A potentially important role for t cells and regulatory t cells in Langerhans cell histiocytosis

Publication date: Available online 18 June 2018
Source:Clinical Immunology
Author(s): Jenée M. Mitchell, Stuart P. Berzins, George Kannourakis
Langerhans cell histiocytosis is characterized by lesions containing inflammatory immune cells, including myeloid cells and T cells. Patient mortality remains unacceptably high and new treatment options are required. Several LCH studies have identified aberrant frequencies of T cell subsets with potential immune regulatory properties. High numbers of Foxp3⁺ regulatory T cells and gamma-delta T cells have been reported in patients with LCH, although, the cause of their presence or their significance is not yet clear. This review describes the current understanding of how LCH develops and progresses, focusing on the growing evidence that regulatory T cell subsets may be important and discussing the exciting potential for harnessing these cells to treat LCH using immune based therapies.



https://ift.tt/2I0XGTq

A potentially important role for t cells and regulatory t cells in Langerhans cell histiocytosis

Publication date: Available online 18 June 2018
Source:Clinical Immunology
Author(s): Jenée M. Mitchell, Stuart P. Berzins, George Kannourakis
Langerhans cell histiocytosis is characterized by lesions containing inflammatory immune cells, including myeloid cells and T cells. Patient mortality remains unacceptably high and new treatment options are required. Several LCH studies have identified aberrant frequencies of T cell subsets with potential immune regulatory properties. High numbers of Foxp3⁺ regulatory T cells and gamma-delta T cells have been reported in patients with LCH, although, the cause of their presence or their significance is not yet clear. This review describes the current understanding of how LCH develops and progresses, focusing on the growing evidence that regulatory T cell subsets may be important and discussing the exciting potential for harnessing these cells to treat LCH using immune based therapies.



https://ift.tt/2I0XGTq

Examination of the cut-off values for a questionnaire used to evaluate asthma control in Japanese asthma patients

Publication date: Available online 18 June 2018
Source:Allergology International
Author(s): Yuji Tohda, Soichiro Hozawa, Hiroshi Tanaka
BackgroundThe Japan Asthma Control Survey (JACS) questionnaire, developed as a tool for measuring asthma control levels in Japanese asthma patients, was previously tested for its reliability and validity. However, many of the patients enrolled in the original validation study had mild asthma; thus a re-evaluation including severe cases was required to calculate more reliable cut-off values.MethodsPooled analysis of data from the original validation study and the subsequent medication guidance study including adult patients with severe asthma was conducted to calculate the JACS questionnaire cut-off values and to assess their sensitivity and specificity for identifying "well-controlled", "not well-controlled", and "poorly controlled" asthma as described in the Asthma Prevention and Management Guideline 2015 (JGL2015). The data were from 353 patients with mild to severe persistent asthma classified according to JGL2015.ResultsThe JACS questionnaire cut-off values were 8.0 (sensitivity, 67.9%; specificity, 81.9%) for "well-controlled" and "not well-controlled" and 4.8 (sensitivity, 85.3%; specificity, 53.3%) for "not well-controlled" and "poorly controlled".ConclusionsJACS cut-off values can be expected to be more useful for evaluating asthma control status in clinical practice and clinical research, thus improving asthma treatment, in Japan. This analysis was the original validation study (UMIN000016589) and the subsequent medication guidance study (UMIN000024353).



https://ift.tt/2M5jtLZ

Pediatric case with rice bran allergy induced by epicutaneous sensitization in a family rice shop

Publication date: Available online 18 June 2018
Source:Allergology International
Author(s): Yui Togashi, Naoko Inomata, Aki Suzuki, Amiko Hakuta, Michiko Aihara




https://ift.tt/2MCk9d5

Zoonoses under our noses

Publication date: Available online 18 June 2018
Source:Microbes and Infection
Author(s): Alice R. Cross, Victoria M. Baldwin, Sumita Roy, Angela E. Essex-Lopresti, Joann L. Prior, Nicholas J. Harmer
One Health is an effective approach for the management of zoonotic disease in humans, animals and environments. Examples of the management of bacterial zoonoses in Europe and across the globe demonstrate that One Health approaches of international surveillance, information-sharing and appropriate intervention methods are required to successfully prevent and control disease outbreaks in both endemic and non-endemic regions. Additionally, a One Health approach enables effective preparation and response to bioterrorism threats.



https://ift.tt/2JXQUQ5

Utility of ultrasound of the lymph nodes in patients with high-risk cutaneous squamous cell carcinoma

Abstract

Background

Ultrasound (US) is a non-invasive, highly available and cheap examination of the lymph nodes of the neck. However, currently, there is no agreement of the standard use of US in the detection of metastatic lymph nodes in patients with high-risk cutaneous squamous cell carcinoma (cSCC). The aim of the study was to evaluate ultrasound in the diagnostics of lymph node metastases in cutaneous squamous cell carcinoma and in the light of different "high-risk" factors in cSCC to evaluate who would benefit from US.

Methods

We conducted a review ofliterature on squamous cell carcinoma of the head and neck (HNSCC) and US published in the year 2000 until September 2017. Nine studies and a total of 664 patients were included. The sensitivity, specificity, negative predictive value and accuracy for US were found in the included articles and a cumulative sum for the total cohort was calculated. Further, the results for US were compared to data from CT, PET CT and clinical examination.

Results

Sensitivity for US for the total cohort was 85.9, specificity was 96.3%, negative predictive value (NPV) was 93.1% and accuracy was 92.2%. We found significantly no difference when US was compared to CT and PET CT. CT had a sensitivity, specificity, NPV and accuracy at 82.8, 97.7, 90.9 and 92.32% respectively. Sensitivity, specificity, NPV and accuracy for PET CT were 87.4, 98.1, 95.2 and 95.2% respectively. In contrast, we found clinical examination to have the significantly lowest sensitivity, specificity, NPV and accuracy at 69.6, 80, 61.1 and 73.4%, respectively.

Conclusions

Ultrasound is found to have equal sensitivity, specificity and NPV as CT and PET CT. Further, US is proven significant better than clinical examination. Patients with one or two high-risk factors for metastases could very well benefit from US of neck. However, more studies on US are necessary and further, specific studies on cSCC should be performed in order to see if US of the neck in HNSCC patients is transferable to cSCC.

Level of evidence: Not ratable.

https://ift.tt/2ljQau8

Formation of a sensate forearm stump through neurovascular tissue transplantation

Abstract

The use of neurovascular flaps can help to maximize limb length and gain sensory re-innervation in amputees. We describe the case of a 19-year-old patient who underwent an innovative reconstructive approach aimed at preserving viable limb length with sensory regeneration by using innervated tissue transfer after traumatic upper extremity amputation below the elbow. The forearm length was maximized by means of two neurovascular free flaps that formed a robust, functional, and versatile stump. The mechanism of this reconstruction originated from the practice of placing a double-innervated anterolateral thigh flap over a myocutaneous flap for covering protruding forearm bone shafts. This form of vascularized tissue transplantation helps to minimize the risk of necrosis of radial and ulnar bone shafts. In this patient, an upper arm prosthesis would have been necessary if lower arm bone shafts had been shortened for primary wound closure. Therefore, the newly formed stump enabled the patient to wear a forearm prosthetic instead of a less functional upper arm device. In addition, neurovascular tissue transfer facilitates sensory re-innervation, improvement of the healing process and serving a protective function over the covered area. Through co-adaptation of free nerve endings, neuroma formation can also be prevented. To ensure long-term success, it is vital that the patient be in good mental and physical health, as well as demonstrate the capacity for long-term rehabilitation therapy prior to performing such reconstructions.

Level of Evidence: Level V, therapeutic study.

https://ift.tt/2tjmhO8

Clinical Development of HER3-targeting Monoclonal Antibodies: Perils and Progress

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Wolfgang Jacob, Ian James, Max Hasmann, Martin Weisser
The human epidermal growth factor receptor (HER) family consists of four transmembrane receptor tyrosine kinases: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. They are part of a complex signalling network and stimulate intracellular pathways regulating cell growth and differentiation. So far, monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors targeting EGFR and HER2 have been developed and approved. Recently, focus has turned to HER3 as it may play an important role in resistance to EGFR- and HER2-targeting therapies. HER3-targeting agents have been undergoing clinical evaluation for the last 10 years and currently thirteen mAbs are in phase 1 or 2 clinical studies. Single agent activity has proven to be limited, however, the tolerability was favourable. Thus, combinations of HER3-binding mAbs with other HER-targeting therapies or chemotherapies have been pursued in various solid tumor entities. Data indicate that the HER3-binding ligand heregulin may serve as a response prediction marker for HER3-targeting therapy. Within this review the current status of clinical development of HER3-targeting compounds is described.



https://ift.tt/2ymJC71

Clinical benefit of controversial first line systemic therapies for advanced stage ovarian cancer – ESMO-MCBS scores

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): KE Broekman, M Jalving, H van Tinteren, C Sessa, AKL Reyners
BackgroundThe magnitude of clinical benefit scale (MCBS) was introduced by the European Society of Medical Oncology (ESMO) to quantify the clinical benefit of therapeutic regimens and to prioritise therapies. It distinguishes curative from palliative treatments and ranks their benefit based on overall survival (OS), progression free survival (PFS), quality of life (QoL) and toxicity. Objective of this study on the first line treatment of ovarian cancer was to evaluate the evidence for the current standard of care using the ESMO-MCBSv1.1 with an emphasis on controversial therapeutic options: intraperitoneal chemotherapy, dose-dense paclitaxel and bevacizumab.MethodsPhase III trials, published since 1992, investigating first line systemic treatment of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIB-IV epithelial ovarian cancer were included. Since most studies included patients with FIGO stage IV disease or incomplete debulking, all treatments were judged to be palliative. Treatments were graded 5 to 1 on the ESMO-MCBSv1.1, where grades 5 and 4 represent a high level of clinical benefit.Results55 studies met the inclusion criteria. ESMO-MCBS scores were calculated for eleven studies that showed a statistically significant benefit of the experimental treatment. Intraperitoneal (ip) cisplatin scored a 4 and 3, but two other studies were negative and therefore not scored on the ESMO-MCBS. Dose-dense paclitaxel showed substantial clinical benefit in one study (score 4), but three studies were negative. Addition of bevacizumab also scored a 4 in one study subgroup including high-risk patients but a 2 in another trial with a larger study population.ConclusionBased on ESMO-MCBS scores, dose-dense paclitaxel and intraperitoneal chemotherapy cannot be recommended as standard treatment. Bevacizumab should be considered only in the high-risk population. The ESMO-MCBSv1.1. helps to summarise reported studies on controversial treatment regimens, and identifies their weaknesses.



https://ift.tt/2lheZqo

Locally advanced gastro-oesophageal cancer: recent therapeutic advances and research directions

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Lorenzo Fornaro, Enrico Vasile, Giuseppe Aprile, Thorsten Oliver Goetze, Caterina Vivaldi, Alfredo Falcone, Salah-Eddin Al-Batran
Gastric (GC) and gastro-oesophageal (GOJC) adenocarcinomas are often considered as a single entity, even though differences exist in epidemiology, clinical presentation, molecular biology and treatment options. Locally advanced, resectable disease represents a particularly challenging scenario, as many critical issues need to be addressed. In both GC and GOJC among Western countries, systemic chemotherapy demonstrated the greatest benefit when administered before and after surgery and perioperative chemotherapy has been set as a standard in this setting. Nonetheless, multiple chemotherapy regimens have been tested and direct comparisons have been only recently presented. Adjuvant chemoradiotherapy is an option as well, but several trials have questioned its role when more effective combination regimens are used. With regards to GOJC, preoperative chemoradiotherapy is an alternative to perioperative chemotherapy, as it is associated with higher pathologic responses and a different toxicity profile: however, a definitive comparison with chemotherapy is ongoing. Herein, we review the current options for the treatment of resectable GC and GOJC and the main open questions in the management of these patients, trying to depict an update of the available algorithms for everyday practice. Moreover, we summarize the design and preliminary results of the randomized trials in progress that will hopefully give definitive answers to the most debated issues in the field.



https://ift.tt/2ynq2aT

Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Sven Otto, Christoph Pautke, Tim Van den Wyngaert, Daniela Niepel, Morten Schiødt
Medication-related osteonecrosis of the jaw (MRONJ) is primarily an adverse side effect of denosumab or bisphosphonates (particularly when used at high doses to prevent skeletal-related events [SREs] in patients with cancer and bone metastases) or possibly anti-angiogenic cancer treatment. While the implementation of preventive measures over recent years has reduced the risk of MRONJ in patients with bone metastases due to cancer, it is imperative to balance the risk of MRONJ against the beneficial effects of treatment with denosumab or bisphosphonates on the skeletal health of patients. Despite growing awareness of MRONJ within the medical community, there is a lack of large-scale, prospective clinical studies in this rapidly evolving field. Discussing preventive measures with patients and implementing them, both before and during treatment with bisphosphonates or denosumab, is the best option to reduce the risk of MRONJ. In particular, avoiding bone trauma and preventing and treating dental infections before and during denosumab or bisphosphonate therapy is crucial to minimize the risk of MRONJ. If MRONJ develops, conservative (non-surgical) treatment can provide symptom relief, but achieving mucosal closure remains challenging. When management of symptoms and mucosal healing are the ultimate goals of therapy, or after failure of conservative treatment, a surgical approach may be beneficial. This critical review, based on a best-evidence review of currently available literature, provides clear practical guidelines to help to prevent, manage and treat MRONJ. Overall, a multidisciplinary, pragmatic approach to MRONJ should be adopted, prioritizing patient's quality of life and management of their skeletal malignant disease.



https://ift.tt/2lk4JxK

The poor design of clinical trials of statins in oncology may explain their failure – lessons for drug repurposing

Publication date: Available online 18 June 2018
Source:Cancer Treatment Reviews
Author(s): Marwan I. Abdullah, Elizabeth de Wolf, Mohammed J. Jawad, Alan Richardson
Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an "undruggable" target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug.



https://ift.tt/2tdTUke

Transoral Thyroid and Parathyroid Surgery Vestibular Approach: A Framework for Assessment and Safe Exploration

Thyroid, Ahead of Print.


https://ift.tt/2M4UwAt

Autopsy as a Source of Discovery in Cardiovascular Medicine: Then and Now.

Author: Thiene, Gaetano MD; Saffitz, Jeffrey E. MD, PhD

Page: 2683-2685

https://ift.tt/2K1l3l0

Autopsy 2018: Still Necessary, Even if Occasionally Not Sufficient.

Author: Goldman, Lee MD, MPH

Page: 2686-2688

https://ift.tt/2K20JMM

Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD Study.

Author: Tseng, Zian H. MD, MAS; Olgin, Jeffrey E. MD; Vittinghoff, Eric PhD; Ursell, Philip C. MD; Kim, Anthony S. MD, MAS; Sporer, Karl MD; Yeh, Clement MD; Colburn, Benjamin MD; Clark, Nina M. BS; Khan, Rana BA; Hart, Amy P. MD; Moffatt, Ellen MD

Page: 2689-2700

https://ift.tt/2K4sRlV

Cardiac and Noncardiac Causes of Apparent Sudden Arrhythmic Deaths: Shadows in a Spectrum.

Author: Myerburg, Robert J. MD

Page: 2701-2704

https://ift.tt/2JVD1BP

Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series.

Author: Shanks, Garrett W. BS *,; Tester, David J. BS *,; Ackerman, Jaeger P. BS; Simpson, Michael A. PhD; Behr, Elijah R. MD; White, Steven M. MD, PhD; Ackerman, Michael J. MD, PhD

Page: 2705-2715

https://ift.tt/2K68tRy

Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders.

Author: Junttila, M. Juhani MD *,; Holmstrom, Lauri BM *,; Pylkas, Katri PhD; Mantere, Tuomo PhD; Kaikkonen, Kari MD; Porvari, Katja PhD; Kortelainen, Marja-Leena MD; Pakanen, Lasse MD; Kerkela, Risto MD; Myerburg, Robert J. MD; Huikuri, Heikki V. MD

Page: 2716-2726

https://ift.tt/2I2vEXw

Bringing Autopsies Into the Molecular Genetic Era.

Author: Judge, Daniel P. MD; Brown, Emily E. MGC, CGC

Page: 2727-2729

https://ift.tt/2K45HMg

Cardiac Implantable Electronic Device Interrogation at Forensic Autopsy: An Underestimated Resource?.

Author: Lacour, Philipp MD *,; Buschmann, Claas MD *,; Storm, Christian MD; Nee, Jens MD; Parwani, Abdul Shokor MD; Huemer, Martin MD; Attanasio, Philipp MD; Boldt, Leif-Hendrik MD; Rauch, Geraldine PhD; Kucher, Andreas PhD; Pieske, Burkert MD; Haverkamp, Wilhelm MD; Blaschke, Florian MD

Page: 2730-2740

https://ift.tt/2I1tE1P

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis.

Author: Herrington, David M. MD, MHS *,; Mao, Chunhong PhD; Parker, Sarah J. PhD; Fu, Zongming PhD; Yu, Guoqiang PhD; Chen, Lulu MS; Venkatraman, Vidya MS; Fu, Yi MS; Wang, Yizhi MS; Howard, Timothy D. PhD; Jun, Goo PhD; Zhao, Caroline F.; Liu, Yongmei PhD; Saylor, Georgia; Spivia, Weston R. MS; Athas, Grace B. PhD; Troxclair, Dana MD; Hixson, James E. PhD *,; Vander Heide, Richard S. MD, PhD, MBA *,; Wang, Yue PhD *,; Van Eyk, Jennifer E. PhD *,

Page: 2741-2756

https://ift.tt/2K4sOXh

Correction to: Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury.

Author:

Page: e853

https://ift.tt/2I2vm2S

SPARTAN promotes genetic diversification of the immunoglobulin-variable gene locus in avian DT40 cells

Publication date: Available online 18 June 2018
Source:DNA Repair
Author(s): Arisa Nakazato, Kinumi Kajita, Masato Ooka, Remi Akagawa, Takuya Abe, Shunichi Takeda, Dana Branzei, Kouji Hirota
Prolonged replication arrest on damaged templates is a cause of fork collapse, potentially resulting in genome instability. Arrested replication is rescued by translesion DNA synthesis (TLS) and homologous recombination (HR)-mediated template switching. SPARTAN, a ubiquitin-PCNA-interacting regulator, regulates TLS via mechanisms incompletely understood. Here we show that SPARTAN promotes diversification of the chicken DT40 immunoglobulin-variable λ gene by facilitating TLS-mediated hypermutation and template switch-mediated gene-conversion, both induced by replication blocks at abasic sites. SPARTAN^-/- and SPARTAN^-/-/Polη^-/-/Polζ^-/- cells showed defective and similar decrease in hypermutation rates, as well as alterations in the mutation spectra, with decreased dG-to-dC transversions and increased dG-to-dA transitions. Strikingly, SPARTAN^-/- cells also showed reduced template switch-mediated gene-conversion at the immunoglobulin locus, while being proficient in HR-mediated double strand break repair, and sister chromatid recombination. Notably, SPARTAN's ubiquitin-binding zinc-finger 4 domain, but not the PCNA interacting peptide domain or its DNA-binding domain, was specifically required for the promotion of immunoglobulin gene-conversion, while all these three domains were shown to contribute similarly to TLS. In all, our results suggest that SPARTAN mediates TLS in concert with the Polη-Polζ pathway and that it facilitates HR-mediated template switching at a subset of stalled replication forks, potentially by interacting with unknown ubiquitinated proteins.



https://ift.tt/2ymlRMq

Immune check-point in cervical cancer

Publication date: Available online 18 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): F. De Felice, C. Marchetti, I. Palaia, R. Ostuni, L. Muzii, V. Tombolini, P. Benedetti Panici
Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival.We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC.



https://ift.tt/2JZisI3

The changing scenario of 1st line therapy in non-oncogene addicted NSCLCs in the era of immunotherapy

Publication date: Available online 18 June 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): A Russo, T Franchina, GRR Ricciardi, G Toscano, S Schifano, G Lo Certo, A Battaglia, E Pantò, M Scaffidi Fonti, V Adamo
During the last two decades front-line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) has profoundly changed moving from the old "one size fits all" concept to a "histology-based" approach and then, for a small subgroup of patients to a "molecularly-selected" one. The development of immune checkpoint inhibitors and the unprecedented results reported in 2^nd/3^rd line prompted the evaluation of these novel therapeutic agents in chemotherapy-naïve patients either alone or in combination with platinum-based chemotherapy. Several randomized trials are evaluating the impact of immune-checkpoint inhibitors in 1^st line and some of them have yet produced preliminary evidence of efficacy. However, still a long way to go and several questions are still unanswered, including proper patients selection, optimal sequential/combinatorial use of these agents, appropriate treatment duration, and finally the identification of predictive biomarkers. The aim of this paper is to provide a comprehensive overview on the growing role of immune checkpoint inhibitors in the upfront treatment of advanced non-oncogene addicted NSCLC either as single agent or in combination with other agents.



https://ift.tt/2JVYaMh

Tired and Swollen: A Mono Mimic for Angioedema

Publication date: Available online 18 June 2018
Source:Annals of Allergy, Asthma & Immunology
Author(s): Amie Nguyen, Sandra Christiansen




https://ift.tt/2t6Upgz

Role of complement C5a and histones in septic cardiomyopathy

Publication date: Available online 18 June 2018
Source:Molecular Immunology
Author(s): Fatemeh Fattahi, Lynn M. Frydrych, Guowu Bian, Miriam Kalbitz, Todd J. Herron, Elizabeth A. Malan, Matthew J. Delano, Peter A. Ward
Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca²⁺]i-regulatory enzymes including sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2) and Na⁺/Ca²⁺ exchanger (NCX) as well as Na⁺/K⁺-ATPase in CMs. There is also evidence that CLP causes release of IL-1β via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).



https://ift.tt/2I5ao3K

Common and rare genetic variants of complement components in human disease

Publication date: Available online 18 June 2018
Source:Molecular Immunology
Author(s): Elena Goicoechea de Jorge, Alberto López Lera, Rafael Bayarri-Olmos, Hugo Yebenes, Margarita Lopez-Trascasa, Santiago Rodríguez de Córdoba
Genetic variability in the complement system and its association with disease has been known for more than 50 years, but only during the last decade have we begun to understand how this complement genetic variability contributes to the development of diseases. A number of reports have described important genotype-phenotype correlations that associate particular diseases with genetic variants altering specific aspects of the activation and regulation of the complement system. The detailed functional characterization of some of these genetic variants provided key insights into the pathogenic mechanisms underlying these pathologies, which is facilitating the design of specific anti-complement therapies. Importantly, these analyses have sometimes revealed unknown features of the complement proteins. As a whole, these advances have delineated the functional implications of genetic variability in the complement system, which supports the implementation of a precision medicine approach based on the complement genetic makeup of the patients. Here we provide an overview of rare complement variants and common polymorphisms associated with disease and discuss what we have learned from them.



https://ift.tt/2K2fRNt

Role of complement C5a and histones in septic cardiomyopathy

Publication date: Available online 18 June 2018
Source:Molecular Immunology
Author(s): Fatemeh Fattahi, Lynn M. Frydrych, Guowu Bian, Miriam Kalbitz, Todd J. Herron, Elizabeth A. Malan, Matthew J. Delano, Peter A. Ward
Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca²⁺]i-regulatory enzymes including sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2) and Na⁺/Ca²⁺ exchanger (NCX) as well as Na⁺/K⁺-ATPase in CMs. There is also evidence that CLP causes release of IL-1β via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).



https://ift.tt/2I5ao3K

Common and rare genetic variants of complement components in human disease

Publication date: Available online 18 June 2018
Source:Molecular Immunology
Author(s): Elena Goicoechea de Jorge, Alberto López Lera, Rafael Bayarri-Olmos, Hugo Yebenes, Margarita Lopez-Trascasa, Santiago Rodríguez de Córdoba
Genetic variability in the complement system and its association with disease has been known for more than 50 years, but only during the last decade have we begun to understand how this complement genetic variability contributes to the development of diseases. A number of reports have described important genotype-phenotype correlations that associate particular diseases with genetic variants altering specific aspects of the activation and regulation of the complement system. The detailed functional characterization of some of these genetic variants provided key insights into the pathogenic mechanisms underlying these pathologies, which is facilitating the design of specific anti-complement therapies. Importantly, these analyses have sometimes revealed unknown features of the complement proteins. As a whole, these advances have delineated the functional implications of genetic variability in the complement system, which supports the implementation of a precision medicine approach based on the complement genetic makeup of the patients. Here we provide an overview of rare complement variants and common polymorphisms associated with disease and discuss what we have learned from them.



https://ift.tt/2K2fRNt

Recovery of ilmenite mud as an additive in commercial Portland cements

Abstract

This work is focused on the manufacture of commercial cement using as additive ilmenite mud, a waste generated during TiO₂ pigment production. The cements were produced by adding different proportions of mud (2.5, 5 and 10 wt%) to ordinary Portland cement (OPC). The ilmenite mud and the ilmenite mud cements (IMCs) were characterised physico-chemically by X-ray fluorescence (XRF), inductively coupled plasma mass spectrometry (ICP-MS) and X-ray diffraction (XRD). Moreover, the technological properties of the IMCs were evaluated and compared with a reference material (OPC). Since waste from the TiO₂ industry is classified as a NORM (naturally occurring radioactive material), the concentrations of radionuclides were measured by high-resolution low-background gamma and alpha spectrometry techniques. Finally, the TCLP leaching test (Toxicity Characteristic Leaching Procedure, USEPA), the radiological index ("I") and the Ra equivalent concentration were also calculated to evaluate the environmental risks. As a final conclusion, it can be pointed out that the addition of ilmenite mud to OPC plays a beneficial role since it reduces the heat of hydration, the final setting time, the expansion and the linear retraction compared to standard OPC. The compression strength improves with the addition of up to 5 wt% mud. Moreover, the environmental impact of IMC2.5 and IMC5 can be considered negligible.

https://ift.tt/2liTshb

Retrospondyloptosis of the Spine Secondary to Nonaccidental Trauma

Spinal fracture rates from NAT have been reported in

https://ift.tt/2tjKcwS

The effect of surgical weight loss on obstructive sleep apnoea: A systematic review and meta-analysis

This review aimed to examine the relationship between surgical weight loss and obstructive sleep apnoea (OSA) severity (i.e. apnoea-hypopnoea index [AHI]), and how this relationship is altered by the various respiratory events scoring (RES) criteria used to derive the AHI. A systematic search of the literature was performed up to December 2017. Before-and-after studies were considered due to a paucity of randomised controlled trials (RCTs) available to be reviewed in isolation. Primary outcomes included pre- and post-surgery AHI and body mass index (BMI).

https://ift.tt/2t8KCGS

Tolerability and Efficacy of Ipragliflozin in The Management of Inadequately Controlled Type 2 Diabetes mellitus: A Systematic Review and Meta-analysis

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0579-7860

Aim Ipragliflozin is a new antidiabetic agent that works through enhancing renal glucose excretion. We aim to synthesize evidence from published randomized controlled trials (RCTs) on the safety and efficacy of ipragliflozin in the management of type 2 diabetes mellitus (T2DM). Methods We searched PubMed, Scopus, Web of Science, and Cochrane Central register of clinical trials using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager Version 5.3 for windows. Subgroup and sensitivity analyses were conducted. Results We included 13 RCTs (N=2535 patients) in the final analysis. The overall effect estimates favoured ipragliflozin 50mg monotherapy group over placebo in terms of: HbA1c (Standardized mean difference (SMD)=-1.20%, 95% Confidence interval (95% CI)=[-1.47, -0.93]; p<0.001), fasting plasma glucose (SMD=-1.30 mg/dL, 95% CI [−1.93, −0.67]; p<0.001), fasting serum insulin (SMD=−1.64 μU/mL, 95% CI [−2.70, −0.59]; p=0.002), and body weight (SMD=−0.85 kg, 95% CI [−1.19, −0.51]; p<0.001). Similarly, better glycemic control and significant body weight reduction compared to placebo were attained in ipragliflozin 50 mg combination with metformin, insulin with/without dipeptidyl peptidase-4 inhibitor, sulfonylurea, and pioglitazone. Ipragliflozin, either alone or in combination, exhibits acceptable safety profile. Conclusion The presented meta-analysis provides class one evidence that ipragliflozin is safe and effective in the management of T2DM either as monotherapy or an add-on.
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© Georg Thieme Verlag KG Stuttgart · New York

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Prevalence of food allergens sensitization and food allergies in a group of allergic Honduran children

Food allergy is a public health problem that has increased in the last decade. Despite the increasing rates in children, quality data on the burden of these diseases is lacking particularly in developing count...

https://ift.tt/2JS394Y

An investigation of the effects of capping on internal phosphorus release from sediments under rooted macrophytes ( Phragmites australis ) revegetation

Abstract

In eutrophic lake restorations, in situ capping is an often considered method to control sediment internal phosphorus (P) pollution for mitigating eutrophication status. Subsequent aquatic macrophyte revegetation can directly derive P from the sediment for growth. However, the effects of capping with clean soils on internal P release from sediments under rooted aquatic macrophyte revegetation are still unclear. In the present study, the influences of sediment P remobilization by P. australis revegetation on P inactivation by capping were investigated based on an entire growth simulation study. Our findings showed during the growth of P. australis, tests conducted on total phosphorous (TP), calcium-bound P (Ca-P), loosely bound P (loose-P), organic P (Org-P), and iron-adsorbed P (Fe-P) found significant changes (p < 0.001). Specifically, the mean contents of TP and Ca-P decreased by 291.1 and 224.2 mg kg⁻¹, respectively, while those of Fe-P increased from 26.4 to 124.8 mg kg⁻¹. In addition, sediment mobile-P contents increased coincidentally with the growth of P. australis during the whole course of experiment. Further analysis indicated calculated diffusion fluxes of soluble reactive phosphorus (SRP) generally increased with incubation time, although capping effectively induced the reduction of SRP concentration in pore water and its release to waters. Therefore, sediment P remobilization by P. australis revegetation was able to enhance P lability in lake sediments, with intermediate activation ability compared to other correlated water bodies. This phenomenon was most likely attributed to solubilization of sediment P by organic acids secreted from P. australis rhizosphere. Overall, sediment P remobilization by rooted macrophytes is unfavorable for capping to control internal P release to water column during eutrophic lake restorations.

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CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases

Cell adhesion molecule 1 (CADM1) has been reported as a diagnostic marker for Adult T-cell leukemia/lymphoma (ATLL). Our study suggests that CADM1 is expressed not only in ATLL but also in mycosis fungoides (MF). CADM1 can be useful for differentiating MF from inflammatory skin disorders.

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Prevalence of psoriatic arthritis in patients with psoriasis: A systematic review and meta-analysis of observational and clinical studies

Wide-ranging estimates have been reported for the occurrence of psoriatic arthritis in patients with psoriasis. We found an overall pooled prevalence of 19.7% for psoriatic arthritis in patients with psoriasis and 24.6% in patients with moderate-to-severe disease.Screening psoriasis patients for psoriatic arthritis may be warranted, especially for those with moderate-to-severe disease..

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Retrospective evaluation of fidaxomicin versus oral vancomycin for treatment of Clostridium difficile infections in allogeneic stem cell transplant

Publication date: Available online 18 June 2018
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Laura Prohaska, Zahra Mahmoudjafari, Leyla Shune, Anurag Singh, Tara Lin, Sunil Abhyankar, Siddhartha Ganguly, Dennis Grauer, Joseph McGuirk, Lisa Clough
Objective/backgroundClostridium difficile infection (CDI) is a potential complication during hematopoietic stem cell transplantation (HSCT), and no specific recommendations exist regarding treatment of CDI in allogeneic SCT patients. Use of metronidazole and oral vancomycin has been associated with clinical failure. Fidaxomicin has previously been found noninferior to the use of oral vancomycin for the treatment of CDI, and no studies have compared the use of oral vancomycin with fidaxomicin for the treatment of CDI in allogeneic SCT.MethodsThis retrospective chart review included 96 allogeneic SCT recipients who developed CDI within 100 days following transplantation. Participants were treated with oral vancomycin (n = 52) or fidaxomicin (n = 44). The primary outcome was clinical cure, defined as no need for further retreatment 2 days following completion of initial CDI treatment. Secondary outcomes were global cure, treatment failure, and recurrent disease.ResultsNo differences in clinical cure were observed between patients receiving oral vancomycin or fidaxomicin (75% vs. 75%, p = 1.00). Secondary outcomes were similar between oral vancomycin and fidaxomicin in regards to global cure (66% vs. 67%, p = .508), treatment failure (28% vs. 27%, p = .571), and recurrent disease (7% vs. 5%, p = .747). In a subanalysis of individuals that developed acute graft-versus-host disease following CDI, the difference in mean onset of acute graft-versus-host disease was 21.03 days in the oral vancomycin group versus 32.88 days in the fidaxomicin group (p = .0031).ConclusionThe findings of this study suggest that oral vancomycin and fidaxomicin are comparable options for CDI treatment in allogeneic SCT patients within 100 days following transplant.



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Oral Immunotherapy for Food Allergy -The FAST perspective

Although the practical application of oral immunotherapy for food allergy (FOIT) is routine in Japan1 and common in Europe,2,3 it continues to be controversial in North America.4 It is not the intention of this report to engage in that polemic, but rather to acknowledge that there are at least dozens of allergists in North America treating thousands of food allergic patients with FOIT. We do not contend that collections of anecdotes are the same as data. We do believe, however, that questions arise in the day-to-day practice of food allergy treatment that must be addressed, but are unlikely to be the subject of prospective, controlled trials.

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Heterogeneity and the origins of asthma

It is a well-known fact that there is significant heterogeneity in the origins of asthma in adults and children. This article examines the roots of asthma across the ages including atopy, the role of the microbiome and viral infections, along with comorbidities/confounders such as obesity, aspirin-exacerbated respiratory disease (AERD), neutrophilic asthma, cigarette smoking and the possibility of an asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome.

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Radiographic and histologic characterization of tongue base tissues obtained by transoral robotic surgery in patients with obstructive sleep apnea

Our aim was to radiographically and histologically characterize the tongue base tissues removed after robotic surgery and to analyze their relationship with polysomnographic measurements in obstructive sleep apnea.

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A New Method for Mild Blepharoptosis Correction using Orbital Septum

Blepharoptosis greatly affects the eyelid appearance. Moderate to severe ptosis is easily distinguished. However, mild ptosis is often overlooked or easily missed. The normal upper eyelid is located in the middle horizontal line between the upper edge of the pupil and the upper edge of the cornea while the patient looks straight ahead; that is, the upper eyelid covers 1.5 to 2.0 mm of the cornea. Mild blepharoptosis is diagnosed when the upper eyelid covers the cornea over the normal level to the upper edge of the pupil; the upper eyelid falls about 1 to 2 mm.

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Anatomical Variability of the Infra-mammary Fold and its Dynamics in Relation to Lejour Mammoplasty

The IMF is a defining element in the shape and structure of the female breast. 1 The anatomy and tissue components of the IMF have been a matter of controversy among plastic surgeons and anatomists. Some have attributed formation of the fold to a distinct ligament, 2,3 while others described a superficial fascial system. 4,5 Despite this controversy; most of the plastic surgeons settled on a thought that the preservation of the integrity of the IMF is an important goal in enhancing the aesthetic result in all breast surgeries.

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BAPRAS and BAAPS Scientific Meetings: Are we sticking our noses up at rhinoplasty?

Dear Sir,

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Clenched fist syndrome: a case report

The clenched fist syndrome/psycho-flexed hand, first described in the early 1980s, has not yet entered the major psychiatric textbooks. Curiously, the phenomenon has been illuminated mainly in journals and tex...

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Perinodal Adipose Tissue Participates in Immune Protection through a Lymphatic Vessel-Independent Route [NOVEL IMMUNOLOGICAL METHODS]

Lymphatic vessels remove and transport excess interstitial fluid to lymph nodes (LNs) for fluid balance and immune protection. LNs are typically surrounded by perinodal adipose tissue (PAT). However, PAT is a blood vessel–rich but lymphatic-rare tissue; therefore, how excess fluid in PAT is removed remains unclear. Using C57BL/6 mice, fluorescent dye tracing and transmission electron microscopy results suggest that fluid in PAT can travel to the LN via collagen I⁺ channels (PAT-LN conduits), merge into a collagen-rich space between the PAT and LN capsule (PAT-LN sinus), and may enter the LN via the LN capsule–associated conduits. This newly identified route of fluid flow allows fluid to enter the draining LN even when the afferent lymphatic vessels are blocked, indicating that fluid trafficking in PAT-LN conduits is not dependent on functional lymphatic vessels. Similar to lymphatic vessels, PAT-LN conduits can deliver Ags to the LN for immune protection. Additionally, Staphylococcus aureus from intradermal or i.v. infection may use PAT-LN conduits to infect PAT and stimulate PAT immune protection. Our studies revealed a new route of material exchange between PAT and the LN. Ag accumulation and bacterial infection in PAT demonstrate that PAT not only provides energy and regulatory factors, but can also directly participate in immune protection, indicating a new immune function of PAT for host immunity.

https://ift.tt/2tjfW5j

Myeloid-Derived Suppressor Cells Impair B Cell Responses in Lung Cancer through IL-7 and STAT5 [TUMOR IMMUNOLOGY]

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity, affecting amino acid metabolism and T cell function in the tumor microenvironment. However, it is unknown whether MDSCs regulate B cell responses during tumor progression. Using a syngeneic mouse model of lung cancer, we show reduction in percentages and absolute numbers of B cell subsets including pro–, pre–, and mature B cells in the bone marrow (BM) of tumor-bearing mice. The kinetics of this impaired B cell response correlated with the progressive infiltration of MDSCs. We identified that IL-7 and downstream STAT5 signaling that play a critical role in B cell development and differentiation were also impaired during tumor progression. Global impairment of B cell function was indicated by reduced serum IgG levels. Importantly, we show that anti–Gr-1 Ab-mediated depletion of MDSCs not only rescued serum IgG and IL-7 levels but also reduced TGF-β1, a known regulator of stromal IL-7, suggesting MDSC-mediated regulation of B cell responses. Furthermore, blockade of IL-7 resulted in reduced phosphorylation of downstream STAT5 and B cell differentiation in tumor-bearing mice and administration of TGF-β–blocking Ab rescued these IL-7–dependent B cell responses. Adoptive transfer of BM-derived MDSCs from tumor-bearing mice into congenic recipients resulted in significant reductions of B cell subsets in the BM and in circulation. MDSCs also suppressed B cell proliferation in vitro in an arginase-dependent manner that required cell-to-cell contact. Our results indicate that tumor-infiltrating MDSCs may suppress humoral immune responses and promote tumor escape from immune surveillance.

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Correction: NK Cells Influence Both Innate and Adaptive Immune Responses after Mucosal Immunization with Antigen and Mucosal Adjuvant [CORRECTIONS]

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Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease [INNATE IMMUNITY AND INFLAMMATION]

Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament–binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.

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Genome-Wide Posttranscriptional Dysregulation by MicroRNAs in Human Asthma as Revealed by Frac-seq [SYSTEMS IMMUNOLOGY]

MicroRNAs are small noncoding RNAs that inhibit gene expression posttranscriptionally, implicated in virtually all biological processes. Although the effect of individual microRNAs is generally studied, the genome-wide role of multiple microRNAs is less investigated. We assessed paired genome-wide expression of microRNAs with total (cytoplasmic) and translational (polyribosome-bound) mRNA levels employing subcellular fractionation and RNA sequencing (Frac-seq) in human primary bronchoepithelium from healthy controls and severe asthmatics. Severe asthma is a chronic inflammatory disease of the airways characterized by poor response to therapy. We found genes (i.e., isoforms of a gene) and mRNA isoforms differentially expressed in asthma, with novel inflammatory and structural pathophysiological mechanisms related to bronchoepithelium disclosed solely by polyribosome-bound mRNAs (e.g., IL1A and LTB genes or ITGA6 and ITGA2 alternatively spliced isoforms). Gene expression (i.e., isoforms of a gene) and mRNA expression analysis revealed different molecular candidates and biological pathways, with differentially expressed polyribosome-bound and total mRNAs also showing little overlap. We reveal a hub of six dysregulated microRNAs accounting for ~90% of all microRNA targeting, displaying preference for polyribosome-bound mRNAs. Transfection of this hub in bronchial epithelial cells from healthy donors mimicked asthma characteristics. Our work demonstrates extensive posttranscriptional gene dysregulation in human asthma, in which microRNAs play a central role, illustrating the feasibility and importance of assessing posttranscriptional gene expression when investigating human disease.

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Innate Nutritional Immunity [BRIEF REVIEWS]

Iron (Fe) is an essential micronutrient for both microbes and their hosts. The biologic importance of Fe derives from its inherent ability to act as a universal redox catalyst, co-opted in a variety of biochemical processes critical to maintain life. Animals evolved several mechanisms to retain and limit Fe availability to pathogenic microbes, a resistance mechanism termed "nutritional immunity." Likewise, pathogenic microbes coevolved to deploy diverse and efficient mechanisms to acquire Fe from their hosts and in doing so overcome nutritional immunity. In this review, we discuss how the innate immune system regulates Fe metabolism to withhold Fe from pathogenic microbes and how strategies used by pathogens to acquire Fe circumvent these resistance mechanisms.

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Original Ligand for LT{beta}R Is LIGHT: Insight into Evolution of the LT/LT{beta}R System [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The lymphotoxin (LT)/LTβ receptor (LTβR) axis is crucial for the regulation of immune responses and development of lymphoid tissues in mammals. Despite the importance of this pathway, the existence and function of LT and LTβR remain obscure for nonmammalian species. In this study, we report a nonmammalian LTβR and its ligand. We demonstrate that TNF-New (TNFN), which has been considered orthologous to mammalian LT, was expressed on the cell surface as a homomer in vitro. This different protein structure indicates that TNFN is not orthologous to mammalian LTα and LTβ. Additionally, we found that LTβR was conserved in teleosts, but the soluble form of recombinant fugu LTβR did not bind to membrane TNFN under the circumstance tested. Conversely, the LTβR recombinant bound to another ligand, LIGHT, similar to that of mammals. These findings indicate that teleost LTβR is originally a LIGHT receptor. In the cytoplasmic region of fugu LTβR, recombinant fugu LTβR bound to the adaptor protein TNFR-associated factor (TRAF) 2, but little to TRAF3. This difference suggests that teleost LTβR could potentially activate the classical NF-B pathway with a novel binding domain, but would have little ability to activate an alternative one. Collectively, our results suggested that LIGHT was the original ligand for LTβR, and that the teleost immune system lacked the LT/LTβR pathway. Acquisition of the LT ligand and TRAF binding domain after lobe-finned fish may have facilitated the sophistication of the immune system and lymphoid tissues.

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CD4 T Cell Affinity Diversity Is Equally Maintained during Acute and Chronic Infection [ANTIGEN RECOGNITION AND RESPONSES]

TCR affinity for peptide MHC dictates the functional efficiency of T cells and their propensity to differentiate into effectors and form memory. However, in the context of chronic infections, it is unclear what the overall profile of TCR affinity for Ag is and if it differs from acute infections. Using the comprehensive affinity analysis provided by the two-dimensional micropipette adhesion frequency assay and the common indirect affinity evaluation methods of MHC class II tetramer and functional avidity, we tracked IA^b GP_61–80–specific cells in the mouse model of acute (Armstrong) and chronic (clone 13) lymphocytic choriomeningitis virus infection. In each response, we show CD4 T cell population affinity peaks at the effector phase and declines with memory. Of interest, the range and average relative two-dimensional affinity was equivalent between acute and chronic infection, indicating chronic Ag exposure did not skew TCR affinity. In contrast, functional and tetramer avidity measurements revealed divergent results and lacked a consistent correlation with TCR affinity. Our findings highlight that the immune system maintains a diverse range in TCR affinity even under the pressures of chronic Ag stimulation.

https://ift.tt/2t6ft76

Effects of Influenza on Alveolar Macrophage Viability Are Dependent on Mouse Genetic Strain [INFECTIOUS DISEASE AND HOST RESPONSE]

Secondary bacterial coinfections following influenza virus pose a serious threat to human health. Therefore, it is of significant clinical relevance to understand the immunological causes of this increased susceptibility. Influenza-induced alterations in alveolar macrophages (AMs) have been shown to be a major underlying cause of the increased susceptibility to bacterial superinfection. However, the mechanisms responsible for this remain under debate, specifically in terms of whether AMs are depleted in response to influenza infection or are maintained postinfection, but with disrupted phagocytic activity. The data presented in this article resolves this issue by showing that either mechanism can differentially occur in individual mouse strains. BALB/c mice exhibited a dramatic IFN-–dependent reduction in levels of AMs following infection with influenza A, whereas AM levels in C57BL/6 mice were maintained throughout the course of influenza infection, although the cells displayed an altered phenotype, namely an upregulation in CD11b expression. These strain differences were observed regardless of whether infection was performed with low or high doses of influenza virus. Furthermore, infection with either the H1N1 A/California/04/2009 (CA04) or H1N1 A/PR8/1934 (PR8) virus strain yielded similar results. Regardless of AM viability, both BALB/c and C57BL/6 mice showed a high level of susceptibility to postinfluenza bacterial infection. These findings resolve the apparent inconsistencies in the literature, identify mouse strain–dependent differences in the AM response to influenza infection, and ultimately may facilitate translation of the mouse model to clinical application.

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CD8 Follicular T Cells Promote B Cell Antibody Class Switch in Autoimmune Disease [AUTOIMMUNITY]

CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2–deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2–deficient mice. CD8 T cells express the B cell follicle–localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality.

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Innate Recognition of the Microbiota by TLR1 Promotes Epithelial Homeostasis and Prevents Chronic Inflammation [MUCOSAL IMMUNOLOGY]

There is cross-talk between the intestinal epithelium and the microbiota that functions to maintain a tightly regulated microenvironment and prevent chronic inflammation. This communication is partly mediated through the recognition of bacterial proteins by host-encoded innate receptors, such as TLRs. However, studies examining the role of TLR signaling on colonic homeostasis have given variable and conflicting results. Despite its critical role in mediating immunity during enteric infection of the small intestine, TLR1-mediated recognition of microbiota-derived ligands and their influence on colonic homeostasis has not been well studied. In this study, we demonstrate that defective TLR1 recognition of the microbiome by epithelial cells results in disruption of crypt homeostasis specifically within the secretory cell compartment, including a defect in the mucus layer, ectopic Paneth cells in the colon, and an increase in the number of rapidly dividing cells at the base of the crypt. As a consequence of the perturbed epithelial barrier, we found an increase in mucosal-associated and translocated commensal bacteria and chronic low-grade inflammation characterized by an increase in lineage-negative Sca1⁺Thy1^hi innate lymphoid-like cells that exacerbate inflammation and worsen outcomes in a model of colonic injury and repair. Our findings demonstrate that sensing of the microbiota by TLR1 may provide key signals that regulate the colonic epithelium, thereby limiting inflammation through the prevention of bacterial attachment to the mucosa and exposure to the underlying immune system.

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TRIM29 Negatively Regulates the Type I IFN Production in Response to RNA Virus [INNATE IMMUNITY AND INFLAMMATION]

The innate immunity is critically important in protection against virus infections, and in the case of RNA viral infections, the signaling mechanisms that initiate robust protective innate immunity without triggering autoimmune inflammation remain incompletely defined. In this study, we found the E3 ligase TRIM29 was specifically expressed in poly I:C–stimulated human myeloid dendritic cells. The induced TRIM29 played a negative role in type I IFN production in response to poly I:C or dsRNA virus reovirus infection. Importantly, the challenge of wild-type mice with reovirus led to lethal infection. In contrast, deletion of TRIM29 protected the mice from this developing lethality. Additionally, TRIM29^–/– mice have lower titers of reovirus in the heart, intestine, spleen, liver, and brain because of elevated production of type I IFN. Mechanistically, TRIM29 was shown to interact with MAVS and subsequently induce its K11-linked ubiquitination and degradation. Taken together, TRIM29 regulates negatively the host innate immune response to RNA virus, which could be employed by RNA viruses for viral pathogenesis.

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IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo [CLINICAL AND HUMAN IMMUNOLOGY]

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte–derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF–driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.

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Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity [IMMUNE REGULATION]

Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5–induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention.

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Pillars Article: T-Cell Apoptosis Detected In Situ during Positive and Negative Selection in the Thymus. Nature. 1994. 372: 100-103 [PILLARS OF IMMUNOLOGY]

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Differential Roles of LT{beta}R in Endothelial Cell Subsets for Lymph Node Organogenesis and Maturation [IMMUNE SYSTEM DEVELOPMENT]

Cellular cross-talk mediated by lymphotoxin αβ–lymphotoxin β receptor (LTβR) signaling plays a critical role in lymph node (LN) development. Although the major role of LTβR signaling has long been considered to occur in mesenchymal lymphoid tissue organizer cells, a recent study using a VE-cadherin^creLtbr^fl/fl mouse model suggested that endothelial LTβR signaling contributes to the formation of LNs. However, the detailed roles of LTβR in different endothelial cells (ECs) in LN development remain unknown. Using various cre transgenic mouse models (Tek^cre, a strain targeting ECs, and Lyve1^cre, mainly targeting lymphatic ECs), we observed that specific LTβR ablation in Tek^cre+ or Lyve1^cre+ cells is not required for LN formation. Moreover, double-cre–mediated LTβR depletion does not interrupt LN formation. Nevertheless, Tek^creLtbr^fl/fl mice exhibit reduced lymphoid tissue inducer cell accumulation at the LN anlagen and impaired LN maturation. Interestingly, a subset of ECs (VE-cadherin⁺Tek^cre-low/neg ECs) was found to be enriched in transcripts related to hematopoietic cell recruitment and transendothelial migration, resembling LN high ECs in adult animals. Furthermore, endothelial Tek was observed to negatively regulate hematopoietic cell transmigration. Taken together, our data suggest that although Tek^cre+ endothelial LTβR is required for the accumulation of hematopoietic cells and full LN maturation, LTβR in VE-cadherin⁺Tek^cre-low/neg ECs in embryos might represent a critical portal-determining factor for LN formation.

https://ift.tt/2t7gM5M

MicroRNA-302 Cluster Downregulates Enterovirus 71-Induced Innate Immune Response by Targeting KPNA2 [INNATE IMMUNITY AND INFLAMMATION]

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus–induced IFN expression by targeting NF-B-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy.

https://ift.tt/2thV5PC

Survival of Mice with Gastrointestinal Acute Radiation Syndrome through Control of Bacterial Translocation [IMMUNOTHERAPY AND VACCINES]

Macrophages (M) with the M2b phenotype (Pheno2b-M) in bacterial translocation sites have been described as cells responsible for the increased susceptibility of mice with gastrointestinal acute radiation syndrome to sepsis caused by gut bacteria. In this study, we tried to reduce the mortality of mice exposed to 7–10 Gy of gamma rays by controlling Pheno2b-M polarization in bacterial translocation sites. MicroRNA-222 was induced in association with gamma irradiation. Pheno2b-M polarization was promoted and maintained in gamma-irradiated mice through the reduction of a long noncoding RNA growth arrest–specific transcript 5 (a CCL1 gene silencer) influenced by this microRNA. Therefore, the host resistance of 7–9-Gy gamma-irradiated mice to sepsis caused by bacterial translocation was improved after treatment with CCL1 antisense oligodeoxynucleotide. However, the mortality of 10-Gy gamma-irradiated mice was not alleviated by this treatment. The crypts and villi in the ileum of 10-Gy gamma-irradiated mice were severely damaged, but these were markedly improved after transplantation of intestinal lineage cells differentiated from murine embryonic stem cells. All 10-Gy gamma-irradiated mice given both of the oligodeoxynucleotide and intestinal lineage cells survived, whereas all of the same mice given either of them died. These results indicate that high mortality rates of mice irradiated with 7–10 Gy of gamma rays are reducible by depleting CCL1 in combination with the intestinal lineage cell transplantation. These findings support the novel therapeutic possibility of victims who have gastrointestinal acute radiation syndrome for the reduction of their high mortality rates.

https://ift.tt/2ymlEJr

IL-36{alpha} from Skin-Resident Cells Plays an Important Role in the Pathogenesis of Imiquimod-Induced Psoriasiform Dermatitis by Forming a Local Autoamplification Loop [INNATE IMMUNITY AND INFLAMMATION]

IL-36α (gene symbol Il1f6), a member of the IL-36 family, is closely associated with inflammatory diseases, including colitis and psoriasis. In this study, we found that Il1f6^–/– mice developed milder psoriasiform dermatitis upon treatment with imiquimod, a ligand for TLR ligand 7 (TLR7) and TLR8, whereas Il1f6^–/– mice showed similar susceptibility to dextran sodium sulfate–induced colitis to wild-type mice. These effects were observed in both cohoused and separately housed conditions, and antibiotic treatment did not cancel the resistance of Il1f6^–/– mice to imiquimod-induced dermatitis. Bone marrow (BM) cell transfer revealed that IL-36α expression in skin-resident cells is important for the pathogenesis of dermatitis in these mice. Following stimulation with IL-36α, the expression of Il1f6 and Il1f9 (IL-36), but not Il1f8 (IL-36β), was enhanced in murine BM-derived Langerhans cells (BMLCs) and murine primary keratinocytes but not in fibroblasts from mice. Upon stimulation with agonistic ligands of TLRs and C-type lectin receptors (CLRs), Il1f6 expression was induced in BMLCs and BM-derived dendritic cells. Furthermore, IL-36α stimulation resulted in significantly increased gene expression of psoriasis-associated Th17-related cytokines and chemokines such as IL-1α, IL-1β, IL-23, CXCL1, and CXCL2 in BMLCs and fibroblasts, and IL-1α, IL-1β, IL-17C, and CXCL2 in keratinocytes. Collectively, these results suggest that TLR/CLR signaling–induced IL-36α plays an important role for the development of psoriasiform dermatitis by enhancing Th17-related cytokine/chemokine production in skin-resident cells via a local autoamplification loop.

https://ift.tt/2ymlj9D

Formation of Immune Complexes with a Tetanus-Derived B Cell Epitope Boosts Human T Cell Responses to Covalently Linked Peptides in an Ex Vivo Blood Loop System [IMMUNOTHERAPY AND VACCINES]

Enhancing T cell responses against both viral and tumor Ags requires efficient costimulation and directed delivery of peptide Ags into APCs. Long peptide vaccines are considered favorable vaccine moieties from a clinical perspective, as they can harbor more than one immunogenic epitope enabling treatment of a broader target population. In addition, longer peptides are not extracellularly loaded on MHC class I; rather, they require intracellular processing and will thereby be presented to T cells mainly by professional APCs, thereby avoiding the risk of tolerance induction. The drawback of peptide vaccines regardless of peptide length is that naked peptides are not actively targeted to and taken up by APCs, and the standard nonconjugated adjuvant-peptide mixtures do not ensure cotargeting of the two to the same APC. We have identified a tetanus toxin–derived B cell epitope that can mediate the formation of immune complexes in the presence of circulating Abs. In this study, we show that these immune complexes improve both Ag uptake by APCs (blood monocytes and CD1c⁺ dendritic cells) and consequently improve CD8⁺ T cell recall responses in a human ex vivo blood loop system. The uptake of the peptide conjugate by blood monocytes is dependent on Abs and the complement component C1q. We envision that this strategy can be used to facilitate active uptake of Ags into APCs to improve T cell responses against pathogens or cancer.

https://ift.tt/2MwowX7

The effects of DMARDs on the expression and function of P-gp, MRPs, BCRP in the treatment of autoimmune diseases

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Yi-jin Wu, Chun Wang, Wei Wei
The ATP-binding cassette (ABC) transporter family is a large class of ATP energy-dependent transmembrane proteins, and its primary function is to use the energy produced by ATP hydrolysis to transfer the substrate bound to the plasma membrane. This family is also closely related to multidrug resistance (MDR) in various diseases. Among the ABC transporter proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) are the main members associated with MDR. At present, the roles of these transporters in therapeutic failures have been extensively studied and reviewed in cancer; however, they have rarely been described in autoimmune diseases (AIDs). AID is a group of chronic inflammatory diseases of unknown aetiology. AID's basic feature is the production of a large number of autoantibodies, which leads to extensive damage to multiple systems and multiple organs. Disease-modifying anti-rheumatic drugs (DMARDs) are commonly used in the treatment of AID, but a considerable number of patients have no response or develop resistance to these drugs over time. This phenomenon may be related to the abnormal expression of the ABC transporter, which leads to a decrease in the amount of drug entering cells that produce MDR. This article reviews the effects of DMARDs on the expression and function of P-gp, MRPs, and BCRP and the related molecular mechanism in the treatment of AID.

Graphical abstract

https://ift.tt/2tkbuTA

Arsenic contamination, subsequent water toxicity, and associated public health risks in the lower Indus plain, Sindh province, Pakistan

Abstract

Arsenic (As) contamination in drinking water is a global public health risk. The present study highlighted the geological and anthropogenic causes of As contamination in groundwater (GW) and surface water (SW) and assessment of their potential health risks in Sindh province of Pakistan. Upon analyzing 720 GW and SW samples from 18 different sites, the estimates of As in groundwater and surface water was observed in the range of 0 to 125 and 0 to 35 μg/L with mean values of 46.8 and 15.43 μg/L respectively. Majority of the samples exceeded WHO permissible limit of As (10 μg/L) with higher concentration detected in groundwater samples compared to surface water. Moreover, both of these sample sources were found not potable based on physicochemical characteristics. The results of statistical analysis (correlation analysis, principal component analysis (PCA), and hierarchy cluster analysis (HCA)) indicate that natural mobilization of As in groundwater is believed to be enhanced by the pH-based reductive dissolution of iron hydroxide (FeOH) and competitive sorption of bicarbonate minerals in the presence of microorganisms along with evaporative enrichment while water logging, coal mining, and excessive use of pesticides are believed to be the anthropogenic causes of As enrichment. Furthermore, enormous health risk was associated with As in terms of chronic daily intake (CRI), hazard quotient (HQ), and cancer risk probability (CR) in GW and SW. Mean HQ values in GW were 4.47 mg/kg/day in adults and 3.89 mg/kg/day in children (standard HQ ≤ 1) and was 1.43 and 1.28 mg/kg/day in SW. Mean CR value in both GW and SW was found higher than the safe limit (10⁻⁶) having a mean of 2 × 10⁻³ in GW and 7 × 10⁻⁴ (mg/kg/day) in SW. These findings suggest that majority of the sampling sites carry serious public health risk due to high As values and hence demands exigent remedial and management measures.

https://ift.tt/2JYU3zk

Negative affect and past month binge eating may drive perceptions of loss of control

Publication date: 1 September 2018
Source:Appetite, Volume 128
Author(s): A.R. Bottera, A.M. Thiel, K.P. De Young
ObjectiveTo evaluate how subjective control over intake is influenced by objective aspects of consumption, negative affect, and recent binge eating.Method105 participants with or without current binge eating (BE) consumed a meal replacement shake following a 12-hour overnight fast in a 2 × 2 design: participants were instructed to either consume the entire shake (no control) or decide on their own how much to consume (affirmative control). They were allotted either 5 (fast) or 15 (slow) minutes to complete the task. Participants reported on subjective control and negative affect following consumption.ResultsCompared to the slow condition, participants in the fast condition reported higher negative affect after eating. Individuals without a history of BE reported lower subjective control in the no control compared to the affirmative control condition; however, this pattern was reversed among those with BE, such that individuals reported higher subjective control following consumption in the no control condition. In addition, subjective control was positively associated with negative affect in the no control condition whereas it was negatively associated with negative affect in the affirmative control condition.DiscussionEating rate influences affect, and subjective control over eating may be the result of an interaction of objective control with affect. Thus, distress may drive perceptions of control. This should be directly tested in future studies and has implications for how we understand BE.



https://ift.tt/2JM8g6p

No effect of focused attention whilst eating on later snack food intake: Two laboratory experiments

Publication date: 1 September 2018
Source:Appetite, Volume 128
Author(s): Victoria Whitelock, Suzanne Higgs, Jeffrey M. Brunstrom, Jason C.G. Halford, Eric Robinson
Focusing attention on food during a meal has been shown to reduce later snack consumption. We report the results of two studies that aimed to replicate this effect and to elucidate the underlying mechanisms. We hypothesised that focused attention during a lunchtime meal would improve visual memory and/or memory for the satiating effects of the meal, and that this would reduce later food intake. In Study 1, participants (N = 108, 52.8% female, BMI M = 25.75 kg/m²) were randomly allocated to eat a fixed lunchtime meal while listening to instructions that encouraged them to pay attention to the sensory properties of the meal (focused attention condition), or to one of two control conditions. To determine whether the effect of focused attention on later food intake is influenced by meal satisfaction, in a second study, participants (N = 147, 100% female, BMI M = 25.15 kg/m²) were given either a satisfying or dissatisfying lunch. In both studies, after 3 h participants ate snack food ad libitum and completed assessments of their memory for the recent lunch. In both studies there was no effect of focused attention on later food intake. In Study 2, the effect of focused attention on later food intake was not moderated by meal satisfaction. In both studies focused attention did not improve memory for the lunch meal. The present studies failed to replicate the effect of focused attention on later food intake and this may be because focused attention did not improve memory for the lunchtime meal. Further research should examine the conditions under which attention during eating influences memory encoding and food intake.



https://ift.tt/2JY48MX

Transcatheter Tricuspid Valve Interventions: Landscape, Challenges, and Future Directions

Abstract

Tricuspid regurgitation is a common finding in patients with left-sided valvular or myocardial disease, often being a marker for late-stage chronic heart failure with a grim prognosis. However, isolated tricuspid valve surgery remains infrequent and is associated with the highest mortality among all valve procedures. Hence, a largely unmet clinical need exists for less invasive therapeutic options in these patients. In recent times, multiple percutaneous therapies have been developed for treating severe tricuspid regurgitation, including tricuspid valve repair and, more recently replacement, opening an entirely new venue for managing tricuspid regurgitation. The aim of this review is to provide an updated overview and a clinical perspective on novel transcatheter tricuspid valve therapies, highlighting potential challenges and future directions.

https://ift.tt/2JXSzp1

Critical Appraisal of the 2018 ACC Scientific Sessions Late-Breaking Trials From a Statistician's Perspective

Abstract

The late-breaking clinical trials presentations at the American College of Cardiology Scientific Sessions in March 2018 are an important contribution to the field of cardiology. This paper presents a constructive critical appraisal of 7 key studies: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), VEST (Vest Prevention of Early Sudden Death Trial), SECURE-PCI (Statins Evaluation in Coronary Procedures and Revascularization), TREAT (Ticagrelor in Patients with ST-Elevation Myocardial Infarction treated with Pharmacological Thrombolysis), POISE (PeriOperative ISchemic Evaluation), SMART-DATE (Safety of 6-Month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome), and CVD-REAL 2 (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors). For each study, our aim is to document and interpret the main findings, noting particularly when "positive spin" appears to occur, and to provide a balanced account of each study, paying attention to both constructive new findings and study limitations. These topical examples also provide useful general insights on what to look for when critiquing clinical trial presentations and publications.

https://ift.tt/2t7yG8w

JACC Instructions for Authors

https://ift.tt/2JLQ50O

Myocardial Edema and Prognosis in Amyloidosis

AbstractBackground

Prognosis in light-chain (AL) and transthyretin (ATTR) amyloidosis is influenced by cardiac involvement. ATTR amyloidosis has better prognosis than AL amyloidosis despite more amyloid infiltration, suggesting additional mechanisms of damage in AL amyloidosis.

Objectives

The aim of the study was to assess the presence and prognostic significance of myocardial edema in patients with amyloidosis.

Methods

The study recruited 286 patients: 100 with systemic AL amyloidosis, 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 on ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid), 11 asymptomatic individuals with amyloidogenic TTR gene mutations, and 30 healthy volunteers. All subjects underwent cardiovascular magnetic resonance with T1 and T2 mapping and 16 underwent endomyocardial biopsy.

Results

Myocardial T2 was increased in amyloidosis with the degree of elevation being highest in untreated AL patients (untreated AL amyloidosis 56.6 ± 5.1 ms; treated AL amyloidosis 53.6 ± 3.9 ms; ATTR amyloidosis 54.2 ± 4.1 ms; each p < 0.01 compared with control subjects: 48.9 ± 2.0 ms). Left ventricular (LV) mass and extracellular volume fraction were higher in ATTR amyloidosis compared with AL amyloidosis while LV ejection fraction was lower (p < 0.001). Histological evidence of edema was present in 87.5% of biopsy samples ranging from 5% to 40% myocardial involvement. Using Cox regression models, myocardial T2 predicted death in AL amyloidosis (hazard ratio: 1.48; 95% confidence interval: 1.20 to 1.82) and remained significant after adjusting for extracellular volume fraction and N-terminal pro–B-type natriuretic peptide (hazard ratio: 1.32; 95% confidence interval: 1.05 to 1.67).

Conclusions

Myocardial edema is present in cardiac amyloidosis by histology and cardiovascular magnetic resonance T2 mapping. T2 is higher in untreated AL amyloidosis compared with treated AL and ATTR amyloidosis, and is a predictor of prognosis in AL amyloidosis. This suggests mechanisms additional to amyloid infiltration contributing to mortality in amyloidosis.

https://ift.tt/2tk3zFS

Troponin Release and Reversible Left Ventricular Dysfunction After Transient Pressure Overload

AbstractBackground

The authors previously demonstrated that brief ischemia elicits cardiac troponin I (cTnI) release and myocyte apoptosis in the absence of necrosis. It remains uncertain whether other pathophysiological stresses can produce apoptosis and transient cTnI release without ischemia.

Objectives

This study sought to determine whether a transient increase in left ventricular (LV) preload elicits cTnI release in the absence of ischemia.

Methods

Propofol-anesthetized swine (N = 13) received intravenous phenylephrine (PE) (300 μg/min) for 1 h to increase left ventricular end-diastolic pressure (LVEDP) to ~30 mm Hg. Serial cTnI and echocardiographic function were assessed for 24 h, and myocardial tissue was analyzed for apoptosis and necrosis.

Results

PE infusion increased systolic blood pressure from 137 ± 14 mm Hg to 192 ± 11 mm Hg (mean ± SD; p < 0.001) and increased LVEDP from 17 ± 2 mm Hg to 30 ± 5 mm Hg (p < 0.001). Myocardial flow measurements demonstrated no evidence of ischemia. Hemodynamics normalized rapidly after PE, but LV ejection fraction remained depressed (32 ± 21% vs. 58 ± 7%; p < 0.01) with normalization after 24 h (51 ± 16%; p = 0.31). Baseline transcoronary cTnI release was low (16 ± 20 ng/l) but increased to 856 ± 956 ng/l (p = 0.01) 1 h after LVEDP elevation. Circulating cTnI rose above the 99th percentile within 30 min and remained elevated at 24 h (1,462 ± 1,691 ng/l). Pathological analysis demonstrated myocyte apoptosis at 3 h (31.3 ± 11.9 myocytes/cm² vs. 4.6 ± 3.7 myocytes/cm²; p < 0.01), that normalized after 24 h (6.2 ± 5.6 myocytes/cm²; p = 0.46) without histological necrosis.

Conclusions

Transient elevations of LVEDP lead to cTnI release, apoptosis, and reversible stretch-induced stunning in the absence of ischemia. Thus, preload-induced myocyte injury may explain many cTnI elevations seen in the absence of clinical signs or symptoms of myocardial ischemia.

https://ift.tt/2tk3EcE

Protocol-Driven CI-AKI Prevention in the Cath Lab

https://ift.tt/2JNJVx1

Correction

https://ift.tt/2MEAKN8

Angioscopic Evaluation of Spontaneously Ruptured Aortic Plaques

AbstractBackground

Spontaneous ruptured aortic plaques (SRAP), which might cause atheromatous embolization, are thought to be mainly iatrogenic and have not been observed directly.

Objectives

The purpose of this study was to clarify the incidence, types, and dimensions of SRAP using angioscopy.

Methods

In a cross-sectional study, 324 consecutive patients diagnosed with or suspected of having coronary artery disease were subjected to intra-aortic scans with nonobstructive angioscopy. Samples of SRAP were taken from the aorta. The dimensions of cholesterol crystals of atheromatous materials were measured with a polarizing microscope and compared with those of the ghost images of cholesterol crystals.

Results

SRAP were detected in 262 patients (80.9%); 120 of 262 patients had ruptured aortic plaques below the diaphragmatic level. Samples were successfully obtained from 96 patients. The detected numbers of atheromatous material, fibrin, macrophage, and calcification were 237 (49.1%), 244 (50.6%), 111 (23.0%), and 127 (26.3%) out of 482 samples, respectively. The median lengths and widths of the sampled plaques were 254 μm (interquartile range [IQR]: 100 to 685 μm) and 148 μm (IQR: 535 to 423.5 μm), respectively. The lengths and widths of the cholesterol crystals isolated from atheromatous materials were 40 μm (IQR: 32.7 to 53.7 μm), and 30 μm (IQR: 23 to 38 μm), respectively, compared with the respective dimensions of the ghost images of 86 μm (IQR: 53 to 119) and 13 μm (IQR: 7 to 18 μm). No embolic symptoms were observed within 24 h of general care via cardiac catheterization.

Conclusions

SRAP are commonly scattered, and their dimensions were smaller than previously recognized. (Detecting Ruptured Aortic Plaques by Nonobstructive Angioscopy; UMIN000029772)

https://ift.tt/2ymvzi3

Unraveling the Mystery of Troponin Elevation in Heart Failure

https://ift.tt/2MAfdFC

Is Spontaneous Rupture of Aortic Plaques Truly More Common Than Believed?

https://ift.tt/2t4KvMO

Cardiovascular Magnetic Resonance in Cardiac Amyloidosis: T1 Is Not Enough

https://ift.tt/2t7yFS0

Correction

https://ift.tt/2tjfh3t

Cardio-Oncology for GenNext: A Missing Piece of the Training Puzzle

https://ift.tt/2JVBfAU

Geriatric Cardiology: Two Decades of Progress and Strategy for the Future

https://ift.tt/2tk3nGE

Additional Arterial Conduits in Coronary Artery Bypass Surgery: Finally Coming of Age

https://ift.tt/2MEBdPo

RESPONSE: A Call to Action for Established Cardio-Oncologists: Time to Train the Future

https://ift.tt/2MEB5iS

Noninvasive Assay for Donor Fraction of Cell-Free DNA in Pediatric Heart Transplant Recipients

https://ift.tt/2tjfFPt

Aortic Stenosis, Left Ventricular Remodeling, and Renin-Angiotensin System Blockade

https://ift.tt/2Myvr1P

Reply: Aortic Stenosis, Left Ventricular Remodeling, and Renin-Angiotensin System Blockade

https://ift.tt/2tjfwvp

Revascularization Strategies in Patients With Acute MI and Cardiogenic Shock

https://ift.tt/2t90ZDt

Androgen Receptor and Ki67 Expression and Survival Outcomes in Non-small Cell Lung Cancer

Abstract

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30–3.70; HR 1.92, 95% CI 1.07–3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31–4.36 for AR− Ki67+ vs HR 1.54, 95% CI 0.44–5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.

https://ift.tt/2JXt7Qn

The Optimal Dose of Sevoflurane Via Anaconda® in Post-operative Patient Underwent Head & Neck Surgery

Condition:   Patients Who Needs Sedation After Head & Neck Surgery
Interventions:   Procedure: Naso-tracheal group;   Procedure: tracheostomy group
Sponsor:   Yonsei University
Recruiting

https://ift.tt/2t40RVY

Postural Garment Versus Exercises for Women With Cervical Pain

Conditions:   Posture;   Cervical Pain
Interventions:   Other: Exercises;   Device: Posture garment
Sponsor:   University of Andorra
Recruiting

https://ift.tt/2M2pI3c

The Optimal Dose of Sevoflurane Via Anaconda® in Post-operative Patient Underwent Head & Neck Surgery

Condition:   Patients Who Needs Sedation After Head & Neck Surgery
Interventions:   Procedure: Naso-tracheal group;   Procedure: tracheostomy group
Sponsor:   Yonsei University
Recruiting

https://ift.tt/2t40RVY

Postural Garment Versus Exercises for Women With Cervical Pain

Conditions:   Posture;   Cervical Pain
Interventions:   Other: Exercises;   Device: Posture garment
Sponsor:   University of Andorra
Recruiting

https://ift.tt/2M2pI3c

Flexible glassy grid structure for rapid degradation of azo dye

Publication date: 5 October 2018
Source:Materials & Design, Volume 155
Author(s): R. Li, X.J. Liu, H. Wang, Y. Wu, K.C. Chan, Z.P. Lu
Degradation of organic contaminants in industrial wastewaters has become a worldwide conundrum and attracted extensive attention. In this paper, we report a flexible grid structure with uniform mesh fabricated by plain weaving melt-extracted Fe80B20 glassy micro-wires, and the produced wire grid with a dosage of 0.3 g/L can completely degrade 0.2 g/L DB 15 azo dyes for <30 min at room temperature. The calculated degradation efficiency of the sample is approximately 4.3 min, 2.1 times faster than that of the Fe80B20 glassy ribbons and 28 times for commercial pure Fe powders. The enhanced degradation performance is primarily attributed to the uniform grid structure with high internal surface area in addition to the intrinsic activity of metallic glasses. Our findings not only provide high-performance candidate for degrading and filtering wastewater with organic pollutant simultaneously, but also promote the practical applications of metallic glasses as functional materials.

Graphical abstract

https://ift.tt/2li1RS3

Data on eye movements in people with glaucoma and peers with normal vision

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): Daniel S. Asfaw, Pete R. Jones, Nicholas D. Smith, David P. Crabb
Eye movements of glaucoma patients have been shown to differ from age-similar control groups when performing everyday tasks, such as reading (Burton et al., 2012; Smith et al., 2014) [1,2], visual search (Smith et al., 2012) [3], face recognition (Glen et al., 2013) [4], driving, and viewing static images (Smith et al., 2012) [5]. Described here is the dataset from a recent publication in which we compared the eye-movements of 44 glaucoma patients and 32 age-similar controls, while they watched a series of short video clips taken from television programs (Crabb et al., 2018) [6]. Gaze was recorded at 1000 Hz using a remote eye-tracker. We also provide demographic information and results from a clinical examination of vision for each participant.



https://ift.tt/2lf6f3Z

Faculty commitment, effectiveness of job responsibilities and the moderating role of institutional support: A survey data set

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): H.O. Falola, O.A. Oludayo, D.M. Akinnusi, A.O. Osibanjo, O.P. Salau
The main objective of this paper is to present the data set which depicts faculty commitment and effectiveness of job responsibilities in a changing world and the moderating role of the university׳s support system. The population of the study consisted all the 1912 Faculty members of six selected private universities in Southwest, Nigeria [5]. The sample size determination formula by [5] was adopted, resulting in the selection of 400 respondents to whom a structured questionnaire was administered accordingly. Only 343 copies of the questionnaire were valid and used for this data set. Structural equation modeling, which combines factor analysis and multiple regression, was used to present the structural relationship between dependent and independent variables. When the data is analysed, it will help to determine the degree of relationship and the strength of significance between the observed variables and the latent constructs.



https://ift.tt/2ykF6WJ

Survey data on Vietnamese retail investors׳ trading behavior and their psychological and behavioral patterns

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): Thuy Chung Phan, Marc Oliver Rieger, Mei Wang
The data article describes self-assessments of 621 Vietnamese retail investors on their trading behavior, psychological attributes and socio-demographic characteristics. The dataset was obtained from a randomized survey of 3144 Vietnamese participants on financial attitudes and practice that has been used in Phan et al. [5]. A supplemental material data contains the full text, codes and numerical values of survey instruments. Discussion of theoretical frameworks and the development of hypothesis and measurement of survey variables are found in the associated research article [6].



https://ift.tt/2lfABTX

Comparative behavior between sunscreens based on free or encapsulated UV filters in term of skin penetration, retention and photo-stability

Publication date: 30 August 2018
Source:European Journal of Pharmaceutical Sciences, Volume 121
Author(s): Arianna C. Cozzi, Paola Perugini, Samuel Gourion-Arsiquaud
BackgroundThe growing incidence of photodamaging effects caused by UV radiation (e.g. sunburn, skin cancer) has increased the attention from health authorities which recommend the topical application of sunscreens to prevent these skin damages. The economic stakes for those companies involved in this international market are to develop new UV filters and innovative technologies to provide the most efficient, flexible and robust sunscreen products. Today the development of innovative and competitive sunscreen products is a complex formulation challenge. Indeed, the current sunscreens must protect against skin damages, while also being safe for the skin and being sensory and visually pleasant for the customers when applied on the skin. Organic UV filters, while proposing great advantages, also present the risk to penetrate the stratum corneum and diffuse into underlying structures with unknown consequences; moreover, their photo-stability are noted thorny outcomes in sunscreen development and subsequent performance. In recent years, the evaluation of the interaction between skin and sunscreen in terms of penetration after topical application has been considered from European authority but still its testing as their photo-stability assessment are not mandatory in most countries.ObjectiveThis study, based on in-vitro approaches, was performed to evaluate and compare the retention and the penetration of organic UV filters in free or encapsulated form inside the skin as well as their respective photo-stability.MethodsSunscreen formulation with a combination of Avobenzone and Octocrylene in "free form" and a formulation using the same UV filters but encapsulated in a sol-gel silica capsule, were analyzed and compared by FTIR Imaging Spectroscopy. Tape stripping method was used to investigate the penetration of these UV filters inside the stratum corneum. Their photo-stabilities were evaluated by spectroscopic measurements (FTIR, UV/Vis) and standard measurements were calculated: AUC (Area Under the Curve) and SPF (Sun Protection Factor).ResultWith traditional formulation, the organic UV filters penetrated significantly into the stratum corneum while the same UV filters combined with encapsulation technology remained on the skin surface. The encapsulation technology also improved significantly their stability.ConclusionEncapsulation technology is a promising strategy to improve the efficacy of sunscreen product using organic UV filters and to reduce safety problem. On the other hand, this study highlighted the pertinence of the FTIR Spectroscopy to test, compare and investigate sunscreen formulations.

Graphical abstract

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