Exploratory study of atmospheric methane enhancements derived from natural gas use in the Houston urban area

Publication date: March 2018
Source:Atmospheric Environment, Volume 176
Author(s): Nancy P. Sanchez, Chuantao Zheng, Weilin Ye, Beata Czader, Daniel S. Cohan, Frank K. Tittel, Robert J. Griffin
The extensive use of natural gas (NG) in urban areas for heating and cooking and as a vehicular fuel is associated with potentially significant emissions of methane (CH4) to the atmosphere. Methane, a potent greenhouse gas that influences the chemistry of the atmosphere, can be emitted from different sources including leakage from NG infrastructure, transportation activities, end-use uncombusted NG, landfills and livestock. Although significant CH4 leakage associated with aging local NG distribution systems in the U.S. has been reported, further investigation is required to study the role of this infrastructure component and other NG-related sources in atmospheric CH4 enhancements in urban centers. In this study, neighborhood-scale mobile-based monitoring of potential CH4 emissions associated with NG in the Greater Houston area (GHA) is reported. A novel dual-gas 3.337 μm interband cascade laser-based sensor system was developed and mobile-mode deployed for simultaneous CH4 and ethane (C2H6) monitoring during a period of over 14 days, corresponding to ∼ 90 h of effective data collection during summer 2016. The sampling campaign covered ∼250 exclusive road miles and was primarily concentrated on eight residential zones with distinct infrastructure age and NG usage levels. A moderate number of elevated CH4 concentration events (37 episodes) with mixing ratios not exceeding 3.60 ppmv and associated with atmospheric background enhancements below 1.21 ppmv were observed during the field campaign. Source discrimination analyses based on the covariance between CH4 and C2H6 levels indicated the predominance of thermogenic sources (e.g., NG) in the elevated CH4 concentration episodes. The volumetric fraction of C2H6 in the sources associated with the thermogenic CH4 spikes varied between 2.7 and 5.9%, concurring with the C2H6 content in NG distributed in the GHA. Isolated CH4 peak events with significantly higher C2H6 enhancements (∼11%) were observed at industrial areas and locations with high density of petroleum and gas pipelines in the GHA, indicating potential variability in Houston's thermogenic CH4 sources.



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Detection of nuclear testing from surface concentration measurements: Analysis of radioxenon from the February 2013 underground test in North Korea

Publication date: March 2018
Source:Atmospheric Environment, Volume 176
Author(s): R.J. Kurzeja, R.L. Buckley, D.W. Werth, S.R. Chiswell
A method is outlined and tested to detect low level nuclear or chemical sources from time series of concentration measurements. The method uses a mesoscale atmospheric model to simulate the concentration signature from a known or suspected source at a receptor which is then regressed successively against segments of the measurement series to create time series of metrics that measure the goodness of fit between the signatures and the measurement segments. The method was applied to radioxenon data from the Comprehensive Test Ban Treaty (CTBT) collection site in Ussuriysk, Russia (RN58) after the Democratic People's Republic of Korea (North Korea) underground nuclear test on February 12, 2013 near Punggye. The metrics were found to be a good screening tool to locate data segments with a strong likelihood of origin from Punggye, especially when multiplied together to a determine the joint probability. Metrics from RN58 were also used to find the probability that activity measured in February and April of 2013 originated from the Feb 12 test. A detailed analysis of an RN58 data segment from April 3/4, 2013 was also carried out for a grid of source locations around Punggye and identified Punggye as the most likely point of origin. Thus, the results support the strong possibility that radioxenon was emitted from the test site at various times in April and was detected intermittently at RN58, depending on the wind direction. The method does not locate unsuspected sources, but instead, evaluates the probability of a source at a specified location. However, it can be extended to include a set of suspected sources. Extension of the method to higher resolution data sets, arbitrary sampling, and time-varying sources is discussed along with a path to evaluate uncertainty in the calculated probabilities.



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Removal of lead and cadmium from aqueous solutions by using 4-amino-3-hydroxynaphthalene sulfonic acid-doped polypyrrole films

Abstract

Water pollution by heavy metals is a great health concern worldwide. Lead and cadmium are among the most toxic heavy metals because they are dangerous for the human and aquatic lives. In this work, the removal of lead and cadmium from aqueous solutions has been studied using electrosynthesized 4-amino-3-hydroxynaphthalene-1-sulfonic acid-doped polypyrrole (AHNSA-PPy) films as a new adsorbent. Two distinct methods, including the immersion method, based on the Pb²⁺ and Cd²⁺ spontaneous removal by impregnation of the polymer in the solution, and the electro-elimination method, consisting of removal of Pb²⁺ and Cd²⁺ ions from the solution by applying a small electrical current (5 mA) to the polymer film, were developed: the evolution of Pb²⁺ and Cd²⁺ concentrations with time was monitored by inductively coupled plasma optical emission spectrometry (ICP-OES). The effect of pH on the adsorption and electro-elimination of Pb²⁺ and Cd²⁺ using the AHNSA-PPy film was investigated and optimized, showing that the ionic adsorption and electro-elimination processes were highly pH-dependent. The kinetics of Pb²⁺ and Cd²⁺ adsorption and electro-elimination were found to follow second-order curves. The maximum adsorption capacity values of the AHNSA-PPy film were 64.0 and 50.4 mg/g, respectively, for Pb²⁺ and Cd²⁺. The removal efficiency values were, respectively, for Pb²⁺ and Cd²⁺, 80 and 63% by the immersion method, and 93 and 85% by the electro-elimination method. Application of both methods to Senegal natural waters, fortified with Pb²⁺ and Cd²⁺, led to removal efficiency values of, respectively for Pb²⁺ and Cd²⁺, 76–77 and 58–59% by the immersion method, and of 82–90 and 80–83%, by the electro-elimination method.

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Is insufficient pulmonary air support the cause of dysphonia in chronic obstructive pulmonary disease?

Publication date: Available online 8 January 2018
Source:Auris Nasus Larynx
Author(s): Megahed M. Hassan, Mona T. Hussein, Ahmed Mamdouh Emam, Usama M. Rashad, Ibrahim Rezk, Al Hussein Awad
ObjectiveOptimal pulmonary air support is essential pre-requisite for efficient phonation. The objective is to correlate pulmonary and vocal functions in chronic obstructive pulmonary disease (COPD) to find out whether the reduced pulmonary function per se could induce dysphonia.MethodsIn this prospective case-control study, sixty subjects with stable COPD underwent evaluation of pulmonary and vocal functions. The pulmonary functions measured include {Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF)}. The vocal functions were {jitter, shimmer, noise-to-harmonic ratio, pitch perturbation quotient, amplitude perturbation quotient, maximum phonation time (MPT), sound pressure level, phonatory efficiency, resistance and power. A control group (n=35) underwent the same measurements. These functions were compared between subjects and controls. Also, correlation of the vocal and pulmonary functions was conducted.ResultsThirty five (58.3%) of COPD subjects have dysphonia. The pulmonary functions were lower in all COPD group than in the control group (P<0.001 for all parameters). Also, the FVC, FEV1, PEF and MMEF % of predicted values were significantly lower in subjects with dysphonia (n=35) than those without dysphonia (n=25) with P values 0.0018, <0.001, 0.0011 and 0.0026 respectively. In addition, the MPT in all subjects showed positive correlations to the 5 pulmonary functions (P=0.004 for FEV1/FVC ratio and P<0.001 for the rest). Also, the phonatory efficiency showed significant positive correlations with the pulmonary functions FVC, FEV1, PEF and MMEF (P=0.001, 0.001, 0.002 and 0.001 respectively). Unlike efficiency, the phonatory resistance revealed significant negative correlations with these pulmonary functions in the same order (P=0.001, 0.003, 0.002, 0.001 respectively).ConclusionDysphonia is a common comorbidity with COPD which attributed to multifactorial etiologies. The lower the pulmonary function in COPD patients is the more likely to have dysphonia. Decreased pulmonary function was associated with reduced MPT and phonatory efficiency but with increased phonatory resistance. The reduced pulmonary functions in COPD can be the underlying cause of the altered vocal function and dysphonia. Great part of this dysphonia is functional, and hence, can be corrected by voice therapy in compensated subjects. Further researches are needed to evaluate the efficacy of voice therapy in these patients.



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BRCA1 mutation spectrum, functions and therapeutic strategies: The story so far

Publication date: Available online 8 January 2018
Source:Current Problems in Cancer
Author(s): Babita Sharma, Raman Preet Kaur, Sonali Raut, Anjana Munshi




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Adipocytokines and Breast Cancer

Publication date: Available online 8 January 2018
Source:Current Problems in Cancer
Author(s): Jiajia Li, Xianghui Han
A substantial number of studies have revealed that a growing list of cancers might be influenced by obesity. In this regard, one of the most prominent and well characterized cancers is breast cancer, the leading cause of cancer death among women. Obesity is associated with an increased risk for the occurrence and development of breast cancer particular in postmenopausal women. Moreover, the relationship between adiposity and breast cancer risk is complex, with associations that differ depending on when body size is assessed (e.g., pre- versus postmenopausal obesity) and when breast cancer is diagnosed (i.e., pre- versus postmenopausal disease). Obesity is mainly due to excessive fat accumulation in the regional tissue. Adipocytes in obese individuals produce endocrine, inflammatory, and angiogenic factors to affect adjacent breast cancer cells. Adipocytokines, are biologically active polypeptides that are produced either exclusively or substantially by adipocytes, play a critical and complex role, and act by endocrine, paracrine, and autocrine pathways in the malignant progression of breast cancer. Furthermore, the increased levels of leptin, resistin and decreased adiponectin secretion are directly associated with breast cancer development. And there are also many studies indicating that adipocytokines could mediate the survival, growth, invasion, and metastasis of breast cancer cells by different cellular and molecular mechanisms to reduce the survival time and prompt the malignancy. In present review, we discuss the correlations between several adipocytokines and breast cancer cells in obesity as well as the underlying signaling pathways to provide the novel ideas for the prevention and treatment of breast cancer.



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Drug Development and Clinical Trial Design in Pancreatico-biliary malignancies

Publication date: Available online 8 January 2018
Source:Current Problems in Cancer
Author(s): Jennifer Harrington, Louise Carter, Bristi Basu, Natalie Cook
Pancreatico-biliary tumours arise from the pancreas, bile duct and Ampulla of Vater. Despite their close anatomical location, they have different aetiology and biology. However, they uniformly share a poor prognosis, with no major improvements observed in overall survival over decades, even in the face of progress in diagnostic imaging, surgical techniques and advances in systemic and loco-regional radiation therapies. To date, cytotoxic treatment has been associated with modest benefits in the advanced disease setting, and survival for patients with stage IV disease has not exceeded a year. Therefore, there is a pressing need to identify better treatments which may impact more significantly. . Frequently, encouraging signals of potential efficacy for novel agents in early phase clinical trials have been followed by disappointing failures in larger Phase III trials [1,2] , raising the valid question of how drug development can be optimised for patients with pancreatic adenocarcinoma and biliary tract malignancies (P-B tumours).In this paper we summarise the current therapeutic options for these patients and their limitations. The biological context of these cancers is reviewed, highlighting features that may make them resistant to standard chemotherapeutics and could be potential therapeutic targets. We discuss the role of early phase clinical trials, defined as Phase I and non-randomised Phase 2 trials, within the clinical context and current therapeutic landscape of P-B tumours and postulate how translational studies and trial design may enable better realisation of emerging targets together with a proposed model for future patient management. A detailed summary of current Phase I clinical trials in P-B tumours is provided.



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Primary Hepatic Marginal zone Lymphoma: A rare coincidence

Publication date: Available online 8 January 2018
Source:Current Problems in Cancer
Author(s): Soumya Surath Panda, Manas Baisakh, Adyakinkar Panda, Hemlata Das
Primary hepatic lymphoma (PHL) is an extremely rare disease and is often misdiagnosed. The optimal therapy is still unclear and the outcomes are uncertain. Among PHLs, a primary hepatic low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is still rarer. The present study reports the case of an elderly female diagnosed with primary hepatic lymphoma (MALT lymphoma) and treated with single agent rituximab. After 18 months, she had a progressive disease and developed Waldenstorms Macroglobulinemia concomitantly. To date, the patient has received two cycles of the RCOP (rituximab, cyclophosphamide, vincristine, and prednisone) regimen and patient′s condition is presently stable. This case is reported for its rarity and to convey the importance of the meticulous examination of the tissue. Diagnosis of this condition is important, because the disease is treatable.



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Exogenous Cushing syndrome due to misuse of potent topical steroid

Abstract

We report an infant with exogenous Cushing syndrome after being treated for 2 months with a potent topical corticosteroid via the mother's application of topical clobetasol for diaper rash without a prescription. We emphasize that potent topical steroids should be used with great caution, especially when used under occlusion (e.g., diaper area) and that parents should be warned about potential side effects of these medications, particularly when used in infants.

http://ift.tt/2DbVFTH

Doing the math: A simple approach to topical timolol dosing for infantile hemangiomas

Abstract

Topical timolol maleate has recently gained popularity as a treatment for superficial infantile hemangiomas, but calculating a safe dose of timolol can be time consuming, which may limit the medication's use in fast-paced clinical environments. This report offers a simplified calculation of the maximum daily safe dosage as 1 drop of medication per kilogram of body weight.

http://ift.tt/2D9ZLvj

Mood changes with methotrexate therapy for dermatologic disease

Abstract

Neurotoxicity and cognitive effects of low-dose methotrexate for rheumatologic disease have often been described, but the neuropsychiatric effects of low-dose methotrexate for cutaneous disease have been underreported in the dermatology literature. We describe two children who experienced mood changes with methotrexate treatment for lichen sclerosus with morphea overlap and psoriasis, with rapid resolution of these symptoms after methotrexate cessation. We also detail possible mechanisms underlying psychiatric changes with methotrexate therapy.

http://ift.tt/2mfkXJ4

Pityriasis lichenoides: Long-term follow-up study

Abstract

Background/Objectives

Pityriasis lichenoides is an uncommon papulosquamous disorder of unknown etiology. The objective of this study was to review the clinical features and treatment responses of individuals with pityriasis lichenoides seen at a tertiary referral center.

Methods

Seventy-five patients diagnosed with pityriasis lichenoides between 1997 and 2013 were reviewed, and 46 had long-term follow-up via telephone interviews.

Results

Fifty (67%) patients were diagnosed with pityriasis lichenoides chronica, 22 (29%) with pityriasis lichenoides et varioliformis acuta, and 3 (4%) with mixed pityriasis lichenoides chronica and pityriasis lichenoides et varioliformis acuta features. Mean ± standard deviation age at onset was 12 ± 13 years (median 8 years). Disease duration was significantly shorter for patients with pityriasis lichenoides et varioliformis acuta (35 ± 35 months) than for those with pityriasis lichenoides chronica (at least 78 ± 48 months). At long-term follow-up, 23 of 28 (82%) patients with pityriasis lichenoides chronica and 3 of 16 (19%) with pityriasis lichenoides et varioliformis acuta had active disease. None progressed to lymphomatoid papulosis or cutaneous T-cell lymphoma. Ten of 23 active pityriasis lichenoides chronica cases had residual pigmentary change independent of race and lasted at least 35 ± 20 months. The most effective treatments were phototherapy (47% response rate), heliotherapy (33%), topical corticosteroids (27%), and antibiotics (25%).

Conclusion

Pityriasis lichenoides is a predominantly pediatric disorder. The time course of pityriasis lichenoides chronica is significantly longer than that of pityriasis lichenoides et varioliformis acuta. Pityriasis lichenoides chronica may persist with pigmentary alterations in the absence of other signs of active inflammation. Treatment response is often limited, particularly for patients with pityriasis lichenoides chronica.

http://ift.tt/2mfa6iB

Incidence, outcomes, and resource use in children with Stevens-Johnson syndrome and toxic epidermal necrolysis

Abstract

Background/Objectives

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions, typically to drugs or infection. The incidence and outcomes of these conditions in children are unknown. The objective of this study was to report the overall burden of Stevens-Johnson syndrome and toxic epidermal necrolysis in children in the United States.

Methods

We performed a retrospective cohort analysis of children and adolescents younger than 18 years of age using the 2009 and 2012 Kids' Inpatient Database.

Results

We identified 1486 children and adolescents hospitalized with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis. The national incidence per 100 000 was 6.3 for Stevens-Johnson syndrome, 0.7 for Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome, and 0.5 for toxic epidermal necrolysis. The highest incidence in children was in those aged 11-15 years (38.4 per 100 000). Toxic epidermal necrolysis and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome were associated with longer stay, greater mortality, and higher hospital charges than those with Stevens-Johnson syndrome. Hospital mortality was highest in children with toxic epidermal necrolysis and in children aged 0-5 years.

Conclusions

The incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in children is higher than reported in adults, and there are significant age-based variations in incidence and outcomes across the pediatric population. Further study is needed to determine the most effective treatment strategies to reduce costs and improve outcomes in children hospitalized with severe cutaneous reactions.

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Towards an international language for Incontinence-Associated Dermatitis (IAD): design and evaluation of psychometric properties of the Ghent Global IAD Categorisation Tool (GLOBIAD) in 30 countries

Summary

Background

Incontinence-associated dermatitis (IAD) is a specific type of irritant contact dermatitis with different levels of severity. An internationally accepted instrument to assess the severity of IAD in adults with established diagnostic accuracy, agreement, and reliability is needed to support clinical practice and research.

Objectives

To design and psychometrically evaluate the Ghent Global IAD Categorisation Tool (GLOBIAD).

Methods

The design was based on expert consultation using a three-round Delphi procedure with 34 experts from 13 countries. The instrument was tested using IAD photographs reflecting different severity levels in a sample of 823 health professionals in 30 countries. Measures for diagnostic accuracy (sensitivity and specificity), agreement, inter-rater reliability (multi-rater Fleiss kappa), and intra-rater reliability (Cohen's Kappa) were assessed.

Results

The GLOBIAD consists of two categories according to the presence of persistent redness (Cat.1) and skin loss (Cat.2), both subdivided based on the presence of clinical signs of infection. The agreement for differentiating between Cat.1 and Cat.2 was 0.86 [95% confidence interval (CI) 0.86-0.87], with a sensitivity of 90% and a specificity of 84%. The overall agreement was 0.55 (95%CI 0.55-0.56). The Fleiss Kappa for differentiating between Cat.1 and Cat.2 was 0.65 (95%CI 0.65-0.65). The overall Fleiss Kappa was 0.41 (95%CI 0.41-0.41). The Cohen's Kappa for differentiating between Cat.1 and Cat.2 was 0.76 (95%CI 0.75-0.77). The overall Cohen's Kappa was 0.61 (95%CI 0.59-0.62).

Conclusions

The development of the GLOBIAD is a major step forward towards a better systematic assessment of IAD in clinical practice and research worldwide. Further validation is however needed.

This article is protected by copyright. All rights reserved.

http://ift.tt/2CWu4sU

Towards an international language for Incontinence-Associated Dermatitis (IAD): design and evaluation of psychometric properties of the Ghent Global IAD Categorisation Tool (GLOBIAD) in 30 countries

Summary

Background

Incontinence-associated dermatitis (IAD) is a specific type of irritant contact dermatitis with different levels of severity. An internationally accepted instrument to assess the severity of IAD in adults with established diagnostic accuracy, agreement, and reliability is needed to support clinical practice and research.

Objectives

To design and psychometrically evaluate the Ghent Global IAD Categorisation Tool (GLOBIAD).

Methods

The design was based on expert consultation using a three-round Delphi procedure with 34 experts from 13 countries. The instrument was tested using IAD photographs reflecting different severity levels in a sample of 823 health professionals in 30 countries. Measures for diagnostic accuracy (sensitivity and specificity), agreement, inter-rater reliability (multi-rater Fleiss kappa), and intra-rater reliability (Cohen's Kappa) were assessed.

Results

The GLOBIAD consists of two categories according to the presence of persistent redness (Cat.1) and skin loss (Cat.2), both subdivided based on the presence of clinical signs of infection. The agreement for differentiating between Cat.1 and Cat.2 was 0.86 [95% confidence interval (CI) 0.86-0.87], with a sensitivity of 90% and a specificity of 84%. The overall agreement was 0.55 (95%CI 0.55-0.56). The Fleiss Kappa for differentiating between Cat.1 and Cat.2 was 0.65 (95%CI 0.65-0.65). The overall Fleiss Kappa was 0.41 (95%CI 0.41-0.41). The Cohen's Kappa for differentiating between Cat.1 and Cat.2 was 0.76 (95%CI 0.75-0.77). The overall Cohen's Kappa was 0.61 (95%CI 0.59-0.62).

Conclusions

The development of the GLOBIAD is a major step forward towards a better systematic assessment of IAD in clinical practice and research worldwide. Further validation is however needed.

This article is protected by copyright. All rights reserved.

http://ift.tt/2CWu4sU

Risk Factors Affecting the Prognosis of Descending Necrotizing Mediastinitis From Odontogenic Infection.

Related Articles

Risk Factors Affecting the Prognosis of Descending Necrotizing Mediastinitis From Odontogenic Infection.

J Oral Maxillofac Surg. 2017 Dec 13;:

Authors: Qu L, Liang X, Jiang B, Qian W, Zhang W, Cai X

Abstract
PURPOSE: Descending necrotizing mediastinitis (DNM) is a serious complication of head and neck infections and has an excessively high mortality rate owing to the lack of understanding of DNM. We assessed the clinical characteristics, diagnosis, treatment, and outcomes of odontogenic DNM and evaluated the risk factors affecting the prognosis of DNM to provide an up-to-date overview for clinical practice.
MATERIALS AND METHODS: We performed a retrospective cohort study, enrolling a sample of patients with DNM due to odontogenic infection who had been referred from January 2013 to December 2016. The patients were classified into the surviving and deceased groups. The primary predictors in the present study were the presence of multiple comorbidities, complications, demographic data (age, gender), laboratory tests (white blood cell count, percentage of neutrophils), and time (duration before diagnosis, length of hospital stay). The primary outcome variable was the patient outcome (dead or alive). The continuous variables were evaluated using Student's t test or the t test, and the categorical and binary variables were compared using the χ2 test or Fisher exact test.
RESULTS: A total of 81 patients (68 men, 13 women; median age of 57.2 ± 12.2 years) were included. The mortality was 4.9%. The most frequent cause of DNM was periapical periodontitis (66.7%). The lower posterior molars were involved in 39.5% of the cases. Treatment consisted of antibiotic therapy, aggressive transcervical mediastinal drainage (n = 74), and thoracotomy (n = 7). The associated risk factors for mortality were complications (P < .005) and severe sepsis or septic shock (P < .001) on bivariate analysis.
CONCLUSIONS: Septic shock and complications were the risk factors that correlated with a poor prognosis. A timely diagnosis and use of aggressive mediastinal drainage are fundamental to reducing the incidence of complications and the development of septic shock in odontogenic DNM patients.

PMID: 29306716 [PubMed - as supplied by publisher]

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Linear and cyclic amylose derivatives having brush like side groups in solution: Amylose tris(n-octadecylcarbamate)s

Publication date: 14 February 2018
Source:Polymer, Volume 137
Author(s): Akiyuki Ryoki, DongChan Kim, Shinichi Kitamura, Ken Terao
Seven linear amylose tris(n-octadecylcarbamate) (ATODC) samples ranging in the weight-average molar mass Mw from 2.4 × 10⁴ to 1.5 × 10⁶ g mol⁻¹ and their seven cyclic analogues (cATODC) of which Mw are from 3.6 × 10⁴ to 1.9 × 10⁵ g mol⁻¹ were prepared to characterize their conformation in tetrahydrohuran (THF), in 2-octanone (MHK), and in tert-butyl methyl ether (MTBE). Light and small-angle X-ray scattering and viscosity measurements in dilute solution were employed to determine the particle scattering function P(q), the z-average mean-square radius of gyration 〈S²〉z, and the intrinsic viscosity [η]. The obtained data were analyzed in terms of the wormlike chain model to determine the helix pitch per residue h and the Kuhn segment length λ⁻¹ which is a measure of the chain stiffness and equal to twice the persistence length. The parameters indicate that the linear ATODC has an appreciably extended local helical structure and high chain stiffness while the latter parameter λ⁻¹ in THF is lower than those for amylose alkylcarbamates with shorter side chains. This is most likely due to the repulsion between relatively long side groups. This chain extension and less stiff main chain were more significantly observed for the cyclic chains. Lyotropic liquid crystallinity in concentrated solutions supports the high rigidity of ATODC and cATODC chains in solution.

Graphical abstract

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Largely improved mechanical properties of a biodegradable polyurethane elastomer via polylactide stereocomplexation

Publication date: 14 February 2018
Source:Polymer, Volume 137
Author(s): Haili Wang, Jiangtao Yu, Huagao Fang, Haibing Wei, Xiaohong Wang, Yunsheng Ding
Thermoplastic polyurethane elastomers (PUEs) consisting of biodegradable poly (ε-caprolactone) (PCL) and low toxic aliphatic diisocyanates are of great potential in biomedical applications, but the inferior mechanical strength and elastic recovery at large strain have limited their practical utilization. Inspired by the outstanding thermal and mechanical properties of stereocomplex (SC) PLA, a thermoplastic PUE that contains SC crystallites (SC-PU) was prepared via racemically blending the PLA stereoisomers-based polyurethanes. The formation of SC crystallites in SC-PU was confirmed by WAXD and ATR-FTIR techniques. The effects of stereocomplexation on its thermal, morphological and mechanical properties were investigated. The results show that the SC crystalline domains, acting as 'additional reinforcing phases', endow the improved performance of SC-PU in tensile strength, Young's modulus, elastic recovery, and other properties. This study may provide a new method to improve the inferior mechanical properties of biodegradable PUEs based on PCL and aliphatic diisocyanates, which can contribute to the expansion of their applications in widespread fields.

Graphical abstract

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Imatinib-induced pseudoporphyria

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Imatinib-induced pseudoporphyria

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The effect of single and repeated prefrontal intermittent theta burst stimulation on cortical reactivity and working memory

Publication date: Available online 8 January 2018
Source:Brain Stimulation
Author(s): Sung Wook Chung, Nigel C. Rogasch, Kate E. Hoy, Paul B. Fitzgerald
BackgroundWith an increasing interest in the use of theta burst stimulation (TBS) as a cognitive enhancer and a potential therapeutic tool for psychiatric disorders, there is a need to identify optimal parameters of TBS in the prefrontal cortex.Objective/HypothesisThis study examined the effect of two blocks of prefrontal intermittent TBS (iTBS) on cortical reactivity and working memory performance, compared to one block of iTBS and sham stimulation. We hypothesized that greater cortical effects would be obtained with two blocks of iTBS.MethodsEighteen healthy participants attended three experimental sessions and received either sham, one block or two blocks of iTBS with a 15-min interval. Concurrent transcranial magnetic stimulation with electroencephalography (TMS-EEG) was used to assess the change in cortical reactivity via TMS-evoked potentials. Working memory performance was assessed using the N-back task. Cluster-based permutation statistics and two-way ANOVAs were used for neurophysiological and behavioural data, respectively.ResultsBoth single and two blocks of iTBS resulted in a significant increase in the amplitude of TMS-evoked N100 and P200. No significant differences were observed between active conditions in either neurophysiological changes or working memory performance, and both failed to improve working memory performance relative to sham.ConclusionsTwo blocks of iTBS did not result in stronger measured effects as compared to one block of iTBS. Future studies are needed to identify the optimal stimulation pattern in order to achieve a desired effect. It is also important to establish the best approach in quantifying neuromodulatory effects targeting the prefrontal cortex.



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Effects of TDCS dosage on working memory in healthy participants

Publication date: Available online 8 January 2018
Source:Brain Stimulation
Author(s): Stevan Nikolin, Donel Martin, Colleen K. Loo, Tjeerd W. Boonstra
BackgroundTranscranial direct current stimulation (tDCS) has been found to improve working memory (WM) performance in healthy participants following a single session. However, results are mixed and the overall effect size is small. Interpretation of these results is confounded by heterogeneous study designs, including differences in tDCS dose (current intensity) and sham conditions used.AimsWe systematically investigated the effect of tDCS dose on working memory using behavioural and neurophysiological outcomes.MethodsIn a single-blind parallel group design, 100 participants were randomised across five groups to receive 15 min of bifrontal tDCS at different current intensities (2 mA, 1 mA, and three sham tDCS conditions at 0.034 mA, 0.016 mA, or 0 mA). EEG activity was acquired while participants performed a WM task prior to, during, and following tDCS. Response time, accuracy and an event-related EEG component (P3) were evaluated.ResultsWe found no significant differences in response time or performance accuracy between current intensities. The P3 amplitude was significantly lower in the 0 mA condition compared to the 0.034 mA, 1 mA and 2 mA tDCS conditions. Changes in WM accuracy were moderately correlated with changes in frontal P3 amplitude (channel Fz) following tDCS compared to baseline levels (r = 0.34).ConclusionsWorking memory was not significantly altered by tDCS, regardless of dose. The P3 amplitude showed that stimulation at 1 mA, 2 mA and a sham condition (0.034 mA) had biological effects, with the largest effect size for 1 mA stimulation. These findings indicate higher sensitivity of neurophysiological outcomes to tDCS and suggests that sham stimulation previously considered inactive may alter neuronal function.



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Size-based separation methods of circulating tumor cells

Publication date: Available online 8 January 2018
Source:Advanced Drug Delivery Reviews
Author(s): Si-Jie Hao, Yuan Wan, Yi-Qiu Xia, Xin Zou, Si-Yang Zheng
Circulating tumor cells (CTCs) originate from the primary tumor mass and enter into the peripheral bloodstream. Compared to other "liquid biopsy" portfolios such as exosome, circulating tumor DNA/RNA (ctDNA/RNA), CTCs have incomparable advantages in analyses of transcriptomics, proteomics, and signal colocalization. Hence, CTCs hold the key to understanding the biology of metastasis and play a vital role in cancer diagnosis, treatment monitoring, and prognosis. Size-based enrichment featureS prominently in CTC isolation. It is a label-free, simple and fast method. Enriched CTCs remain unmodified and viable for a wide range of subsequent analyses. In this review, we comprehensively summarize the differences of size and deformability between CTCs and blood cells, which would facilitate the development of technologies of size-based CTC isolation. Then we review representative size-/deformability-based technologies available for CTC isolation and highlight the recent achievements in molecular analysis of isolated CTCs. To wrap up, we discuss the substantial challenges facing the field, and elaborate on prospects.

Graphical abstract

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Molecular analysis of circulating tumors cells: Biomarkers beyond enumeration

Publication date: Available online 8 January 2018
Source:Advanced Drug Delivery Reviews
Author(s): William L. Hwang, Haley M. Pleskow, David T. Miyamoto
Advances in our molecular understanding of cancer biology have paved the way to an expanding compendium of molecularly-targeted therapies, accompanied by the urgent need for biomarkers that enable the precise selection of the most appropriate therapies for individual cancer patients. Circulating biomarkers such as circulating tumor cells (CTCs) are poised to fill this need, since they are "liquid biopsies" that can be performed non-invasively and serially, and may capture the spectrum of spatial and temporal tumor heterogeneity better than conventional tissue biopsies. Increasing evidence suggests that moving beyond the enumeration of CTCs towards more sophisticated molecular analyses can provide actionable data that may predict and potentially improve clinical outcomes. In this review, we discuss the potential of molecular CTC analyses to serve as prognostic and predictive biomarkers to guide cancer therapy and early cancer detection. As technologies to capture and analyze CTCs continue to increase in sophistication, we anticipate that the potential clinical applications of CTCs will grow exponentially in the coming years.

Graphical abstract

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Movement-related neural processing in people with congenital mirror movements beyond the (cortical) surface

Publication date: Available online 8 January 2018
Source:Clinical Neurophysiology
Author(s): Renzo Manara, Alessandro Salvalaggio, Angela Favaro, Fabrizio Esposito




http://ift.tt/2CVa6xA

The cortical focus in childhood absence epilepsy; evidence from nonlinear analysis of scalp EEG recordings

Publication date: Available online 8 January 2018
Source:Clinical Neurophysiology
Author(s): Ptolemaios G Sarrigiannis, Yifan Zhao, Fei He, Stephen A Billings, Kathleen Baster, Chris Rittey, John Yianni, Panagiotis Zis, Hualiang Wei, Marios Hadjivassiliou, Richard Grünewald
ObjectiveTo determine the origin and dynamic characteristics of the generalised hyper-synchronous spike and wave (SW) discharges in childhood absence epilepsy (CAE).MethodsWe applied nonlinear methods, the error reduction ratio (ERR) causality test and cross-frequency analysis, with a nonlinear autoregressive exogenous (NARX) model, to electroencephalograms (EEGs) from CAE, selected with stringent electro-clinical criteria (17 cases, 42 absences). We analysed the pre-ictal and ictal strength of association between homologous and heterologous EEG derivations and estimated the direction of synchronisation and corresponding time lags.ResultsA frontal/fronto-central onset of the absences is detected in 13 of the 17 cases with the highest ictal strength of association between homologous frontal followed by centro-temporal and fronto-central areas. Delays consistently in excess of 4 ms occur at the very onset between these regions, swiftly followed by the emergence of "isochronous" (0-2ms) synchronisation but dynamic time lag changes occur during SW discharges.ConclusionsIn absences an initial cortico-cortical spread leads to dynamic lag changes to include periods of isochronous interhemispheric synchronisation, which we hypothesize is mediated by the thalamus.SignificanceAbsences from CAE show ictal epileptic network dynamics remarkably similar to those observed in WAG/Rij rats which guided the formulation of the cortical focus theory.



http://ift.tt/2mbEBFg

Ischemic Stroke Mandates Cross-Disciplinary Collaboration.

Author: Fisher, Marc MD; Hill, Joseph A. MD, PhD

Page: 103-105

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Prevention of "Failure": Is It a Failure of Prevention?.

Author: Nambi, Vijay MD, PhD; Deswal, Anita MD, MPH; Ballantyne, Christie M. MD

Page: 106-108

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Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline.

Author: Muntner, Paul PhD; Carey, Robert M. MD; Gidding, Samuel MD; Jones, Daniel W. MD; Taler, Sandra J. MD; Wright, Jackson T. Jr MD, PhD; Whelton, Paul K. MB, MD, MSc

Page: 109-118

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Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease.

Author: Wanner, Christoph MD; Lachin, John M. ScD; Inzucchi, Silvio E. MD; Fitchett, David MD; Mattheus, Michaela Dipl Biomath; George, Jyothis MBBS, PhD, FRCP; Woerle, Hans J. MD; Broedl, Uli C. MD; von Eynatten, Maximilian MD; Zinman, Bernard MD; On behalf of the EMPA-REG OUTCOME Investigators

Page: 119-129

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Sodium/Glucose Cotransporter 2 Inhibitors in Patients With Diabetes Mellitus and Chronic Kidney Disease: Turning the Page.

Author: Plutzky, Jorge MD; Bakris, George MD

Page: 130-133

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Influence of Baseline Diastolic Blood Pressure on Effects of Intensive Compared With Standard Blood Pressure Control.

Author: Beddhu, Srinivasan MD; Chertow, Glenn M. MD; Cheung, Alfred K. MD; Cushman, William C. MD; Rahman, Mahboob MD; Greene, Tom PhD; Wei, Guo MS; Campbell, Ruth C. MD; Conroy, Margaret MD; Freedman, Barry I. MD; Haley, William MD; Horwitz, Edward MD; Kitzman, Dalane MD; Lash, James MD; Papademetriou, Vasilios MD; Pisoni, Roberto MD; Riessen, Erik MD; Rosendorff, Clive MD, PhD; Watnick, Suzanne G. MD; Whittle, Jeffrey MD; Whelton, Paul K. MB, MD, MSc; for the SPRINT Research Group

Page: 134-143

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Benefits and Risks of Antihypertensive Treatment: How Far Can Diastolic Blood Pressure Be Lowered?.

Author: Zanchetti, Alberto MD; Thomopoulos, Costas MD

Page: 144-147

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Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Diagnosing and Ranking Its Causes Using Personalized O2 Pathway Analysis.

Author: Houstis, Nicholas E. MD, PhD; Eisman, Aaron S. BS; Pappagianopoulos, Paul P. MEd; Wooster, Luke BA; Bailey, Cole S. BA; Wagner, Peter D. MD; Lewis, Gregory D. MD

Page: 148-161

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Can Oxygen Transport Analysis Tell Us Why People With Heart Failure With Preserved Ejection Fraction Feel So Poorly?.

Author: Borlaug, Barry A. MD

Page: 162-165

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Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries.

Author: Suna, Gonca MD, PhD; Wojakowski, Wojciech MD; Lynch, Marc MSc; Barallobre-Barreiro, Javier PhD; Yin, Xiaoke PhD; Mayr, Ursula MD; Baig, Ferheen MSc; Lu, Ruifang PhD; Fava, Marika PhD; Hayward, Robert BSc; Molenaar, Chris PhD; White, Stephen J. PhD; Roleder, Tomasz MD; Milewski, Krzysztof P. MD; Gasior, Pawel MD; Buszman, Piotr P. MD; Buszman, Pawel MD; Jahangiri, Marjan MD; Shanahan, Catherine M. PhD; Hill, Jonathan MD; Mayr, Manuel MD, PhD

Page: 166-183

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Early Detection of Subclinical Myocardial Damage in Chronic Aortic Regurgitation and Strategies for Timely Treatment of Asymptomatic Patients.

Author: Lee, Joe K.T. MD; Franzone, Anna MD, PhD; Lanz, Jonas MD; Siontis, George C.M. MD, PhD; Stortecky, Stefan MD; Grani, Christoph MD; Roost, Eva MD; Windecker, Stephan MD; Pilgrim, Thomas MD

Page: 184-196

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High Costs and Caution Yield Slow Start for New Heart Drugs.

Author: Kuehn, Bridget M.

Page: 197-199

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Bayes Syndrome: What Is It?.

Author: Baranchuk, Adrian MD; Torner, Pelayo MD; de Luna, Antoni Bayes MD, PhD

Page: 200-202

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Accelerometer-Measured Physical Activity and Sedentary Behavior in Relation to All-Cause Mortality: The Women's Health Study.

Author: Lee, I-Min MBBS, ScD; Shiroma, Eric J. ScD; Evenson, Kelly R. MS, PhD; Kamada, Masamitsu PhD; LaCroix, Andrea Z. PhD; Buring, Julie E. ScD

Page: 203-205

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Risks of Overinterpreting Interim Data: Lessons From the TOTAL Trial (Thrombectomy With PCI Versus PCI Alone in Patients With STEMI).

Author: Jolly, Sanjit S. MD, MSc; Gao, Peggy MSc; Cairns, John A. MD; Yusuf, Salim MBBS, DPhil; Bhatt, Deepak L. MD, MPH; Wyse, D. George MD, PhD; Wells, George A. MSc, PhD; Dzavik, Vladimir MD

Page: 206-209

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Letter by Chen and Shen Regarding Article, "Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning".

Author: Chen, Weiqian PhD; Shen, Zhenya MD

Page: 210-211

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Response by Marban and de Couto to Letter Regarding Article, "Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning".

Author: Marban, Eduardo MD, PhD; de Couto, Geoffrey PhD

Page: 212

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Letter by Ianiro et al Regarding Article, "Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium".

Author: Ianiro, Gianluca MD; Cammarota, Giovanni MD; Gasbarrini, Antonio MD

Page: 213-214

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Letter by Jin-shan and Xue-bin Regarding Article, "Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions".

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

Page: 215-216

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Quantitative Analysis Of Lipid Debris Accumulation Caused By Cuprizone Induced Myelin Degradation In Different Cns Areas

Publication date: Available online 8 January 2018
Source:Brain Research Bulletin
Author(s): Attila Ozsvár, Róbert Szipőcs, Zoltán Ozsvár, Judith Baka, Pál Barzó, Gábor Tamás, Gábor Molnár
Degradation of myelin sheath is thought to be the cause of neurodegenerative diseases, such as multiple sclerosis (MS), but definitive agreement on mechanism of how myelin is lost is currently lacking. Autoimmune initiation of MS has been recently questioned by proposing that the immune response is a consequence of oligodendrocyte degeneration. To study the process of myelin breakdown, we induced demyelination with cuprizone and applied coherent anti-Stokes Raman scattering (CARS) microscopy, a non-destructive label-free method to image lipid structures in living tissue. We confirmed earlier results showing a brain region dependent myelin destructive effect of cuprizone. In addition, high resolution in situ CARS imaging revealed myelin debris forming lipid droplets alongside myelinated axon fibers. Quantification of lipid debris with a custom-made software for segmentation and three dimensional reconstruction revealed brain region dependent accumulation of lipid drops inversely correlated to the thickness of myelin sheaths. Finally, we confirmed that in situ CARS imaging is applicable to living human brain tissue in brain slices derived from a patient. Thus, CARS microscopy is potent tool for quantitative monitoring of myelin degradation at unprecedented spatiotemporal resolution during oligodendrocyte damage. We think that accumulation of lipid drops around degrading myelin might be instrumental in triggering subsequent inflammatory processes.



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The effects of melatonin and curcumin on the expression of SIRT2, Bcl-2 and Bax in the hippocampus of adult rats

Publication date: Available online 8 January 2018
Source:Brain Research Bulletin
Author(s): Arzu Keskin-Aktan, Kazime Gonca Akbulut, Çiğdem Yazici-Mutlu, Gizem Sonugur, Müge Ocal, Hakan Akbulut
ObjectiveThough the mechanisms are not clearly understood, melatonin and curcumin have been reported to have neuroprotective effects. However, the mechanisms of neuroprotective effects of melatonin and curcumin in the brain are not clearly understood. In the current study, we investigated the effects of melatonin and curcumin treatments on oxidative stress parameters, the expression of SIRT2, Bcl-2 and Bax in the hippocampus.MethodsA total of twenty-four adult (13 months-old) male Wistar rats were divided into four groups: Control (1% ethanol:PBS), s.c. for 30 days), dimethyl sulfoxide (10%, s.c. for 30 days), Melatonin (10 mg/kg/day, s.c. for 30 days), Curcumin (30 mg/kg/day, i.p. for 30 days) and Salermide (100 μM, i.p. for 30 days). The levels of malondialdehyde (MDA) glutathione (GSH) were measured as oxidative stress parameters in the hippocampus. The expression levels of SIRT2, Bcl-2 and Bax proteins were tested by western blotting and the SIRT2 protein levels of the hippocampal region was measured by a sandwich ELISA method.ResultsMelatonin and curcumin significantly decreased MDA and SIRT2 expression in the hippocampus (p < 0.05). Accordingly, a significant increase in the GSH levels of curcumin-treated group and melatonin-treated group was observed. Melatonin, but not curcumin, significantly increased the Bcl-2 expression of the hippocampal region. There was a significant correlation between SIRT2 and MDA levels (p < 0.05).DiscussionIn conclusion, our results suggest that melatonin may increase cell survival in the hippocampus via decreasing oxidative stress and SIRT2 expression and increasing Bcl-2 expression.



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Viable tumor in salvage neck dissections in head and neck cancer: Relation with initial treatment, change of lymph node size and human papillomavirus

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Karlijn van den Bovenkamp, Bart Dorgelo, Maartje G. Noordhuis, Bernard F.A.M. van der Laan, Bert van der Vegt, Hendrik P. Bijl, Jan L. Roodenburg, Boukje A.C. van Dijk, Sjoukje F. Oosting, Ed M.D. Schuuring, Johannes A. Langendijk, Gyorgy B. Halmos, Boudewijn E.C. Plaat
ObjectivesTo identify predictive factors for the presence of viable tumor and outcome in head and neck cancer patients who undergo therapeutic salvage neck dissections.Materials and MethodsRetrospective analysis of 76 salvage neck dissections after radiotherapy alone (n = 22), radiotherapy in combination with carboplatin/5-fluorouracil (n = 42) or with cetuximab (n = 12).ResultsViable tumor was detected in 41% of all neck dissections. Univariate analysis revealed initial treatment with radiotherapy without systemic therapy (OR 6.93, 95%CI: 2.28–21.07, p < .001), increased lymph node size after initial treatment compared to pretreatment CT scan (OR 20.48, 95%CI: 2.46–170.73, p = .005), more extensive neck dissections (OR 8.40, 95%CI: 2.94–23.98, p < .001), and human papillomavirus negative cancer (OR 4.22, 95%CI: 1.10–16.22, p = .036) as predictors of viable tumor. Patients with decreased or stable, but persistently enlarged lymph node size after chemoradiation had a significantly lower chance of viable tumor (OR 0.15, 95%CI: 0.05–0.41, p < .001). Disease-specific 5-year survival was 34% in case of viable tumor, and 78% when no viable tumor was found (p < .001).ConclusionsViable tumor in salvage neck dissections is associated with reduced survival. Radiotherapy alone, human papillomavirus negative cancer and increase in lymph node size, are associated with viable tumor in salvage neck dissections. In case of decreased or stable lymph node size after chemoradiation, watchful waiting could be considered.



http://ift.tt/2DaIyC3

Management of treatment failure in restless legs syndrome (Willis-Ekbom disease)

Dopaminergic drugs have been widely used over the last decades for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED). While the majority of studies show an initial improvement in symptoms, longer studies and clinical experience show that either treatment efficacy decreases with time, and/or augmentation develops: dopaminergic augmentation has been reported to be the main reason for treatment discontinuation and treatment failure in RLS/WED.The current review discusses the main reasons for treatment failure in RLS/WED and outlines the most recent expert-based strategies to prevent and manage it.

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Long-term outcomes after percutaneous renal cryoablation performed with adjunctive techniques

Publication date: July–August 2018
Source:Clinical Imaging, Volume 50
Author(s): Faraz Khan, Andrew M. Ho, Joseph E. Jamal, Meyer D. Gershbaum, Aaron E. Katz, Jason C. Hoffmann
ObjectiveTo review the technical success of image-guided percutaneous cryoablation of renal masses in difficult anatomic locations using adjunctive techniques to displace critical structures away from the ablation zone, while also reporting longer-term outcomes within this patient population.MethodsAn IRB approved, retrospective analysis of 92 renal masses treated with percutaneous cryoablation revealed 15 cases utilizing adjunctive techniques. Tumor size and distance to adjacent organ before and after adjunctive technique and long-term outcomes were evaluated.ResultsThe adjunctive techniques used were hydrodissection (n=15) and angioplasty balloon interposition (n=1). Before and after adjunctive technique, median tumor proximity to closest organ was 4mm and 26mm, respectively. All cases had appropriate ablation zones and protection of adjacent critical structures. There is no evidence of recurrence or complication on follow-up (median 51months).ConclusionsAdjunctive techniques to ablate renal masses in difficult locations provide technical success, safety, and favorable long-term outcomes.



http://ift.tt/2CUbxgD

Sustained improvement of psoriasis associated with HCV after virologic response to sofosbuvir/ribavirin

Publication date: Available online 8 January 2018
Source:Arab Journal of Gastroenterology
Author(s): Asem Ahmed Elfert
An 18 year old boy attended a dermatology clinic outside our hospital and diagnosed with psoriasis. His skin lesions over both ankles (Fig. 1) did not improve at all with potent local steroids twice for 3 months, then 3 times daily for another 3 months. His dermatologist talked to him about using methotrexate and asked for liver function tests before starting the systemic therapy.His ALT and AST were doubled. The patient came to our Hepatology clinic worried about his elevated liver enzymes. We asked for viral markers. His HCV-Ab was positive, and PCR for HCV-RNA was 650,000 IU/ml.Treatment started with sofosbuvir 400 mg PO once daily plus ribavirin 600 mg at the morning and 400 mg at the evening.After 4 weeks, ALT and AST decreased to normal and PCR for HCV-RNA was <5 IU/ml. All other lab tests were unremarkable. The skin lesions improved markedly (Fig. 2).Now, after 6 months of the end of treatment, sustained virologic response was documented and the skin lesions are almost disappeared without any topical or systemic treatment.



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Double-balloon enteroscopy (DBE) in patients presenting with obscure gastrointestinal bleeding (OGIB)

Publication date: Available online 8 January 2018
Source:Arab Journal of Gastroenterology
Author(s): Esmat Sheba, Ali Farag, Wael Aref, Shaimaa Elkholy, Omar Ashoush
Background and study aimsObscure gastrointestinal bleeding (OGIB) is defined as bleeding of unknown origin that persists or recurs after an initial negative investigation. Identifying the source of OGIB represents a diagnostic challenge that is frequently focused on visualizing the small intestine. Conventional diagnostic methods, such as push enteroscopy, small-bowel follow-through, radionuclide scanning, and angiography, each exhibit inherent limitations. Double balloon enteroscopy (DBE) was designed specifically to evaluate the entire small bowel. DBE allows for better visualization, biopsy of the identified lesions and application of therapeutic techniques. This study sought to assess the role of DBE in the diagnosis and management of patients with OGIB.Patients and methodsThis prospective study was conducted to analyse data from 31 patients presenting with OGIB referred for DBE in the Endoscopy Unit at the Internal Medicine Department of the Faculty of Medicine, Cairo University.ResultsFive patients had lesions in locations other than the small intestine that accounted for GI bleeding. Thus, the potential source of OGIB was defined as the small intestine in 18 of 26 patients (69.2%), and negative DBE findings were noted in eight patients (30.8%). Major findings included small intestinal tumours in eight patients, vascular bleeding lesions in 8 patients and ulcerations in 2 patients. Endoscopic haemostasis was performed in eight patients with vascular lesions. The three patients with Petuz-Jegher syndrome underwent polypectomy of their major polyps. Patients with gastrointestinal tumours were referred for surgery.ConclusionDBE is an excellent endoscopic procedure that has a relatively high diagnostic and therapeutic yield. The procedure is feasible and exhibits a high safety profile with a low complication rate when performed by an experienced endoscopist.



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A difficult diagnosis of coeliac disease: Repeat duodenal histology increases diagnostic yield in patients with concomitant causes of villous atrophy

Publication date: Available online 8 January 2018
Source:Arab Journal of Gastroenterology
Author(s): Gaetano Cristian Morreale, Luigi Maria Montalbano, Maria Cappello, Emanuele Sinagra, Aroldo Rizzo, Antonio Carroccio
Villous atrophy in absence of coeliac disease (CD)-specific antibodies represents a diagnostic dilemma. We report a case of a woman with anaemia, weight loss and diarrhoea with an initial diagnosis of seronegative CD and a histological documented villous atrophy who did not improve on gluten-free diet due to the concomitant presence of common variable immunodeficiency (CVID) and Giardia lamblia infection. This case report confirms that CD diagnosis in CVID patients is difficult; the combination of anti-endomysial antibodies (EmA-IgA), anti-tissue transglutaminase antibodies (tTG-IgAb) antibodies and total IgA is obligatory in basic diagnostic of CD but in CVID are negative. Furthermore, the typical histological aspects of the intestinal mucosa in CVID (absence of plasma cells and switch to the IgD immunoglobulins), cannot rule out a concomitant CD diagnosis. HLA typing in this setting has a low positive predictive value but should be considered. Histological response to a gluten-free diet on repeat biopsy and the concomitant treatment of other causes of villous atrophy leads to a definite diagnosis of CD.



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Inflammation induced ER stress affects absorptive intestinal epithelial cells function and integrity

Publication date: February 2018
Source:International Immunopharmacology, Volume 55
Author(s): Sucheera Chotikatum, Hassan Y. Naim, Nahed El-Najjar
Recent studies have linked impairment of intestinal epithelial function in inflammatory bowel disease to the disturbance of endoplasmic reticulum homeostasis (ER) in response to stress. Most studies are on goblet and Paneth cells, which are considered more susceptible to stress due to their role in the protection of intestinal epithelium against microbes and harmful substances. However, studies on the role of inflammation-induced ER stress in absorptive intestinal cells are scarce. In this study, we show, using Caco-2 cells as a model of intestinal epithelial barrier, that inducing ER stress using a cocktail mixture of pro-inflammatory mediators [TNFα (50ng/ml), MCP1 (50ng/ml), and IL-1β (25ng/ml)] as observed in IBD patients induces ER stress and leads to significant changes in key proteins of the apical (sucrase-isomaltase (SI), dipeptidyl-peptidase (DPPIV), and ezrin) and basolateral (E-cadherin, zonula occludens (ZO-1), and connexin-43) membranes. Aberrant trafficking of SI, DPPIV was observed as early as 8h post-inflammation-induced ER stress and even in the absence of loss of intestinal cell integrity. The observed effect was associated with a re-localization of ezrin, ZO-1, and connexin-43, key differentiation and junction proteins. Collectively, this study shows that disruption of the trafficking of key digestive enzymes of the intestinal epithelium occur in response to inflammation induced ER stress before the loss of monolayer integrity.



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Quantitative CT Assessment of Gynecomastia in the General Population and in Dialysis, Cirrhotic, and Obese Patients

Publication date: Available online 8 January 2018
Source:Academic Radiology
Author(s): Eyal Klang, Nayroz Kanana, Alon Grossman, Steve Raskin, Jana Pikovsky, Miri Sklair, Lior Heller, Shelly Soffer, Edith M. Marom, Eli Konen, Marianne Michal Amitai
Rationale and ObjectivesGynecomastia is the benign enlargement of the male breast because of proliferation of the glandular component. To date, there is no radiological definition of gynecomastia and no quantitative evaluation of breast glandular tissues in the general male population. The aims of this study were to supply radiological-based measurements of breast glandular tissue in the general male population, to quantitatively assess the prevalence of gynecomastia according to age by decades, and to evaluate associations between gynecomastia and obesity, cirrhosis, and dialysis.Materials and MethodsThis retrospective study included 506 men who presented to the emergency department following trauma and underwent chest-abdominal computed tomography. Also included were 45 patients undergoing hemodialysis and 50 patients with cirrhosis who underwent chest computed tomography. The incidence and size of gynecomastia for all the study population were calculated.ResultsBreast tissue diameters of 22 mm, 28 mm, and 36 mm corresponded to 90th, 95th, and 97.5th cumulative percentiles of diameters in the general male population. Peaks of gynecomastia were shown in the ninth decade and in boys aged 13–14 years. Breast tissue diameter did not correlate with body mass index (r = −0.031). Patients undergoing hemodialysis and patients with cirrhosis had higher percentages (P < .0001) of breast tissue diameters above 22 mm, 28 mm, and 36 mm.ConclusionsBreast tissue diameter is a simple and reliable quantitative tool for the assessment of gynecomastia. This method provides the ability to determine the incidence of gynecomastia by age in the general population. Radiological gynecomastia should be defined as 22 mm, 28 mm, or 36 mm (90th, 95th, and 97.5th percentiles, respectively). Radiological gynecomastia is not associated with obesity, but is associated with cirrhosis and dialysis.



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Tracking diet variety in childhood and its association with eating behaviours related to appetite: The generation XXI birth cohort

Publication date: 1 April 2018
Source:Appetite, Volume 123
Author(s): Sofia Vilela, Marion M. Hetherington, Andreia Oliveira, Carla Lopes
Research on the influence of early eating habits on eating behaviours related to appetite using a prospective approach is scarce, especially in children. The aim of this study was to explore the relationship between changes in diet variety from 4 to 7 years of age and appetitive traits measured at 7 years of age. Participants are from the population-based birth cohort Generation XXI (2005–2006). The present analysis included 4537 children with complete data on a food frequency questionnaire (FFQ) at both ages, and on the Children's Eating Behaviour Questionnaire at 7y. A healthy diet variety index (HDVI) was calculated at both ages using data from the FFQ. To assess tracking of diet variety, tertiles of HDVI scores were calculated and then re-categorized as 'maintain: low', 'maintain: high', 'increase' and 'decrease'. Although the HDVI score decreased from 4 to 7y (p < .001), it showed a high stability, a positive predictive value, and a fair agreement. Increasing diet variety, compared to maintaining a low variety, was inversely associated with the 'Desire to Drink' (β = −0.090, 95%CI: 0.174; −0.006) and 'Satiety Responsiveness' (β = −0.119, 95%CI: 0.184; −0.054) subdimensions and positively with 'Enjoyment of Food' (β = 0.098, 95%CI: 0.023; 0.172) and 'Emotional Overeating' (β = 0.073, 95%CI: 0.006; 0.139). Those classified as either increase or maintain a high diet variety, in comparison with maintaining a low variety, had lower scores of 'Food Fussiness'. In conclusion, diet variety decreased from 4 to 7y with a fair tracking. Children with a higher diet variety were less fussy, had a lower desire to drink and a higher general interest in food.



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Parental feeding practices to manage snack food intake: Associations with energy intake regulation in young children

Publication date: 1 April 2018
Source:Appetite, Volume 123
Author(s): Nadia Corsini, Lisa Kettler, Vanessa Danthiir, Carlene Wilson
BackgroundLittle attention has been directed to understanding the relationship between restriction and regulation of snack food intake in toddlers.ObjectiveThe aim of this study was to examine the effects of parental restriction of toddlers' eating of snacks in the absence of hunger (EAH) and to examine the impact of three contextual factors; snack food access, frequency of snack food consumption, and attraction to snack food.Design64 parents and toddlers (aged 22–36 months) took part in a protocol to measure EAH (defined as kJ of energy-dense snack foods consumed). Mean EAH was 199 kJ (SD = 299), with 43 children consuming at least some snacks. Restriction was measured with the Child Feeding Questionnaire Restriction subscale. Snack food access was measured with Allow Access from the Toddler Snack Food Feeding Questionnaire (TSFFQ), snack food consumption was measured with a short snack food frequency questionnaire, and attraction to snack foods was measured with Child's Attraction from the TSFFQ. Moderated regression analyses tested interactions between Restriction and contextual factors in predicting EAH.ResultsEAH was associated with Restriction (r = 0.25, p = .05, 95% CI 0.004 - 0.47). There was an interaction between Restriction and accessibility of snack foods (R² change = 0.08, p = .025); restriction was associated with EAH only when access to snack foods in the home was, on average, higher. The effect of Restriction on EAH was not moderated by frequency of snack food consumption or Child's Attraction.ConclusionsThese finding have practical relevance and reinforce the importance of the home food environment for managing young children's snack food intake.



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An RNA-seq screen of P. gingivalis LPS treated human gingival fibroblasts

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): Yufeng Xie, Mengjun Sun, Yiru Xia, Rong Shu
Backgroundand objective: In gingival tissues, lipopolysaccharide (LPS) from Porphyromonas gingivalis (P. gingivalis) is the most critical stimulator for inducing inflammatory response. Human gingival fibroblasts (HGFs) are the major constituents of gingival connective tissues. The aim of this study was to investigate P. gingivalis LPS induced whole transcriptional profile in HGFs and the potential crosstalk between microRNAs (miRNAs) and inflammatory cytokines.MethodsRNA-seq was performed on HGFs with and without P. gingivalis LPS treatment. The gene expression of selected inflammatory cytokines and miRNAs induced by LPS at different time points was evaluated by quantitative RT-PCR. The protein expression of chemokines was further confirmed by ELISA.ResultsInterestingly, most of the significantly changed genes (198/204) were up-regulated at 4 h after 10 μg/ml LPS stimulation, including inflammatory cytokines and miRNAs. Confirmed by quantitative RT-PCR, the mRNA levels of IL-1β, IL-6 and IL-8 showed single up-regulation peak (4 h/6 h) after 1 μg/ml and 10 μg/ml LPS treatment. Similarly, 1 μg/ml LPS induced single up-regulation peak (8 h) of miRNA-146a, −146b and −155 expression. However, 10 μg/ml LPS induced the increased expression of miRNA-146a and −155 at both early stage (2 h/4 h) and late stage (24 h).ConclusionTaken together, we investigated P. gingivalis LPS induced whole transcriptional profile, and the different behaviors of miRNA expression induced by different doses of LPS in HGFs.



http://ift.tt/2CHx200

Ultrastructural damage in Streptococcus mutans incubated with saliva and histatin 5.

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): A.M. Fernández-Presas, Y. Márquez Torres, R. García González, A. Reyes Torres, I. Becker Fauser, H. Rodríguez Barrera, B. Ruíz García, R. Toloza Medina, J. Delgado Domínguez, J.L. Molinarí Soriano
ObjectiveTo study the ultrastructural alterations induced in Streptococcus mutans (ATCC 25175) incubated with saliva, saliva plus histatin 5 and histatin 5.MethodsS. mutans incubated with saliva histatin 5 or a combination of both were morphologically analyzed and counted. The results were expressed as (CFU)ml⁻¹. Ultrastructural damage was evaluated by transmission electron microscopy. Ultrastructural localization of histatin 5 was examined using immunogold labeling. Apoptotic cell death was determined by flow cytometry (TUNEL).ResultsA decrease in the bacteria numbers was observed after incubation with saliva, saliva with histatin 5 or histatin 5 compared to the control group (p<0.0001). Ultrastructural damage in S. mutans incubated with saliva was found in the cell wall. Saliva plus histatin 5 induced a cytoplasmic granular pattern and decreased the distance between the plasma membrane bilayers, also found after incubation with histatin 5, together with pyknotic nucleoids. Histatin 5 was localized on the bacterial cell walls, plasma membranes, cytoplasm and nucleoids. Apoptosis was found in the bacteria incubated with saliva (63.9%), saliva plus histatin 5 (71.4%) and histatin 5 (29.3%). Apoptosis in the control bacteria was 0.2%.ConclusionsAntibacterial activity against S. mutans and the morphological description of damage induced by saliva and histatin 5 was demonstrated. Pyknotic nucleoids observed in S. mutans exposed to saliva, saliva plus histatin 5 and histatin 5 could be an apoptosis-like death mechanism. The knowledge of the damage generated by histatin 5 and its intracellular localization could favor the design of an ideal peptide as a therapeutic agent.



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SUPRAGINGIVAL AND SUBGINGIVAL MICROBIOTA FROM PATIENTS WITH POOR ORAL HYGIENE SUBMITTED TO RADIOTHERAPY FOR HEAD AND NECK CANCER TREATMENT

Publication date: Available online 8 January 2018
Source:Archives of Oral Biology
Author(s): Elerson Gaetti-Jardim, Ellen Cristina Gaetti Jardim, Christiane Marie Schweitzer, Júlio Cesar Leite da Silva, Murilo Moura Oliveira, Danilo Chizzolini Masocatto, Cauê Monteiro dos Santos
ObjectiveThis case-control study aimed to evaluate the effects of conventional radiotherapy (RT) on the prevalence and populations of oral microorganisms in head and neck cancer patients who did not receive adequate preventive dental care. It was hypothesized that side effects of radiotherapy could be associated with radiation dose, microbiological aspects, and socioeconomic conditions of the patients.DesignTwenty-eight dentate patients with head and neck cancer submitted to RT were included in the study. Radiation dose received varied from 4320 to 7020 cGy. Patients with the same demographic and health conditions, but no history of cancer or antineoplastic treatment were used as controls. Clinical examinations were carried out before RT, 15–22 days after starting RT, immediately after and 6 months after RT. Supra and subgingival biofilms were collected and cultivated onto selective and non-selective media. Isolates were identified by biochemical and physiological characteristics. Stimulated and unstimulated salivary flow rate and saliva buffer capacity were also determined.ResultsMucositis, dermatitis, xerostomia, dysgeusia, dysphagia and candidiasis were common after starting RT and during the treatment period. Xerostomia was followed by a decrease in salivary pH and buffer capacity, which showed association with the increase of cariogenic cocci and yeast populations, which were also associated with deterioration of hygiene. Candida and family Enterobacteriaceae showed increased prevalence with RT, and were associated with the occurrence of mucositis and xerostomia.ConclusionsModifications in oral biofilms of irradiated patients showed association with xerostomia and hygiene conditions, which reinforces the necessity of improving patient compliance to oral health care programs.



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BET’ing on Dual JAK/BET Inhibition as a Therapeutic Strategy for Myeloproliferative Neoplasms

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Qingfei Jiang, Catriona Jamieson
In this issue of Cancer Cell, Kleppe et al. describe a combination strategy designed to inhibit BET bromodomain and JAK/STAT signaling as a method for effectively inhibiting NF-κB and cytokine production in myeloproliferative neoplasms (MPNs). The results provide a strong rationale for clinical evaluation of dual BET/JAK inhibition in MPNs.

Teaser

In this issue of Cancer Cell, Kleppe et al. describe a combination strategy designed to inhibit BET bromodomain and JAK/STAT signaling as a method for effectively inhibiting NF-κB and cytokine production in myeloproliferative neoplasms (MPNs). The results provide a strong rationale for clinical evaluation of dual BET/JAK inhibition in MPNs.


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Characterizing the Killer Colorectal Carcinomas

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Stanley R. Hamilton
In this issue of Cancer Cell, Yaeger et al. report mutations, copy number variations, and selected rearrangements from a large series of metastatic colorectal carcinomas and primaries that produced metastases. The results provide important insights into differences in anatomical site of origin, age at onset, etiologic factors, and therapeutic responses.

Teaser

In this issue of Cancer Cell, Yaeger et al. report mutations, copy number variations, and selected rearrangements from a large series of metastatic colorectal carcinomas and primaries that produced metastases. The results provide important insights into differences in anatomical site of origin, age at onset, etiologic factors, and therapeutic responses.


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A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Yali Xu, Joseph P. Milazzo, Tim D.D. Somerville, Yusuke Tarumoto, Yu-Han Huang, Elizabeth L. Ostrander, John E. Wilkinson, Grant A. Challen, Christopher R. Vakoc
Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of the TAF4 histone-fold fragment can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.

Graphical abstract

Teaser

Xu et al. show that TAF12 is a coactivator of MYB and protects MYB from degradation. TAF12, in a heterodimer with TAF4, interacts with the transactivation domain of MYB. Perturbation of this interaction by squelching TAF12 impairs MYB activity and leads to regression of acute myeloid leukemia in mouse models.


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TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast Cancer

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Álvaro de Mingo Pulido, Alycia Gardner, Shandi Hiebler, Hatem Soliman, Hope S. Rugo, Matthew F. Krummel, Lisa M. Coussens, Brian Ruffell
Intratumoral CD103⁺ dendritic cells (DCs) are necessary for anti-tumor immunity. Here we evaluated the expression of immune regulators by CD103⁺ DCs in a murine model of breast cancer and identified expression of TIM-3 as a target for therapy. Anti-TIM-3 antibody improved response to paclitaxel chemotherapy in models of triple-negative and luminal B disease, with no evidence of toxicity. Combined efficacy was CD8⁺ T cell dependent and associated with increased granzyme B expression; however, TIM-3 expression was predominantly localized to myeloid cells in both human and murine tumors. Gene expression analysis identified upregulation of Cxcl9 within intratumoral DCs during combination therapy, and therapeutic efficacy was ablated by CXCR3 blockade, Batf3 deficiency, or Irf8 deficiency.

Graphical abstract

Teaser

de Mingo Pulido et al. show that intratumoral CD103⁺ dendritic cells (DCs) highly express TIM-3. Anti-TIM-3 antibody promotes CXCL9 expression by these DCs, which enhances the function of CD8⁺ T cells, thereby improving paclitaxel's therapeutic activity in breast cancer models.


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Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Dana M. Gwinn, Alex G. Lee, Marcela Briones-Martin-del-Campo, Crystal S. Conn, David R. Simpson, Anna I. Scott, Anthony Le, Tina M. Cowan, Davide Ruggero, E. Alejandro Sweet-Cordero
KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.

Teaser

Gwinn et al. show that oncogenic KRAS regulates amino acid homeostasis and cellular response to nutrient stress via ATF4. They identify ASNS as a key target of the KRAS-ATF4 axis in KRAS-driven non-small-cell lung cancer, revealing a therapeutic vulnerability in asparagine biosynthesis.


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Hedgehog Pathway Drives Fusion-Negative Rhabdomyosarcoma Initiated From Non-myogenic Endothelial Progenitors

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Catherine J. Drummond, Jason A. Hanna, Matthew R. Garcia, Daniel J. Devine, Alana J. Heyrana, David Finkelstein, Jerold E. Rehg, Mark E. Hatley
Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that histologically resembles embryonic skeletal muscle. RMS occurs throughout the body and an exclusively myogenic origin does not account for RMS occurring in sites devoid of skeletal muscle. We previously described an RMS model activating a conditional constitutively active Smoothened mutant (SmoM2) with aP2-Cre. Using genetic fate mapping, we show SmoM2 expression in Cre-expressing endothelial progenitors results in myogenic transdifferentiation and RMS. We show that endothelium and skeletal muscle within the head and neck arise from Kdr-expressing progenitors, and that hedgehog pathway activation results in aberrant expression of myogenic specification factors as a potential mechanism driving RMS genesis. These findings suggest that RMS can originate from aberrant development of non-myogenic cells.

Graphical abstract

Teaser

Using genetic fate mapping, Drummond et al. show that hedgehog pathway activation in endothelial progenitors results in aberrant expression of myogenic specification factors, myogenic transdifferentiation, and rhabdomyosarcoma (RMS). The finding may explain how RMS develops in sites devoid of skeletal muscle.


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Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Rona Yaeger, Walid K. Chatila, Marla D. Lipsyc, Jaclyn F. Hechtman, Andrea Cercek, Francisco Sanchez-Vega, Gowtham Jayakumaran, Sumit Middha, Ahmet Zehir, Mark T.A. Donoghue, Daoqi You, Agnes Viale, Nancy Kemeny, Neil H. Segal, Zsofia K. Stadler, Anna M. Varghese, Ritika Kundra, Jianjiong Gao, Aijazuddin Syed, David M. Hyman, Efsevia Vakiani, Neal Rosen, Barry S. Taylor, Marc Ladanyi, Michael F. Berger, David B. Solit, Jinru Shia, Leonard Saltz, Nikolaus Schultz
Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.

Graphical abstract

Teaser

Yaeger et al. perform prospective sequencing of metastatic colorectal cancers (mCRCs). Right-sided primary microsatellite stable mCRCs are associated with increased oncogenic mutations whereas most left-sided tumors lack identifiable genetic mitogenic signaling alterations but highly express mitogenic ligands.


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Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): A. Gordon Robertson, Juliann Shih, Christina Yau, Ewan A. Gibb, Junna Oba, Karen L. Mungall, Julian M. Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M. Lichtenberg, Melanie Kucherlapati, Patrick K. Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A. Bristow, Katherine A. Hoadley, Lisa Iype, Matthew T. Chang, Andrew D. Cherniack, Christopher Benz, Gordon B. Mills, Roel G.W. Verhaak, Klaus G. Griewank, Ina Felau, Jean C. Zenklusen, Jeffrey E. Gershenwald, Lynn Schoenfield, Alexander J. Lazar, Mohamed H. Abdel-Rahman, Sergio Roman-Roman, Marc-Henri Stern, Colleen M. Cebulla, Michelle D. Williams, Martine J. Jager, Sarah E. Coupland, Bita Esmaeli, Cyriac Kandoth, Scott E. Woodman




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Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Xuxu Sun, Sam C. Wang, Yonglong Wei, Xin Luo, Yuemeng Jia, Lin Li, Purva Gopal, Min Zhu, Ibrahim Nassour, Jen-Chieh Chuang, Thomas Maples, Cemre Celen, Liem H. Nguyen, Linwei Wu, Shunjun Fu, Weiping Li, Lijian Hui, Feng Tian, Yuan Ji, Shuyuan Zhang, Mahsa Sorouri, Tae Hyun Hwang, Lynda Letzig, Laura James, Zixi Wang, Adam C. Yopp, Amit G. Singal, Hao Zhu




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Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Qianghu Wang, Baoli Hu, Xin Hu, Hoon Kim, Massimo Squatrito, Lisa Scarpace, Ana C. deCarvalho, Sali Lyu, Pengping Li, Yan Li, Floris Barthel, Hee Jin Cho, Yu-Hsi Lin, Nikunj Satani, Emmanuel Martinez-Ledesma, Siyuan Zheng, Edward Chang, Charles-Etienne Gabriel Sauvé, Adriana Olar, Zheng D. Lan, Gaetano Finocchiaro, Joanna J. Phillips, Mitchel S. Berger, Konrad R. Gabrusiewicz, Guocan Wang, Eskil Eskilsson, Jian Hu, Tom Mikkelsen, Ronald A. DePinho, Florian Muller, Amy B. Heimberger, Erik P. Sulman, Do-Hyun Nam, Roel G.W. Verhaak




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11q23 deletion syndrome (Jacobsen syndrome) with severe bleeding: a case report

11q23 deletion syndrome, also known as Jacobsen syndrome, is characterized by growth retardation, psychomotor retardation, facial dysmorphism, multiple congenital abnormalities, and thrombocytopenia. In 11q23 ...

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Anesthesia for Same Day Discharge After Craniotomy: Review of a Single Center Experience

Same day discharge or outpatient surgery for intracranial procedures has become possible with the advent of image-guided minimally invasive approaches to surgery and availability of short-acting anesthetic agents. In addition, patient satisfaction and the benefits of avoiding hospital stay have resulted in the evolution of neurosurgical day surgery. We reviewed our experience and the available literature to determine the perioperative factors involved which have promoted and will improve this concept in the future. Craniotomy and biopsy for supratentorial brain tumors and surgical clipping of intact cerebral aneurysms have been successfully performed as day surgeries. Patient perceptions and satisfaction surveys have helped in better understanding and delivery of care and successful outcomes. There are major differences in health care across the globe along with socioeconomic, medicolegal, and ethical disparities, which must be considered before widespread application of this approach. Nevertheless, collaborative effort by surgeons, anesthesiologists, and nurses can help in same day discharge of patients after cranial neurosurgery. Veena Sheshadri, MD, Department of Neuroanesthesia and Neurocritical Care, Gleneagles Global Hospitals, Bengaluru, Karnataka, India. All the authors contributed substantially to the conception and design of the manuscript and to the interpretation of data. S.V., V.L., and M.P.: contributed to the literature search, acquisition, and analysis of data. The authors have no funding or conflicts of interest to disclose. Address correspondence to: Lashmi Venkatraghavan, MD, FRCA, FRCPC, Department of Anesthesia, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada (e-mail: lashmi.venkatraghavan@uhn.on.ca). Received May 29, 2017 Accepted November 28, 2017 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

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Innate Sex Bias of Staphylococcus aureus Skin Infection Is Driven by {alpha}-Hemolysin [INFECTIOUS DISEASE AND HOST RESPONSE]

Numerous studies have reported sex bias in infectious diseases, with bias direction dependent on pathogen and site of infection. Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs), yet sex bias in susceptibility to S. aureus SSTI has not been described. A search of electronic health records revealed an odds ratio of 2.4 for S. aureus SSTI in males versus females. To investigate the physiological basis of this bias, we compared outcomes between male and female mice in a model of S. aureus dermonecrosis. Consistent with the epidemiological data, female mice were better protected against SSTI, with reduced dermonecrosis followed later by increased bacterial clearance. Protection in females was disrupted by ovariectomy and restored by short-term estrogen administration. Importantly, this sex bias was mediated by a sex-specific response to the S. aureus–secreted virulence factor α-hemolysin (Hla). Infection with wild-type S. aureus suppressed inflammatory cytokine production in the skin of female, but not male, mice when compared with infection with an isogenic hla deletion mutant. This differential response was conserved following injection with Hla alone, demonstrating a direct response to Hla independent of bacterial burden. Additionally, neutrophils, essential for clearing S. aureus, demonstrated sex-specific S. aureus bactericidal capacity ex vivo. This work suggests that sex-specific skin innate responsiveness to Hla and neutrophil bactericidal capacity play important roles in limiting S. aureus SSTI in females. Understanding the molecular mechanisms controlling this sex bias may reveal novel targets to promote host innate defense against S. aureus skin infection.

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Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis [INNATE IMMUNITY AND INFLAMMATION]

In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca²⁺-dependent mechanisms causing pathological bone loss. Ca²⁺-dependent CREB/c-fos activation via Ca²⁺-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca²⁺ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca²⁺-activated K⁺ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca²⁺-induced NFAT-dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-B ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1^–/– and TRAM-34 treatment significantly reduced the expression of osteoclast-specific genes (p < 0.05) alongside decreased osteoclast formation (p < 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca²⁺ imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca²⁺ amplitudes in BMMs by ~50% (p < 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1^–/– reduced RANKL+/–TNF-stimulated phosphorylation of CREB and expression of c-fos in BMMs (p < 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity (p < 0.01). These data indicate that KCa3.1 regulates Ca²⁺-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis.

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Cytoplasmic Linker Protein CLIP170 Negatively Regulates TLR4 Signaling by Targeting the TLR Adaptor Protein TIRAP [INNATE IMMUNITY AND INFLAMMATION]

Cytoplasmic linker protein 170 (CLIP170) is a CAP-Gly domain–containing protein that is associated with the plus end of growing microtubules and implicated in various cellular processes, including the regulation of microtubule dynamics, cell migration, and intracellular transport. Our studies revealed a previously unrecognized property and role of CLIP170. We identified CLIP170 as one of the interacting partners of Brucella effector protein TcpB that negatively regulates TLR2 and TLR4 signaling. In this study, we demonstrate that CLIP170 interacts with the TLR2 and TLR4 adaptor protein TIRAP. Furthermore, our studies revealed that CLIP170 induces ubiquitination and subsequent degradation of TIRAP to negatively regulate TLR4-mediated proinflammatory responses. Overexpression of CLIP170 in mouse macrophages suppressed the LPS-induced expression of IL-6 and TNF-α whereas silencing of endogenous CLIP170 potentiated the levels of proinflammatory cytokines. In vivo silencing of CLIP170 in C57BL/6 mice by CLIP170-specific small interfering RNA enhanced LPS-induced IL-6 and TNF-α expression. Furthermore, we found that LPS modulates the expression of CLIP170 in mouse macrophages. Overall, our experimental data suggest that CLIP170 serves as an intrinsic negative regulator of TLR4 signaling that targets TIRAP.

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Foxp1 Negatively Regulates T Follicular Helper Cell Differentiation and Germinal Center Responses by Controlling Cell Migration and CTLA-4 [IMMUNE REGULATION]

T follicular helper (Tfh) cells play an essential role in the formation of germinal centers (GC) and generation of high-affinity Abs. The homing of activated CD4⁺ T cells into B cell follicles and the involvement of key costimulatory and coinhibitory molecules are critical in controlling both the initiation and the magnitude of GC responses. Meanwhile, studies have shown that a high number of single clone B cells leads to intraclonal competition, which inhibits the generation of high-affinity Abs. Our previous work has shown that transcription factor Foxp1 is a critical negative regulator of Tfh cell differentiation. In this study, we report that the deletion of Foxp1 leads to a high proportion of activated CD4⁺ T cells homing into B cell follicles with faster kinetics, resulting in earlier GC formation. In addition, we show that Foxp1-deficient Tfh cells restore the generation of high-affinity Abs when cotransferred with high numbers of single clone B cells. We find that Foxp1 regulates the expression levels of cytotoxic T lymphocyte–associated Ag-4 (CTLA-4) in activated CD4⁺ T cells and that Ctla4 is a direct Foxp1 target. Finally, we demonstrate that CTLA-4 expression on conventional CD4⁺ T cells plays a cell-intrinsic role in Tfh cell differentiation in vivo, and CTLA-4 blockade helps abolish the intraclonal competition of B cells in generating high-affinity Abs.

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Osteoblasts Are Rapidly Ablated by Virus-Induced Systemic Inflammation following Lymphocytic Choriomeningitis Virus or Pneumonia Virus of Mice Infection in Mice [INFECTIOUS DISEASE AND HOST RESPONSE]

A link between inflammatory disease and bone loss is now recognized. However, limited data exist on the impact of virus infection on bone loss and regeneration. Bone loss results from an imbalance in remodeling, the physiological process whereby the skeleton undergoes continual cycles of formation and resorption. The specific molecular and cellular mechanisms linking virus-induced inflammation to bone loss remain unclear. In the current study, we provide evidence that infection of mice with either lymphocytic choriomeningitis virus (LCMV) or pneumonia virus of mice (PVM) resulted in rapid and substantial loss of osteoblasts from the bone surface. Osteoblast ablation was associated with elevated levels of circulating inflammatory cytokines, including TNF-α, IFN-, IL-6, and CCL2. Both LCMV and PVM infections resulted in reduced osteoblast-specific gene expression in bone, loss of osteoblasts, and reduced serum markers of bone formation, including osteocalcin and procollagen type 1 N propeptide. Infection of Rag-1–deficient mice (which lack adaptive immune cells) or specific depletion of CD8⁺ T lymphocytes limited osteoblast loss associated with LCMV infection. By contrast, CD8⁺ T cell depletion had no apparent impact on osteoblast ablation in association with PVM infection. In summary, our data demonstrate dramatic loss of osteoblasts in response to virus infection and associated systemic inflammation. Further, the inflammatory mechanisms mediating viral infection-induced bone loss depend on the specific inflammatory condition.

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Time-Restricted Feeding Alters the Innate Immune Response to Bacterial Endotoxin [INNATE IMMUNITY AND INFLAMMATION]

An important entraining signal for the endogenous circadian clock, independent of light, is food intake. The circadian and immune systems are linked; forced desynchrony of the circadian clock via nighttime light exposure or genetic ablation of core clock components impairs immune function. The timing of food intake affects various aspects of the circadian clock, but its effects on immune function are unknown. We tested the hypothesis that temporal desynchrony of food intake alters innate immune responses. Adult male Swiss Webster mice were provided with food during the night, the day, or ad libitum for 4 wk, followed by administration of LPS prior to the onset of either the active phase (zeitgeber time [ZT]12: Experiment 1) or the inactive phase (ZT0: Experiment 2). Three hours after LPS administration, blood was collected, and serum was tested for bacteria-killing capacity against Escherichia coli, as a functional assay of immune function. Additionally, cytokine expression was examined in the serum (protein), spleen, and hypothalamus (mRNA). Day-fed mice suppressed bacteria-killing capacity and serum cytokine responses to LPS during the active phase (ZT12). Night-fed mice increased bactericidal capacity, as well as serum and hypothalamic mRNA responses of certain proinflammatory cytokines during the active phase. Only day-fed mice enhanced serum cytokine responses when LPS challenge occurred during the inactive phase (ZT0); this did not result in enhanced bactericidal capacity. These data suggest that mistimed feeding has functional relevance for immune function and provide further evidence for the integration of the circadian, metabolic, and immune systems.

http://ift.tt/2maVP5E

mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production [INNATE IMMUNITY AND INFLAMMATION]

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE₂, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE₂ levels and is highly expressed at sites of inflammation. PGE₂ is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen–CFA immunization response, lack of mPGES1 impaired the numbers of CD4⁺ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1^–/– CD4⁺ cells showed impaired IL-17A, IFN-, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE₂ by cocultured APCs synergized with that of Ag-experienced CD4⁺ T cells, with mPGES1 competence in the APC compartment enhancing CD4⁺ IL-17A and IFN- responses. However, in contrast with CD4⁺ cells that were Ag primed in vivo, exogenous PGE₂ inhibited proliferation and skewed IL-17A to IFN- production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE₂ production that impacts effector T cell IL-17A and IFN- responses.

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In This Issue [IN THIS ISSUE]

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Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-{beta}-Mediated Tumor Immune Evasion [TUMOR IMMUNOLOGY]

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4⁺ T cells that sequester Pam₃Cys₄ (CD4⁺ T^Pam3) become primed for T_h1 differentiation. CD4⁺ T^Pam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β–OVA–expressing thymomas, produce high amounts of IFN- and sensitize tumors to PD-1/programmed cell death ligand 1 blockade–induced rejection. In contrast, naive OT2 cells without Pam₃Cys₄ cargo are prone to TGF-β–dependent inducible regulatory Foxp3⁺ CD4⁺ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4⁺ T^Pam3 cells are resistant to TGF-β–mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88–dependent PI3K signaling pathway. These data show that CD4⁺ T^Pam3 cells are capable of T_h1 differentiation in the presence of TGF-β, suggesting a novel approach to adoptive cell therapy.

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