Use of α2-Adrenergic Agonists to Improve Surgical Field Visibility in Endoscopy Sinus Surgery: A Systematic Review of Randomised Controlled Trials

Publication date: Available online 18 December 2017
Source:Clinical Therapeutics
Author(s): Maria Angeles Quijada-Manuitt, Yolanda Escamilla, Antonio Vallano, Alda Cardesín, Manuel Bernal-Sprekelsen, Caridad Pontes
PurposeWe assessed the evidence for the use of α2-adrenergic agonists (A2AAs) in bleeding control and field quality in endoscopic sinus surgery.MethodsWe systematically reviewed randomized clinical trials (RCTs) assessing A2AAs in endoscopic sinus surgery. Abstracts were reviewed by 2 investigators for eligibility, and selected articles were fully reviewed. Data on study design, population, A2AA drug and control groups, bleeding and surgical field quality outcomes, and adverse effects were extracted and synthesized.FindingsA total of 13 RCTs that included 896 individuals (7 double-blind trials, 5 single-blind trials, and 1 open-label trial) were selected that assessed the efficacy of clonidine (6 RCTs, 407 patients), dexmedetomidine (6 RCT, 423 patients), or both (1 RCT, 66 patients). Clonidine was compared with placebo (3 RCTs), midazolam (1 RCT), and remifentanil (2 RCTs). Dexmedetomidine was compared with esmolol (2 RCTs), remifentanil (2 RCTs), nitroglycerin and esmolol (1 RCT), and magnesium sulfate (1 RCT). Clonidine and dexmedetomidine were compared in 1 RCT. Clonidine reduced the proportion of individuals with an impaired surgical field by 23% vs placebo (number needed to treat = 4). Clonidine was better than midazolam and remifentanil in 2 trials, and dexmedetomidine was better than magnesium sulfate and esmolol in 2 trials but was not superior to esmolol, remifentanil, or nitroglycerin in 4 trials. Dexmedetomidine produced significantly better differences in bleeding outcomes versus clonidine. Adverse events were infrequent and mainly caused by hypotension or bradycardia.ImplicationsRCTs consistently report that A2AAs reduce bleeding and improve surgical field quality during endoscopic sinus surgery. Adverse event reporting was often omitted in RCTs. Well-designed RCTs with appropriate sample sizes are desirable to identify the best A2AAs and confirm their potential effects on clinical outcomes.



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Association between the clinical and histopathological classifications of actinic keratosis and the efficacy of topical imiquimod treatment

Abstract

We investigated the association between the clinical and histopathological classifications of actinic keratosis (AK) and the efficacy of topical imiquimod treatment. Forty patients (55 lesions) with AK were treated with topical 5% imiquimod and the efficacy of imiquimod for AK was evaluated based on the clinical/histopathological changes. The complete remission (CR) rates in patients with the different clinical classifications of AK were 85.4% (erythematous type) and 46.2% (hyperkeratotic type). The CR rates in the different histopathological classifications of AK were 80% (hypertrophic type), 81.8% (atrophic type) and 42.9% (bowenoid type). The results revealed that determining the clinical and histopathological type of AK was important for selecting a therapeutic method. The topical imiquimod treatment could be expected to be more effective for AK clinically classified as the erythematous type, or histopathologically classified as the atrophic or hypertrophic type. However, it would be expected to be less effective for the treatment of AK clinically classified as the hyperkeratotic type or histopathologically classified as the bowenoid type. Our observations suggest that we can predict the efficacy of topical imiquimod therapy in AK by determining its clinical and histopathological type.

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Purpura fulminans in congenital protein C deficiency successfully treated with fresh frozen plasma and thrombomodulin

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Case of subungual tumoral melanosis: The detection of melanoma cells and dermoscopic features

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Successful treatment with rituximab in a Japanese patient with systemic sclerosis-associated interstitial lung disease resistant to oral steroid and cyclophosphamide

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Diagnostic criteria, severity classification and guideline of lichen sclerosus et atrophicus

Abstract

We established diagnostic criteria and severity classification of lichen sclerosus et atrophicus, because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there is no clinical guideline for lichen sclerosus et atrophicus in Japan, so we proposed its clinical guideline. The clinical guidelines were formulated by clinical questions and recommendations on the basis of evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guidelines easy to use and reliable including the newest evidence, and to present guidance for various clinical problems in treatment of lichen sclerosus et atrophicus.

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Intraoral ultrasonography to measure tumor thickness of oral cancer: A systematic review and meta-analysis

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Thomas J.W. Klein Nulent, Rob Noorlag, Ellen M. Van Cann, Frank A. Pameijer, Stefan M. Willems, Adrian Yesuratnam, Antoine J.W.P. Rosenberg, Remco de Bree, Robert J.J. van Es
Early oral cancer is preferably treated by surgery. Its complete removal is essential for locoregional control and disease-free survival. Inadequate resection margins require adjuvant therapy such as re-resection or (chemo)radiation, that causes extra morbidity and oral discomfort. Intraoral ultrasonography (US) is reported to be of value in determining tumor thickness. Intraoperative visualization of the tumor may facilitate the resection and ensure adequate surgical margins. Furthermore, accurate prediction of tumor thickness could help determine the treatment strategy of the clinically node-negative neck, as thickness and depth of invasion are predictors of cervical metastasis as well as prognosticators of survival. The 8th edition of the American Joint Committee on Cancer staging system for oral squamous cell carcinoma has included depth of invasion as parameter for cT-stage. The aim of this review is to analyze the accuracy of intraoral US in determining tumor thickness in oral cancer.A systematic search was conducted, and the quality of the included papers was assessed using the QUADAS-2 tool for diagnostic accuracy studies. Subsequently, a meta-analysis was performed on the available individual participant data of 240 patients.Most of the twelve included studies focused on T1-2 tongue cancer (n = 129). Meta-analysis showed a high correlation in tumor thickness within this subgroup as measured by intraoral US and histopathology (r = 0.82, p < .001), with minor overestimation of 0.5 mm on US. It is concluded that intraoral US is very accurate in determining tumor thickness in early oral tongue cancer.



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Postoperative staging of the neck dissection using extracapsular spread and lymph node ratio as prognostic factors in HPV-negative head and neck squamous cell carcinoma patients

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Katarina Majercakova, Cristina Valero, Montserrat López, Jacinto García, Nuria Farré, Miquel Quer, Xavier León
ObjectivesThe presence of nodes with extracapsular spread (ECS) and the lymph node ratio (LNR) have prognostic competence in the pathologic evaluation of patients with a head and neck squamous cell carcinoma (HNSCC) treated with a neck dissection. The purpose of this study is to assess the effect of ECS & LNR on prognosis of HPV negative HNSCC patients treated with neck dissection and to compare to 8th edition TNM/AJCC classification.Materials and methodsWe carried out a retrospective study of 1383 patients with HNSCC treated with a neck dissection between 1985 and 2013. We developed a classification of the patients according to the presence of nodes with ECS and the LNR value with a recursive partitioning analysis (RPA) model.ResultsWe obtained a classification tree with four terminal nodes: for patients without ECS (including patients pN0) the cut-off point for LNR was 1.6%, while for patients with lymph nodes with ECS it was 11.4%. The 5-year disease-specific survival for patients without ECS/LNR < 1.6% was 83.3%; for patients without ECS/LNR ≥ 1.6% it was 61.5%; for patients with ECS/LNR < 11.4% it was 33.7%; and for patients with ECS/LNR ≥ 11.4% it was 18.5%. The classification obtained with RPA had better discrimination between categories than the 8th edition of the TNM/AJCC classification.ConclusionECS status and LNR value proved high prognostic capacity in the pathological evaluation of the neck dissection. The combination of ECS and LNR improved the predictive capacity of the 8th edition of the TNM/AJCC classification in HPV-negative HNSCC patients.



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The Investigated Question and Study Design in Cross-sectional Studies Response to “Chronic Urticaria and the Metabolic Syndrome: a Cross-sectional Community-based Study of 11,261 Patients” Authors Reply

We read with interest the letter by Soria et al. We have been studying Chronic Urticaria (CU) for several years. During this time, we have evaluated the disease and associated conditions from several aspects. The study presented by Soria et al. compared the severity of CU between a small group of obese CU patients and another small group of non-obese CU patients, all recruited in inpatient clinics of a hospital setting.

This article is protected by copyright. All rights reserved.

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Two novel mutations in the TSC2 gene causing severe phenotype in nervous system and skin in a patient with tuberous sclerosis complex

Tuberous sclerosis complex (TSC1, OMIM 191100 and TSC2 OMIM 613254) is an autosomal dominant neurocutaneous disorder that affects multiple organs, associated with the development of wide spread hamartomatous lesions including brain, eyes, lungs, heart, liver, kidneys and skin. Mutations in the tumor suppressor genes, TSC1 at 9q34 and TSC2 at 16p13.3, which encode the proteins hamartin and tuberin respectively, detected in approximately 85-90% of the cases. The majority of cases occur sporadically, with a family history found in only 30% of patients.

This article is protected by copyright. All rights reserved.

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Hyperkalzämie

Zusammenfassung

Die Hyperkalzämie stellt ein häufiges klinisches Problem dar. Normalerweise ist die Kalziumkonzentration im Blutserum streng reguliert. Eine Hyperkalzämie tritt auf, wenn das Gleichgewicht zwischen intestinaler Kalziumaufnahme, renaler Kalziumexkretion und ossärem Kalziumstoffwechsel gestört ist. Der erste Schritt in der Evaluation der Hyperkalzämie besteht darin, diese durch eine wiederholte Messung zu bestätigen. Zusätzlich sollten Albumin und Eiweiß bestimmt werden, um ein korrigiertes Kalzium zu berechnen. Der nächste diagnostische Schritt ist die Messung des Serumparathormons, um zwischen einer nebenschilddrüsenbedingten und einer nicht nebenschilddrüsenbedingten Form zu unterscheiden. Bei den nebenschilddrüsenbedingten Hyperkalzämien stellt der primäre Hyperparathyreoidismus (PHPT) die mit Abstand häufigste Form dar. Ein symptomatischer PHPT sollte, wenn möglich, operativ saniert werden. Ein niedriger Wert (<20 pg/ml) für das intakte Parathormon (PTH) spricht hingegen für das Vorliegen einer nicht nebenschilddrüsenbedingten Hyperkalzämie. In einem solchen Fall empfiehlt sich die Bestimmung von Parathormon-related Protein (PTHrP) sowie der Vitamin-D-Metaboliten. In der überwiegenden Mehrzahl der Fälle mit dieser Konstellation liegt eine tumorbedingte Hyperkalzämie vor. 80–90 % aller Hyperkalzämien sind durch einen PHPT oder eine Tumorhyperkalzämie bedingt, während viele andere Ursachen entsprechend selten sind. Ist keine Operation beim PHPT gewünscht oder handelt es sich um eine Tumorhyperkalzämie, stehen medikamentöse Therapieformen zur Verfügung.

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Endoscopic transpterygoid approach to a mass in a child

Publication date: Available online 18 December 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Dong Hoon Lee, Hee Jo Baek, Tae Mi Yoon, Joon Kyoo Lee, Sang Chul Lim
The endoscopic transterygoid approach to the petrous apex is a feasible/alternative approach in carefully selected patients with specific favorable anatomy, even children. This approach, unlike traditional approaches, spares cochlear and vestibular function. We report a case of a six-year-old boy with embryonal rhabdomyosarcoma of the petrous apex that was diagnosed via the endoscopic transpterygoid approach.



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Editors, contents and cover information

Publication date: January 2018
Source:Trends in Biochemical Sciences, Volume 43, Issue 1





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TCR Signaling: Mechanisms of Initiation and Propagation

Publication date: Available online 18 December 2017
Source:Trends in Biochemical Sciences
Author(s): Adam H. Courtney, Wan-Lin Lo, Arthur Weiss
The mechanisms by which a T cell detects antigen using its T cell antigen receptor (TCR) are crucial to our understanding of immunity and the harnessing of T cells therapeutically. A hallmark of the T cell response is the ability of T cells to quantitatively respond to antigenic ligands derived from pathogens while remaining inert to similar ligands derived from host tissues. Recent studies have revealed exciting properties of the TCR and the behaviors of its signaling effectors that are used to detect and discriminate between antigens. Here we highlight these recent findings, focusing on the proximal TCR signaling molecules Zap70, Lck, and LAT, to provide mechanistic models and insights into the exquisite sensitivity and specificity of the TCR.



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Forecasting Faces in the Cortex

Publication date: Available online 18 December 2017
Source:Trends in Cognitive Sciences
Author(s): Lucy S. Petro, Lars Muckli
Although theories of predictive coding in the brain abound, we lack key pieces of neuronal data to support these theories. Recently, Schwiedrzik and Freiwald found neurophysiological evidence for predictive codes throughout the face-processing hierarchy in macaque cortex. We highlight how these data enhance our knowledge of cortical information processing, and the impact of this more broadly.



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Alterations in comprehensive geriatric assessment decrease survival of elderly patients with cancer

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): M. Frasca, P. Soubeyran, C. Bellera, M. Rainfray, K. Leffondre, S. Mathoulin-Pélissier
IntroductionA comprehensive geriatric assessment (CGA) evaluating several domains of health is recommended for elderly patients with cancer. Effects of altered domains on the risk of death in this population need to be clarified. The aim of this study was to estimate the independent association of each CGA domain to overall survival (OS).MethodPatients included in the ONCODAGE cohort completed a CGA at baseline. Cox models (one per domain) estimated the hazard ratio (HR) of death for each CGA domain. Directed Acyclic Graphs (DAGs) selected specific sets of adjustment factors for each model.ResultsThe analysis included 1264 patients (mean age: 78 years, women: 70%). Median follow-up was 5.2 years, and 446 patients died. Each altered domain had a detrimental effect on survival, sometimes dependent on gender, age, education or time from inclusion. Nutritional status had a time-varying effect, with higher mortality rates if altered only within the first 3 years of follow-up. In case of altered mobility, the risk of death was higher only for the youngest patients and, in case of altered autonomy, only for the youngest women. An altered neurological state led to higher mortality rates; this effect increased with the level of education. Patients with altered psychological status or more than four comorbidities at baseline had also higher mortality rates.ConclusionsPatients with an altered CGA domain have a higher risk of death than those without any alteration. The effect of some alterations is different in some subgroups or at a given time of the treatments.



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A randomised phase II trial of docetaxel versus docetaxel plus carboplatin in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Esther W. Bouman-Wammes, H. Pieter van den Berg, Linda de Munck, Aart Beeker, Carolien H. Smorenburg, Walter L. Vervenne, Juleon L.L.M. Coenen, Henk M.W. Verheul, Winald R. Gerritsen, Alfons J.M. Van den Eertwegh
BackgroundDocetaxel is standard first-line chemotherapy for patients with metastatic castration–resistant prostate carcinoma (mCRPC). Docetaxel re-challenge has never been tested in a prospective randomised controlled study. As some studies support the addition of carboplatin to docetaxel, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel re-treatment in docetaxel pre-treated mCRPC patients.MethodsPatients with mCRPC with a progression-free interval of ≥3 months after initial docetaxel treatment were randomised between docetaxel 75 mg/m² or docetaxel 60 mg/m² plus carboplatin AUC4. The primary end-point was progression-free survival (PFS; PSA/RECIST).ResultsOwing to insufficient recruitment, the study was discontinued early after inclusion of 75 patients (targeted 150) PFS and overall survival (OS) were comparable between both groups (median PFS 12.7 months (95% CI 9.9–17.5 months) with docetaxel monotherapy and 11.7 months (95% CI 8.5–21.0 months) with combination therapy (p = 0.98); OS 18.5 months (95% CI 11.8–24.5 months) versus 18.9 months (95% CI 16.0–23.7 months) (p = 0.79). An interim analysis (SEQTEST) showed that the null hypothesis could already be excepted, and no significant difference between both study arms was expected if inclusion would be completed. The incidence of grade 3–4 infections and gastrointestinal side-effects was numerical higher in the carboplatin arm (p = 0.056).ConclusionThis early terminated study suggests no benefit from the addition of carboplatin to docetaxel re-treatment in patients with mCRPC, whereas the combination resulted in more toxicity. Re-treatment with docetaxel monotherapy appears to be feasible, save and effective for patients with mCRPC and an initial good response to docetaxel.Trial registrationNTR3070.



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Timing of tracheostomy in patients with prolonged endotracheal intubation: a systematic review

Abstract

The objective of this article is to evaluate the appropriate timing of tracheostomy in patients with prolonged intubationregarding the incidence of hospital-acquired pneumonia, mortality, length of stay in intensive care unit (ICU) and duration of artificial ventilation. The study included published articles yielded by a search concerning timing of tracheostomy in adult and pediatric patients with prolonged intubation. The search was limited to articles published in English language in the last 30 years (between 1987 and 2017). For the 690 relevant articles, we applied our inclusion and exclusion criteria and only 43 articles were included. 41 studies in the adult age group including 222,501 patients and 2 studies in pediatric age group including 140 patients met our criteria. Studies in adult age group were divided into three groups according to the methodology of determining the cut off timing for early tracheostomy, they were divided into studies that considered early tracheostomy within the first 7, 14 or 21 days of endotracheal intubation, while in pediatric age group the cut off timing for early tracheostomy was within the first 7 days of endotracheal intubation. There was a significant difference in favor of early tracheostomy in adults' three groups and pediatric age group as early tracheostomy was superior regarding reduced duration of mechanical ventilation, with less mortality rates and less duration of stay in ICU. Regarding hospital-acquired pneumonia, it was significantly less in adult groups but with no significant difference in pediatric age group (3 patients out of 72 pediatric patient with early tracheostomy had pneumonia compared to 11 patients out of 68 with late tracheostomy). Studies defining early tracheostomy as that done within 7 days of intubation had better results than those defining early tracheostomy as that done within 14 or 21 days of intubation. In conclusion, early tracheostomy within 7 days of intubation should be done for both adults and pediatric patients with prolonged intubation.

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YouTube as a source of information on skin bleaching: a content analysis

Summary

Background

Skin bleaching is a common, yet potentially harmful body modification practice.

Aim

To describe the characteristics of the most widely viewed YouTube™ videos related to skin bleaching.

Methods

The search term 'skin bleaching' was used to identify the 100 most popular English-language YouTube videos relating to the topic. Both descriptive and specific information were noted.

Results

Among the 100 manually coded skin-bleaching YouTube videos in English, there were 21 consumer-created videos, 45 internet-based news videos, 30 television news videos and 4 professional videos. Excluding the 4 professional videos, we limited our content categorization and regression analysis to 96 videos. Approximately 93% (89/96) of the most widely viewed videos mentioned changing how you look and 74% (71/96) focused on bleaching the whole body. Of the 96 videos, 63 (66%) of videos showed/mentioned a transformation. Only about 14% (13/96) mentioned that skin bleaching is unsafe. The likelihood of a video selling a skin bleaching product was 17 times higher in internet videos compared with consumer videos (OR = 17.00, 95% CI 4.58–63.09, P < 0.001). Consumer-generated videos were about seven times more likely to mention making bleaching products at home compared with internet-based news videos (OR = 6.86, 95% CI 1.77–26.59, P < 0.01).

Conclusions

The most viewed YouTube video on skin bleaching was uploaded by an internet source. Videos made by television sources mentioned more information about skin bleaching being unsafe, while consumer-generated videos focused more on making skin-bleaching products at home.

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Methylglyoxal displays colorectal cancer-promoting properties in the murine models of azoxymethane and CT26 isografts

Publication date: Available online 18 December 2017
Source:Free Radical Biology and Medicine
Author(s): Jer-An Lin, Chi-Hao Wu, Gow-Chin Yen
Methylglyoxal (MG), a highly reactive carbonyl species (RCS) with pro-oxidant and proinflammatory properties, may be a colon tumor-promoting factor in food and biological systems. In the present study, we found that consumption of MG significantly deteriorated azoxymethane (AOM)-induced colonic preneoplastic lesions in ICR mice, in which biomarkers of oxidative stress and inflammation within the body and feces induced by MG-fueled carbonyl stress may have played important roles. Interestingly, exposure to MG also led to increases in the serum low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio and fecal bile acid levels in mice, which may be critical factors involved in MG-induced colonic lesions. Additionally, MG treatment (50mg/kg body weight (BW); intraperitoneally) promoted tumor growth of CT26 isografts in mice partly by carbonyl stress-evoked protumorigenic responses, including low-grade inflammation and oxidative stress. Furthermore, primary tumor cells isolated from mice with MG-induced CT26 isografts had greater proliferative and migratory activities as well as stem-like properties compared to those isolated from the vehicle controls. Excitingly, enhanced expression or activation of proteins that modulate cell survival, proliferation, or migration/invasion was also observed in those cells. In conclusion, it is conceivable that MG-induced carbonyl stress may be the pivotal promoter involved in colon cancer progression.

Graphical abstract

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PKCδ-dependent p47phox activation mediates methamphetamine-induced dopaminergic neurotoxicity

Publication date: Available online 18 December 2017
Source:Free Radical Biology and Medicine
Author(s): Duy-Khanh Dang, Eun-Joo Shin, Dae-Joong Kim, Hai-Quyen Tran, Ji Hoon Jeong, Choon-Gon Jang, Ole Petter Ottersen, Seung-Yeol Nah, Jau-Shyong Hong, Toshitaka Nabeshima, Hyoung-Chun Kim
Protein kinase C (PKC) has been recognized to activate NADPH oxidase (PHOX). However, the interaction between PKC and PHOX in vivo remains elusive. Treatment with methamphetamine (MA) resulted in a selective increase in PKCδ expression out of PKC isoforms. PKCδ co-immunoprecipitated with p47phox, and facilitated phosphorylation and membrane translocation of p47phox. MA-induced increases in PHOX activity and reactive oxygen species were attenuated by knockout of p47phox or PKCδ. In addition, MA-induced impairments in the Nrf-2-related glutathione synthetic system were also mitigated by knockout of p47phox or PKCδ. Glutathione-immunoreactivity was co-localized in Iba-1-labeled microglial cells and in NeuN-labeled neurons, but not in GFAP-labeled astrocytes, reflecting the necessity for self-protection against oxidative stress by mainly microglia. Buthionine-sulfoximine, an inhibitor of glutathione biosynthesis, potentiated microglial activation and pro-apoptotic changes, leading to dopaminergic losses. These neurotoxic processes were attenuated by rottlerin, a pharmacological inhibitor of PKCδ, genetic inhibitions of PKCδ [i.e., PKCδ knockout mice (KO) and PKCδ antisense oligonucleotide (ASO)], or genetic inhibition of p47phox (i.e., p47phox KO or p47phox ASO). Rottlerin did not exhibit any additive effects against the protective activity offered by genetic inhibition of p47phox. Therefore, we suggest that PKCδ is a critical regulator for p47phox activation induced by MA, and that Nrf-2-dependent GSH induction via inhibition of PKCδ or p47phox, is important for dopaminergic protection against MA insult.

Graphical abstract

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NADPH Oxidase 4 and Endothelial Nitric Oxide Synthase Contribute to Endothelial Dysfunction Mediated by Histone Methylations in Metabolic Memory

Publication date: Available online 18 December 2017
Source:Free Radical Biology and Medicine
Author(s): Yunfei Liao, Luoning Gou, Lulu Chen, Xueyu Zhong, Dongxue Zhang, Hangang Zhu, Xiaodan Lu, Tianshu Zeng, Xiuling Deng, Yuming Li
"Metabolic memory" is identified as a phenomenon that transient hyperglycemia can be remembered by vasculature for quite a long term even after reestablishment of normoglycemia. NADPH oxidases (Noxs) and endothelial nitric oxide synthase (eNOS) are important enzymatic sources of reactive oxygen species (ROS) in diabetic vasculature. The aim of this study is to explore the roles of epigenetics and ROS derived from Noxs and eNOS in the metabolic memory. In this study, we demonstrated that vascular ROS was continuously activated in endothelium induced by transient high glucose, as well as sustained vascular endothelial dysfunction. The Nox4 and uncoupled eNOS are the major sources of ROS, while inhibition of Nox4 and eNOS significantly attenuated oxidative stress and almost recovered the endothelial function in metabolic memory. Furthermore, the aberrant histone methylation (H3K4me1, H3K9me2, and H3K9me3) at promoters of Nox4 and eNOS are the main causes for the persistent up-regulation of these two genes. Modifying the histone methylation could reduce the expression levels of Nox4 and eNOS, thus obviously attenuating endothelial dysfunction. These results indicate that histone methylation of Nox4 and eNOS play a key role in metabolic memory and may be the potential intervention targets for metabolic memory.

Graphical abstract

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Detection of Intra-Articular Screw Penetration of Proximal Humerus Fractures

Publication date: Available online 18 December 2017
Source:Academic Radiology
Author(s): Xiaoyang Jia, Yanxi Chen, Minfei Qiang, Kun Zhang, Haobo Li, Yuchen Jiang, Yijie Zhang
Rationale and ObjectiveScrew penetration is the common complication of proximal humerus fractures treated with locking plates. This study compared postoperative plain radiography to computed tomography (CT) for their abilities in determining screw penetration, and was to evaluate whether advanced imaging modalities (two-dimensional [2D] CT; three-dimensional [3D] CT) could increase surgeons' level of confidence regarding their diagnoses.Materials and MethodsTwo observers reviewed radiological images of 134 patients who sustained proximal humerus fractures treated with locking plates. The observers were asked to answer two questions: (1) Is there screw penetrating into glenohumeral joint for this patient (Yes/No)? and (2) On a scale from 0 to 10, how confident are you about this diagnosis: (0–10) (0 = not at all confident; 10 = very confident)? Three evaluations were performed: (1) plain radiography alone, (2) radiography and 2D CT 4 weeks later, and (3) radiography in combination with 2D and 3D CT after that. This process was then repeated for intraobserver analysis.ResultsCT obtained almost perfect interobserver and intraobserver agreement (0.818–0.961), which was higher than radiography (0.377–0.655). For incidence of screw penetration, the significant difference was found between radiographs and CT images (P < .0125), but not between 2D and 3D CT images (P > .05). For confidence of diagnosis, the differences between imaging modalities were significant (all P < .001).ConclusionsWe suggest that postoperative CT scans (especially 3D CT images) should be used to evaluate the intra-articular screw penetration of proximal humerus fractures, especially when surgeons have not enough confidence in determining screw penetration using radiography alone.



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Ambient nanoparticles/nanominerals and hazardous elements from coal combustion activity: implications on energy challenges and health hazards

Publication date: Available online 18 December 2017
Source:Geoscience Frontiers
Author(s): Binoy K. Saikia, Jyotilima Saikia, ShahadevRabha, Luis F.O. Silva, Robert Finkelman
Coal is the most abundant fossil fuel in the world. Because of the growth of coal mining, coal-fired power plants, and coal-burning industries the increase of the emission of particulates (coarse, fine or ultrafine) is of great concern. There is a relationship between increasing human morbidity and mortality and progressive environmental air pollution caused by these types of particles. Thus, the knowledge of the physico-chemical composition and ambient concentrations of coal-derived nanoparticles will improve pollution control strategy. Given the current importance of this area of research, the advanced characterization of this coal combustion-derived nanoparticles/nanominerals as well as hazardous elements is likely to be one of the hottest research fields in coming days. In this review, we try to compile the existing knowledge on coal-derived nanoparticles/nanominerals and discuss the advanced level of characterization techniques for future research. This review also provides some of aspects of health risks associated with exposure to ambient nanoparticles. In addition, the presence of some of the hazardous elements in coal and coal combustion activities is also reviewed.

Graphical abstract

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Tinea capitis mimicking dissecting cellulitis in three children

Abstract

Tinea capitis mimicking dissecting cellulitis is a rare presentation, and there is a paucity of information regarding this presentation in the literature. Three children 10-14 years of age who presented with an unusual clinical manifestation of tinea capitis that clinically resembled dissecting cellulitis are reported. The patients were treated with systemic antifungals for 3-4 months. Treatment success was measured according to repeat fungal cultures and clinical assessment of hair regrowth at follow-up visits. All three patients had resolution of infection, with negative repeat fungal cultures and complete hair regrowth without scarring. These cases highlight a rare inflammatory subtype of tinea capitis that can be easily misdiagnosed and therefore improperly treated, prolonging the duration of infection.

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Building a state space for song learning

Publication date: April 2018
Source:Current Opinion in Neurobiology, Volume 49
Author(s): Emily Lambert Mackevicius, Michale Sean Fee
The songbird system has shed light on how the brain produces precisely timed behavioral sequences, and how the brain implements reinforcement learning (RL). RL is a powerful strategy for learning what action to produce in each state, but requires a unique representation of the states involved in the task. Songbird RL circuitry is thought to operate using a representation of each moment within song syllables, consistent with the sparse sequential bursting of neurons in premotor cortical nucleus HVC. However, such sparse sequences are not present in very young birds, which sing highly variable syllables of random lengths. Here, we review and expand upon a model for how the songbird brain could construct latent sequences to support RL, in light of new data elucidating connections between HVC and auditory cortical areas. We hypothesize that learning occurs via four distinct plasticity processes: 1) formation of 'tutor memory' sequences in auditory areas; 2) formation of appropriately-timed latent HVC sequences, seeded by inputs from auditory areas spontaneously replaying the tutor song; 3) strengthening, during spontaneous replay, of connections from HVC to auditory neurons of corresponding timing in the 'tutor memory' sequence, aligning auditory and motor representations for subsequent song evaluation; and 4) strengthening of connections from premotor neurons to motor output neurons that produce the desired sounds, via well-described song RL circuitry.



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Engineered cell and tissue models of pulmonary fibrosis

Publication date: Available online 18 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Aswin Sundarakrishnan, Ying Chen, Lauren D. Black, Bree B. Aldridge, David L. Kaplan
Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3 years' post diagnosis. Treatments for IPF are limited to two FDA approved treatments, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre-clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis.

Graphical abstract

http://ift.tt/2AXMLXN

Recognized Outstanding Reviewers for Circulation in 2017.

Author: Hill, Joseph A. MD, PhD; de Lemos, James A. MD; McGuire, Darren K. MD, MHSc; on behalf of the Circulation Editors Team

Page: 2399

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Absence of an Ideal Observer II: The Agonizing Search for Experts Without a Conflict of Interest.

Author: Packer, Milton MD

Page: 2400-2402

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Embolic Stroke.

Author: Ntaios, George MD; Hart, Robert G. MD

Page: 2403-2405

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Radiation-Induced DNA Damage in Operators Performing Endovascular Aortic Repair.

Author: El-Sayed, Tamer *,; Patel, Ashish S. PhD *,; Cho, Jun S.; Kelly, James A.; Ludwinski, Francesca E. PhD; Saha, Prakash PhD; Lyons, Oliver T. PhD; Smith, Alberto PhD; Modarai, Bijan PhD; Guy's and St Thomas' Cardiovascular Research Collaborative; Tyrrell, M; Gkoutzios, P; Abisi, S; Black, S; Zayed, H; Bell, RE; Sallam, M; Biasi, L; Patel, SD; Donati, T; Dialynas, M; Sandford, B; Redwood, S; Perera, S; Pavlidis, A; Prendergast, B; Gill, J

Page: 2406-2416

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Health Risks of Ionizing Radiation: Dr Roentgen Today.

Author: Chambers, Charles E. MD

Page: 2417-2419

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Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy.

Author: Rowin, Ethan J. MD; Hausvater, Anais MD; Link, Mark S. MD; Abt, Patrick MD; Gionfriddo, William MD; Wang, Wendy MPH; Rastegar, Hassan MD; Estes, N. A. Mark MD; Maron, Martin S. MD; Maron, Barry J. MD

Page: 2420-2436

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Atrial Fibrillation in Hypertrophic Cardiomyopathy: New Light on an Old Problem.

Author: Spirito, Paolo MD

Page: 2437-2439

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Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Author: Bohula, Erin A. MD, DPhil; Wiviott, Stephen D. MD; Giugliano, Robert P. MD, SM; Blazing, Michael A. MD; Park, Jeong-Gun PhD; Murphy, Sabina A. MPH; White, Jennifer A. MS; Mach, Francois MD; Van de Werf, Frans MD, PhD; Dalby, Anthony J. MD, DPhil, MB, ChB; White, Harvey D. DSc; Tershakovec, Andrew M. MD, MPH; Cannon, Christopher P. MD; Braunwald, Eugene MD

Page: 2440-2450

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Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2.

Author: Caruso, Paola PhD; Dunmore, Benjamin J. PhD; Schlosser, Kenny PhD; Schoors, Sandra MSc, PhD; Dos Santos, Claudia PhD; Perez-Iratxeta, Carol PhD; Lavoie, Jessie R. PhD; Zhang, Hui MD, PhD; Long, Lu PhD; Flockton, Amanda R. BS; Frid, Maria G. PhD; Upton, Paul D. PhD; D'Alessandro, Angelo PhD; Hadinnapola, Charaka MA, MB BChir; Kiskin, Fedir N. MRes; Taha, Mohamad BSc; Hurst, Liam A. PhD; Ormiston, Mark L. PhD; Hata, Akiko PhD; Stenmark, Kurt R. MD; Carmeliet, Peter MD, PhD; Stewart, Duncan J. MD *,; Morrell, Nicholas W. MD *,

Page: 2451-2467

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Cardiac Imaging in Patients With Ventricular Tachycardia.

Author: Mahida, Saagar MD, PhD; Sacher, Frederic MD, PhD; Dubois, Remi PhD; Sermesant, Maxime PhD; Bogun, Frank MD; Haissaguerre, Michel MD; Jais, Pierre MD; Cochet, Hubert MD, PhD

Page: 2491-2507

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Pyruvate Kinase and Warburg Metabolism in Pulmonary Arterial Hypertension: Uncoupled Glycolysis and the Cancer-Like Phenotype of Pulmonary Arterial Hypertension.

Author: Archer, Stephen L. MD

Page: 2486-2490

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Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis.

Author: Zhang, Hui MD, PhD; Wang, Daren PhD; Li, Min PhD; Plecita-Hlavata, Lydie PhD; D'Alessandro, Angelo PhD; Tauber, Jan PhD; Riddle, Suzette PhD; Kumar, Sushil PhD; Flockton, Amanda BS; McKeon, B. Alexandre MS; Frid, Maria G. PhD; Reisz, Julie A. PhD; Caruso, Paola PhD; El Kasmi, Karim C. MD, PhD; Jezek, Petr PhD; Morrell, Nicholas W. MD; Hu, Cheng-Jun PhD; Stenmark, Kurt R. MD

Page: 2468-2485

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Efforts Aim to Promote Safer Anticoagulant Prescribing.

Author: Kuehn, Bridget M.

Page: 2508-2509

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Highlights From the Circulation Family of Journals.

Author:

Page: 2510-2515

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Low-Dose Exposure to Ionizing Radiation Deregulates the Brain-Specific MicroRNA-134 in Interventional Cardiologists.

Author: Borghini, Andrea MSc, PhD; Vecoli, Cecilia MSc, PhD; Mercuri, Antonella MSc; Carpeggiani, Clara MD; Piccaluga, Emanuela MD; Guagliumi, Giulio MD; Picano, Eugenio MD, PhD; Andreassi, Maria Grazia MSc, PhD

Page: 2516-2518

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Left Ventricular Hypertrophy Revisited: Cell and Matrix Expansion Have Disease-Specific Relationships.

Author: Treibel, Thomas A. PhD *,,; Kozor, Rebecca PhD *,; Menacho, Katia MD; Castelletti, Silvia MD; Bulluck, Heerajnarain PhD; Rosmini, Stefania MD; Nordin, Sabrina MD; Maestrini, Viviana MD; Fontana, Marianna PhD; Moon, James C. MD

Page: 2519-2521

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Letter by Farina Regarding Article, "A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative".

Author: Farina, Alberto PharmD

Page: 2522-2523

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Response by Hess and Hiatt to Letter Regarding Article, "A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative".

Author: Hess, Connie N. MD, MHS; Hiatt, William R. MD

Page: 2524-2525

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Letter by Jin-Shan and Xue-Bin Regarding Article, "Out-of-Hospital Cardiac Arrest: An Underlying Reversible Cause".

Author: Jin-Shan, He MD; Xue-Bin, Li MD

Page: 2526

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Response by Derkenne et al Regarding Article, "Out-of-Hospital Cardiac Arrest: An Underlying Reversible Cause".

Author: Derkenne, Clement MD; Jost, Daniel MD; Robert, Jimmy MD; Tourtier, Jean-Pierre PhD; On behalf of the Paris Fire Brigade Cardiac Task Force

Page: 2527-2528

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The dynamic engram: fear memories and the basolateral amygdala

Publication date: Available online 18 December 2017
Source:Brain Research Bulletin
Author(s): Patrick Davis, Leon G. Reijmers
Great progress is being made in our understanding of how the brain stores and retrieves memories, which is exemplified by continuous discoveries of novel spatial and temporal components of so-called memory engrams. These discoveries have led to the realization that engrams are controlled by complex spatiotemporal dynamics across scales that span from molecules to brain regions, and from milliseconds to years. Moreover, it is now clear that across the lifetime of an engram, many of its spatial and temporal properties are not fixed, but instead change in complex ways. The dynamic nature of engrams is especially relevant in the case of fear memories, whose contributions to an animal's fitness depend on a delicate balance of stability and flexibility. Though most fear memories last a lifetime for an obvious reason, their expression also needs to be highly regulated to prevent the maladaptive behavior caused by anxiety disorders. To achieve the right balance of stability and flexibility, fear engrams are subjected to complex spatiotemporal dynamics, making them informative examples of the "dynamic engram". This review will focus on the contributions of the basolateral amygdala (BLA) to the dynamic properties of fear engrams.



http://ift.tt/2yUhaVj

Monitoring biocalcification potential of Lysinibacillus sp. isolated from alluvial soils for improved compressive strength of concrete

Publication date: Available online 18 December 2017
Source:Microbiological Research
Author(s): Rajneesh Vashisht, Sampan Attri, Deepak Sharma, Abhilash Shukla, Gunjan Goel
The present study reports the potential of newly isolated calcite precipitating bacteria isolated from alluvial soil to improve the strength and durability of concrete. A total of sixteen samples of alluvial soil and sewage were collected from the different locations of province Solan (India). For isolation, enrichment culture technique was used to enrich calcite precipitating strains in Urea broth. After enrichment, fourteen distinct bacterial strains were obtained on Urea agar. Based on qualitative and quantitative screening for urease activity, five isolates were obtained possessing higher calcite formation and urease activities (38–77 μmhos/cm) as compared with standard strain of Bacillus megaterium MTCC 1684 (77 μmhos/cm). An isolate I13 identified as Lysinibacillus sp. was selected for self healing property in the concrete mix of M20. An improved compressive strength of 1.5 fold was observed in concrete samples amended with Lysinibacillus sp. over the concrete amended with B. megaterium MTCC 1684 after 28 days of curing. The higher calcite precipitation activity was indicated in Lysinibacillus sp. by FE-SEM micrographs and EDX analysis.



http://ift.tt/2BFRj93

Regeneration of cortical tissue from brain injury by implantation of defined molecular gradient of semaphorin 3A

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Zhen Xu, Wei Wang, Yutian Ren, Wenchong Zhang, Peilin Fang, Linfeng Huang, Xin Wang, Peng Shi
Despite great efforts in the exploration of therapeutic strategies for treating brain injuries, it is still challenging to regenerate neural tissues and to restore the lost function within an injured brain. In this report, we employed a tissue engineering approach to regenerate cortical tissue from brain injury by implantation of defined semaphorin 3A (Sema3A) gradient packaged in a hydrogel based device. Over a thirty-day recovery period, the implanted Sema3A gradient was sufficient to induce substantial migration of neural progenitor cells to the hydrogel and to promote differentiation of these cells for neuroregeneration at the injury site. As revealed by molecular characterization and RNA transcriptome analysis, the regenerated tissues induced by Sema3A gradient exhibited significant similarity to normal cortical tissues. Many genes associated with neuronal migration and stem cell differentiation were significantly up-regulated. In addition, our result suggested a crosstalk between Sema3A and Wnt/β-catenin pathways in course of induced brain regeneration. This study demonstrated an innovative strategy to regenerate brain tissue after traumatic injury by controlling the in vivo chemotactic environment with unprecedented sophistication, and also resolved new insights about Sema3A's role in adult neurogenesis.



http://ift.tt/2oItUyw

Tumor acidity activating multifunctional nanoplatform for NIR-mediated multiple enhanced photodynamic and photothermal tumor therapy

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Junjie Liu, Huining Liang, Menghuan Li, Zhong Luo, Jixi Zhang, Xingming Guo, Kaiyong Cai
The study reports a multifunctional nanoplatform based on mesoporous silica coated gold nanorod (AuNR@MSN) to overcome biological barriers associating with nanocarrier for multiple enhanced photodynamic therapy (PDT) and photothermal therapy (PPT). Indocyanine green (ICG) was loaded into AuNR@MSN and end-capped with β-cyclodextrin (β-CD). Then, a peptide RLA ([RLARLAR]2) with plasma membrane permeability and mitochondria-targeting capacity was anchored to AuNR@MSN via host-gust interaction. Subsequently, a charge-reversible polymer was introduced to endow stealth property. When the nanoplatform extravasates to tumor tissue, the weak acidity in tumor microenvironment could induce the dissociation of charge-reversible polymer and re-exposure of RLA peptide. Such a pH-mediated transition could facilitate the targeted accumulation of the nanoplatform in mitochondria. Upon singular 808 nm laser irradiation, the nanoplatform displayed enhanced PDT effect through the generation of reactive oxygen species (ROS) mediated by the local electric field of AuNR, plasmonic photothermal effect, and leakage of endogenous ROS by mitochondrion-targeted PDT. Meanwhile, local hyperthermia was generated by both ICG and AuNR for PPT. The in vitro and in vivo experiments demonstrated that the composite nanoplatform had good antitumor effect with minimal side effect. This work provides new insight into the development of new phototherapeutics for oncotherapy.



http://ift.tt/2CZRKsw

Multifunctional hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release for enhanced tumor suppression

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Xuhan Liu, Yinghuan Li, Xi Tan, Rong Rao, Yuanyuan Ren, Lingyan Liu, Xiangliang Yang, Wei Liu
Therapeutic efficacy of conventional single PEGylated polymeric micelles is significantly reduced by limited endocytosis and intracellular drug release. To improve drug delivery efficiency, poly (ethylene glycol)-block-poly (l-lactic acid)/(Arg-Gly-Asp-Phe)-poly (aminoethyl ethylene phosphate)-block-poly (l-lactic acid) (PEG-PLLA/RGDF-PAEEP-PLLA) hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release are developed. The optimized hybrid micelles with 6 wt % of RGDF have favorable in vitro and in vivo activities. The hybrid micelles could temporarily shield the targeting efficacy of RGDF at pH 7.4 due to the steric effect exerted by concealment of RGDF peptides in the PEG corona, which strongly decreases the clearance by mononuclear phagocyte system and consequently improves the tumor accumulation. Inside the solid tumor with a lower acidic pH, the hybrid micelles restore the active tumor targeting property with exposed RGDF on the surface of the micelles because of the increased protonation and stretching degree of PAEEP blocks. RGDF-mediated endocytosis improves the tumor cell uptake. The hybrid micelles would also enhance intracellular drug release because of the hydrolysis of the acid/phosphatase-sensitivity of PAEEP blocks in endo/lysosome. Systemic administration of the hybrid micelles significantly inhibits tumor growth by 96% due to the integration of enhanced circulation time, tumor accumulation, cell uptake and intracellular drug release.



http://ift.tt/2oGdyGG

Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene

Publication date: Available online 18 December 2017
Source:Brain and Development
Author(s): Tomoshiro Ito, Masashi Narugami, Kiyoshi Egawa, Hiroyuki Yamamoto, Naoko Asahina, Shinobu Kohsaka, Atsushi Ishii, Shinichi Hirose, Hideaki Shiraishi
Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30 s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis.Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient's younger years.



http://ift.tt/2BvLp7S

Differential effects of a visuospatial attention task on measures of postural control in young and older adults

Publication date: Available online 18 December 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Jeffrey J. Peterson, Kevin G. Keenan
The purpose of this study was to examine the influence of a visuospatial attention task on three measures of postural control in young and older adults. 20 young (19 – 36 years) and 20 older (67 – 91 years) adults performed a choice stepping response time (CSRT) task, a submaximal dorsiflexion force steadiness task, and quiet standing in 3 bilateral stances. All tasks were performed with and without a visuospatial (VS) attention task that involved visualizing a star moving within a 2×2 grid. CSRT increased with the addition of the VS task in both groups (p < .001), with a larger increase for older adults than young adults (p < .001). Older adults were less steady while performing the dorsiflexion task with the VS task (p < .001), while the VS task did not influence steadiness in young adults (p = .235). Performance during quiet standing was not influenced by the VS task in any stance (p > .084). The findings suggest that visuospatial attention differentially affects postural control in young and older adults and the effect is task-specific. These findings suggest the need to include stepping and force control tasks to further determine what role visuospatial attention plays in postural control.



http://ift.tt/2kJaQuL

Primary surgical management with radial forearm free flap reconstruction in T4 oropharyngeal cancer: Complications and functional outcomes

Functional outcomes and complication rates after open surgery for advanced-stage oropharyngeal cancers are rarely reported. These measures are critical for choice of treatment modality and patient counseling. We describe the long term functional outcomes and associated complications of primary surgical management of T4 oropharyngeal cancers reconstructed with radial forearm free flaps.

http://ift.tt/2kJ2TWr

Least Injurious Mechanical Ventilation in Pulmonary Resection Surgery

No abstract available

http://ift.tt/2kh22wJ

To Clot or Not to Clot: Understanding Coagulopathy in Liver Disease

No abstract available

http://ift.tt/2ke55WA

Unadjusted Bivariate Two-Group Comparisons: When Simpler is Better

Hypothesis testing involves posing both a null hypothesis and an alternative hypothesis. This basic statistical tutorial discusses the appropriate use, including their so-called assumptions, of the common unadjusted bivariate tests for hypothesis testing and thus comparing study sample data for a difference or association. The appropriate choice of a statistical test is predicated on the type of data being analyzed and compared. The unpaired or independent samples t test is used to test the null hypothesis that the 2 population means are equal, thereby accepting the alternative hypothesis that the 2 population means are not equal. The unpaired t test is intended for comparing dependent continuous (interval or ratio) data from 2 study groups. A common mistake is to apply several unpaired t tests when comparing data from 3 or more study groups. In this situation, an analysis of variance with post hoc (posttest) intragroup comparisons should instead be applied. Another common mistake is to apply a series of unpaired t tests when comparing sequentially collected data from 2 study groups. In this situation, a repeated-measures analysis of variance, with tests for group-by-time interaction, and post hoc comparisons, as appropriate, should instead be applied in analyzing data from sequential collection points. The paired t test is used to assess the difference in the means of 2 study groups when the sample observations have been obtained in pairs, often before and after an intervention in each study subject. The Pearson chi-square test is widely used to test the null hypothesis that 2 unpaired categorical variables, each with 2 or more nominal levels (values), are independent of each other. When the null hypothesis is rejected, 1 concludes that there is a probable association between the 2 unpaired categorical variables. When comparing 2 groups on an ordinal or nonnormally distributed continuous outcome variable, the 2-sample t test is usually not appropriate. The Wilcoxon-Mann-Whitney test is instead preferred. When making paired comparisons on data that are ordinal, or continuous but nonnormally distributed, the Wilcoxon signed-rank test can be used. In analyzing their data, researchers should consider the continued merits of these simple yet equally valid unadjusted bivariate statistical tests. However, the appropriate use of an unadjusted bivariate test still requires a solid understanding of its utility, assumptions (requirements), and limitations. This understanding will mitigate the risk of misleading findings, interpretations, and conclusions.

http://ift.tt/2kh20oB

Anesthesia & Analgesia: Update and a Year in Review

No abstract available

http://ift.tt/2kh1YNv

A Novel Method of Evaluating Key Factors for Success in a Multifaceted Critical Care Fellowship Using Data Envelopment Analysis

BACKGROUND: The current system of summative multi-rater evaluations and standardized tests to determine readiness to graduate from critical care fellowships has limitations. We sought to pilot the use of data envelopment analysis (DEA) to assess what aspects of the fellowship program contribute the most to an individual fellow's success. DEA is a nonparametric, operations research technique that uses linear programming to determine the technical efficiency of an entity based on its relative usage of resources in producing the outcome. DESIGN: Retrospective cohort study. SUBJECTS AND SETTING: Critical care fellows (n = 15) in an Accreditation Council for Graduate Medical Education (ACGME) accredited fellowship at a major academic medical center in the United States. METHODS: After obtaining institutional review board approval for this retrospective study, we analyzed the data of 15 anesthesiology critical care fellows from academic years 2013–2015. The input-oriented DEA model develops a composite score for each fellow based on multiple inputs and outputs. The inputs included the didactic sessions attended, the ratio of clinical duty works hours to the procedures performed (work intensity index), and the outputs were the Multidisciplinary Critical Care Knowledge Assessment Program (MCCKAP) score and summative evaluations of fellows. RESULTS: A DEA efficiency score that ranged from 0 to 1 was generated for each of the fellows. Five fellows were rated as DEA efficient, and 10 fellows were characterized in the DEA inefficient group. The model was able to forecast the level of effort needed for each inefficient fellow, to achieve similar outputs as their best performing peers. The model also identified the work intensity index as the key element that characterized the best performers in our fellowship. CONCLUSIONS: DEA is a feasible method of objectively evaluating peer performance in a critical care fellowship beyond summative evaluations alone and can potentially be a powerful tool to guide individual performance during the fellowship.

http://ift.tt/2kgq8aO

Inadvertent Perioperative Hypothermia Induced by Spinal Anesthesia for Cesarean Delivery Might Be More Significant Than We Think: Are We Doing Enough to Warm Our Parturients?

No abstract available

http://ift.tt/2kK0n1V

Society for Obstetric Anesthesia and Perinatology 2017 Meeting Report

No abstract available

http://ift.tt/2kK0kDh

Efficiency, Paths, Goals, and Frontiers in Graduate Education: New Uses for Old Concepts

No abstract available

http://ift.tt/2kITbTL

Pentathol Postcards: Erratum

No abstract available

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Are You Down With TPP? Considering Transpulmonary Pressures as Opposed to Ventilator-Measured Pressures

No abstract available

http://ift.tt/2kLDNpE

Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord

BACKGROUND: Antidepressants are used to treat neuropathic pain and although the detailed mechanisms of their effects are unclear, the descending noradrenergic inhibitory system might play an important role. We tested our hypothesis that repeated administration of duloxetine suppresses neuropathic pain by restoring the descending noradrenergic inhibitory system in rats 6 weeks after spinal nerve ligation (SNL). METHODS: We subcutaneously injected SNL rats with duloxetine (10 mg kg−1 day−1) daily for 3 consecutive days and assessed behavioral hypersensitivity and noxious stimulus–induced analgesia (NSIA) activated by subcutaneous injection of capsaicin. We also performed microdialysis studies of the spinal cord, noradrenaline measurements of homogenized lumbar spinal tissue, and immunohistochemistry of the locus coeruleus. RESULTS: Three daily injections of duloxetine attenuated the mechanical hyperalgesia induced by SNL (SNL treated with vehicle: 88 ± 9.4 g versus SNL treated with duloxetine: 148 ± 13 g, P

http://ift.tt/2kK0ieD

“However Beautiful the Strategy, You Should Occasionally Look at the Results”: Sir Winston Churchill and Medical Checklists

No abstract available

http://ift.tt/2khRX2r

Anaesthesia for the Elderly Patient, 2nd ed.

No abstract available

http://ift.tt/2kLDJGq

Postoperative Atrial Fibrillation and Maslow’s Hammer

No abstract available

http://ift.tt/2kgq7DM

In Response

No abstract available

http://ift.tt/2kLDH1g

The Pediatric Elephant in the Room

No abstract available

http://ift.tt/2kePF4j

Risk of Cognitive Impairment by Sleep-Disordered Breathing

No abstract available

http://ift.tt/2kHwGP8

The Eye of the Beholder

No abstract available

http://ift.tt/2kf0tiM

Preventing Mistransfusions: An Evaluation of Institutional Knowledge and a Response

BACKGROUND: Blood product mistransfusions occur when a process error causes transfusion of incompatible blood products. These events are known sources of negative patient outcomes. One such event demonstrated an institutional knowledge gap and an opportunity to reduce this source of transfusion errors. The focus of this study was to evaluate the application of point of care cognitive aids to bridge potentially lethal knowledge gaps in blood product to patient compatibility. METHODS: A patient-donor ABO antigen compatibility grid for red blood cells (RBC) and fresh frozen plasma (FFP) was developed for creation of a cognitive aid and a blood product safety quiz. Participants included 117 registered nurses and postgraduate medical interns who were given 2 minutes to complete the quiz for establishing institutional controls. A separate group of 111 registered nurses and interns were given the same timed quiz twice, without and then with a blood product compatibility cognitive aid. An analysis of covariance was used to evaluate without cognitive aid versus with cognitive aid quiz results while taking the specialty (nurse versus interns) and baseline score into consideration. The blood bank adopted the grid as a forcing function to be completed before release of blood products. RESULTS: The correct RBC answer percentage increased from 84.7% to 98.3% without and with cognitive aid (average improvement 13.6%, standard deviation [SD] = 18.3%, 95% confidence interval, 10.1%–17.1%, P

http://ift.tt/2kfYOJX

Insight Into Our Technologies: A New Series of Manuscripts in Anesthesia & Analgesia

No abstract available

http://ift.tt/2kgwS8M

In Memorium - Professor Robin AJ Eady, MB BS Lond(1967) MRCP(1970) FRCP(1982) FMedSci(2002) MBE(2014) DSc. (b.29 November 1940 d.2 August 2017)

http://ift.tt/2kHPygV

Perception of ABC (Asymmetry, Borders and Color) Parameters in the Screening for Melanoma. Model Exercise with Experienced Dermatologists

http://ift.tt/2kiyfnx

CXCR3/CXCL10 Axis Shapes Tissue Distribution of Memory Phenotype CD8+ T Cells in Nonimmunized Mice [IMMUNE SYSTEM DEVELOPMENT]

The preimmune repertoire consists of mature T lymphocytes that have not yet been stimulated in the periphery. Memory phenotype (MP) cells have been reported as part of the preimmune repertoire (i.e., T cells bearing memory markers despite lack of engagement with cognate Ag); however, little is known about their trafficking and function. In this study, we hypothesized that MP cells, naive to TCR stimulation, constitute a transient population that traffics to tissues during development. Using mutant and transgenic animals with a monospecific TCR, we discovered increased numbers of MP CD8⁺ T cells circulating in nonimmunized Cxcr3^–/– and Cxcl10^–/– mice compared with wild-type animals. Phenotypic differences included decreased numbers of preimmune MP Ag-specific T cells in the skin and thymus and a distinct pattern of activation upon TCR engagement. Our results show for the first time, to our knowledge, an important role for CXCR3 and CXCL10 in the tissue distribution of preimmune MP cells.

http://ift.tt/2B8azwi

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model [IMMUNOTHERAPY AND VACCINES]

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene–deleted Leishmania donovani (LdCen^–/–) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen^–/–-induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen^–/– parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen^–/–. Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen^–/–-immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-–producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN- abrogated LdCen^–/–-induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R^–/– mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17–mediated protection by LdCen^–/– parasites. This study unveiled the role of IL-23–dependent IL-17 induction in LdCen^–/– parasite-induced immunity and subsequent protection against visceral leishmaniasis.

http://ift.tt/2Baxbwj

A Novel Pkhd1 Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis [IMMUNOGENETICS]

We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 (Pkhd1). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript. A novel NOD congenic mouse expressing aberrant Pkhd1, but lacking the c3 and c4 chromosomal regions (NOD.Abd3), reproduces the immunopathological features of NOD ABD. RNA sequencing of NOD.Abd3 common bile duct early in disease demonstrates upregulation of genes involved in cholangiocyte injury/morphology and downregulation of immunoregulatory genes. Consistent with this, bone marrow chimera studies show that aberrant Pkhd1 must be expressed in the target tissue (cholangiocytes) and the immune system (bone marrow). Mutations of Pkhd1 produce biliary abnormalities in mice but have not been previously associated with autoimmunity. In this study, we eliminate clinical biliary disease by backcrossing this Pkhd1 mutation onto the C57BL/6 genetic background; thus, the NOD genetic background (which promotes autoimmunity) is essential for disease. We propose that loss of functional Pkhd1 on the NOD background produces early bile duct abnormalities, initiating a break in tolerance that leads to autoimmune cholangitis in NOD.Abd3 congenic mice. This model is important for understanding loss of tolerance to cholangiocytes and is relevant to the pathogenesis of several human cholangiopathies.

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Modulation of the Alternative Pathway of Complement by Murine Factor H-Related Proteins [INNATE IMMUNITY AND INFLAMMATION]

Factor H (FH) is a key alternative pathway regulator that controls complement activation both in the fluid phase and on specific cell surfaces, thus allowing the innate immune response to discriminate between self and foreign pathogens. However, the interrelationships between FH and a group of closely related molecules, designated the FH-related (FHR) proteins, are currently not well understood. Whereas some studies have suggested that human FHR proteins possess complement regulatory abilities, recent studies have shown that FHR proteins are potent deregulators. Furthermore, the roles of the FHR proteins have not been explored in any in vivo models of inflammatory disease. In this study, we report the cloning and expression of recombinant mouse FH and three FHR proteins (FHR proteins A–C). Results from functional assays show that FHR-A and FHR-B proteins antagonize the protective function of FH in sheep erythrocyte hemolytic assays and increase cell-surface C3b deposition on a mouse kidney proximal tubular cell line (TEC) and a human retinal pigment epithelial cell line (ARPE-19). We also report apparent K_D values for the binding interaction of mouse C3d with mouse FH (3.85 μM), FHR-A (136 nM), FHR-B (546 nM), and FHR-C (1.04 μM), which directly correlate with results from functional assays. Collectively, our work suggests that similar to their human counterparts, a subset of mouse FHR proteins have an important modulatory role in complement activation. Further work is warranted to define the in vivo context-dependent roles of these proteins and determine whether FHR proteins are suitable therapeutic targets for the treatment of complement-driven diseases.

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IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus [INNATE IMMUNITY AND INFLAMMATION]

Group 2 innate lymphoid cells (ILC2s) reside in multiple organs in the body, where they play roles in immunity, tissue homeostasis, and metabolic regulation. However, little is known about the regulatory mechanisms of ILC2s in different organs. Here, we identified ILC2s in the mouse uterus and found that they express cell surface molecules, including the IL-33 receptor, ST2, that are roughly comparable to those expressed by lung ILC2s. Both in vivo and in vitro treatment with IL-33 induced type 2 cytokine production in uterine ILC2s, suggesting that they respond to IL-33 in a manner similar to ILC2s in other organs. Importantly, uterine ILC2s were nearly absent in ovariectomized mice and were increased in wild-type mice by estrogen administration, whereas lung ILC2s were unaffected by both ovariectomy and estrogen administration. Likewise, a marked reduction in uterine ILC2s was observed in mice deficient in estrogen receptor α or estrogen receptor β. Furthermore, uterine ILC2s highly expressed estrogen receptor α, and in vitro culture of isolated uterine ILC2s with 17β-estradiol modified expression of a number of genes. Finally, an increased prevalence in neonatal mortality was observed in litters from dams lacking the IL-33 receptor, ST2. Taken together, our findings indicate that unlike lung IL2Cs, uterine ILC2s are regulated by female sex hormones, which may specialize them for specific physiological functions.

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A Beginners Guide to Analyzing and Visualizing Mass Cytometry Data [IMMUNOLOGY NOTES AND RESOURCES]

Mass cytometry has revolutionized the study of cellular and phenotypic diversity, significantly expanding the number of phenotypic and functional characteristics that can be measured at the single-cell level. This high-dimensional analysis platform has necessitated the development of new data analysis approaches. Many of these algorithms circumvent traditional approaches used in flow cytometric analysis, fundamentally changing the way these data are analyzed and interpreted. For the beginner, however, the large number of algorithms that have been developed, as well as the lack of consensus on best practices for analyzing these data, raise multiple questions: Which algorithm is the best for analyzing a dataset? How do different algorithms compare? How can one move beyond data visualization to gain new biological insights? In this article, we describe our experiences as recent adopters of mass cytometry. By analyzing a single dataset using five cytometry by time-of-flight analysis platforms (viSNE, SPADE, X-shift, PhenoGraph, and Citrus), we identify important considerations and challenges that users should be aware of when using these different methods and common and unique insights that can be revealed by these different methods. By providing annotated workflow and figures, these analyses present a practical guide for investigators analyzing high-dimensional datasets. In total, these analyses emphasize the benefits of integrating multiple cytometry by time-of-flight analysis algorithms to gain complementary insights into these high-dimensional datasets.

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Toxoplasma gondii Inactivates Human Plasmacytoid Dendritic Cells by Functional Mimicry of IL-10 [INFECTIOUS DISEASE AND HOST RESPONSE]

Plasmacytoid dendritic cells (pDCs) are the major producers of IFN-α, an antiviral cytokine involved in immunomodulation and control of HIV type 1 replication, whereas Toxoplasma gondii is a life-threatening opportunistic infection in AIDS patients. During infection with HIV type 1, human pDCs decrease in circulation and remaining pDC produce lower amounts of IFN-α in response to viral stimulation. In this study, we investigated the impact of coinfection with T. gondii on the innate virus-directed responses of human pDCs. Using intracellular flow cytometry and fluorescence microscopy, we determined that T. gondii invaded but did not induce IFN-α or TNF-α in human pDC. However, T. gondii inhibited IFN-α and TNF-α produced in response to HSV and HIV, thus functionally inactivating pDC. IFN-α production was inhibited only in cells infected by T. gondii, which inhibited neither uptake of GFP-HSV nor localization of TLR9 in CD71⁺ endosomes, directing us to investigate downstream events. Using imaging flow cytometry, we found that both T. gondii and IL-10 inhibited virus-induced nuclear translocation, but not phosphorylation, of IFN response factor 7. Blockade of IFN response factor 7 nuclear translocation and inhibition of the IFN-α response was partially reversed by a deficiency in the T. gondii–derived ROP16 kinase, known to directly phosphorylate STAT3, a critical mediator of IL-10's anti-inflammatory effects. Taken together, our results indicate that T. gondii suppresses pDC activation by mimicking IL-10's regulatory effects through an ROP16 kinase-dependent mechanism. Our findings further imply a convergent mechanism of inhibition of TLR signaling by T. gondii and IL-10 and suggest potential negative consequences of HIV/T. gondii coinfection.

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The Reign of Antibodies: A Celebration of and Tribute to Michael Potter and His Homogeneous Immunoglobulin Workshops [PILLARS OF IMMUNOLOGY]

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Embryonic Lethality and Host Immunity of RelA-Deficient Mice Are Mediated by Both Apoptosis and Necroptosis [INNATE IMMUNITY AND INFLAMMATION]

In mammalian cells, signaling pathways triggered by TNF can be switched from NF-B activation to apoptosis and/or necroptosis. The in vivo mechanisms underlying the mutual regulation of these three signaling pathways are poorly understood. In this article, we report that the embryonic lethality of RelA-deficient mice is partially prevented by the deletion of Rip3 or Mlkl, but it is fully rescued by the combined ablation of Fadd and Rip3 or Mlkl or by blocking RIP1 kinase activity (RIP1^K45A). RelA^–/–Fadd^–/–Rip3^–/– triple-knockout (TKO) and RelA^–/–Rip1^K45A/K45A mice displayed bacterial pneumonia leading to death ~2 wk after birth. Moreover, RelA^–/–Rip1^K45A/K45A mice, but not TKO mice, developed severe inflammation associated with inflammatory skin lesion. Antibiotic treatment improved bacterial pneumonia, extended the lifespan of TKO and RelA^–/–Rip1^K45A/K45A mice, and alleviated skin inflammation in RelA^–/–Rip1^K45A/K45A mice. These results show the mechanisms underlying the in vivo mutual regulation between NF-B activation and the cell death pathway and provide new insights into this interplay in embryonic development and host immune homeostasis.

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Pillars Article: Evidence for Amino Acid Sequence Differences among Proteins Resembling the L-chain Subunits of Immunoglobulins. J. Mol. Biol. 1965. 12: 81-87 [PILLARS OF IMMUNOLOGY]

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In This Issue [IN THIS ISSUE]

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Salmonella Vaccines: Conduits for Protective Antigens [BRIEF REVIEWS]

Vaccines afford a better and more cost-effective approach to combatting infectious diseases than continued reliance on antibiotics or antiviral or antiparasite drugs in the current era of increasing incidences of diseases caused by drug-resistant pathogens. Recombinant attenuated Salmonella vaccines (RASVs) have been significantly improved to exhibit the same or better attributes than wild-type parental strains to colonize internal lymphoid tissues and persist there to serve as factories to continuously synthesize and deliver rAgs. Encoded by codon-optimized pathogen genes, Ags are selected to induce protective immunity to infection by that pathogen. After immunization through a mucosal surface, the RASV attributes maximize their abilities to elicit mucosal and systemic Ab responses and cell-mediated immune responses. This article summarizes many of the numerous innovative technologies and discoveries that have resulted in RASV platforms that will enable development of safe efficacious RASVs to protect animals and humans against a diversity of infectious disease agents.

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The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction [INFECTIOUS DISEASE AND HOST RESPONSE]

Bats host a large number of zoonotic viruses, including several viruses that are highly pathogenic to other mammals. The mechanisms underlying this rich viral diversity are unknown, but they may be linked to unique immunological features that allow bats to act as asymptomatic viral reservoirs. Vertebrates respond to viral infection by inducing IFNs, which trigger antiviral defenses through IFN-stimulated gene (ISG) expression. Although the IFN system of several bats is characterized at the genomic level, less is known about bat IFN-mediated transcriptional responses. In this article, we show that IFN signaling in bat cells from the black flying fox (Pteropus alecto) consists of conserved and unique ISG expression profiles. In IFN-stimulated cells, bat ISGs comprise two unique temporal subclusters with similar early induction kinetics but distinct late-phase declines. In contrast, human ISGs lack this decline phase and remained elevated for longer periods. Notably, in unstimulated cells, bat ISGs were expressed more highly than their human counterparts. We also found that the antiviral effector 2-5A–dependent endoribonuclease, which is not an ISG in humans, is highly IFN inducible in black flying fox cells and contributes to cell-intrinsic control of viral infection. These studies reveal distinctive innate immune features that may underlie a unique virus–host relationship in bats.

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The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques [ANTIGEN RECOGNITION AND RESPONSES]

MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8⁺ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E–targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E–restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8⁺ T cells. Indeed, SIV-specific, Mamu-E–restricted CD8⁺ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4⁺ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E–restricted T cell immunobiology.

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The Activation of Human Dermal Microvascular Cells by Poly(I:C), Lipopolysaccharide, Imiquimod, and ODN2395 Is Mediated by the Fli1/FOXO3A Pathway [INNATE IMMUNITY AND INFLAMMATION]

Endothelial cell (EC) dysfunction has been associated with inflammatory and autoimmune diseases; however, the factors contributing to this dysfunction have not been fully explored. Because activation of TLRs has been implicated in autoimmune diseases, the goal of this study was to determine the effects of TLR ligands on EC function. Human dermal microvascular ECs (HDMECs) treated with TLR3 [Poly(I:C)], TLR4 (LPS), and TLR7 (imiquimod) agonists showed decreased proliferation and a reduced total number of branching tubules in three-dimensional human dermal organoid ex vivo culture. In contrast, the TLR9 ligand class C, ODN2395, increased angiogenesis. The antiproliferative effects of TLR3, TLR4, and TLR7 ligands correlated with significant downregulation of a key regulator of vascular homeostasis, Fli1, whereas TLR9 increased Fli1 levels. Furthermore, Poly(I:C) and LPS induced endothelial to mesenchymal transition that was reversed by the pretreatment with TGF-β neutralizing Ab or re-expression of Fli1. We showed that Fli1 was required for the HDMEC proliferation by transcriptionally repressing FOXO3A. In contrast to TLR9, which suppressed activation of the FOXO3A pathway, TLR3, TLR4, and TLR7 ligands activated FOXO3A as indicated by decreased phosphorylation and increased nuclear accumulation. The inverse correlation between Fli1 and FOXO3A was also observed in the vasculature of scleroderma patients. This work revealed opposing effects of TLR9 and TLR3, TLR4, and TLR7 on the key angiogenic pathways, Fli1 and FOXO3A. Our results provide a mechanistic insight into the regulation of angiogenesis by TLRs and confirm a central role of Fli1 in regulating vascular homeostasis.

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Superoxide Production by NADPH Oxidase Intensifies Macrophage Antiviral Responses during Diabetogenic Coxsackievirus Infection [AUTOIMMUNITY]

Coxsackievirus B infections are suspected environmental triggers of type 1 diabetes (T1D) and macrophage antiviral responses may provide a link to virus-induced T1D. We previously demonstrated an important role for NADPH oxidase (NOX)–derived superoxide production during T1D pathogenesis, as NOX-deficient NOD mice (NOD.Ncf1^m1J) were protected against T1D due, in part, to impaired proinflammatory TLR signaling in NOD.Ncf1^m1J macrophages. Therefore, we hypothesized that loss of NOX-derived superoxide would dampen diabetogenic antiviral macrophage responses and protect from virus-induced diabetes. Upon infection with a suspected diabetogenic virus, Coxsackievirus B3 (CB3), NOD.Ncf1^m1J mice remained resistant to virus-induced autoimmune diabetes. A concomitant decrease in circulating inflammatory chemokines, blunted antiviral gene signature within the pancreas, and reduced proinflammatory M1 macrophage responses were observed. Importantly, exogenous superoxide addition to CB3-infected NOD.Ncf1^m1J bone marrow–derived macrophages rescued the inflammatory antiviral M1 macrophage response, revealing reduction-oxidation–dependent mechanisms of signal transducer and activator of transcription 1 signaling and dsRNA viral sensors in macrophages. We report that superoxide production following CB3 infection may exacerbate pancreatic β cell destruction in T1D by influencing proinflammatory M1 macrophage responses, and mechanistically linking oxidative stress, inflammation, and diabetogenic virus infections.

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Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging [INNATE IMMUNITY AND INFLAMMATION]

Dysregulated inflammation is implicated in the pathobiology of aging, yet platelet–leukocyte interactions and downstream cytokine synthesis in aging remains poorly understood. Platelets and monocytes were isolated from healthy younger (age <45, n = 37) and older (age ≥65, n = 30) adults and incubated together under autologous and nonautologous conditions. Synthesis of inflammatory cytokines by monocytes, alone or in the presence of platelets, was examined. Next-generation RNA-sequencing allowed for unbiased profiling of the platelet transcriptome in aging. Basal IL-8 and MCP-1 synthesis by monocytes alone did not differ between older and younger adults. However, in the presence of autologous platelets, monocytes from older adults synthesized greater IL-8 (41 ± 5 versus 9 ± 2 ng/ml, p < 0.0001) and MCP-1 (867 ± 150 versus 216 ± 36 ng/ml, p < 0.0001) than younger adults. Platelets from older adults were sufficient for upregulating the synthesis of inflammatory cytokines by monocytes. Using RNA-sequencing of platelets followed by validation via RT-PCR and immunoblot, we discovered that granzyme A (GrmA), a serine protease not previously identified in human platelets, increases with aging (~9-fold versus younger adults, p < 0.05) and governs increased IL-8 and MCP-1 synthesis through TLR4 and caspase-1. Inhibiting GrmA reduced excessive IL-8 and MCP-1 synthesis in aging to levels similar to younger adults. In summary, human aging is associated with changes in the platelet transcriptome and proteome. GrmA is present and bioactive in human platelets, is higher in older adults, and controls the synthesis of inflammatory cytokines by monocytes. Alterations in the platelet molecular signature and signaling to monocytes may contribute to dysregulated inflammatory syndromes in older adults.

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Essential Role of CARD14 in Murine Experimental Psoriasis [AUTOIMMUNITY]

Caspase recruitment domain family member 14 (CARD14) was recently identified as a psoriasis-susceptibility gene, but its immunological role in the pathogenesis of psoriasis in vivo remains unclear. In this study, we examined the role of CARD14 in murine experimental models of psoriasis induced by either imiquimod (IMQ) cream or recombinant IL-23 injection. In all models tested, the psoriasiform skin inflammation was abrogated in Card14^–/– mice. Comparison of the early gene signature of the skin between IMQ-cream–treated Card14^–/– mice and Tlr7^–/–Tlr9^–/– mice revealed not only their similarity, but also distinct gene sets targeted by IL-23. Cell type–specific analysis of these mice identified skin Langerin^high Langerhans cells as a potent producer of IL-23, which was dependent on both TLR7 and TLR9 but independent of CARD14, suggesting that CARD14 is acting downstream of IL-23, not TLR7 or TLR9. Instead, a bone marrow chimera study suggested that CARD14 in radio-sensitive hematopoietic cells was required for IMQ-induced psoriasiform skin inflammation, controlling the number of V4⁺ T cells producing IL-17 or IL-22 infiltrating through the dermis to the inflamed epidermis. These data indicate that CARD14 is essential and a potential therapeutic target for psoriasis.

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Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry [SYSTEMS IMMUNOLOGY]

Human CD3⁺CD4⁺ Th cells, FOXP3⁺ T regulatory (Treg) cells, and T regulatory type 1 (Tr1) cells are essential for ensuring peripheral immune response and tolerance, but the diversity of Th, Treg, and Tr1 cell subsets has not been fully characterized. Independent functional characterization of human Th1, Th2, Th17, T follicular helper (Tfh), Treg, and Tr1 cells has helped to define unique surface molecules, transcription factors, and signaling profiles for each subset. However, the adequacy of these markers to recapitulate the whole CD3⁺CD4⁺ T cell compartment remains questionable. In this study, we examined CD3⁺CD4⁺ T cell populations by single-cell mass cytometry. We characterize the CD3⁺CD4⁺ Th, Treg, and Tr1 cell populations simultaneously across 23 memory T cell–associated surface and intracellular molecules. High-dimensional analysis identified several new subsets, in addition to the already defined CD3⁺CD4⁺ Th, Treg, and Tr1 cell populations, for a total of 11 Th cell, 4 Treg, and 1 Tr1 cell subsets. Some of these subsets share markers previously thought to be selective for Treg, Th1, Th2, Th17, and Tfh cells, including CD194 (CCR4)⁺FOXP3⁺ Treg and CD183 (CXCR3)⁺T-bet⁺ Th17 cell subsets. Unsupervised clustering displayed a phenotypic organization of CD3⁺CD4⁺ T cells that confirmed their diversity but showed interrelation between the different subsets, including similarity between Th1–Th2–Tfh cell populations and Th17 cells, as well as similarity of Th2 cells with Treg cells. In conclusion, the use of single-cell mass cytometry provides a systems-level characterization of CD3⁺CD4⁺ T cells in healthy human blood, which represents an important baseline reference to investigate abnormalities of different subsets in immune-mediated pathologies.

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The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation [IMMUNE REGULATION]

T cell differentiation requires appropriate regulation of DNA methylation. In this article, we demonstrate that the methylcytosine dioxygenase ten-eleven translocation (TET)2 regulates CD8⁺ T cell differentiation. In a murine model of acute viral infection, TET2 loss promotes early acquisition of a memory CD8⁺ T cell fate in a cell-intrinsic manner without disrupting Ag-driven cell expansion or effector function. Upon secondary recall, TET2-deficient memory CD8⁺ T cells demonstrate superior pathogen control. Genome-wide methylation analysis identified a number of differentially methylated regions in TET2-deficient versus wild-type CD8⁺ T cells. These differentially methylated regions did not occur at the loci of differentially expressed memory markers; rather, several hypermethylated regions were identified in known transcriptional regulators of CD8⁺ T cell memory fate. Together, these data demonstrate that TET2 is an important regulator of CD8⁺ T cell fate decisions.

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Amplifying IFN-{gamma} Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity [INFECTIOUS DISEASE AND HOST RESPONSE]

Although prophylactic vaccines provide protective humoral immunity against infectious agents, vaccines that elicit potent CD8 T cell responses are valuable tools to shape and drive cellular immunity against cancer and intracellular infection. In particular, IFN-–polarized cytotoxic CD8 T cell immunity is considered optimal for protective immunity against intracellular Ags. Suppressor of cytokine signaling (SOCS)1 is a cross-functional negative regulator of TLR and cytokine receptor signaling via degradation of the receptor–signaling complex. We hypothesized that loss of SOCS1 in dendritic cells (DCs) would improve T cell responses by accentuating IFN-–directed immune responses. We tested this hypothesis using a recombinant Listeria monocytogenes vaccine platform that targets CD11c⁺ DCs in mice in which SOCS1 is selectively deleted in all CD11c⁺ cells. Unexpectedly, in mice lacking SOCS1 expression in CD11c⁺ cells, we observed a decrease in CD8⁺ T cell response to the L. monocytogenes vaccine. NK cell responses were also decreased in mice lacking SOCS1 expression in CD11c⁺ cells but did not explain the defect in CD8⁺ T cell immunity. We found that DCs lacking SOCS1 expression were functional in driving Ag-specific CD8⁺ T cell expansion in vitro but that this process was defective following infection in vivo. Instead, monocyte-derived innate TNF-α and inducible NO synthase–producing DCs dominated the antibacterial response. Thus, loss of SOCS1 in CD11c⁺ cells skewed the balance of immune response to infection by increasing innate responses while decreasing Ag-specific adaptive responses to infectious Ags.

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Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells [IMMUNE REGULATION]

The NFAT family transcription factors play crucial roles in immunological and other biological activities. NFAT3 is rarely expressed in T cells, and the mechanisms and significance of the specific NFAT3 downregulation in T cells have been unknown. In human CD4⁺ T cells, overexpression of NFAT1 and NFAT3 enhanced and suppressed IL-2 expression, respectively. NFAT3 downregulation in Jurkat cells using RNA interference technology augmented IL-2 expression, whereas a knockdown of NFAT1, NFAT2, and NFAT4 suppressed it. The promoter/enhancer activity of the NFAT-binding site in the IL-2 gene was upregulated and downregulated by NFAT1 and NFAT3, respectively. A study employing NFAT1/NFAT3 chimeric molecules revealed that the region in NFAT3 responsible for NFAT promoter activity inhibition was located within its N-terminal transactivation domain, Ca²⁺-regulatory domain, and DNA-binding domain. Downregulation of NFAT3 expression in T cells is mediated by lower chromatin accessibility and enhancer activity in its promoter in comparison with aortic smooth muscle cells expressing endogenous NFAT3. The binding sites of T-box transcription factor TBX5 and NK-2 transcription factor–related locus 5 Nkx2.5, which were expressed at higher levels in aortic smooth muscle cells than in T cells, were located within the –387 to +97 NFAT3 promoter region, exhibiting the maximum enhancer activity. Mutating the binding site of TBX5 but not Nkx2.5 diminished the NFAT3 promoter activity, whereas the overexpression of TBX5 enhanced it. Introduction of TBX5 into CD4⁺ T cells enhanced the expression of NFAT3 and suppressed that of IL-2. TBX5 deficiency-mediated downregulation of NFAT3 is crucial for the high cytokine-producing activity of T cells.

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NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis [INFECTIOUS DISEASE AND HOST RESPONSE]

Reactive oxygen species (ROS) produced by NADPH phagocyte oxidase isoform (NOX2) are critical for the elimination of intracellular pathogens in many infections. Despite their importance, the role of ROS following infection with the eukaryotic pathogen Leishmania has not been fully elucidated. We addressed the role of ROS in C57BL/6 mice following intradermal infection with Leishmania amazonensis. Despite equivalent parasite loads compared with wild-type (WT) mice, mice deficient in ROS production by NOX2 due to the absence of the gp91 subunit (gp91^phox–/–) had significantly more severe pathology in the later stages of infection. Pathology in gp91^phox–/– mice was not associated with alterations in CD4⁺ T cell–mediated immunity but was preceded by enhanced neutrophil accumulation at the dermal infection site. Ex vivo analysis of infected versus uninfected neutrophils revealed a deficiency in infection-driven apoptosis in gp91^phox–/– mice versus WT mice. gp91^phox–/– mice presented with higher percentages of healthy or necrotic neutrophils but lower percentages of apoptotic neutrophils at early and chronic time points. In vitro infection of gp91^phox–/– versus WT neutrophils also revealed reduced apoptosis and CD95 expression but increased necrosis in infected cells at 10 h postinfection. Provision of exogenous ROS in the form of H₂O₂ reversed the necrotic phenotype and restored CD95 expression on infected gp91^phox–/– neutrophils. Although ROS production is typically viewed as a proinflammatory event, our observations identify the importance of ROS in mediating appropriate neutrophil apoptosis and the importance of apoptosis in inflammation and pathology during chronic infection.

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The WNT7B protein promotes the migration and differentiation of human dental pulp cells partly through WNT/beta-catenin and c-Jun N-terminal kinase signalling pathways

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Hongyang Lv, Jing Yang, Chenglin Wang, Fanyuan Yu, Dingming Huang, Ling Ye
ObjectiveThe aim of this study is to investigate the role of the WNT7B protein in the migration and differentiation of human dental pulp cells (HDPCs).DesignThe effect of recombinant human WNT7B (rhWNT7B) on the proliferation and migration of HDPCs was evaluated by 5-ethynyl-2′-deoxyuridine (EdU), immunofluorescence staining of Ki67, flow cytometry and scratch assay; the differentiation of HDPCs was measured by alkaline phosphatase (ALP) staining, alizarin red staining, ALP activity, qPCR and western blot. The activation of the WNT/beta-catenin (WNT/β-catenin) and c-Jun N-terminal kinase (JNK) pathways was analysed by western blot, immunocytochemistry and dual luciferase assays. XAV939 and SP600125，the inhibitors of the WNT/β-catenin and JNK pathways, were further applied to verify the mechanism.ResultsrhWNT7B repressed the proliferation but did not affect the apoptosis of HDPCs. In the presence of rhWNT7B, ALP and alizarin red staining were increased substantially in the HDPCs with osteogenic induction; the gene expression of Runx2 and Col1 in HDPCs was quite elevated compared with that induced in osteogenic medium without WNT7B measured by qPCR; The ALP activity was also increased with rhWNT7B stimulation in HDPCs after 7-day odontogenic culture; Western blot revealed that the expression of dentin sialophosphoprotein (DSPP) of HDPCs was up-regulated significantly with the addition of WNT7B as well. Further study showed that rhWNT7B activated the WNT/β-catenin and JNK signalling pathways in the differentiation of HDPCs. XAV939 and SP600125 can partly offset the effect of the WNT7B-induced differentiation of HDPCs.ConclusionWNT7B promoted the differentiation of HDPCs partly through the WNT/β-catenin and JNK signalling pathways.



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FDA OKs Tofacitinib (Xeljanz) for Active Psoriatic Arthritis

The JAK inhibitor is indicated for patients who have failed to respond adequately or are intolerant to methotrexate or other disease-modifying antirheumatic drugs.
FDA Approvals

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Porous chitosan microspheres containing zinc ion for enhanced thrombosis and hemostasis

Publication date: 1 April 2018
Source:Materials Science and Engineering: C, Volume 85
Author(s): Meng Pan, Zonghao Tang, Jianbing Tu, Zhengchao Wang, Qinhui Chen, Rongdong Xiao, Haiqing Liu
Quick hemostats for non-lethal massive traumatic bleeding in battlefield and civilian accidents are important for reducing mortality and medical costs. Chitosan (CS) has been widely used as a clinic hemostat. To enhance its hemostatic efficiency, Zn²⁺ in the form of zinc alginate (ZnAlg) was introduced to CS to make porous CS@ZnAlg microspheres with ZnAlg component on the surface. Such microspheres were prepared by successive steps of micro-emulsion, polyelectrolyte adhesion, and thermally induced phase separation. Their structure and hemostatic performance were analyzed by SEM, FT-IR, XPS and a series of in vitro hemostatic experiments including thromboelastography analysis. The composite microspheres had an outer and internal interconnected porous structure. Their size, surface area, and water absorption ratio were ca. 70μm, 48m²/g, and 1850%, respectively. Compared to the neat chitosan microspheres, the CS@ZnAlg microspheres showed shorter onset of clot formation, much faster in vitro and in vivo whole blood clotting, bigger clot, less blood loss, and shorter hemostatic time in the rat liver laceration and tail amputation models. The synergetic hemostatic effects from (1) the electrostatic attraction between chitosan component and red blood cells, (2) the activation of coagulation factor XII by Zn²⁺ of zinc alginate component, and (3) physical blocking by microsphere matrix, contributed to the enhanced hemostatic performance of CS@ZnAlg microspheres.



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