of competitive binding against pre-bound fluorescent indicators, employment of fluorescent functional monomers and embedding of fluorescence substances, and novel rational designs of hierarchical architecture (core-shell/hollow and mesoporous structures), post-imprinting modification, and ratiometric fluorescence detection. Furthermore, MI-FL sensor based microdevices are discussed, involving micromotors, test strips and microfluidics, which are more portable for rapid point-of-care detection and in-field diagnosing. Finally, the current challenges and future perspectives of MI-FL sensors are proposed.



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Monitoring of bacteria biofilms forming process by in-situ impedimetric biosensor chip

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Lulu Liu, Yi Xu, Feiyun Cui, Ye Xia, Li Chen, Xiaojing Mou, Junjiang Lv
A biosensor chip integrated interdigital microelectrodes was proposed and applied to monitor the formation process of Salmonella and E. coli biofilms in this paper. The biosensor chip was composed of a glass substrate with interdigital microelectrodes and PDMS layer with micro cavities. The electrochemical impedance spectroscopy (EIS) of Salmonella and E. coli biofilms was measured by the biosensor chip using alternating voltage of 100 mv in the frequency range from 1 Hz to 100 kHz for 48 h. It was illustrated that the changes of impedance spectroscopy of biofilms occurred with culture time. Furthermore, impedance spectroscopy of biofilms was fitted by an equivalent circuit model including the biofilms capacitance (Cb) and the biofilms resistance (Rb) parameters. The results indicated that the Cb presented a tendency to decrease first and then rise with culture time, while the Rb was in the opposite direction. These changing trends were consistent with the formation process of biofilms that bacteria adhered to electrodes surface, and then formed mature biofilms, finally escaped from biofilms. In addition, it was also demonstrated that the changing trends of Cb and Rb with culture time were quite different between Salmonella and E. coli. The results obtained by impedance detection were in accordance with the results of using crystal violet staining to analyze biofilms formation process, under the same conditions for bacterial culture. The biosensor chip provided a promising platform for further study of biofilms owing to its unique advantages of real time, continuity, and non-invasion for bacteria biofilms detection and in-situ monitoring.



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Rapid, highly sensitive detection of Gram-negative bacteria with lipopolysaccharide based disposable aptasensor

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Jian Zhang, Rania Oueslati, Cheng Cheng, Ling Zhao, Jiangang Chen, Raul Almeida, Jayne Wu
Gram-negative bacteria are one of the most common microorganisms in the environment. Their differential detection and recognition from Gram-positive bacteria has been attracting much attention over the years. Using Escherichia coli (E. coli) as a model, we demonstrated on-site detection of Gram-negative bacteria by an AC electrokinetics-based capacitive sensing method using commercial microelectrodes functionalized with an aptamer specific to lipopolysaccharides. Dielectrophoresis effect was utilized to enrich viable bacteria to the microelectrodes rapidly, achieving a detection limit of 102 cells/mL within a 30 s′ response time. The sensor showed a negligible response to Staphylococcus aureus (S. aureus), a Gram-positive species. The developed sensor showed significant advantages in sensitivity, selectivity, cost, operation simplicity, and response time. Therefore, this sensing method has shown great application potential for environmental monitoring, food safety, and real-time diagnosis.



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Red blood cells aggregability measurement of coagulating blood in extracorporeal circulation system with multiple-frequency electrical impedance spectroscopy

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Jianping Li, Achyut Sapkota, Daisuke Kikuchi, Daisuke Sakota, Osamu Maruyama, Masahiro Takei
Red blood cells (RBCs) aggregability AG of coagulating blood in extracorporeal circulation system has been investigated under the condition of pulsatile flow. Relaxation frequency fc from the multiple-frequency electrical impedance spectroscopy is utilized to obtain RBCs aggregability AG. Compared with other methods, the proposed multiple-frequency electrical impedance method is much easier to obtain non-invasive measurement with high speed and good penetrability performance in biology tissues. Experimental results show that, RBCs aggregability AG in coagulating blood falls down with the thrombus formation while that in non-coagulation blood almost keeps the same value, which has a great agreement with the activated clotting time (ACT) fibrinogen concertation (Fbg) tests. Modified Hanai formula is proposed to quantitatively analyze the influence of RBCs aggregation on multiple-frequency electrical impedance measurement. The reduction of RBCs aggregability AG is associated with blood coagulation reaction, which indicates the feasibility of the high speed, compact and cheap on-line thrombus measurement biosensors in extracorporeal circulation systems.



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Molecularly imprinted polymers-based electrochemical DNA biosensor for the determination of BRCA-1 amplified by SiO2@Ag

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Min You, Shuai Yang, Wanxin Tang, Fan Zhang, Pingang He
A novel electrochemical DNA (E-DNA) biosensing strategy was designed and used for the detection of breast cancer susceptibility gene (BRCA-1). The biosensor was based on gold nanoparticles-reduced graphene oxide (AuNPs-GO) modified glass carbon electrode (GCE) covered with the layer of molecularly imprinted polymers (MIPs) synthesized with rhodamine B (RhB) as template, methacrylic acid (MAA) as the monomer, and Nafion as additive. The signal amplification tracing tag SiO2@Ag NPs were prepared by covering AgNPs on the surface of SiO2 nanoparticles in situ, and then DNA probes were modified on AgNPs by Ag-S bond, forming the composites SiO2@Ag/DNA. In presence of target DNA (T-DNA), homogeneous hybridization was performed with SiO2@Ag/DNA and RhB labeled DNA, and the resulting SiO2@Ag/dsDNA/RhB was specifically recognized by MIPs via the interaction between imprinting cavities and RhB. Under optimal conditions, the proposed biosensor exhibited wide linear range from 10 fM to 100 nM, low detection limit of 2.53 fM (S/N = 3), excellent selectivity, reproducibility, stability, and feasibility in serum analysis. Overall, these findings suggest the promising prospects of the proposed biosensing strategy in clinical diagnostics.



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EMR-based medical knowledge representation and inference via Markov random fields and distributed representation learning

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Publication date: Available online 23 April 2018
Source:Artificial Intelligence in Medicine
Author(s): Chao Zhao, Jingchi Jiang, Yi Guan, Xitong Guo, Bin He
ObjectiveElectronic medical records (EMRs) contain medical knowledge that can be used for clinical decision support (CDS). Our objective is to develop a general system that can extract and represent knowledge contained in EMRs to support three CDS tasks—test recommendation, initial diagnosis, and treatment plan recommendation—given the condition of a patient.MethodsWe extracted four kinds of medical entities from records and constructed an EMR-based medical knowledge network (EMKN), in which nodes are entities and edges reflect their co-occurrence in a record. Three bipartite subgraphs (bigraphs) were extracted from the EMKN, one to support each task. One part of the bigraph was the given condition (e.g., symptoms), and the other was the condition to be inferred (e.g., diseases). Each bigraph was regarded as a Markov random field (MRF) to support the inference. We proposed three graph-based energy functions and three likelihood-based energy functions. Two of these functions are based on knowledge representation learning and can provide distributed representations of medical entities. Two EMR datasets and three metrics were utilized to evaluate the performance.ResultsAs a whole, the evaluation results indicate that the proposed system outperformed the baseline methods. The distributed representation of medical entities does reflect similarity relationships with respect to knowledge level.ConclusionCombining EMKN and MRF is an effective approach for general medical knowledge representation and inference. Different tasks, however, require individually designed energy functions.



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Thyroid® High-Impact Articles

thy.2018.28.issue-4.png

FREE ACCESS through May 7, 2018.
Read now:

Latest Impact Factor: 5.515
The Official Journal of: American Thyroid Association®

 Seasonal Changes in Serum Thyrotropin Concentrations Observed from Big Data Obtained During Six Consecutive Years from 2010 to 2015 at a Single Hospital in Japan 
Ai Yoshihara, Jaeduk Yoshimura Noh, Natsuko Watanabe, Kenji Iwaku, Yo Kunii, Hidemi Ohye, Miho Suzuki, Masako Matsumoto, Nami Suzuki, Kiminori Sugino, Linda M. Thienpont, Akira Hishinuma, Koichi Ito  

Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers
Melissa G. Lechner, Chirag M. Vyas, Ole-Petter R. Hamnvik, Erik K. Alexander, P. Reed Larsen, Toni K. Choueiri, Trevor E. Angell  

Quantitative Analysis of the Benefits and Risk of Thyroid Nodule Evaluation in Patients ≥70 Years Old
Zhihong Wang, Chirag M. Vyas, Olivia Van Benschoten, Matt A. Nehs, Francis D. Moore, Jr., Ellen Marqusee, Jeffrey F. Krane, Matthew I. Kim, Howard T. Heller, Atul A. Gawande, Mary C. Frates, Peter M. Doubilet, Gerard M. Doherty, Nancy L. Cho, Edmund S. Cibas, Carol B. Benson, Justine A. Barletta, Ann Marie Zavacki, P. Reed Larsen, Erik K. Alexander, Trevor E. Angell

Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969-2013
Sarah H. Nash, Anne P. Lanier, Molly B. Southworth  

Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk
Joel Xue Yi Lim, Min En Nga, Dedrick Kok Hong Chan, Wee Boon Tan,Rajeev Parameswaran, Kee Yuan Ngiam

The post <i>Thyroid<sup>®</sup></i> High-Impact Articles appeared first on American Thyroid Association.



https://ift.tt/2K7fHBI

Thyroid® High-Impact Articles

thy.2018.28.issue-4.png

FREE ACCESS through May 7, 2018.
Read now:

Latest Impact Factor: 5.515
The Official Journal of: American Thyroid Association®

 Seasonal Changes in Serum Thyrotropin Concentrations Observed from Big Data Obtained During Six Consecutive Years from 2010 to 2015 at a Single Hospital in Japan 
Ai Yoshihara, Jaeduk Yoshimura Noh, Natsuko Watanabe, Kenji Iwaku, Yo Kunii, Hidemi Ohye, Miho Suzuki, Masako Matsumoto, Nami Suzuki, Kiminori Sugino, Linda M. Thienpont, Akira Hishinuma, Koichi Ito  

Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers
Melissa G. Lechner, Chirag M. Vyas, Ole-Petter R. Hamnvik, Erik K. Alexander, P. Reed Larsen, Toni K. Choueiri, Trevor E. Angell  

Quantitative Analysis of the Benefits and Risk of Thyroid Nodule Evaluation in Patients ≥70 Years Old
Zhihong Wang, Chirag M. Vyas, Olivia Van Benschoten, Matt A. Nehs, Francis D. Moore, Jr., Ellen Marqusee, Jeffrey F. Krane, Matthew I. Kim, Howard T. Heller, Atul A. Gawande, Mary C. Frates, Peter M. Doubilet, Gerard M. Doherty, Nancy L. Cho, Edmund S. Cibas, Carol B. Benson, Justine A. Barletta, Ann Marie Zavacki, P. Reed Larsen, Erik K. Alexander, Trevor E. Angell

Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969-2013
Sarah H. Nash, Anne P. Lanier, Molly B. Southworth  

Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk
Joel Xue Yi Lim, Min En Nga, Dedrick Kok Hong Chan, Wee Boon Tan,Rajeev Parameswaran, Kee Yuan Ngiam

The post <i>Thyroid<sup>®</sup></i> High-Impact Articles appeared first on American Thyroid Association.



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Moderators of angiogenesis in muscle flaps: a non-randomised animal study

A muscle flap can survive a pedicle injury under favourable conditions. In the reconstruction of compound limb injuries, the wound milieu is variable and may affect the rate and manner of neovascularisation. Our aim is to determine the effect of some key clinical variables on neovascularisation in muscle flaps in an animal model.

https://ift.tt/2JgfCdN

Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Abstract

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.



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Lipocalin 2 Plays an Important Role in Regulating Inflammation in Retinal Degeneration [IMMUNE REGULATION]

It has become increasingly important to understand how retinal inflammation is regulated because inflammation plays a role in retinal degenerative diseases. Lipocalin 2 (LCN2), an acute stress response protein with multiple innate immune functions, is increased in ATP-binding cassette subfamily A member 4 (Abca4)–/– retinol dehydrogenase 8 (Rdh8)–/– double-knockout mice, an animal model for Stargardt disease and age-related macular degeneration (AMD). To examine roles of LCN2 in retinal inflammation and degeneration, Lcn2–/–Abca4–/–Rdh8–/– triple-knockout mice were generated. Exacerbated inflammation following light exposure was observed in Lcn2–/–Abca4–/–Rdh8–/– mice as compared with Abca4–/–Rdh8–/– mice, with upregulation of proinflammatory genes and microglial activation. RNA array analyses revealed an increase in immune response molecules such as Ccl8, Ccl2, and Cxcl10. To further probe a possible regulatory role for LCN2 in retinal inflammation, we examined the in vitro effects of LCN2 on NF-B signaling in human retinal pigmented epithelial (RPE) cells differentiated from induced pluripotent stem cells derived from healthy donors. We found that LCN2 induced expression of antioxidant enzymes heme oxygenase 1 and superoxide dismutase 2 in these RPE cells and could inhibit the cytotoxic effects of H2O2 and LPS. ELISA revealed increased LCN2 levels in plasma of patients with Stargardt disease, retinitis pigmentosa, and age-related macular degeneration as compared with healthy controls. Finally, overexpression of LCN2 in RPE cells displayed protection from cell death. Overall these results suggest that LCN2 is involved in prosurvival responses during cell stress and plays an important role in regulating inflammation during retinal degeneration.



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Occupational dermatitis: how to identify the exposures, make the diagnosis, and treat the disease.

Key messages:

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Red meat and processed meat intake and risk of cutaneous melanoma in white women and men: Two prospective cohort studies

Epidemiological studies investigating red and processed meat intake and melanoma have been limited and inconclusive., We found an inverse association between red and processed meat intake and melanoma., Because processed meat and potentially red meat may contain carcinogens, our findings need to be replicated in other populations.

https://ift.tt/2vEUnjL

Subcutaneous Infiltration of Carbon Dioxide (Carboxytherapy) for Abdominal Fat Reduction: A Randomized Clinical Trial

Patients have shown an increasing preference for more non-invasive fat reduction options. Five weeks after study initiation and one week after the fifth treatment session, carboxytherapy reduced abdominal fat more than sham treatment, but there was no difference at 28 weeks. This study showed only a transient benefit for carboxytherapy.

https://ift.tt/2qT3GrK

The Impact of Hormonal Contraceptives on Breast Cancer Pathology

Abstract

This retrospective case series study, using data obtained through questionnaires and histopathological diagnoses from 656 patients enrolled in the Department of Defense (DoD) Clinical Breast Care Project (CBCP), evaluated associations between hormonal contraceptive use and breast cancer pathology including benign breast pathologies. Three combination hormonal contraceptive agents (COCs) Lo Ovral (LO), Ortho Novum (ON), and Ortho Tri-Cyclen (OTC) were evaluated as they represented the most commonly used hormonal contraceptives in our cohort. The results of this study suggest that the ever use of LO + ON + OTC does not influence the overall incidence of benign breast condition or malignant disease compared to other COCs; however, patients that have used OTC had an association with a diagnosis of benign or luminal A pathologies whereas ON was associated with a diagnosis of benign and DCIS; LO showed no association with any diagnosis—benign or malignant. Patients that have used LO or ON were more likely to be diagnosed with breast cancer at age ≥ 40 years whereas patients that had ever used OTC were likely to be diagnosed before the age of 40. Caucasians were less likely to have used OTC and more likely to have used ON; however, use of either hormonal agent positively correlated with premenopausal status at diagnosis and having a benign condition. Age at diagnosis, ethnicity, BMI, family history, menstruation status, and duration of use were all independent predictors of different histopathological subtypes. We conclude that patient-specific variables should be considered when deciding on which type of hormonal contraceptive to use to minimize the risk of developing breast cancer or a breast-related pathology.



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In This Issue [IN THIS ISSUE]



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IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages [INNATE IMMUNITY AND INFLAMMATION]

Rapid initiation and timely resolution of inflammatory response in macrophages are synergistic events that are known to be equally critical to optimal host defense against pathogen infections. However, the regulation of these processes, in particular by a specific cellular metabolic program, has not been well understood. In this study, we found that IFN regulatory factor 2 (IRF2) underwent an early degradation in a proteasome-mediated pathway in LPS-treated mouse macrophages, followed by a later recovery of the expression via transactivation. We showed that IRF2 was anti-inflammatory in that knockdown of this protein promoted the production of LPS-induced proinflammatory mediators. Mechanistically, although IRF2 apparently did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α–dependent expression of glycolytic genes and thereby cellular glycolysis, sequential events necessary for the IRF2 anti-inflammatory activity. We found that macrophages in endotoxin tolerant state demonstrated deficiency in LPS-augmented glycolysis, which was likely caused by failed downregulation of IRF2 and the ensuing upregulation of the glycolytic genes in these cells. In contrast to observations with LPS, knockdown of IRF2 decreased IL-4–induced macrophage alternative activation. The pro–IL-4 activity of IRF2 was dependent on KLF4, a key mediator of the alternative activation, which was transcriptionally induced by IRF2. In conclusion, our data suggest that IRF2 is an important regulator of the proinflammatory response in macrophages by controlling HIF-1α–dependent glycolytic gene expression and glycolysis. This study also indicates IRF2 as a novel therapeutic target to treat inflammatory disorders associated with dysregulations of macrophage activations.



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Comment on "Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease" [LETTERS TO THE EDITOR]



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Local Stimulation of Liver Sinusoidal Endothelial Cells with a NOD1 Agonist Activates T Cells and Suppresses Hepatitis B Virus Replication in Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

Functional maturation of liver sinusoidal endothelial cells (LSECs) induced by a NOD1 ligand (diaminopimelic acid [DAP]) during viral infection has not been well defined. Thus, we investigated the role of DAP-stimulated LSEC maturation during hepatitis B virus (HBV) infection and its potential mechanism in a hydrodynamic injection (HI) mouse model. Primary LSECs were isolated from wild-type C57BL/6 mice and stimulated with DAP in vitro and in vivo and assessed for the expression of surface markers as well as for their ability to promote T cell responses via flow cytometry. The effects of LSEC maturation on HBV replication and expression and the role of LSECs in the regulation of other immune cells were also investigated. Pretreatment of LSECs with DAP induced T cell activation in vitro. HI-administered DAP induced LSEC maturation and subsequently enhanced T cell responses, which was accompanied by an increased production of intrahepatic cytokines, chemokines, and T cell markers in the liver. The HI of DAP significantly reduced the HBsAg and HBV DNA levels in the mice. Importantly, the DAP-induced anti-HBV effect was impaired in the LSEC-depleted mice, which indicated that LSEC activation and T cell recruitment into the liver were essential for the antiviral function mediated by DAP application. Taken together, the results showed that the Ag-presenting ability of LSECs was enhanced by DAP application, which resulted in enhanced T cell responses and inhibited HBV replication in a mouse model.



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Response to Comment on "Therapeutic Application of an Extract of Helicobacter pylori Ameliorates the Development of Allergic Airway Disease" [LETTERS TO THE EDITOR]



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Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties [INNATE IMMUNITY AND INFLAMMATION]

Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA–encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA–encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of β-arrestin. In summary, we identify several novel FPR-activating peptides with sequences present in the N termini of mitochondrial DNA–encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.



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Specialized Antitumor Functions for Skin {gamma}{delta} T Cells [PILLARS OF IMMUNOLOGY]



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Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling [IMMUNOTHERAPY AND VACCINES]

Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)–based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling–deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.



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Pillars Article: Regulation of Cutaneous Malignancy by {gamma}{delta} T Cells. Science. 2001. 294: 605-609 [PILLARS OF IMMUNOLOGY]



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S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis [INNATE IMMUNITY AND INFLAMMATION]

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.



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Contribution of the Immune Response to Phage Therapy [BRIEF REVIEWS]

Therapeutic phages are being employed for vaccination and treatment of cancer and bacterial infections. Their natural immunogenicity triggers intertwined interactions with innate and adaptive immune cells that might influence therapy. Phage- and bactierial-derived pathogen-associated molecular patterns released after bacterial lysis have been proposed to stimulate local innate immune responses, which could promote antitumor immunity or bacterial clearance. Conversely, immunogenicity of phages induces phage-specific humoral memory, which can hamper therapeutic success. This review outlines the current knowledge on the different types of immune responses elicited by phages and their potential benefits and adverse side effects, when applied therapeutically. This review further summarizes the knowledge gaps and defines the key immunological questions that need to be addressed regarding the clinical application of antibacterial phage therapy.



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Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network [INNATE IMMUNITY AND INFLAMMATION]

Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70.



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Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming [CUTTING EDGE]

The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1–dependent secretion of the proinflammatory cytokines IL-1β and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.



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Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1+ T Cells in Human Colorectal Cancer [TUMOR IMMUNOLOGY]

Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8+ T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3+ Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma–associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.



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Characterization of the Antigenic Heterogeneity of Lipoarabinomannan, the Major Surface Glycolipid of Mycobacterium tuberculosis, and Complexity of Antibody Specificities toward This Antigen [ANTIGEN RECOGNITION AND RESPONSES]

Lipoarabinomannan (LAM), the major antigenic glycolipid of Mycobacterium tuberculosis, is an important immunodiagnostic target for detecting tuberculosis (TB) infection in HIV-1–coinfected patients, and is believed to mediate a number of functions that promote infection and disease development. To probe the human humoral response against LAM during TB infection, several novel LAM-specific human mAbs were molecularly cloned from memory B cells isolated from infected patients and grown in vitro. The fine epitope specificities of these Abs, along with those of a panel of previously described murine and phage-derived LAM-specific mAbs, were mapped using binding assays against LAM Ags from several mycobacterial species and a panel of synthetic glycans and glycoconjugates that represented diverse carbohydrate structures present in LAM. Multiple reactivity patterns were seen that differed in their specificity for LAM from different species, as well as in their dependence on arabinofuranoside branching and nature of capping at the nonreducing termini. Competition studies with mAbs and soluble glycans further defined these epitope specificities and guided the design of highly sensitive immunodetection assays capable of detecting LAM in urine of TB patients, even in the absence of HIV-1 coinfection. These results highlighted the complexity of the antigenic structure of LAM and the diversity of the natural Ab response against this target. The information and novel reagents described in this study will allow further optimization of diagnostic assays for LAM and may facilitate the development of potential immunotherapeutic approaches to inhibit the functional activities of specific structural motifs in LAM.



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Elastin Shapes Small Molecule Distribution in Lymph Node Conduits [IMMUNOGENETICS]

The spatial and temporal Ag distribution determines the subsequent T cell and B cell activation at the distinct anatomical locations in the lymph node (LN). It is well known that LN conduits facilitate small Ag distribution in the LN, but the mechanism of how Ags travel along LN conduits remains poorly understood. In C57BL/6J mice, using FITC as a fluorescent tracer to study lymph distribution in the LN, we found that FITC preferentially colocalized with LN capsule–associated (LNC) conduits. Images generated using a transmission electron microscope showed that LNC conduits are composed of solid collagen fibers and are wrapped with fibroblastic cells. Superresolution images revealed that high-intensity FITC is typically colocalized with elastin fibers inside the LNC conduits. Whereas tetramethylrhodamine isothiocyanate appears to enter LNC conduits as effectively as FITC, fluorescently-labeled Alexa-555–conjugated OVA labels significantly fewer LNC conduits. Importantly, injection of Alexa-555–conjugated OVA with LPS substantially increases OVA distribution along elastin fibers in LNC conduits, indicating immune stimulation is required for effective OVA traveling along elastin in LN conduits. Finally, elastin fibers preferentially surround lymphatic vessels in the skin and likely guide fluid flow to the lymphatic vessels. Our studies demonstrate that fluid or small molecules are preferentially colocalized with elastin fibers. Although the exact mechanism of how elastin fibers regulate Ag trafficking remains to be explored, our results suggest that elastin can be a potentially new target to direct Ag distribution in the LN during vaccine design.



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ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis [AUTOIMMUNITY]

ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr181-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr181-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.



https://ift.tt/2Fb9hOl

Lysosome-Mediated Plasma Membrane Repair Is Dependent on the Small GTPase Arl8b and Determines Cell Death Type in Mycobacterium tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Mycobacterium tuberculosis is an extremely successful pathogen, and its success is widely attributed to its ability to manipulate the intracellular environment of macrophages. A central phenomenon of tuberculosis pathology enabling immune evasion is the capacity of virulent M. tuberculosis (H37Rv) to induce macrophage necrosis, which facilitates the escape of the mycobacteria from the macrophage and spread of infection. In contrast, avirulent M. tuberculosis (H37Ra) induces macrophage apoptosis, which permits Ag presentation and activation of adaptive immunity. Previously, we found that H37Rv induces plasma membrane microdisruptions, leading to necrosis in the absence of plasma membrane repair. In contrast, H37Ra permits plasma membrane repair, which changes the host cell death modality to apoptosis, suggesting that membrane repair is critical for sequestering the pathogen in apoptotic vesicles. However, mechanisms of plasma membrane repair induced in response to M. tuberculosis infection remain unknown. Plasma membrane repair is known to induce a Ca2+-mediated signaling, which recruits lysosomes to the area of damaged plasma membrane sites for its resealing. In this study, we found that the small GTPase Arl8b is required for plasma membrane repair by controlling the exocytosis of lysosomes in cell lines and in human primary macrophages. Importantly, we found that the Arl8b secretion pathway is crucial to control the type of cell death of the M. tuberculosis–infected macrophages. Indeed, Arl8b-depleted macrophages infected with avirulent H37Ra undergo necrotic instead of apoptotic cell death. These findings suggest that membrane repair mediated by Arl8b may be an important mechanism distinguishing avirulent from virulent M. tuberculosis–induced necrotic cell death.



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Downregulation of CD3{zeta} in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype [AUTOIMMUNITY]

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3 in SLE NK cells. We studied CD3 levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3 levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3. We found reduced CD3 expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3 expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3 levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN- and TNF. In contrast, CD3 levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3-silenced NKL and CD3-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3 levels. Our results demonstrate a differential role for CD3 in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3 confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.



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Altered Ratio of T Follicular Helper Cells to T Follicular Regulatory Cells Correlates with Autoreactive Antibody Response in Simian Immunodeficiency Virus-Infected Rhesus Macaques [INFECTIOUS DISEASE AND HOST RESPONSE]

Individuals with chronic HIV-1 infection have an increased prevalence of autoreactive Abs. Many of the isolated HIV broadly neutralizing Abs from these individuals are also autoreactive. However, the underlying mechanism(s) that produce these autoreactive broadly neutralizing Abs remains largely unknown. The highly regulated coordination among B cells, T follicular helper (TFH) cells, and T follicular regulatory (TFR) cells in germinal centers (GCs) of peripheral lymphatic tissues (LTs) is essential for defense against pathogens while also restricting autoreactive responses. We hypothesized that an altered ratio of TFH/TFR cells in the GC contributes to the increased prevalence of autoreactive Abs in chronic HIV infection. We tested this hypothesis using a rhesus macaque (RM) SIV model. We measured the frequency of TFH cells, TFR cells, and GC B cells in LTs and anti-dsDNA and anti-phospholipid Abs from Indian RMs, with and without SIV infection. We found that the frequency of anti-dsDNA and anti-phospholipid Abs was much higher in chronically infected RMs (83.3% [5/6] and 66.7% [4/6]) than in acutely infected RMs (33.3% [2/6] and 18.6% [1/6]) and uninfected RMs (0% [0/6] and 18.6% [1/6]). The increased ratio of TFH/TFR cells in SIV infection correlated with anti-dsDNA and anti-phospholipid autoreactive Ab levels, whereas the frequency of TFR cells alone did not correlate with the levels of autoreactive Abs. Our results provide direct evidence that the ratio of TFH/TFR cells in LTs is critical for regulating autoreactive Ab production in chronic SIV infection and possibly, by extension, in chronic HIV-1 infection.



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The Effects of Reflux on the Elderly

Reflux-related complaints are a frequent cause for otolaryngology consultation, and with the aging population the concerns specific to the elderly reflux patient are critical. The elderly patient is less likely to present with typical laryngopharyngeal reflux (LPR) or gastroesophageal reflux disease (GERD) symptoms. Importantly, elderly patients typically have objective findings more severe than the level of the symptoms. Therefore, upfront invasive esophageal testing as opposed to an initial medical therapy trial is the recommended management strategy. For all patients irrespective of age, lifestyle and diet modifications continue to represent the cornerstone of medical management for LPR and GERD.

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Endocrine Surgery in the Geriatric Population

Age must be a factor when considering endocrine surgery. Age itself is a risk factor for complications after thyroidectomy, specifically pulmonary, infectious, and cardiac complications. For this reason, in patients with nodular thyroid disease or thyroid microcarcinoma, length of observation must be measured against age and surgical risk. Outcomes of thyroid surgery in geriatric patients can be improved with several measures, including careful preoperative risk stratification based on comorbidities and frailty. In this population subset, it is imperative to have an earnest discussion with patients, their families, and any surrogate decision maker regarding potential outcomes of treatment versus observation.

https://ift.tt/2qVVLsT

Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia

Abstract

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.



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In vivo methods for acute modulation of gene expression in the central nervous system

Publication date: Available online 22 April 2018
Source:Progress in Neurobiology
Author(s): Andrzej W. Cwetsch, Bruno Pinto, Annalisa Savardi, Laura Cancedda
Accurate and timely expression of specific genes guarantees the healthy development and function of the brain. Indeed, variations in the correct amount or timing of gene expression lead to improper development and/or pathological conditions. Almost forty years after the first successful gene transfection in in vitro cell cultures, it is currently possible to regulate gene expression in an area-specific manner at any step of central nervous system development and in adulthood in experimental animals in vivo, even overcoming the very poor accessibility of the brain. Here, we will review the diverse approaches for acute gene transfer in vivo, highlighting their advantages and disadvantages with respect to the efficiency and specificity of transfection as well as to brain accessibility. In particular, we will present well-established chemical, physical and virus-based approaches suitable for different animal models, pointing out their current and future possible applications in basic and translational research as well as in gene therapy.



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Non-imaged based method for matching brains in a common anatomical space for cellular imagery

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Publication date: Available online 22 April 2018
Source:Journal of Neuroscience Methods
Author(s): Maëllie Midroit, Marc Thevenet, Arnaud Fournel, Joelle Sacquet, Moustafa Bensafi, Marine Breton, Laura Chalençon, Matthias Cavelius, Anne Didier, Nathalie Mandairon
BackgroundCellular imagery using histology sections is one of the most common techniques used in Neuroscience. However, this inescapable technique has severe limitations due to the need to delineate regions of interest on each brain, which is time consuming and variable across experimenters.New MethodWe developed algorithms based on a vectors field elastic registration allowing fast, automatic realignment of experimental brain sections and associated labeling in a brain atlas with high accuracy and in a streamlined way. Thereby, brain areas of interest can be finely identified without outlining them and different experimental groups can be easily analyzed using conventional tools. This method directly readjusts labeling in the brain atlas without any intermediate manipulation of images.ResultsWe mapped the expression of cFos, in the mouse brain (C57Bl/6J) after olfactory stimulation or a non-stimulated control condition and found an increased density of cFos-positive cells in the primary olfactory cortex but not in non-olfactory areas of the odor-stimulated animals compared to the controls.Comparison with Existing Method(s)Existing methods of matching are based on image registration which often requires expensive material (two-photon tomography mapping or imaging with iDISCO) or are less accurate since they are based on mutual information contained in the images. Our new method is non-imaged based and relies only on the positions of detected labeling and the external contours of sections.ConclusionsWe thus provide a new method that permits automated matching of histology sections of experimental brains with a brain reference atlas.



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An integrated system for synchronous detection of neuron spikes and dopamine activities in the striatum of Parkinson monkey brain

Publication date: Available online 23 April 2018
Source:Journal of Neuroscience Methods
Author(s): Shengwei Xu, Yu Zhang, Song Zhang, Guihua Xiao, Mixia Wang, Yilin Song, Fei Gao, Ziyue Li, Ping Zhuang, Piu Chan, Guoxian Tao, Feng Yue, Xinxia Cai
BackgroundSynchronous detecting neuron spikes and dopamine (DA) activities in the non-human primate brain play an important role in understanding of Parkinson's disease (PD). At present, most experiments are carried out by combing of electrodes and commercial instruments, which are inconvenient, time-consuming and inefficient.New methodHerein, this study describes a novel integrated system for monitoring neuron spikes and DA activities in non-human primate brain synchronously. This system integrates an implantable sensor, a dual-function head-stage and a low noise detection instrument.MethodsThe system was developed efficiently by using the key technologies of noise reduction, interference protection and differential amplification. To demonstrate the utility of this system, synchronous recordings of electrophysiological signals and DA were in vivo performed in a monkey before and after treated as a Parkinson model monkey.ResultsThe system typically exhibited input-referred noise levels of only ∼ 3 μVRMS, input impedance levels of up to 5.1 GΩ, and a sensitivity of 14.075 pA/μM for DA and could detect electrophysiological signals and DA without mutual interference. In monkey experiments, lower DA concentrations in the striatum and more intensive spikes of the Parkinson model monkey than the normal one were synchronously recorded efficiently.Comparison with existing methodsThis integrated system will not only significantly simplify the experimental operation and improve the experimental efficiency, but also improve the signal quality and synchronization performance.ConclusionsThis integrated system, which is practical, efficient and convenient, can be widely used for the study of PD and other neurological disorders.



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Geometry Processing of Conventionally Produced Mouse Brain Slice Images

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Publication date: Available online 22 April 2018
Source:Journal of Neuroscience Methods
Author(s): Nitin Agarwal, Xiangmin Xu, M. Gopi
Background:Brain mapping research in most neuroanatomical laboratories relies on conventional processing techniques, which often introduce histological artifacts such as tissue tears and tissue loss.New Method:In this paper we present techniques and algorithms for automatic registration and 3D reconstruction of conventionally produced mouse brain slices in a standardized atlas space. This is achieved first by constructing a virtual 3D mouse brain model from annotated slices of Allen Reference Atlas (ARA). Virtual re-slicing of the reconstructed model generates ARA-based slice images corresponding to the microscopic images of histological brain sections. These image pairs are aligned using a geometric approach through contour images. Histological artifacts in the microscopic images are detected and removed using Constrained Delaunay Triangulation before performing global alignment. Finally, non-linear registration is performed by solving Laplace's equation with Dirichlet boundary conditions.Results:Our methods provide significant improvements over previously reported registration techniques for the tested slices in 3D space, especially on slices with significant histological artifacts. Further, as one of the application we count the number of neurons in various anatomical regions using a dataset of 51 microscopic slices from a single mouse brain.Comparison with Existing Method(s):To the best of our knowledge the presented work is the first that automatically registers both clean as well as highly damaged high-resolutions histological slices of mouse brain to a 3D annotated reference atlas space.Conclusions:This work represents a significant contribution to this subfield of neuroscience as it provides tools to neuroanatomist for analyzing and processing histological data.



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Customizable Cap Implants for Neurophysiological Experimentation

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Publication date: Available online 22 April 2018
Source:Journal of Neuroscience Methods
Author(s): Jackson D. Blonde, Megan Roussy, Rogelio Luna, Borna Mahmoudian, Roberto A. Gulli, Kevin C. Barker, Jonathan C. Lau, Julio C. Martinez-Trujillo
BackgroundSeveral primate neurophysiology laboratories have adopted acrylic-free, custom-fit cranial implants. These implants are often comprised of titanium or plastic polymers, such as polyether ether ketone (PEEK). Titanium is favored for its mechanical strength and osseointegrative properties whereas PEEK is notable for its lightweight, machinability, and MRI compatibility. Recent titanium/PEEK implants have proven to be effective in minimizing infection and implant failure, thereby prolonging experiments and optimizing the scientific contribution of a single primate.New MethodWe created novel, customizable PEEK 'cap' implants that contour to the primate's skull. The implants were created using MRI and/or CT data, SolidWorks software and CNC-machining.ResultsThree rhesus macaques were implanted with a PEEK cap implant. Head fixation and chronic recordings were successfully performed. Improvements in design and surgical technique solved issues of granulation tissue formation and headpost screw breakage.Comparison with existingmethods Primate cranial implants have traditionally been fastened to the skull using acrylic and anchor screws. This technique is prone to skin recession, infection, and implant failure. More recent methods have used imaging data to create custom-fit titanium/PEEK implants with radially extending feet or vertical columns. Compared to our design, these implants are more surgically invasive over time, have less force distribution, and/or do not optimize the utilizable surface area of the skull.ConclusionsOur PEEK cap implants served as effective and affordable means to perform electrophysiological experimentation while reducing surgical invasiveness, providing increased strength, and optimizing useful surface area.



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Silencing the insular-striatal circuit decreases alcohol self-administration and increases sensitivity to alcohol

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Publication date: 1 August 2018
Source:Behavioural Brain Research, Volume 348
Author(s): Anel A. Jaramillo, Kalynn Van Voorhies, Patrick A. Randall, Joyce Besheer
Internal drug states/cues can impact drug taking, as pretreatment with a moderate to high alcohol dose (i.e., loading dose) can decrease subsequent alcohol self-administration, alcohol-seeking, and relapse-like drinking. The insular cortex (IC) is implicated in processing information about internal states and findings show that silencing the IC and its projections to the nucleus accumbens core (AcbC) enhance sensitivity to the interoceptive effects of alcohol. Therefore, the goal of the present work was to determine the functional role of IC-AcbC projections in modulating the effects of alcohol pretreatment on operant alcohol self-administration. Long-Evans rats were trained to self-administer a sweetened alcohol solution (15% alcohol (v/v) + 2% sucrose (w/v)) and on test sessions received pretreatment with an alcohol loading dose. A chemogenetic strategy (i.e., hM4D Designer Receptors Exclusively Activated by Designer Drugs [DREADDs]) was implemented to silence the IC-AcbC projections and test the functional role of the insular-striatal circuitry in regulating self-administration following the alcohol loading doses. Alcohol self-administration decreased following pre-session treatment with alcohol, confirming titration of alcohol drinking following a loading dose of alcohol. Chemogenetic silencing of IC-AcbC projections decreased alcohol self-administration under baseline conditions (i.e., water loading dose) and the reduction in self-administration of an alcohol loading dose, implicating a role for this circuit in the maintenance of alcohol self-administration and suggesting increased sensitivity to the alcohol loading dose. These findings provide evidence for the critical nature of insular-striatal circuitry in ongoing alcohol self-administration, and specifically in relation to interoceptive/internal cues that can impact alcohol drinking.



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Reply: The Case of Dynamic CHA2DS2-VASc Score: Beyond Risk Prediction



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1-Year Outcomes of Transcatheter Mitral Valve Replacement in Patients With Severe Mitral Annular Calcification

AbstractBackground

The risk of surgical mitral valve replacement in patients with severe mitral annular calcification (MAC) is high. Several patients worldwide with severe MAC have been treated successfully with transcatheter mitral valve replacement (TMVR) using balloon-expandable aortic transcatheter valves. The TMVR in MAC Global Registry is a multicenter registry that collects data on outcomes of these procedures.

Objectives

The goal of this study was to evaluate 1-year outcomes in this registry.

Methods

This study was a multicenter retrospective review of clinical outcomes.

Results

A total of 116 extreme surgical risk patients with severe MAC underwent TMVR; 106 had a procedure date >1 year before data-lock and were included in the analysis. Their mean age was 73 ± 12 years, and 68% were female. The mean Society of Thoracic Surgeons score was 15.3 ± 11.6%, and 90% were in New York Heart Association functional class III or IV. Thirty-day and 1-year all-cause mortality was 25% and 53.7%, respectively. Most patients who survived 30 days were alive at 1 year (49 of 77 [63.6%]), and the majority (71.8%) were in New York Heart Association functional class I or II. Echocardiography data at 1 year were available in 34 patients. Mean left ventricular ejection fraction was 58.6 ± 11.2%, mean mitral valve area was 1.9 ± 0.5 cm2, mean mitral gradient was 5.8 ± 2.2 mm Hg, and 75% had zero or trace mitral regurgitation.

Conclusions

TMVR with balloon-expandable aortic valves in extreme surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. Most patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms and transcatheter valve performance. The role of TMVR in patients with MAC requires further evaluation in clinical trials.



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Cerebrovascular Events After Cardiovascular Procedures: Risk Factors, Recognition, and Prevention Strategies

Abstract

Stroke has long been a devastating complication of any cardiovascular procedure that unfavorably affects survival and quality of life. Over time, strategies have been developed to substantially reduce the incidence of stroke after traditional cardiovascular procedures such as coronary artery bypass grafting, isolated valve surgery, and carotid endarterectomy. Subsequently, with the advent of minimally invasive technologies including percutaneous coronary intervention, carotid artery stenting, and transcatheter valve therapies, operators were faced with a new host of procedural risk factors, and efforts again turned toward identifying novel ways to reduce the risk of stroke. Fortunately, by understanding the procedural factors unique to these new techniques and applying many of the lessons learned from prior experiences, we are seeing significant improvements in the safety of these new technologies. In this review, the authors: 1) carefully analyze data from different cardiac procedural experiences ranging from traditional open heart surgery to percutaneous coronary intervention and transcatheter valve therapies; 2) explore the unique risk factors for stroke in each of these areas; and 3) describe how these risks can be mitigated with improved patient selection, adjuvant pharmacotherapy, procedural improvements, and novel technological advancements.



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Transcatheter Mitral Valve Replacement for Severe Mitral Annular Calcification: Is it Ready for Prime Time?



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Reply: Early Cardiac Resynchronization Therapy for Left Bundle Branch Block-Associated Cardiomyopathies



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Metabolically Healthy Obesity, Transition to Metabolic Syndrome, and Cardiovascular Risk

AbstractBackground

Debate over the cardiometabolic risk associated with metabolically healthy obesity (MHO) continues. Many studies have investigated this relationship by examining MHO at baseline with longitudinal follow-up, with inconsistent results.

Objectives

The authors hypothesized that MHO at baseline is transient and that transition to metabolic syndrome (MetS) and duration of MetS explains heterogeneity in incident cardiovascular disease (CVD) and all-cause mortality.

Methods

Among 6,809 participants of the MESA (Multi-Ethnic Study of Atherosclerosis) the authors used Cox proportional hazards and logistic regression models to investigate the joint association of obesity (≥30 kg/m2) and MetS (International Diabetes Federation consensus definition) with CVD and mortality across a median of 12.2 years. We tested for interaction and conducted sensitivity analyses for a number of conditions.

Results

Compared with metabolically healthy normal weight, baseline MHO was not significantly associated with incident CVD; however, almost one-half of those participants developed MetS during follow-up (unstable MHO). Those who had unstable MHO had increased odds of CVD (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.14 to 2.25), compared with those with stable MHO or healthy normal weight. Dose response for duration of MetS was significantly and linearly associated with CVD (1 visit with MetS OR: 1.62; 95% CI: 1.27 to 2.07; 2 visits, OR: 1.92; 95% CI: 1.48 to 2.49; 3+ visits, OR: 2.33; 95% CI: 1.89 to 2.87; p value for trend <0.001) and MetS mediated approximately 62% (44% to 100%) of the relationship between obesity at any point during follow-up and CVD.

Conclusions

Metabolically healthy obesity is not a stable or reliable indicator of future risk for CVD. Weight loss and lifestyle management for CVD risk factors should be recommended to all individuals with obesity.



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Prior Authorization Reform for Better Patient Care



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Dangers and Long-Term Outcomes in Metabolically Healthy Obesity: The Impact of the Missing Fitness Component



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Left Bundle Branch Block-Associated Cardiomyopathies and Early Cardiac Resynchronization Therapy: Conceptualizing a Tailored Approach



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Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial

AbstractBackground

Although clopidogrel is still frequently used in patients with acute coronary syndromes (ACS), its efficacy is hampered by interpatient response variability caused by genetic polymorphisms associated with clopidogrel's metabolism.

Objectives

The goal of this study was to evaluate whether selecting antiplatelet therapy (clopidogrel, prasugrel, or ticagrelor) on the basis of a patient's genetic and clinical characteristics leads to better clinical outcomes compared with the standard of care, which bases the selection on clinical characteristics alone.

Methods

Patients hospitalized for ACS were randomly assigned to standard of care or the pharmacogenomic arm, which included the genotyping of ABCB1, CYP2C19*2, and CYP2C19*17 using an ST Q3 system that provides data within 70 min at each patient's bedside. The patients were followed up for 12 ± 1 month for the primary composite endpoint of cardiovascular death and the first occurrence of nonfatal myocardial infarction, nonfatal stroke, and major bleeding defined according to Bleeding Academic Research Consortium type 3 to 5 criteria.

Results

After enrolling 888 patients, the study was prematurely stopped. Clopidogrel was used more frequently in the standard-of-care arm (50.7% vs. 43.3%), ticagrelor in the pharmacogenomic arm (42.6% vs. 32.7%; p = 0.02), and prasugrel was equally used in both arms. The primary endpoint occurred in 71 patients (15.9%) in the pharmacogenomic arm and in 114 (25.9%) in the standard-of-care arm (hazard ratio: 0.58; 95% confidence interval: 0.43 to 0.78; p < 0.001).

Conclusions

A personalized approach to selecting antiplatelet therapy for patients with ACS may reduce ischemic and bleeding events. (Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes [PHARMCLO]; NCT03347435)



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JACC Instructions for Authors



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Pharmacogenomic Testing to Select Antiplatelet Therapy



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Domain Management Approach to Heart Failure in the Geriatric Patient: Present and Future

Abstract

Heart failure (HF) is a quintessential geriatric cardiovascular condition, with more than 50% of hospitalizations occurring in adults age 75 years or older. In older patients, HF is closely linked to processes inherent to aging, which include cellular and structural changes to the myocardium, vasculature, and skeletal muscle. In addition, HF cannot be considered in isolation of physical functioning, or without the social, psychological, and behavioral dimensions of illness. The role of frailty, depression, cognitive impairment, nutrition, and goals of care are each uniquely relevant to the implementation and success of medical therapy. In this paper, we discuss a model of caring for older adults with HF through a 4-domain framework that can address the unique multidimensional needs and vulnerabilities of this population. We believe that clinicians who embrace this approach can improve health outcomes for older adults with HF.



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Neoatherosclerosis 5 Years After Bioresorbable Vascular Scaffold Implantation

AbstractBackground

Data regarding neoatherosclerosis after everolimus-eluting bioresorbable vascular scaffold (BVS) (ABSORB BVS Rev. 1.1, Abbott Vascular, Santa Clara, California) implantation are limited.

Objectives

This study investigated the findings of neoatherosclerosis at 5 years after BVS 1.1 implantation by using multi-imaging modalities, including optical coherence tomography (OCT).

Methods

Patients included in the ABSORB EXTEND (ABSORB EXTEND Clinical Investigation) trial at Shonan Kamakura General Hospital underwent OCT at baseline after the index procedure and at 1 and 5 years. Intimal plaque distributions in the in-scaffold and out-scaffold segments were analyzed.

Results

Twenty patients (22 lesions) with stable angina pectoris were enrolled. The median follow-up duration was 67 months (interquartile range: 65 to 69 months), and the mean age was 69 ± 8 years. Patients with diabetes mellitus (25%) were included. Based on the baseline angiogram, 10 (46%) lesions were type B2/C lesions. At 1 and 5 years of follow-up, significant differences in the prevalence of in-scaffold lipid-laden neointima (17% vs. 61%; p = 0.04), calcification (28% vs. 94%; p < 0.01), neovascularization (6% vs. 78%; p < 0.01), and thin-cap fibroatheroma (0% vs. 22%; p = 0.02) were found. In the out-scaffold segments, no significant difference in the plaque prevalence between 1 and 5 years was noted.

Conclusions

The occurrence and progression of in-scaffold neoatherosclerosis with luminal narrowing was observed at 5 years after BVS 1.1 implantation. The small size of the current study warrants confirmation in larger study. (ABSORB EXTEND Clinical Investigation [ABSORB EXTEND]; NCT01023789)



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JACC: Basic to Translational Science: The Apple That Falls Closely to the JACC Family Tree



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Long-Term Assessment of Bioresorbable Coronary Scaffolds: Disappearing Stents, Reappearing Atherosclerosis



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The Case of Dynamic CHA2DS2-VASc Score: Beyond Risk Prediction



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Propranolol Versus Metoprolol for Treatment of Electrical Storm in Patients With Implantable Cardioverter-Defibrillator

AbstractBackground

Electrical storm (ES), characterized by unrelenting recurrences of ventricular arrhythmias, is observed in approximately 30% of patients with implantable cardioverter-defibrillators (ICDs) and is associated with high mortality rates.

Objectives

Sympathetic blockade with β-blockers, usually in combination with intravenous (IV) amiodarone, have proved highly effective in the suppression of ES. In this study, we compared the efficacy of a nonselective β-blocker (propranolol) versus a β1-selective blocker (metoprolol) in the management of ES.

Methods

Between 2011 and 2016, 60 ICD patients (45 men, mean age 65.0 ± 8.5 years) with ES developed within 24 h from admission were randomly assigned to therapy with either propranolol (160 mg/24 h, Group A) or metoprolol (200 mg/24 h, Group B), combined with IV amiodarone for 48 h.

Results

Patients under propranolol therapy in comparison with metoprolol-treated individuals presented a 2.67 times decreased incidence rate (incidence rate ratio: 0.375; 95% confidence interval: 0.207 to 0.678; p = 0.001) of ventricular arrhythmic events (tachycardia or fibrillation) and a 2.34 times decreased rate of ICD discharges (incidence rate ratio: 0.428; 95% CI: 0.227 to 0.892; p = 0.004) during the intensive care unit (ICU) stay, after adjusting for age, sex, ejection fraction, New York Heart Association functional class, heart failure type, arrhythmia type, and arrhythmic events before ICU admission. At the end of the first 24-h treatment period, 27 of 30 (90.0%) patients in group A, while only 16 of 30 (53.3%) patients in group B were free of arrhythmic events (p = 0.03). The termination of arrhythmic events was 77.5% less likely in Group B compared with Group A (hazard ratio: 0.225; 95% CI: 0.112 to 0.453; p < 0.001). Time to arrhythmia termination and length of hospital stay were significantly shorter in the propranolol group (p < 0.05 for both).

Conclusions

The combination of IV amiodarone and oral propranolol is safe, effective, and superior to the combination of IV amiodarone and oral metoprolol in the management of ES in ICD patients.



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