Japanese guidelines for adult asthma 2017

Publication date: Available online 11 February 2017
Source:Allergology International
Author(s): Masakazu Ichinose, Hisatoshi Sugiura, Hiroyuki Nagase, Masao Yamaguchi, Hiromasa Inoue, Hironori Sagara, Jun Tamaoki, Yuji Tohda, Mitsuru Munakata, Kohei Yamauchi, Ken Ohta
Adult bronchial asthma is characterized by chronic airway inflammation, and presents clinically with variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma induces airway remodeling, leading to intractable asthma. The number of patients with asthma has increased; however, the number of patients who die of asthma has decreased (1.2 per 100,000 patients in 2015). The goal of asthma treatment is to enable patients with asthma to attain normal pulmonary function and lead a normal life, without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management by therapeutic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high levels. Long-acting β2-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonist are recommended as add-on drugs, while anti-immunoglobulin E antibody and oral steroids are considered for the most severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled β2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by choosing treatment steps for asthma in accordance with the severity of exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-induced asthma, and pregnancy are also important issues that need to be considered in asthma therapy.



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Screening for Prostate Cancer

Publication date: Available online 11 February 2017
Source:Seminars in Oncology
Author(s): Rosalyn W. Stewart, Sergio Lizama, Kimberly Peairs, Heather F. Sateia, Youngjee Choi
This review comprises a general overview of the impact and risk factors for prostate cancer. Evidenced-based professional society prostate cancer screening guideline recommendations are reviewed, and our approach to a case is presented.



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Isotrifoliol inhibits pro-inflammatory mediators by suppression of TLR/NF-κB and TLR/MAPK signaling in LPS-induced RAW264.7 cells

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Hua Li, Jeong-Hyun Yoon, Hyo-Jun Won, Hyeon-Seon Ji, Heong Joo Yuk, Ki Hun Park, Ho-Yong Park, Tae-Sook Jeong
Soybeans, produced by Glycine max (L.) Merr., contain high levels of isoflavones, such as genistein and daidzein. However, soy leaves contain more diverse and abundant flavonol glycosides and coumestans, as compared to the soybean. This study investigated the anti-inflammatory effects of the major coumestans present in soy leaf (coumestrol, isotrifoliol, and phaseol) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Coumestans significantly reduced LPS-induced nitric oxide (NO), prostaglandin E2 (PGE2), and reactive oxygen species (ROS) production; isotrifoliol had the most potent anti-inflammatory activity. Isotrifoliol reduced LPS-mediated induction of mRNA expression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNFα), and chemokines, such as chemokine (C-C motif) ligand (CCL) 2, CCL3, and CCL4. Isotrifoliol prevented NF-κB p65 subunit activation by reducing the phosphorylation and degradation of the inhibitor of NF-κB. And isotrifoliol significantly suppressed phosphorylation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). Furthermore, isotrifoliol suppressed LPS-induced Toll-like Receptor (TLR) signaling pathway, including mRNA expression of TNF receptor associated factor 6, transforming growth factor beta-activated kinase 1 (TAK1), TAK1 binding protein 2 (TAB2), and TAB3. These results demonstrate that isotrifoliol exerts an anti-inflammatory effect by suppressing the expression of inflammatory mediators via inhibition of TLR/NF-κB and TLR/MAPK signaling in LPS-induced RAW264.7 macrophages. Therefore, isotrifoliol can be used as an anti-inflammatory agent, and coumestan-rich soy leaf extracts may provide a useful dietary supplement.

Graphical abstract

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Offering Hope in Healthcare: An Important Nursing Reality

             Hope is an important nursing reality as most patients need hope to cope with their stressors and improve the quality of life (Hammer, Mogensen, & Hall, 2009; Alidina & Tettero, 2010). Hope is mainly needed ...

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Chemotherapy in Advanced Age – Weighing a Hefty Cost against Slim Odds of Success

Elderly patients are predicted to represent, in the near future, the largest group of cancer patients. This demographic is already coming into place, with a longer average lifespan and improved access to medical facilities. Thus ...

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Combined subjective and quantitative analysis of magnetic resonance images could improve the diagnostic performance of deep myometrial invasion in endometrial cancer

Publication date: Available online 10 February 2017
Source:Clinical Imaging
Author(s): Lei Deng, Qiu-ping Wang, Rui Yan, Nan Yu, Lu Bai, Xiao-yi Duan, You-min Guo
PurposeTo evaluate whether the combination of subjective magnetic resonance imaging (MRI) and quantitative analysis by using the exponential ADC (EADC) value of the peri-endometrial zone can improve the diagnostic performance of deep myometrial invasion in endometrial cancer patients.Materials and methodsWe prospectively evaluated 111 patients with either cervical cancer (normal endometria group) or endometrial cancer (endometrial cancer group). Two radiologists assessed all preoperative MR images with T1, T2, and diffusion-weighted imaging. The EADC value of the peri-endometrial zone was measured. Sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic curve (Az) were calculated for Subjective MRI, an EADC cutoff value of the peri-endometrial zone and the combination of the two methods in assessing the prediction of deep myometrial invasion.ResultsSpecificity for EADC cutoff of the peri-endometrial zone was higher (0.93) than for Subjective MRI (0.80), as were the positive predictive values (EADC, 0.79; visual, 0.60). Sensitivity for the combined test was higher (0.88) than for Subjective MRI (0.71) and the EADC cutoff value (0.65), as were the negative predictive values (the combined test, 0.94; vs. EADC, 0.79; vs. Subjective MRI, 0.60). There were no differences in Az between the three methods (P>0.05), but the combined test had the highest Az.ConclusionsCombined with conventional Subjective MRI, calculating EADC value of the peri-endometrial zone could improve the accuracy of preoperative assessment of deep myometrial invasion in endometrial cancer patients, and maybe helpful in tailoring a surgical approach for intervention.



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Cost-effectiveness of diagnostic evaluation strategies for individuals with stable chest pain syndrome and suspected coronary artery disease

Publication date: Available online 10 February 2017
Source:Clinical Imaging
Author(s): James K. Min, Amanda Gilmore, Erica C. Jones, Daniel S. Berman, Wijnand J. Stuijfzand, Leslee J. Shaw, Ken O'Day, Ibrahim Danad
PurposeTo determine lifetime cost-effectiveness of diagnostic evaluation strategies for individuals with stable chest pain and suspected coronary artery disease (CAD).MethodsExercise treadmill testing (ETT), stress echocardiography (SE), myocardial perfusion scintigraphy (MPS), coronary computed tomographic angiography (CCTA), and invasive coronary angiography (ICA) were assessed alone, or in succession to each other.ResultsInitial ETT followed by imaging wherein ETT was equivocal or unable to be performed appeared more cost-effective than any strategy employing initial testing by imaging.ConclusionAs pre-test likelihood of CAD varies, different modalities including SE, CCTA, and MPS result in improved costs and enhanced effectiveness.



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Safety of the oral cholera vaccine in pregnancy: Retrospective findings from a subgroup following mass vaccination campaign in Dhaka, Bangladesh

Publication date: Available online 11 February 2017
Source:Vaccine
Author(s): Ashraful Islam Khan, Mohammad Ali, Fahima Chowdhury, Amit Saha, Iqbal Ansary Khan, Arifuzzaman Khan, Afroza Akter, Muhammad Asaduzzaman, Md. Taufiqul Islam, Alamgir Kabir, Young Ae You, Nirod Chandra Saha, Alejandro Cravioto, John D. Clemens, Firdausi Qadri
BackgroundPregnant women are vulnerable to complications of cholera. Killed oral cholera vaccines (OCV) are not recommended for pregnant women though there is no evidence of harmful effects during pregnancy. We evaluated the effect of a killed OCV, Shanchol™, on pregnancy outcomes during an effectiveness trial of the vaccine in urban Bangladesh.MethodologyIndividuals ⩾1year were invited to participate in the trial, conducted in 2011 in Dhaka, Bangladesh. Pregnancy by history was an exclusion criterion and all women of reproductive age (15–49years) were verbally questioned about pregnancy at enrollment and prior to vaccination. Out of 48,414 women of reproductive age 286 women received the OCV unknowingly while pregnant. Out of these, we could recruit 69 women defined as exposed to OCV. Accordingly, we selected 69 pregnant women randomly from those who did not take the OCV (non-exposed to OCV). We evaluated adverse pregnancy outcome (spontaneous miscarriages, still births, or congenital malformations) between those who were exposed to OCV and those who were not exposed to OCV.ResultsAbout 16% of pregnant women exposed to OCV had pregnancy loss, as compared to 12% of unvaccinated pregnant women (P=0.38). One congenital anomaly was observed and occurred in women non-exposed to OCV group. Models that adjusted for baseline characteristics that were unbalanced between the exposed and non-exposed groups, revealed a no elevation of risk of adverse pregnancy outcomes in vaccinees versus non-vaccinees (Adj. OR (95% CI): 0.45 (0.11–1.88).ConclusionsNo excess of adverse fetal outcomes associated with receipt of OCV was observed in this study.Trial registration: Clinical Trials.gov number NCT01339845.



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Effect of Dual-mode and Dual-site Non-invasive Brain Stimulation on Freezing of Gait in Patients with Parkinson’s Disease

Publication date: Available online 11 February 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Won Hyuk Chang, Min Soo Kim, Eunhee Park, Jin Whan Cho, Jinyoung Youn, Yun Kwan Kim, Yun-Hee Kim
ObjectiveTo investigate the effect of dual-mode non-invasive brain stimulation (NIBS) with high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex of the lower leg and anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex compared with rTMS alone in patients with Parkinson's disease (PD) with freezing of gait (FOG).DesignRandomized, double-blind, controlled study.SettingOutpatient rehabilitation clinics.ParticipantsThirty-two patients diagnosed as PD with FOG.InterventionsPatients in the dual-mode group underwent five consecutive daily sessions of dual-mode NIBS with high-frequency rTMS and tDCS simultaneously, whereas patients in the rTMS group underwent high-frequency rTMS and sham tDCS.Main Outcome MeasureAssessments of FOG, motor, ambulatory and cognitive function were performed three times: at baseline before NIBS, immediately after NIBS, and one week after cessation of NIBS.ResultsSerious adverse effects were not observed in either group. Significant changes over time were observed in FOG, motor and ambulatory function in each group, although there was no significant difference between the two groups. Executive function showed significant improvement after NIBS only in the dual-mode group.ConclusionsThese results suggest the potential for dual-mode NIBS to modulate two different cortices simultaneously. Dual-mode NIBS might be considered a novel therapeutic approach for patients with PD.



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Relying on Restraints in Psychiatric Settings: Distasteful yet Necessary?

In a medical context, restraint is defined as "forcible confinement or control of a subject, as of a confused, disoriented, psychotic, or irrational person". Counsel and Care UK, (2002) calls it the "intentional restriction of ...

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Vacuum-assisted decellularization: an accelerated protocol to generate tissue-engineered human tracheal scaffolds

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Colin R. Butler, Robert E. Hynds, Claire Crowley, Kate H.C. Gowers, Leanne Partington, Nicholas J. Hamilton, Carla Carvalho, Manuela Platé, Edward R. Samuel, Alan J. Burns, Luca Urbani, Martin A. Birchall, Mark W. Lowdell, Paolo De Coppi, Sam M. Janes
Patients with large tracheal lesions unsuitable for conventional endoscopic or open operations may require a tracheal replacement but there is no present consensus of how this may be achieved. Tissue engineering using decellularized or synthetic tracheal scaffolds offers a new avenue for airway reconstruction. Decellularized human donor tracheal scaffolds have been applied in compassionate-use clinical cases but naturally derived extracellular matrix (ECM) scaffolds demand lengthy preparation times. Here, we compare a clinically applied detergent-enzymatic method (DEM) with an accelerated vacuum-assisted decellularization (VAD) protocol. We examined the histological appearance, DNA content and extracellular matrix composition of human donor tracheae decellularized using these techniques. Further, we performed scanning electron microscopy (SEM) and biomechanical testing to analyze decellularization performance. To assess the biocompatibility of scaffolds generated using VAD, we seeded scaffolds with primary human airway epithelial cells in vitro and performed in vivo chick chorioallantoic membrane (CAM) and subcutaneous implantation assays. Both DEM and VAD protocols produced well-decellularized tracheal scaffolds with no adverse mechanical effects and scaffolds retained the capacity for in vitro and in vivo cellular integration. We conclude that the substantial reduction in time required to produce scaffolds using VAD compared to DEM (approximately 9 days vs. 3–8 weeks) does not compromise the quality of human tracheal scaffold generated. These findings might inform clinical decellularization techniques as VAD offers accelerated scaffold production and reduces the associated costs.



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Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Wei Zhu, Xin Qu, Jie Zhu, Xuanyi Ma, Sherrina Patel, Justin Liu, Pengrui Wang, Cheuk Sun Edwin Lai, Maling Gou, Yang Xu, Kang Zhang, Shaochen Chen
Living tissues rely heavily on vascular networks to transport nutrients, oxygen and metabolic waste. However, there still remains a need for a simple and efficient approach to engineer vascularized tissues. Here, we created prevascularized tissues with complex three-dimensional (3D) microarchitectures using a rapid bioprinting method – microscale continuous optical bioprinting (μCOB). Multiple cell types mimicking the native vascular cell composition were encapsulated directly into hydrogels with precisely controlled distribution without the need of sacrificial materials or perfusion. With regionally controlled biomaterial properties the endothelial cells formed lumen-like structures spontaneously in vitro. In vivo implantation demonstrated the survival and progressive formation of the endothelial network in the prevascularized tissue. Anastomosis between the bioprinted endothelial network and host circulation was observed with functional blood vessels featuring red blood cells. With the superior bioprinting speed, flexibility and scalability, this new prevascularization approach can be broadly applicable to the engineering and translation of various functional tissues.



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Editorial board

Publication date: April 2017
Source:Biomaterials, Volume 123





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I act, therefore I err: EEG correlates of success and failure in a virtual throwing game

Publication date: Available online 11 February 2017
Source:International Journal of Psychophysiology
Author(s): Boris Yazmir, Miriam Reiner
What are the neural responses to success and failure in a throwing task? To answer this question, we compared Event Related Potentials (ERPs) correlated with success and failure during a highly-ecological-virtual game. Participants played a tennis-like game in an immersive 3D virtual world, against a computer player, by controlling a virtual tennis racket with a force feedback robotic arm.Results showed that success, i.e. hitting the target, and failure, by missing the target, evoked ERP's that differ by peak, latencies, scalp signal distributions, sLORETA source estimation, and time-frequency patterns. The success related grand averaged ERP at the Cz electrode, had two peaks - a negative peak at 244ms and a positive peak at 12ms, prior to the actual successful hit, suggesting a possible process of prediction of success. The grand averaged ERP correlated with failure at Cz, had two peaks, a negative peak at about 107ms and a positive peak at about 311ms post failure. These results suggest different top-down and bottom-up loops for success and failure, which seem to be rooted in the spatial arrangement of the virtual game. Although the latency of the latter is consistent with the error related potentials reported in the literature, the characteristic is unique to this specific error, and differ significantly from other error related potentials in the same environment. These results further provide a basis for EEG based assessment and prediction of user's successful or erroneous movements, and design of the feedback loop in EEG based Brain-Computer Interfaces.



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Effectiveness of photodynamic therapy in Bowen's disease: a retrospective observational study in 423 lesions

Abstract

Background

Photodynamic therapy (PDT) is a well-known technique that is often used for treating superficial precancerous and cancerous skin lesions. However, only a handful of studies, with a relatively small number of treated lesions, have been carried out on the effectiveness of PDT for Bowen's disease (BD).

Objectives

This study aimed to assess the effectiveness and recurrence risk of PDT in the treatment of BD. The secondary objectives were to determine what factors affected the response rates and the cosmetic result of the treatment.

Method

In this retrospective observational study, the electronic patient charts at Sahlgrenska University Hospital (SUH) in Gothenburg, Sweden were searched to find all patients diagnosed with BD that were treated with PDT between January 1, 2002 and December 31, 2014. Data was collected regarding clinical response at the first follow-up visit, recurrences during later follow-up visits and other relevant patient and tumour characteristics.

Results

In total, 423 BD lesions in 335 patients were included in the study. The mean FU duration was 11.2 months (range 0.2-151 months). The complete response rate at the first FU visit was 77.5% for all BD lesions. During later FU visits, another 60 recurrences were observed, which resulted in a recurrence rate of 18.3%. Thus, the overall clearance rate after FU was 63.4% for all BD lesions. Significant risk factors for unsuccessful treatment in the present study were large lesion size (>2cm) and a single PDT session.

Conclusion

This study shows that PDT is a relatively effective treatment modality for BD.

This article is protected by copyright. All rights reserved.

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Expression of programmed death-1 in cutaneous extranodal natural killer/T-cell lymphoma and its effect on clinical findings and biological behavior

Abstract

Background

Recent studies have evaluated the expression of programmed death-1 (PD-1) and its prognostic value in malignant T-cell lymphomas.

Objectives

This study investigated whether the positivity of PD-1 was associated with the clinical characteristics of cutaneous extranodal NK/T-cell lymphoma (ENKTL) and evaluated its effects on survival outcomes.

Methods

Forty-one patients with cutaneous ENKTL were included. Clinical features and survival outcomes were analyzed according to the positivity of PD-1.

Results

There was no significant difference between primary cutaneous ENKTL and secondary cutaneous ENKTL in the expression of PD-1. The degree of disease dissemination was not affected by the positivity of PD-1. Higher positivity for PD-1 was associated with lesions presenting erythematous to purpuric patches that are mainly composed of small tumor cells. Cutaneous ENKTL presenting nodular lesions had a significantly lower number of PD-1-positive infiltrating cells than those with other clinical morphologies. There was no significant effect of PD-1 expression on outcomes such as overall and progression-free survival.

Limitations

The present study used a retrospective design and had a small sample size.

Conclusion

Higher PD-1 positivity is associated with small-cell-predominant cutaneous ENKTL. However, PD-1 expression has no prognostic value in cutaneous ENKTL.

This article is protected by copyright. All rights reserved.

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Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis

Abstract

Background

Continuous treatment is recommended for patients with moderate-to-severe psoriasis, however, treatment may need to be interrupted in routine clinical practice.

Objective

To assess outcomes in patients continuously treated with ixekizumab versus those who interrupted therapy and were subsequently retreated with ixekizumab (IXE).

Methods

This analysis used data pooled from 2 phase 3 trials, UNCOVER-1 and UNCOVER-2. Patients were randomized to placebo (PBO), IXE every 4 (Q4W), or IXE every 2 weeks (Q2W) for 12 weeks. Patients with a static Physician's Global Assessment (sPGA) 0,1 at Week 12 were re-randomized to IXEQ4W, IXE every 12 weeks (not presented), or PBO. We examined outcomes in patients who were continuously treated (IXEQ2W/IXEQ4W; IXEQ4W/Q4W) or withdrawn (IXEQ2W/PBO; IXEQ4W/PBO), and in patients who were withdrawn and retreated with IXEQ4W for 24 weeks after disease relapse (sPGA ≥3).

Results

1226 treated patients achieved an sPGA 0,1 at Week 12 and entered the maintenance phase; of these patients, 402 and 416 were re-randomized to PBO and IXEQ4W, respectively. Among patients interrupting treatment, 157 (82.2%) of IXEQ4W/PBO and 176 (83.4%) of IXEQ2W/PBO had an sPGA ≥3 by Week 60; median time to relapse was approximately 20 weeks irrespective of induction dose. At Week 60, continuously treated patients maintained high levels of PASI and sPGA responses (90.0% PASI 75 IXEQ2W/Q4W; 81.9% sPGA 0,1 IXEQ2W/Q4W, Non-Responder Imputation). After 24 weeks of retreatment with IXEQ4W (IXEQ2W/PBO and IXEQ4W/PBO), 87.0% (107/123) and 95.1% (97/102) (observed), respectively, of patients recaptured PASI 75 and 70.7% (104/147) and 82.3% (107/130) (observed) recaptured an sPGA 0,1. Overall, adverse events in continuously treated and retreated patients were comparable.

Conclusion

High levels of response were sustained with continuous ixekizumab treatment through 60 weeks. Most patients who were withdrawn experienced disease relapse and most of those patients recaptured response after 24 weeks of retreatment.

This article is protected by copyright. All rights reserved.

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Epstein-Barr Virus in the Pathogenesis of Oral Cancers

Abstract

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral lifecycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.

This article is protected by copyright. All rights reserved.

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Can modern diagnostics help in successful treatment of cervical necrotizing fasciitis?

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Can modern diagnostics help in successful treatment of cervical necrotizing fasciitis?

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Salmonella proteomics under oxidative stress reveals coordinated regulation of antioxidant defense with iron metabolism and bacterial virulence

Publication date: Available online 11 February 2017
Source:Journal of Proteomics
Author(s): Jiaqi Fu, Linlu Qi, Mo Hu, Yanhua Liu, Kaiwen Yu, Qian Liu, Xiaoyun Liu
Salmonella Typhimurium is a bacterial pathogen that can cause widespread gastroenteritis. Salmonella encounters reactive oxygen species both under free-living conditions and within their mammalian host during infection. To study its response to oxidative stress, we performed the first large-scale proteomic profiling of Salmonella upon exposure to H2O2. Among 1600 detected proteins, 83 proteins showed significantly altered abundance. Interestingly, only a subset of known antioxidants was induced, likely due to distinct regulatory mechanisms. In addition, we found elevation of several Salmonella acquired phage products with potential contribution to DNA repair under oxidative stress. Furthermore, we observed robust induction of iron-uptake systems and disruption of these pathways led to bacterial survival defects under H2O2 challenge. Importantly, this work is the first to report that oxidative stress severely repressed the Salmonella type III secretion system (T3SS), reducing its virulence.Biological significanceSalmonella, a Gram-negative bacterial pathogen, encounters reactive oxygen species (ROS) both endogenously and exogenously. To better understand its response to oxidative stress, we performed the first large-scale profiling of Salmonella protein expression upon H2O2 treatment. Among 1600 quantified proteins, the abundance of 116 proteins was altered significantly. Notably, iron acquisition systems were induced to promote bacterial survival under oxidative stress. Furthermore, we are the first to report that oxidative stress severely repressed Salmonella type III secretion system and hence reduced its virulence. We believe that these findings will not only help us better understand the molecular mechanisms that Salmonella has evolved to counteract ROS but also the global impact of oxidative stress on bacterial physiology.

Graphical abstract

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The Science of Quality Improvement

Publication date: March 2017
Source:Academic Radiology, Volume 24, Issue 3
Author(s): Jason N. Itri, Eric Bakow, Linda Probyn, Nadja Kadom, Phuong-Anh T. Duong, Lori Mankowski Gettle, Mishal Mendiratta-Lala, Elena P. Scali, Ronald S. Winokur, Matthew E. Zygmont, Justin W. Kung, Andrew B. Rosenkrantz
Scientific rigor should be consistently applied to quality improvement (QI) research to ensure that healthcare interventions improve quality and patient safety before widespread implementation. This article provides an overview of the various study designs that can be used for QI research depending on the stage of investigation, scope of the QI intervention, constraints on the researchers and intervention being studied, and evidence needed to support widespread implementation. The most commonly used designs in QI studies are quasi-experimental designs. Randomized controlled trials and cluster randomized trials are typically reserved for large-scale research projects evaluating the effectiveness of QI interventions that may be implemented broadly, have more than a minimal impact on patients, or are costly. Systematic reviews of QI studies will play an important role in providing overviews of evidence supporting particular QI interventions or methods of achieving change. We also review the general requirements for developing quality measures for reimbursement, public reporting, and pay-for-performance initiatives. A critical part of the testing process for quality measures includes assessment of feasibility, reliability, validity, and unintended consequences. Finally, publication and critical appraisal of QI work is discussed as an essential component to generating evidence supporting QI initiatives in radiology.



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Cervical cancer incidence in elderly women-biology or screening history?

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Elsebeth Lynge, Stefan Lönnberg, Sven Törnberg
AimIn many countries, the age-specific pattern of cervical cancer incidence is currently bipolar with peaks at for instance 45 and 65 years of age. Consequently, a large proportion of cervical cancer cases are presently diagnosed in women above the screening age. The purpose of the study was to determine whether this bipolar pattern in age-specific incidence of cervical cancer reflects underlying biology or can be explained by the fact that the data come from birth cohorts with different screening histories.MethodsCombination of historical data on cervical screening and population-based cancer incidence data from Denmark 1943–2013, Finland and Norway 1953–2013, and Sweden 1958–2013.ResultsSince the implementation of screening, the incidence of cervical cancer has decreased for each successive birth cohort. All birth cohorts showed a unipolar age-specific pattern. In unscreened women in Denmark and Sweden, the incidence peaked around the age of 50; the peak was less marked in Finland; while peak age for unscreened women could not be determined for Norway due to widespread opportunistic screening. The current old-age peak in the incidence of cervical cancer represents residuals from unscreened or underscreened birth cohorts.ConclusionThe current bipolar pattern in age-specific incidence of cervical cancer can largely be explained by the different screening histories of successive birth cohorts. While it is reasonable to offer screening to elderly women today, birth cohort trends in disease burden should be carefully monitored to justify permanent changes in upper screening age.



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Geriatric factors and outcomes in metastatic colorectal cancer

Publication date: Available online 10 February 2017
Source:European Journal of Cancer
Author(s): Demetris Papamichael, Matti Aapro




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Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions

Publication date: Available online 11 February 2017
Source:Trends in Immunology
Author(s): Robin A. Aglietti, Erin C. Dueber
Pyroptosis is an inflammatory form of cell death that not only protects multicellular organisms from invading pathogenic bacteria and microbial infections, but can also lead to sepsis and lethal septic shock if overactivated. Here, we present an overview of recent developments within the pyroptosis field, beginning with the discovery of Gasdermin D (GSDMD) as a substrate of caspase-1 and caspase-11 upon detection of cytosolic lipopolysaccharide (LPS). Cleavage releases the N-terminal domain of GSDMD, causing it to form cytotoxic pores in the plasma membrane of cells. We further discuss the implications for the rest of the gasdermin (GSDM) family, which are emerging as mediators of programmed cell death in a variety of processes that regulate cellular differentiation and proliferation.



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Adjuvant therapy in patients with Ductal Carcinoma in Situ of the breast: The Pandora’s box

Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Matteo Lazzeroni, Barbara K Dunn, Giancarlo Pruneri, Barbara Alicja Jereczek-Fossa, Roberto Orecchia, Bernardo Bonanni, Andrea DeCensi
Most patients with ductal carcinoma in situ of the breast (DCIS) are eligible for breast conservation treatment. The key management decision is whether to add radiotherapy and/or endocrine therapy to minimize the risk of a subsequent recurrence. Recent analyses indicating a lack of benefit in terms of breast cancer-associated mortality have suggested that more conservative approaches, omitting adjuvant therapy or even surgery, may be advisable. These mortality observations are directly influenced by widespread use of mammographic screening which has opened a Pandora's box of subclinical DCIS and early invasive lesions. Confusion as to how aggressively such possibly indolent lesions should be treated has led to misunderstandings among patients and medical professionals. While awaiting further prospective evidence from clinical trials, we endorse an active treatment of DCIS as the standard of care. Our rationale is two-fold: invasive recurrences are associated with an increase in breast cancer mortality, which is not the only relevant endpoint for DCIS. The benefit of complete surgical excision, adjuvant radiotherapy and endocrine treatment in preventing recurrence and invasive progression has been demonstrated in DCIS. The challenge now is how to identify DCIS patients who will not progress to invasive carcinoma even without complete excision and, at the other extreme, those patients at the highest risk who require mastectomy for local control. The current controversies over whether and which adjuvant therapy should be implemented can at least in part be addressed by developing effective doctor-patient communications that enable mutual understanding about the management of this biologically heterogeneous disease.



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Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy

Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Chiara Ciccarese, Francesco Massari, Roberto Iacovelli, Michelangelo Fiorentino, Rodolfo Montironi, Vincenzo Di Nunno, Francesca Giunchi, Matteo Brunelli, Giampaolo Tortora
Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. Recent genomic profiling studies have deeply improved the knowledge of the genomic landscape of localized and metastatic PCa. The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. Moreover, somatic or germline aberrations of DNA repair genes (DRGs) have been observed at high frequency, supporting the potential role of platinum derivatives and PARP inhibitors as effective therapeutic strategies.In the future, the identification of driver mutations present at a specific stage of the disease, the classification PCa based on specific molecular alterations, and the selection of the most appropriate therapy based on biomarkers predictors of response represent the foundations for an increasingly more accurate personalized medicine.



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Targeting the Programmed Death-1 Pathway in Lymphoid Neoplasms

Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Chi Young Ok, Ken H. Young
Programmed death-1 (PD-1) is a co-inhibitory molecule and is seen in CD4+ and CD8+ T cells. Upon binding to its ligands, programmed death ligand-1 (PD-L1) and -2 (PD-L2), PD-1 negatively regulates interleukin 2 (IL-2) production and T cell proliferation. Activated effector T-cells, which kill cancer cells, can be affected by PD-1 signaling in some lymphoid neoplasm that express PD-L1 or PD-L2. PD-L1 expression in tumor cells can be induced by extrinsic signal (i.e. interferon gamma) or intrinsic signals, such as genetic aberrations involving 9p24.1, latent Epstein-Barr virus infection, PD-L1 3'- untranslated region disruptions, and activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Anti-PD-1 therapy improves the overall response rate to treatment in patients with lymphoid neoplasms, particularly relapsed/refractory classical Hodgkin lymphoma. Inspired by their success in treating patients with classical Hodgkin lymphoma, medical practitioners have expanded PD-1 therapy, given as a single therapy or in combination with other drugs, to patients with other types of lymphoma. In this review, current clinical trials with anti-PD-1 or anti-PD-L1 drugs are summarized. The results of numerous clinical trials will broaden our understanding of PD-1 pathway and shall expand the list of patients who will get benefit from these agents including those who suffer from lymphoid neoplasms.

Graphical abstract

http://ift.tt/2l21zQF

The Expanding Role of Immunotherapy

Publication date: Available online 11 February 2017
Source:Cancer Treatment Reviews
Author(s): Juan Martin-Liberal, María Ochoa de Olza, Cinta Hierro, Alena Gros, Jordi Rodon, Josep Tabernero
The use of agents able to modulate the immune system to induce or potentiate its anti-tumour activity is not a new strategy in oncology. However, the development of new agents such as immune checkpoint inhibitors has achieved unprecedented efficacy results in a wide variety of tumours, dramatically changing the landscape of cancer treatment in recent years. Ipilimumab, nivolumab, pembrolizumab or atezolizumab are now standard of care options in several malignancies and new indications are being approved on a regular basis in different tumours. Moreover, there are many other novel immunotherapy strategies that are currently being assessed in clinical trials. Agonists of co-stimulatory signals, adoptive cell therapies, vaccines, virotherapy and others have raised interest as therapeutic options against cancer. In addition, many of these novel approaches are being developed both in monotherapy and as part of combinatory regimes in order to synergize their activity. The results from those studies will help to define the expanding role of immunotherapy in cancer treatment in a forthcoming future.



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Enzastaurin: A Lesson in Drug Development

Publication date: Available online 11 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): T. Bourhill, A. Narendran, R.N. Johnston
Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic.



http://ift.tt/2l1k1bS

IL-33 dysregulates regulatory T (Treg) cells and impairs established immunological tolerance in the lungs

Using mouse models, Chen et al. showed that IL-33 dysregulated Treg cells in the lungs of mice toward a "Th2 cell-like" phenotype and impaired established immunological tolerance in the lungs.

http://ift.tt/2lDb2Ly

Enteric helminth-induced type-I interferon signalling protects against pulmonary virus infection through interaction with the microbiota

Strictly enteric helminth infection protects against RSV-infection through microbiota-dependent induction of type I interferon in the lung, a novel mechanism which in the future may reveal new targets for the prevention and treatment of RSV infection.

http://ift.tt/2kfCnGH

The effect of arsenic chemical form and mixing regime on arsenic mass transfer from soil to magnetite

Abstract

This study investigated the effect of chemical forms of arsenic (As) and soil-magnetite mixing regimes on As mass transfer in magnetite-amended soil. Two soil samples with different component ratios of As chemical forms were prepared. In the absence of magnetite, the amount of desorbable As was strongly dependent on the fraction of easily extractable As in soil. Contact of the soils with magnetite in a slurry phase significantly reduced soil As concentration for both soils. Changes in As concentrations in soil, magnetite, and water by the slurry phase contact were simulated using an As mass transfer model. The model parameters were determined independently for each process of As soil desorption and magnetite sorption. The experimentally measured As mass transfer from soil to magnetite was significantly greater than the simulation result. By sequential extraction, it was observed that the soil As concentration was significantly reduced not only for easily extractable As, but also for relatively strongly bound forms of As. Enclosing the magnetite in a dialysis bag substantially limited the As mass transfer from soil to magnetite. These results suggest that improving the mixture between Fe oxides and soils can facilitate the effectiveness of As stabilization using Fe oxides.

http://ift.tt/2kFe83q

Membrane scouring to control fouling under fluidization of non-adsorbing media for wastewater treatment

Abstract

Gas sparging is used as a traditional way to control membrane fouling in submerged membrane bioreactors (MBRs) in wastewater treatment. However, the gas sparging accounts for the largest fraction in operational cost to run the MBR systems. In this study, membrane fouling was controlled by integrating scouring media with gas sparging to reduce fouling rate at relatively low operational energy. Comparative study was performed using a fluidized membrane reactor treating synthetic feed solutions between polyethylene terephthalate (PET) scouring media (SM) fluidized by gas sparging (GS), liquid recirculation (LR), and combination of them to control membrane fouling. Addition of PET scouring media reduced the gas flow rate by 67% more with 30% less in fouling rate than gas sparing only. Combined usage of gas sparging and liquid recirculation to fluidize the PET scouring media (LR + GS + SM) showed 37% lower in fouling rate than that obtained by the scouring media fluidized by liquid recirculation (LR + SM) only through the reactor. The LR + GS + SM configuration reduced energy consumption by 90% more than that required by gas sparging alone. Mechanical cleaning driven by fluidizing PET scouring media could reduce membrane fouling due to removing deposit of inorganic particles from membrane surface effectively. However, the PET scouring media was not very effective to reduce membrane fouling caused by organic colloids which are expected to contribute pore fouling significantly.

http://ift.tt/2kUCx3y

Atmospheric wet deposition of nitrogen in a subtropical watershed in China: characteristics of and impacts on surface water quality

Abstract

Atmospheric wet deposition of nitrogen (N) is an important process in global N cycling, having significant impacts on both water quality and aquatic ecosystems worldwide. The aims of this study were to clarify the N wet deposition first flush effect and estimate the contribution of N wet deposition on both N export and water quality in a subtropical watershed. Results showed that total nitrogen (TN) flux was 41.72 kg N hm⁻² year⁻¹ and dissolved total nitrogen (DTN) was 23.18 kg N hm⁻² year⁻¹, respectively. Light rain events lead to the highest DTN and dissolve inorganic nitrogen (DIN) concentrations of wet deposition. Rainstorm concentrations were lowest during spring rainfall–runoff events. In contrast to the baseflow, the different N forms were higher than they were under the rainfall–runoff. Rainfall event contributions on N export were greater than 93.2% in the watershed for the whole year. Finally, TN concentrations were higher than river eutrophication thresholds for the entire watershed.

http://ift.tt/2kFe9V2

Pediatric Multiple Sclerosis presenting as Area Postrema Syndrome

Publication date: Available online 11 February 2017
Source:Pediatric Neurology
Author(s): Sara Vila-Bedmar, Fernando Ostos-Moliz, Ana Camacho-Salas




http://ift.tt/2lD2Uux

Ferrimagnetic Ni2+ doped Mg-Zn spinel ferrite nanoparticles for high density information storage

Publication date: 15 May 2017
Source:Journal of Alloys and Compounds, Volume 704
Author(s): Rohit Sharma, Prashant Thakur, Pankaj Sharma, Vineet Sharma
In the present paper, Ni²⁺ doped Mg0.5Zn0.5−xNixFe2O4 (x = 0, 0.125, 0.250, 0.375, 0.500) ferrite samples prepared by co-precipitation route have been characterized by XRD, FT-IR, FE-SEM, VSM, UV Visible and PL spectroscopy for various physical properties. A transition from superparamagnetic behavior (x = 0) to soft ferrimagnetic nature (x > 0) with Ni²⁺ addition has been reported. With reduction in crystallite size, ferrite nano-particles have shown an increase in coercivity with lower saturation magnetization. An increase in remanence ratio with Ni²⁺content has been observed. The optical band gap of the prepared samples has been calculated using Tauc plots and have been found to increase with increase in Ni²⁺content from 4.50 eV (x = 0) to 5.60 eV (x = 0.500). The PL spectra show band edge emission at lower energy than optical band gap energy for all samples. A cation distribution has been proposed and based on this some theoretical parameters have been calculated which supports our experimental results. Modest values of coercivity and saturation magnetization indicates that these materials may be used in high density information storage devices.



http://ift.tt/2kUP1If

Metal fractionation in sludge from sewage UASB treatment

Publication date: 15 May 2017
Source:Journal of Environmental Management, Volume 193
Author(s): A.F.M. Braga, M. Zaiat, G.H.R. Silva, F.G. Fermoso
This study evaluates the trace metal composition and fractionation in sludge samples from anaerobic sewage treatment plants from six cities in Brazil. Ten metals were evaluated: Ni, Mn, Se, Co, Fe, Zn, K, Cu, Pb and Cr. Specific methanogenic activity of the sludge was also evaluated using acetic acid as the substrate. Among the essential trace metals for anaerobic digestion, Se, Zn, Ni and Fe were found at a high percentage in the organic matter/sulfide fraction in all sludge samples analyzed. These metals are less available for microorganisms than other metals, i.e., Co and K, which were present in significant amounts in the exchangeable and carbonate fractions. Cu is not typically reported as an essential metal but as a possible inhibitor. One of the samples showed a total Cu concentration close to the maximal amount allowed for reuse as fertilizer. Among the non-essential trace metals, Pb was present in all sludge samples at similar low concentrations and was primarily present in the residual fraction, demonstrating very low availability. Cr was found at low concentrations in all sludge samples, except for the sludge from STP5; interestingly, this sludge presented the lowest specific methanogenic activity, indicating possible Cr toxicity.

Graphical abstract

http://ift.tt/2kFh3J9

Contribution of Guanine Nucleotide Exchange Factor Vav2 to NLRP3 Inflammasome Activation in Mouse Podocytes During Hyperhomocysteinemia

Publication date: Available online 11 February 2017
Source:Free Radical Biology and Medicine
Author(s): Sabena M. Conley, Justine M. Abais-Battad, Xinxu Yuan, Qinghua Zhang, Krishna M. Boini, Pin-Lan Li
NADPH oxidase (NOX)-derived reactive oxygen species (ROS) have been demonstrated to mediate the activation of NOD-like receptor protein 3 (NLRP3) inflammasomes in podocytes in response to elevated levels of homocysteine (Hcys). However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The present study tested whether the guanine nucleotide exchange factor Vav2 mediates Rac1-mediated NOX activation in response to elevated Hcys leading to NLRP3 inflammasome activation in podocytes and consequent glomerular injury. In a mouse model of hyperhomocysteinemia (hHcys), we found that mice with hHcys (on the FF diet) or oncoVav2 (a constitutively active form of Vav2) transfection in the kidney exhibited increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1 and elevated IL-1β levels in glomeruli, indicating the formation and activation of the NLRP3 inflammasome. This glomerular NLRP3 inflammasome activation was accompanied by podocyte dysfunction and glomerular injury, even sclerosis. Local transfection of Vav2 shRNA plasmids significantly attenuated hHcys-induced NLRP3 inflammasome activation, podocyte injury, and glomerular sclerosis. In cultured podocytes, Hcys treatment and oncoVav2 transfection were also found to increase NLRP3 inflammasome formation and activation, which were all inhibited by Vav2 shRNA. Furthermore, Vav2 shRNA prevented Hcys-induced podocyte damage as shown by restoring Hcys-impaired VEGF secretion and podocin production. This inhibitory action of Vav2 shRNA on Hcys-induced podocyte injury was associated with reduction of Rac1 activity and ROS production. These results suggest that elevated Hcys levels activate Vav2 and thereby increase NOX activity leading to ROS production, which triggers NLRP3 inflammasome activation, podocyte dysfunction and glomerular injury.

Graphical abstract

http://ift.tt/2kFc9w1

Protective role of p53 in acetaminophen hepatotoxicity

Publication date: Available online 11 February 2017
Source:Free Radical Biology and Medicine
Author(s): Yazhen Huo, Shutao Yin, Mingzhu Yan, Sanda Win, Tin Aung Than, Mariam Aghajan, Hongbo Hu, Neil Kaplowitz
p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout. Mice were treated with APAP (300mg/kg) i.p. and after 24h in all three conditions, the liver injury was more severe as reflected in higher ALT levels and great area of necrosis in histology of the liver. Conversely, a p53 activator, nutlin-3a, decreased the liver injury induced by APAP. In the p53 inhibition models, enhanced sustained JNK activation was seen in the early time course, while the JNK was suppressed with the p53 activator. In conclusion, p53 plays a novel protective role in APAP induced liver injury through inhibiting the activation of JNK, a key mediator in APAP-induced oxidative stress.

Graphical abstract

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Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA

Publication date: Available online 11 February 2017
Source:Journal of Autoimmunity
Author(s): Akitaka Shibata, Kazumitsu Sugiura, Yasuhide Furuta, Yoshiko Mukumoto, Osamu Kaminuma, Masashi Akiyama
BackgroundIL36RN encodes the IL-36 receptor antagonist (IL-36Ra), and loss-of-function mutations in IL36RN define a recessively inherited autoinflammatory disease named "deficiency of IL-36Ra" (DITRA). DITRA causes systemic autoinflammatory diseases, including generalized pustular psoriasis (GPP), an occasionally life-threatening disease that is characterized by widespread sterile pustules on the skin, fever and other systemic symptoms. GPP can present at any age, and provocative factors include various infections, medicines and pregnancy.ObjectiveWe aimed to elucidate the role of toll-like receptor 4 (TLR4) signaling in DITRA and to innovate an efficient treatment for DITRA.MethodsWe generated Il36rn^−/− mice and treated them with TLR4 agonist to establish DITRA model mice. Furthermore, we administrated TLR4 antagonist TAK-242 to the model mice to inhibit the DITRA symptoms.ResultIl36rn^−/− mice treated by TLR4 agonist showed autoinflammatory symptoms in skin, articulation and liver. Thus, we established model mice for DITRA or GPP that show cutaneous, articular, and hepatic autoinflammatory symptoms typical of DITRA or GPP: sterile pustules on the skin, liver abscesses and enthesitis of the hind paws. Additionally, these symptoms were canceled by TAK-242 administration. We demonstrated the inhibitory effects of the TLR4 antagonist TAK-242 on the autoinflammatory symptoms exhibited by the DITRA models.ConclusionWe suggested that blockage of TLR4 signaling is a promising treatment for DITRA and GPP.



http://ift.tt/2kflPP9

Corrigendum to “Knowing, planning for and fearing death: Do adults with intellectual disability and disability staff differ?” [Res. Dev. Disabil. 49–50 (2016) 47–59]

Publication date: Available online 10 February 2017
Source:Research in Developmental Disabilities
Author(s): Roger J. Stancliffe, Michele Y. Wiese, Sue Read, Gail Jeltes, Josephine M. Clayton




http://ift.tt/2kUFLUv

Compliance instead of flexibility? On age-related differences in cognitive control during visual search

Publication date: Available online 11 February 2017
Source:Neurobiology of Aging
Author(s): Christine Mertes, Edmund Wascher, Daniel Schneider
The effect of healthy aging on cognitive control of irrelevant visual information was investigated by using event-related potentials (ERPs). Participants performed a spatial cuing task where an irrelevant color cue that was either contingent (color search) or non-contingent (shape search) on the attentional set was presented prior to a target with different stimulus-onset asynchronies (SOAs). In the contingent condition, attentional capture appeared independent of age and persisted over the SOAs but was markedly pronounced for elderly people. Accordingly, ERP analyses revealed that both older and younger adults initially selected the irrelevant cue when it was contingent on the attentional set and transferred spatial cue information into working memory. However, only younger adults revealed inhibitory mechanisms to compensate for attentional capture. It is proposed that this age-related lack of reactive inhibition leads to stickiness in visual processing whenever information is contingent on the attentional set, unveiling older adults' "Achilles' heel" in cognitive control.



http://ift.tt/2kEYs03

Association of Matrix Metalloproteinase Levels with Collagen Degradation in the Context of Abdominal Aortic Aneurysm

Publication date: Available online 10 February 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): V. Klaus, F. Tanios-Schmies, C. Reeps, M. Trenner, E. Matevossian, H.-H. Eckstein, J. Pelisek
Objective/BackgroundMatrix metalloproteinases (MMPs) have already been identified as key players in the pathogenesis of abdominal aortic aneurysm (AAA). However, the current data remain inconclusive. In this study, the expression of MMPs at mRNA and protein levels were investigated in relation to the degradation of collagen I and collagen III.MethodsTissue samples were obtained from 40 patients with AAA undergoing open aortic repair, and from five healthy controls during kidney transplantation. Expression of MMPs 1, 2, 3, 7, 8, 9, and 12, and tissue inhibitor of metalloproteinase (TIMP)1, and TIMP2 were measured at the mRNA level using quantitative reverse transcription polymerase chain reaction. At the protein level, MMPs, collagen I, and collagen III, and their degradation products carboxy-terminal collagen cross-links (CTX)-I and CTX-III, were quantified via enzyme linked immunosorbent assay. In addition, immunohistochemistry and gelatine zymography were performed.ResultsIn AAA, significantly enhanced mRNA expression was observed for MMPs 3, 9, and 12 compared with controls (p ≤ .001). MMPs 3, 9, and 12 correlated significantly with macrophages (p = .007, p = .018, and p = .015, respectively), and synthetic smooth muscle cells with MMPs 1, 2, and 9 (p = .020, p = .018, and p = .027, respectively). At the protein level, MMPs 8, 9, and 12 were significantly elevated in AAA (p = .006, p = .0004, and p < .001, respectively). No significant correlation between mRNA and protein was observed for any MMP. AAA contained significantly reduced intact collagen I (twofold; p = .002), whereas collagen III was increased (4.6 fold; p < .001). Regarding degraded collagen I and III relative to intact collagens, observations were inverse (1.4 fold increase for CTX-1 [p < .001]; fivefold decrease for CTX-III [p = .004]). MMPs 8, 9, and 12 correlated with collagen I (p = .019, p < .001, and p = 0.003, respectively), collagen III (p = .015, p < .001, and p < .001, respectively), and degraded collagen I (p = .012, p = .049, and p = .001, respectively).ConclusionNo significant relationship was found between mRNA and protein and MMP levels. MMPs 9 and 12 were overexpressed in AAA at the mRNA and protein level, and MMP-8 at the protein level. MMP-2 was detected in synthetic SMCs. Collagen I and III showed inverse behaviour in AAA. In particular, MMPs 8, 9, and 12 appear to be associated with collagen I, collagen III, and their degradation products.



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Enzastaurin: A Lesson in Drug Development

Publication date: Available online 11 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): T. Bourhill, A. Narendran, R.N. Johnston
Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. It was initially developed as an isozyme specific inhibitor of protein kinase Cβ (PKCβ), which is involved in both the AKT and MAPK signalling pathways that are active in many cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. In this review, we will discuss the development of enzastaurin from drug design to clinical testing, exploring target identification, validation and preclinical assessment. Finally, we will consider the clinical evaluation of enzastaurin as an example of the challenges associated with drug development. In particular, we discuss the poor translation of drug efficacy from preclinical animal models, inappropriate end point analysis, limited standards in phase I clinical trials, insufficient use of biomarker analysis and also patient stratification, all of which contributed to the failure to achieve approval of enzastaurin as an anticancer therapeutic.



http://ift.tt/2l1k1bS

Inducible turnover of optineurin regulates T cell activation

Publication date: May 2017
Source:Molecular Immunology, Volume 85
Author(s): Angela Montecalvo, Simon C. Watkins, Jordan Orange, Lawrence P. Kane
Optineurin (Optn) is an adaptor protein with homology to NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) complex. Dysregulation of Optn has been linked to neurodegenerative, autoimmune and bone diseases. Optn shares a high degree of homology with NEMO, but is not part of the same high-molecular weight complex containing IKKα and IKKβ. Despite its homology with NEMO and the fact that it has been the subject of extensive study in several cell types, there are no published studies addressing the role of Optn during T cell activation. Here we demonstrate that ectopic expression of Optn down-regulates TCR-induced NF-κB activation and TNF-α production, in a manner dependent on ubiquitin-binding. Conversely, knock-down of Optn enhances NF-κB activation and the production of TNF-α. Consistent with a negative regulatory role for this protein, we observed transient loss of Optn after TCR stimulation in both cell lines and in primary murine T cells. The acute loss of Optn appears to be due to both protein degradation and exocytosis, the latter via activation-induced exosomes. This study therefore provides novel information regarding the role of Optn during TCR activation, suggesting the possible importance of Optn during inflammation and/or autoimmune diseases.



http://ift.tt/2l5liyn

Inducible turnover of optineurin regulates T cell activation

Publication date: May 2017
Source:Molecular Immunology, Volume 85
Author(s): Angela Montecalvo, Simon C. Watkins, Jordan Orange, Lawrence P. Kane
Optineurin (Optn) is an adaptor protein with homology to NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) complex. Dysregulation of Optn has been linked to neurodegenerative, autoimmune and bone diseases. Optn shares a high degree of homology with NEMO, but is not part of the same high-molecular weight complex containing IKKα and IKKβ. Despite its homology with NEMO and the fact that it has been the subject of extensive study in several cell types, there are no published studies addressing the role of Optn during T cell activation. Here we demonstrate that ectopic expression of Optn down-regulates TCR-induced NF-κB activation and TNF-α production, in a manner dependent on ubiquitin-binding. Conversely, knock-down of Optn enhances NF-κB activation and the production of TNF-α. Consistent with a negative regulatory role for this protein, we observed transient loss of Optn after TCR stimulation in both cell lines and in primary murine T cells. The acute loss of Optn appears to be due to both protein degradation and exocytosis, the latter via activation-induced exosomes. This study therefore provides novel information regarding the role of Optn during TCR activation, suggesting the possible importance of Optn during inflammation and/or autoimmune diseases.



http://ift.tt/2l5liyn

The role of point-of-care 3-hydroxybutyrate testing in patients with type 2 diabetes undergoing coronary angiography

Abstract

Purpose

Ketone bodies, 3-hydroxybutyrate (3BOHB), and acetoacetate derive from increased free fatty acid beta-oxidation, thus reflecting marked insulin deprivation with or without decompensated diabetes. Objectives of this study were (1) to determine circulating levels of 3BOHB in patients with and without type 2 diabetes (T2DM), before and after an elective coronary angiography; (2) to detect 3BOHB modification during the procedure; (3) to study possible associations between 3BOHB and clinical parameters/outcomes.

Methods

Sixteen T2DM (72 ± 11 years) and 22 matched controls (71 ± 12 years) undergoing elective coronary angiography were enrolled. In all subjects, biohumoral parameters were determined at hospital admission. Point-of-care determinations of 3BOHB, glucose, and creatinine were performed, at 7 a.m, immediately before and after the procedure. The duration of the fasting period and of the procedure was recorded.

Results

T2DM had significantly higher fasting (0.538 ± 0.320 vs 0.255 ± 0.197 mM/l;   p = 0.005) and pre-procedural (0.725 ± 0.429 vs 0.314 ± 0.205; p = 0.002) 3BOHB concentrations than controls. Similarly, absolute increment of 3BOHB from the morning value was significantly greater in T2DM (0.369 ± 0.252 vs 0.127 ± 0.135 in controls; p = 0.002). Significant correlations were observed between pre-procedure 3BOHB and glucose levels (r = 0.586; p < 0.0001) and between pre-procedure 3BOHB and fasting creatinine concentrations (r = 0.364; p = 0.029).

Conclusions

An overnight fasting period and a concomitantly stressful condition induce inappropriate 3BOHB increase in T2DM. Point-of-care capillary 3BOHB may be useful before any procedural/surgical intervention in these patients.

http://ift.tt/2kgjWge

A nano-scaled and multi-layered recombinant fibronectin/cadherin chimera composite selectively concentrates osteogenesis-related cells and factors to aid bone repair

Publication date: Available online 11 February 2017
Source:Acta Biomaterialia
Author(s): Junchao Xing, Tieniu Mei, Keyu Luo, Zhiqiang Li, Aijun Yang, Zhilin Li, Zhao Xie, Zehua Zhang, Shiwu Dong, Tianyong Hou, Jianzhong Xu, Fei Luo
Easily accessible and effective bone grafts are in urgent need in clinic. The selective cell retention (SCR) strategy, by which osteogenesis-related cells and factors are enriched from bone marrow into bio-scaffolds, holds great promise. However, the retention efficacy is limited by the relatively low densities of osteogenesis-related cells and factors in marrow; in addition, a lack of satisfactory surface modifiers for scaffolds further exacerbates the dilemma. To address this issue, a multi-layered construct consisting of a recombinant fibronectin/cadherin chimera was established via a layer-by-layer self-assembly technique (LBL-rFN/CDH) and used to modify demineralised bone matrix (DBM) scaffolds. The modification was proven stable and effective. By the mechanisms of physical interception and more importantly, chemical recognition (fibronectin/integrins), the LBL-rFN/CDH modification significantly improved the retention efficacy and selectivity for osteogenesis-related cells, e.g., monocytes, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), and bioactive factors, e.g., bFGF, BMP-2 and SDF-1α. Moreover, the resulting composite (designated as DBM-LBL-rFN/CDH) not only exhibited a strong MSCs-recruiting capacity after SCR, but also provided favourable microenvironments for the proliferation and osteogenic differentiation of MSCs. Eventually, bone repair was evidently improved. Collectively, DBM-LBL-rFN/CDH presented a suitable biomaterial for SCR and a promising solution for tremendous need for bone grafts.Statement of significanceThere is an urgent need for effective bone grafts. With the potential of integrating osteogenicity, osteoinductivity and osteoconductivity, selective cell retention (SCR) technology brings hope for developing ideal grafts. However, it is constrained by low efficacy and selectivity. Thus, we modified demineralized bone matrix with nano-scaled and multi-layered recombinant fibronectin/cadherin chimera (DBM-rFN/CDH-LBL), and evaluate its effects on SCR and bone repair. DBM-rFN/CDH-LBL significantly improved the efficacy and selectivity of SCR via physical interception and chemical recognition. The post-enriched DBM-rFN/CDH-LBL provided favourable microenvironments to facilitate the migration, proliferation and osteogenic differentiation of MSCs, thus accelerating bone repair. Conclusively, DBM-rFN/CDH-LBL present a novel biomaterial with advantages including high cost-effectiveness, more convenient for stroage and transport and can be rapidly constructed intraoperatively.

Graphical abstract

http://ift.tt/2kU4AzU

Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced growth factor retention promote hMSC chondrogenesis and articular cartilage integrity with reduced hypertrophy

Publication date: Available online 11 February 2017
Source:Acta Biomaterialia
Author(s): Qian Feng, Sien Lin, Kunyu Zhang, Chaoqun Dong, Tianyi Wu, Heqin Huang, Xiaohui Yan, Li Zhang, Gang Li, Liming Bian
Recently, hyaluronic acid (HA) hydrogels have been extensively researched for delivering cells and drugs to repair damaged tissues, particularly articular cartilage. However, the in vivo degradation of HA is fast, thus limiting the clinical translation of HA hydrogels. Furthermore, HA cannot bind proteins with high affinity because of the lack of negatively charged sulfate groups. In this study, we conjugated sulfate groups to HA. These sulfated HA exhibit significantly slower degradation by hyaluronidase compared to the wild type HA. We hypothesize that sulfation reduces the available HA octasaccharide substrate needed for the effective catalytic action of hyaluronidase. Moreover, the sulfated HA significantly improve the protein sequestration, thereby effectively extending the availability of the proteinaceous drugs in the hydrogels. In the following in vitro study, we demonstrate that the sulfation exerts no negative effect on the viability of human mesenchymal stem cells (hMSCs). Furthermore, the sulfated HA promotes the chondrogenesis and suppresses the hypertrophy of hMSCs both in vitro and in vivo. Moreover, animal research demonstrate that the sulfated HA hydrogels avert the cartilage abrasion and hypertrophy in the animal osteoarthritis joints. Collectively, our findings demonstrate that the sulfated HA is a promising biomaterial for regenerative medicine applications including cartilage repair.Statement of significanceIn this paper, we conjugated sulfate to hyaluronic acid (HA) and demonstrated the slow degradation and growth factor delivery of sulfated HA. Futhermore, in vitro and in vivo culture of hMSCs laden HA hydrogels proved that the sulfation of HA hydrogels not only promotes the chondrogenesis of hMSCs but also suppresses hypertrophic differentiation of the chondrogenically induced hMSCs. The animal OA model study showed that the injected sulfated HA hydrogels significantly reduced the cartilage abrasion and hypertrophy in the animal OA joints. We believe that this study will provide important insights into the design and optimization of the HA-based hydrogels as the scaffold materials for cartilage regeneration and OA treatment in clinical setting.

Graphical abstract

http://ift.tt/2kUaMb6

Primary mediastinal large B cell lymphoma in a woman who is human immunodeficiency virus positive presenting with superior vena cava syndrome: a case report

The risk of non-Hodgkin lymphoma is increased 200-fold in individuals seropositive for human immunodeficiency virus compared to those free from human immunodeficiency virus. Human immunodeficiency virus-associ...

http://ift.tt/2lASfQk

Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiotherapy

Publication date: Available online 11 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Andrew Bang, Tyler J. Wilhite, Luke Pike, Daniel N. Cagney, Ayal A. Aizer, Allison Taylor, Alexander Spektor, Monica Krishnan, Patrick A. Ott, Tracy A. Balboni, F. Stephen Hodi, Jonathan D. Schoenfeld
PurposeImmune checkpoint inhibitors are increasingly used in the treatment of metastatic cancers and associated with immune-related adverse events (ir-AEs) such as pneumonitis. Many patients receiving these agents also receive palliative radiotherapy, yet data regarding the tolerability of combined treatment are sparse. We aimed to characterize potential toxicities and relevant risks.Methods and MaterialsWe retrospectively reviewed records from patients with metastatic non-small cell lung cancer, melanoma or renal cell cancer who received at least one cycle of a CTLA-4 or PD-1 inhibitor and radiation. Ir-AEs, defined using CTCAE v4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed.ResultsWe identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-two patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-eight patients experienced at least one ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any grade ir-AEs as compared to either individually (71% vs. 29%, p=0.0008). Any grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy compared with 23% of other patients (p=0.06) and more often in patients who received higher EQD2 (p=0.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.ConclusionsOur data suggests the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well-tolerated, with manageable ir-AEs that did not appear to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments and future confirmatory studies are needed, this information can help guide clinical practice for patients on immune checkpoint therapy who require palliative radiotherapy.

Teaser

Metastatic cancer patients are increasingly treated with immune checkpoint inhibitors. We analyzed immune-related adverse events (ir-AEs) in 133 patients treated with radiation and immune checkpoint blockade. Although there was a trend towards an association between ir-AEs and radiation administered within 14 days of immunotherapy (39% vs. 23%, p=0.06), we didn't identify increases in serious ir-AEs or relationships between radiation fields encompassing the lung and bowel and specific ir-AEs such as pneumonitis and colitis.


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Primary mediastinal large B cell lymphoma in a woman who is human immunodeficiency virus positive presenting with superior vena cava syndrome: a case report

The risk of non-Hodgkin lymphoma is increased 200-fold in individuals seropositive for human immunodeficiency virus compared to those free from human immunodeficiency virus. Human immunodeficiency virus-associ...

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Incidental finding of 131I uptake in mesenteric cystic lymphangioma on post-therapy 131I SPECT/CT imaging

Publication date: Available online 10 February 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): G. Shao, Y. Zhao, J. Song, S. Li




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Refractory sleep apnea caused by tubal tonsillar hypertrophy

Publication date: Available online 11 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Seok Chan Hong, Hyun Jin Min, Kyung Soo Kim
Snoring/sleep apnea are usual symptoms of adenotonsillar hypertrophy, and adenotonsillectomy is usually recommended. In rare cases, symptoms remain after surgery, and tubal tonsil hypertrophy could be the cause. We experienced a pediatric patient whose symptoms were refratory snoring/sleep apnea although he previously underwent three times of adenotonsillectomy. We diagnosed tubal tonsil hypertrophy which was the cause of refractory symptoms, and decided to perform volume reduction with radiofrequency ablation. We suggest that tubal tonsil hypertrophy should be taken into account of the cause of refractory sleep apnea after adenotonsillectomy, and volume reduction with radiofrequency may be an effective method.



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A case of acute clival osteomyelitis in a 7-year-old boy secondary to infection of a Thornwaldt cyst

Publication date: Available online 11 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Yasmine Benadjaoud, Nathalie Klopp-Dutote, Morgane Choquet, Elodie Brunel, Raphaël Guiheneuf, Cyril Page
Clival osteomyelitis is a potentially life-threatening infection that can occur in healthy children. It can be related to congenital anomalies. We report the case of a 7-year-old boy with Streptococcus intermedius and Fusobacterium clival osteomyelitis arising from a Thornwaldt cyst situated in a fossa navicularis magna of the occipital bone. Multidisciplinary management is necessary to ensure rapid improvement and complete healing.



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Pycnodysostosis at Otorhinolaryngology

Publication date: Available online 11 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Muhammet Fatih Topuz, Adem Binnetoglu, Murat Sarı, Tekin Baglam, Serap Turan
AimPycnodysostosis is a rare autosomal, recessive, skeletal dysplasia caused by a mutation in the cathepsin k gene. Pycnodysostosis is characterized by short stature, characteristic facial appearance (delayed closure of fontanelles and cranial sutures, mandibular hypoplasia and angle disorder, blue sclera), and acroosteolysis of the distal phalanges. Our aim was to describe the otorhinolaryngologic findings, differential diagnoses, various treatment options, and followup in eight cases of pycnodysostosis.MethodThis retrospective clinical study used data from eight patients diagnosed with pycnodysostosis by a single pediatric endocrinologist primarily based on clinical and radiographic findings. All patients were referred to the otorhinolaryngology outpatient clinic by the pediatric endocrinology unit of the Marmara University between February 2013 and March 2015. Detailed medical histories were obtained in all cases and otorhinolaryngologic physical examination, blood assays, electrocardiogram, lateral skull X-rays, chest radiograph, cephalometric investigations, tympanograms, and audiograms were also carried out. Sleep videos of patients were recorded and those with upper airway problems were evaluated for sleep apnea by polysomnography. Informed consent form was obtained from the parents of all patients.ResultsEight patients (7 females and 1 male) displaying proportionate dwarfism were included in the study. They had a mean age of 14.7 years (range: 13-16 y), the mean height of 141.3 cm (range 132-155 cm), and mean weight of 44.4 kg (range: 39.6-49.3 kg). All patients had facial dysmorphism with frontal bossing and the hands and feet had short digits with overlying cutaneous wrinkles that tapered off with large overriding nails. Midfacial hypoplasia and malocclusion were observed in seven of the eight patients (87.5%), four (50%) had micrognathia, and five (62.5%) had proptosis. Tympanograms and audiograms of all patients were type A and normal, and the mean of the pure tone audiogram was 13.3 dB (range: 10-16 dB). All patients had a narrow and grooved palate with disturbed dentition; two of them (25%) had mild markedness of the tongue base, five (62.5%) had grade 3 and three (37.5%) had grade 2 tonsillar hypertrophy, and five (62.5%) had adenoid hypertrophy. One patient (12.5%) had grade 3 Mallampati, four (50%) showed grade 2 Mallampati while three (37.5%) patients displayed grade 1 Mallampati score. Further, while six (75%) patients had no uvular pathology, one (12.5%) patient presented with uvular elongation and another patient had a bifid uvula. Cephalometric measurements such as PAS-UP (mean 5.67 mm; range: 5.0-7.6 mm) and PAS-TP (mean 9.61 mm; range: 8.5 - 12.2 mm) were lower than that of normal subjects. Video recordings showed that six of the eight patients (75%) had respiratory distress and four (50%) had sleep apnea. Polysomnography in these patients with sleep apnea showed that two had mild OSA (AHI: 18.2 and 20.1 events/hour) and two had severe OSA (AHI: 53.4 and 62.8 events/hour). For upper airway problems, an adenotonsillectomy was performed in two (25%) patients while two others required an adenoidectomy. Positive pressure ventilation was recommended in two patients with persistent sleep apnea after adeno/adenotonsillectomy. However, because of the parental objections, the follow-up polysomnographs could not be obtained.ConclusionPycnodysostosis is a very rare form of bone dysplasia. Otorhinolaryngologically, proper follow-up of these patients and appropriate treatment of upper airway problems are important to achieve an acceptable quality of life. Adeno/adenotonsillectomy and positive pressure ventilation, used as conservative approaches in treating upper airway problems, are effective and could be used instead of an aggressive surgery such as tracheotomy or maxillomandibular advancement. This study, to the best of our knowledge, is the largest case series on pycnodysostosis.



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Motorized injector-assisted intrascleral intraocular lens fixation

Publication date: Available online 11 February 2017
Source:The Kaohsiung Journal of Medical Sciences
Author(s): Jia-Horung Hung, Shih-Hao Wang, Yu-Ti Teng, Sheng-Min Hsu
For eyes with deficient capsular support, intraocular lens (IOL) implantation has long been a technical challenge. Recently, intrascleral fixation of the haptics of a three-piece posterior chamber IOL has become a popular option. In this procedure, externalization of the leading haptic during IOL injection is a stressful step. We present a modified technique to improve the ease and safety of this step. Our modified technique involves IOL injection with a motorized injector with several important modifications described here. With these modifications, a surgeon can easily maintain the correct orientation of the IOL in a well-controlled manner during IOL injection. The records of 13 patients who underwent this technique were retrospectively evaluated. Corrected-distance visual acuity improved significantly after surgery (p<0.05). No postoperative retinal detachment, endophthalmitis, IOL decentration, or vitreous hemorrhage was noted during the follow-up period. In conclusion, the motorized injector-assisted intrascleral IOL fixation technique is a safe and effective alternative to the conventional procedure. This technique makes the process of leading haptic externalization easier and more controllable.



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Cell-type specific role of the RNA-binding protein, NONO, in the DNA double-strand break response in the mouse testes.

Publication date: Available online 10 February 2017
Source:DNA Repair
Author(s): Shuyi Li, Feng-jue Shu, Zhentian Li, Lahcen Jaafar, Shourong Zhao, William S. Dynan
The tandem RNA recognition motif protein, NONO, was previously identified as a candidate DNA double-strand break (DSB) repair factor in a biochemical screen for proteins with end-joining stimulatory activity. Subsequent work showed that NONO and its binding partner, SFPQ, have many of the properties expected for bona fide repair factors in cell-based assays. Their contribution to the DNA damage response in intact tissue in vivo has not, however, been demonstrated. Here we compare DNA damage sensitivity in the testes of wild-type mice versus mice bearing a null allele of the NONO homologue (Nono ^gt). In wild-type mice, NONO protein was present in Sertoli, peritubular myoid, and interstitial cells, with an increase in expression following induction of DNA damage. As expected for the product of an X-linked gene, NONO was not detected in germ cells. The Nono ^gt/0 mice had at most a mild testis developmental phenotype in the absence of genotoxic stress. However, following irradiation at sublethal, 2–4 Gy doses, Nono ^gt/0 mice displayed a number of indicators of radiosensitivity as compared to their wild-type counterparts. These included higher levels of persistent DSB repair foci, increased numbers of apoptotic cells in the seminiferous tubules, and partial degeneration of the blood-testis barrier. There was also an almost complete loss of germ cells at later times following irradiation, evidently arising as an indirect effect reflecting loss of stromal support. Results demonstrate a role for NONO protein in protection against direct and indirect biological effects of ionizing radiation in the whole animal.



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Precision Surgery and Avoiding Over-treatment

Publication date: Available online 11 February 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Ava Hosseini, Amal L. Khoury, Laura J. Esserman
Over-diagnosis and over-treatment are a consequence of greater awareness about breast cancer, more intensive screening, and the resultant identification of more cases of breast cancer that are low or ultralow risk. This is an area that represents an important opportunity to optimize the delivery of appropriate targeted therapy for breast cancer patients. Despite the evolution of breast cancer care over the last few decades and our ability to tailor treatment to biology, a one-size fits all approach is still prevalent in the local and regional management of and screening for breast cancer, failing to reflect the unique biology and tumor characteristics of each patient. In this review, we explore how we can use new tools to better define tumor biology and also how we can change current clinical practices based on already available data. Every surgeon should be knowledgeable about how to craft personalized breast cancer care in the areas of systemic therapy, adjuvant radiation therapy, management of ductal carcinoma in situ (DCIS), precision surgery, and breast cancer screening.



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Improvement in postoperative mortality in elective gastrectomy for gastric cancer: Analysis of predictive factors in 1066 patients from a single centre

Publication date: Available online 10 February 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Enrique Norero, Eduardo Vega, Cristian Diaz, Gabriel Cavada, Marco Ceroni, Cristian Martínez, Eduardo Briceño, Fernando Araos, Paulina Gonzalez, Sergio Baez, Eduardo Vinuela, Mario Caracci, Alfonzo Diaz
BackgroundGastrectomy represents the main treatment for gastric adenocarcinoma. This procedure is associated with substantial morbidity and mortality. The aim of this study was to evaluate the postoperative mortality changes across the study period and to identify predictive factors of 30-day mortality after elective gastrectomy for gastric cancer.MethodsThis was a retrospective cohort study of a prospective database from a single centre. Patients treated with an elective gastrectomy from 1996 to 2014 for gastric adenocarcinoma were included. We compared postoperative mortality between four time periods: 1996–2000, 2001–2005, 2006–2010, and 2011–2014. Univariate and multivariate analyses were applied to identify predictors of 30-day postoperative mortality.ResultsWe included 1066 patients (median age 65 years; 67% male). The 30-day mortality rate was 4.7%. Mortality decreased across the four time periods; from 6.5% to 1.8% (P = 0.022). In the univariate analysis, age, ASA score, albumin < 3.5, multivisceral resection, splenectomy, intrathoracic esophagojejunal anastomosis, R status, and T status were significantly associated with postoperative mortality. In the multivariate analysis, ASA class 3 (OR 10.06; CI 1.97-51.3; P = 0.005) and multivisceral resection (OR 1.6; CI 1.09-2.36; P = 0.016) were associated with higher postoperative 30-day mortality; surgery between 2011 and 2014 was associated with lower postoperative 30-day mortality (OR 0.55; CI 0.33-0.15; P = 0.030).ConclusionThere was a decrease in postoperative 30-day mortality during this 18-year period at our institution. We have identified ASA score and multivisceral resection as predictors of 30-day mortality for elective gastrectomy for cancer.



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Contralateral Occlusion Test: The effect of external ear canal occlusion on hearing thresholds

Publication date: Available online 10 February 2017
Source:Acta Otorrinolaringológica Española
Author(s): Luis Roque Reis, Paulo Fernandes, Pedro Escada
Introduction and goalsBedside testing with tuning forks may decrease turnaround time and improve decision making for a quick qualitative assessment of hearing loss. The purpose of this study was to quantify the effects of ear canal occlusion on hearing, in order to decide which tuning fork frequency is more appropriate to use for quantifying hearing loss with the Contralateral Occlusion Test.MethodsTwenty normal-hearing adults (forty ears) underwent sound field pure tone audiometry with and without ear canal occlusion. Each ear was tested with the standard frequencies. The contralateral ear was suppressed with by masking. Ear occlusion was performed by two examiners.ResultsParticipants aged between 21 and 30 years (25.6±3.03 years) showed an increase in hearing thresholds with increasing frequencies from 19.94dB (250Hz) to 39.25dB (2000Hz). The threshold difference between occluded and unoccluded conditions was statistically significant and increased from 10.69dB (250Hz) to 32.12dB (2000Hz). There were no statistically significant differences according to gender or between the examiners.ConclusionThe occlusion effect increased the hearing thresholds and became more evident with higher frequencies. The occlusion method as performed demonstrated reproducibility. In the Contralateral Occlusion Test, 256Hz or 512Hz tuning forks should be used for diagnosis of mild hearing loss, and a 2048Hz tuning fork should be used for moderate hearing loss.



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A note on workplace psychopathic bullying – Measuring its frequency and severity

Publication date: Available online 11 February 2017
Source:Aggression and Violent Behavior
Author(s): Clive Boddy, Ross Taplin
In this short paper we discuss methods of measurement for investigating bullying under workplace psychopaths. We find that past estimates of bullying under workplace psychopaths may be too low due to the use of inadequate scales. We conclude that the use of actual numerical values is preferential for measuring psychopathic bullying due to the highly skewed nature of the results. Further, non-numerical measures of the severity of bullying may also need to adopt extreme end point descriptors in order to capture the severe violence of the threats that may be made by a psychopathic manager.



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Editorial Board & Aims and Scope

Publication date: February 2017
Source:Nano Today, Volume 12





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Enhanced oral bioavailability of docetaxel in rats combined with myricetin: In situ and in vivo evidences

Publication date: 1 April 2017
Source:European Journal of Pharmaceutical Sciences, Volume 101
Author(s): Tianyun Hao, Yunni Ling, Meijuan Wu, Yajing Shen, Yu Gao, Shujun Liang, Yuan Gao, Shuai Qian
The purpose of this study was to investigate the effect of myricetin on the pharmacokinetics of docetaxel in rats. In comparison to oral docetaxel alone (40mg/kg), the bioavailability of docetaxel could be significantly enhanced by 1.6–2.4-fold via oral co-administration with various flavonoids (apigenin, naringenin, baicalein, quercetin and myricetin) at a dosage of 10mg/kg, and myricetin showed the highest bioavailability improvement. Further pharmacokinetic studies demonstrated that the presence of myricetin (5–20mg/kg) enhanced both Cmax and AUC of docetaxel with the highest Cmax (162ng/mL, 2.3-fold) and relative bioavailability (244%) achieved at 10mg/kg of myricetin, while t1/2 was not influenced. In order to explore the reasons for such bioavailability enhancement of docetaxel, rat in situ single-pass intestinal perfusion model and intravenous docetaxel co-administrated with oral myricetin were carried out. After combining with myricetin, the permeability coefficient (Pblood) of docetaxel based on its appearance in mesenteric blood was significantly increased up to 3.5-fold in comparison to that of docetaxel alone. Different from oral docetaxel, the intravenous pharmacokinetics of docetaxel was not affected by co-administration of myricetin, indicating the limited effect of myricetin on the elimination of docetaxel. The above findings suggested that the oral bioavailability enhancement of docetaxel via co-administration with myricetin might be mainly attributed to the enhanced absorption in gastrointestinal tract rather than modulating the elimination of docetaxel.

Graphical abstract

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Breast cancer detection using single-reading of breast tomosynthesis (3D-mammography) compared to double-reading of 2D-mammography: Evidence from a population-based trial

Publication date: April 2017
Source:Cancer Epidemiology, Volume 47
Author(s): Nehmat Houssami, Daniela Bernardi, Marco Pellegrini, Marvi Valentini, Carmine Fantò, Livio Ostillio, Paolina Tuttobene, Andrea Luparia, Petra Macaskill
BackgroundMost population breast cancer (BC) screening programs use double-reading of 2D-mammography. We recently reported the screening with tomosynthesis or standard mammography-2 (STORM-2) trial, showing that double-read tomosynthesis (pseudo-3D-mammography) detected more BC than double-read 2D-mammography. In this study, we compare screen-detection measures for single-reading of 3D-mammography with those for double-reading of 2D-mammography, to inform screening practice.MethodsThis is a secondary analysis based on STORM-2 which prospectively compared 3D-mammography and 2D-mammography in sequential screen-readings. Asymptomatic women ≥49 years who attended population-based screening (Trento, 2013–2015) were recruited. Participants recalled at any screen-read from parallel double-reading arms underwent further testing and/or biopsy. Single-reading of 3D-mammography, integrated with acquired or synthetized 2D-mammograms, was compared to double-reading of 2D-mammograhy alone for screen-detection measures: number of detected BCs, cancer detection rate (CDR), number and percentage of false-positive recall (FPR). Paired binary data were compared using McNemar's test.ResultsScreening detected 90, including 74 invasive, BCs in 85 of 9672 participants. CDRs for single-reading using integrated 2D/3D-mammography (8.2 per 1000 screens; 95% CI 6.5–10.2) or 2D synthetic/3D-mammography (8.4 per 1000 screens; 95% CI: 6.7–10.4) were significantly higher than CDR for double-reading of 2D-mammography (6.3 per 1000 screens; 95% CI: 4.8–8.1), P<0.001 both comparisons. FPR% for single-read 2D/3D-mammography (2.60%; 95% CI: 2.29–2.94), or single-read 2D synthetic/3D-mammography (2.76%; 95% CI: 2.45–3.11), were significantly lower than FPR% for double-read 2D-mammography (3.42%; 95% CI: 3.07–3.80), P<0.001 and P=0.002 respectively.ConclusionsSingle-reading of 3D-mammography (integrated 2D/3D or 2Dsynthetic/3D) detected more BC, and had lower FPR, compared to current practice of double-reading 2D-mammography alone − these findings have implications for population BC screening programs.



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So long, Farewell, Au revoir, Auf Weidersehen. In regard to Overgaard (Radiother Oncol. 2016 Dec; 121(3):345–347)

Publication date: Available online 10 February 2017
Source:Radiotherapy and Oncology
Author(s): Ahmed Salem




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Radiotherapy after Sentinel Lymph Node Biopsy (SLNB) using SIENNA+®, super paramagnetic iron oxide particles (SPIO): Prospective study of tolerance and toxicity

Publication date: Available online 10 February 2017
Source:Radiotherapy and Oncology
Author(s): Youlia M. Kirova, Anne Chilles, Nathalie Ly, Anne Tardivon, Severine Alran




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Corrigendum to “IL-10-producing regulatory B cells are decreased in patients with psoriasis” [J. Dermatol. Sci. 81 (2016) 93–100]

Publication date: Available online 10 February 2017
Source:Journal of Dermatological Science
Author(s): Mitsuha Hayashi, Koichi Yanaba, Yoshinori Umezawa, Yuki Yoshihara, Sota Kikuchi, Yozo Ishiuji, Hidehisa Saeki, Hidemi Nakagawa




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Measles virus infection of human keratinocytes: possible link between measles and atopic dermatitis

Publication date: Available online 10 February 2017
Source:Journal of Dermatological Science
Author(s): Geraldine Gourru-Lesimple, Cyrille Mathieu, Thomas Thevenet, Vanessa Guillaume-Vasselin, Jean-François Jégou, Cindy G. Boer, Katarzyna Tomczak, Luis-Marie Bloyet, Celine Giraud, Sophie Grande, Catherine Goujon, Catherine Cornu, Branka Horvat
BackgroundMeasles virus (MV) infection is marked with a skin rash in the acute phase of the disease, which pathogenesis remains poorly understood. Moreover, the association between measles and progression of skin diseases, such as atopic dermatitis (AD), is still elusive.ObjectiveWe have thus analysed the susceptibility of human keratinocytes to MV infection and explore the potential relationship between MV vaccination and the pathogenesis the AD.MethodsWe performed immunovirological characterisation of MV infection in human keratinocytes and then tested the effect of live attenuated measles vaccine on the progression of AD in adult patients, in a prospective, double-blind study.ResultsWe showed that both human primary keratinocytes and the keratinocyte cell line HaCaT express MV receptors and could be infected by MV. The infection significantly modulated the expression of several keratinocyte-produced cytokines, known to be implicated in the pathogenesis of inflammatory allergic diseases, including AD. We then analysed the relationship between exposure to MV by vaccination and the progression of AD in 20 adults during six weeks. We found a significant decrease in CCL26 and thymic stromal lymphopoietin (TSLP) mRNA in biopsies from acute lesions of vaccinated patients, suggesting MV-induced modulation of skin cytokine expression. Clinical analysis revealed a transient improvement of SCORAD index in vaccinated compared to placebo-treated patients, two weeks after vaccination.ConclusionsAltogether, these results clearly demonstrate that keratinocytes are susceptible to MV infection, which could consequently modulate their cytokine production, resulting with a beneficial effect in the progression of AD. This study provides thus a proof of concept for the vaccination therapy in AD and may open new avenues for the development of novel strategies in the treatment of this allergic disease.



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An entropy-assisted musculoskeletal shoulder model

Publication date: Available online 10 February 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Xu Xu, Jia-hua Lin, Raymond W. McGorry
Optimization combined with a musculoskeletal shoulder model has been used to estimate mechanical loading of musculoskeletal elements around the shoulder. Traditionally, the objective function is to minimize the summation of the total activities of the muscles with forces, moments, and stability constraints. Such an objective function, however, tends to neglect the antagonist muscle co-contraction. In this study, an objective function including an entropy term is proposed to address muscle co-contractions. A musculoskeletal shoulder model is developed to apply the proposed objective function. To find the optimal weight for the entropy term, an experiment was conducted. In the experiment, participants generated various 3-D shoulder moments in six shoulder postures. The surface EMG of 8 shoulder muscles was measured and compared with the predicted muscle activities based on the proposed objective function using Bhattacharyya distance and concordance ratio under different weight of the entropy term. The results show that a small weight of the entropy term can improve the predictability of the model in terms of muscle activities. Such a result suggests that the concept of entropy could be helpful for further understanding the mechanism of muscle co-contractions as well as developing a shoulder biomechanical model with greater validity.



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