Anticoagulant-Related Bleeding and Mortality ∗

http://ift.tt/2h7U0lQ

Is There a Prevention Effect of Fludrocortisone on Vasovagal Syncope?

We read with great interest the paper by Sheldon et al. (1) in a recent issue of the Journal. Although this research did not meet its primary objective of demonstrating that fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%, this study indicated a prevention effect of fludrocortisone for vasovagal syncope.

http://ift.tt/2g1yuTQ

Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension

Background

Pulmonary hypertension (PH) is a common and morbid complication of left heart disease with 2 subtypes: isolated post-capillary pulmonary hypertension (Ipc-PH) and combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Little is known about the clinical or physiological characteristics that distinguish these 2 subphenotypes or if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH).

Objectives

The goal of this study was to test the hypothesis that the hemodynamic and genetic profile of Cpc-PH would more closely resemble PAH than Ipc-PH.

Methods

Vanderbilt University's electronic medical record linked to a DNA biorepository was used to extract demographic characteristics, clinical data, invasive hemodynamic data, echocardiography, and vital status for all patients referred for right heart catheterization between 1998 and 2014. Shared genetic variants between PAH and Cpc-PH compared with Ipc-PH were identified by using pre-existing single-nucleotide polymorphism data.

Results

A total of 2,817 patients with PH (13% Cpc-PH, 52% Ipc-PH, and 20% PAH) were identified. Patients with Cpc-PH were on average 6 years younger, with more severe pulmonary vascular disease than patients with Ipc-PH, despite similar comorbidities and prevalence, severity, and chronicity of left heart disease. After adjusting for relevant covariates, the risk of death was similar between the Cpc-PH and Ipc-PH groups (hazard ratio: 1.14; 95% confidence interval: 0.96 to 1.35; p = 0.15) when defined according to diastolic pressure gradient. We identified 75 shared exonic single-nucleotide polymorphisms between Cpc-PH and PAH enriched in pathways involving cell structure, extracellular matrix, and immune function. These genes are expressed, on average, 32% higher in lungs relative to other tissues.

Conclusions

Patients with Cpc-PH develop pulmonary vascular disease similar to patients with PAH, despite younger age and similar prevalence of obesity, diabetes mellitus, and left heart disease compared with patients with Ipc-PH. An exploratory genetic analysis in Cpc-PH identified genes and biological pathways in the lung known to contribute to PAH pathophysiology, suggesting that Cpc-PH may be a distinct and highly morbid PH subphenotype.

http://ift.tt/2h7TZOO

Bariatric Surgery and the Risk of New-Onset Atrial Fibrillation in Swedish Obese Subjects

Background

Obesity is a risk factor for atrial fibrillation, which in turn is associated with stroke, heart failure, and increased all-cause mortality.

Objectives

The authors investigated whether weight loss through bariatric surgery may reduce the risk of new-onset atrial fibrillation.

Methods

SOS (Swedish Obese Subjects) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary healthcare centers in Sweden. The cohort was recruited between 1987 and 2001. Among 4,021 obese individuals with sinus rhythm and no history of atrial fibrillation, 2,000 underwent bariatric surgery (surgery group), and 2,021 matched obese control subjects received usual care (control group). The outcome, first-time atrial fibrillation, was ascertained by crosschecking the SOS database with the Swedish National Patient Register on inpatient and outpatient diagnosis codes.

Results

During a median follow-up of 19 years, first time atrial fibrillation occurred in 247 patients (12.4%) in the surgical group, and in 340 (16.8%) control subjects. The risk of developing atrial fibrillation was 29% lower in the surgery group versus the control group (hazard ratio: 0.71; 95% confidence interval: 0.60 to 0.83; p Conclusions

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Biological Phenotyping of Combined Post-Capillary and Pre-Capillary Pulmonary Hypertension Focus on Pulmonary Vascular Remodeling ∗

http://ift.tt/2h7XPr7

MicroRNAs in Cardiovascular Disease

Micro-ribonucleic acids (miRNAs) are in the spotlight as post-transcriptional regulators of gene expression. More than 1,000 miRNAs are encoded in the human genome. In this review, we provide an introduction to miRNA biology and research methodology, and highlight advances in cardiovascular research to date. This includes the potential of miRNAs as therapeutic targets in cardiac and vascular disease, and their use as novel biomarkers. Although some miRNA therapies are already undergoing clinical evaluation, we stress the importance of integrating current knowledge of miRNA biology into a systemic context. Discovery studies focus on miRNA effects within one specific organ, whereas the expression of most miRNAs is not restricted to a single tissue. Because most miRNA-based therapies act systemically, this may preclude widespread clinical use. The development of more targeted interventions will bolster well-informed clinical applications, increasing the chances of success and minimizing the risk of setbacks for miRNA-based therapeutics.

http://ift.tt/2g1yfrC

Arrhythmogenic Right Ventricular Cardiomyopathy Clinical Course and Predictors of Arrhythmic Risk

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined.

Objectives

This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy.

Methods

We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals.

Results

A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p Conclusions

http://ift.tt/2h7L4g7

The Effects of Secondary Cardiovascular Prevention on Cancer Risk in Patients With Manifest Vascular Disease

Cardiovascular disease and cancer share important risk factors and pathophysiology, including smoking, obesity, physical inactivity, insulin resistance, and inflammation. As the survival of acute ischemic events has increased notably, the number of patients in the chronic phase of vascular disease is ever growing. We previously showed that, besides an increased risk of new cardiovascular events, these patients have a higher risk of cancer (1). Given the shared risk factors of cardiovascular disease and cancer, interventions for secondary prevention of cardiovascular disease could possibly also lower cancer risk. If so, informing patients about these additional effects of secondary cardiovascular prevention could increase treatment adherence. In this study, we evaluated the effects of meeting cardiovascular treatment goals, as defined in the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for secondary cardiovascular prevention, on cancer risk in patients with manifest vascular disease.

http://ift.tt/2g1BAar

Further Progress in Predicting Life-Threatening Arrhythmias in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy ∗

http://ift.tt/2h7TVyy

Cardiovascular Adverse Events After Aortic Valve Replacement in Mixed Aortic Valve Disease Beyond Ejection Fraction

There are limited data about outcomes after aortic valve replacement (AVR) in patients with mixed aortic valve disease (MAVD) (1). We conducted a retrospective review of all adults with moderate-to-severe MAVD who underwent AVR at Mayo Clinic from January 1, 1994 to December 31, 2014 to determine the occurrence of cardiovascular adverse events (CAE). Moderate-to-severe MAVD was defined as the combination of greater than or moderate aortic stenosis and greater than or moderate aortic regurgitation.

http://ift.tt/2g1xGyl

Later Onset Fabry Disease, Cardiac Damage Progress in Silence Experience With a Highly Prevalent Mutation

Background

Recently, several studies revealed a much higher prevalence of later onset Fabry disease (FD) than previously expected. It suggested that later onset FD might present as an important hidden health issue in certain ethnic or demographic populations in the world. However, the natural history of its phenotype has not been systemically investigated, especially the cardiac involvement.

Objectives

The study analyzed a large-scale newborn screening program for FD to understand the natural course of later onset FD.

Methods

To date, 916,383 newborns have been screened for FD in Taiwan, including more than 1,200 individuals with the common, later onset IVS4+919G>A (IVS4) mutation. Echocardiography was performed in 620 adults with the IVS4 mutation to analyze the prevalence of left ventricular hypertrophy (LVH), and gadolinium-enhanced cardiac magnetic resonance imaging was performed in 129 patients with FD, including 100 IVS4 adults.

Results

LVH was observed in 67% of men and 32% of women older than 40 years. Imaging evidenced significant late gadolinium enhancement in 38.1% of IVS4 men and 16.7% of IVS4 women with the IVS4 mutation but without LVH. Seventeen patients underwent endomyocardial biopsies, which revealed significant globotriaosylceramide substrate accumulation in their cardiomyocytes.

Conclusions

Significant cardiomyocyte substrate accumulation in IVS4 patients led to severe and irreversible cardiac fibrosis before development of LVH or other significant cardiac manifestations. Thus, it might be too late to start enzyme replacement therapy after the occurrence of LVH or other significant cardiac manifestations in patients with later onset FD. This study also indicated the importance of newborn screening for early detection of the insidious, ongoing, irreversible cardiac damage in patients with later onset FD.

http://ift.tt/2h7MNCa

Reply Is There a Prevention Effect of Fludrocortisone on Vasovagal Syncope?

We thank Dr. Zhu and colleagues for their kind interest and insightful comments on our paper (1). They first question whether we sought a sex-specific interaction with the investigational treatment. As noted in the legend for Table 2 of our paper (1), sex itself was not a significant, independent variable associated with outcome.

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GLA-Ring Opportunities and Challenges for Fabry Disease ∗

http://ift.tt/2h7N4VT

Reply Ectopic Fat Deposition and Diabetes Mellitus

We thank Drs. Gaborit and Dutour for their interest in our paper (1). We acknowledge the lack of assessment of epicardial adipose tissue (EAT) volumes in healthy control subjects, which was due to concerns regarding unnecessary ionizing radiation exposure with coronary computed tomographic angiography. We agree that magnetic resonance imaging (MRI) is highly suitable for adipose tissue imaging. Dark blood prepared, T₁-weighted, multislice turbo spin-echo pulse sequence with a water suppression pre-pulse is an established MRI technique for reliable volumetric measurement of EAT volumes (2). Fat quantification on the basis of steady-state free precession cine imaging (i.e., the magnetic resonance images available to us) is unreliable in our experience. However, the addition of the established technique for assessment of EAT volumes would have extended scanning time for our participants to an unacceptable length. Acquiring multiparametric cardiovascular and liver magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy protocol demanded a long scanning duration. Therefore, computed tomographic angiography, already part of the study protocol to rule out significant coronary artery stenosis, was used for EAT volume quantification, which allowed imaging of the coronary arteries and assessment of EAT volumes without additional scan time. This is a typical example of the challenge to find the balance between the desirable and the practical, regarding the amount of information we can obtain in a clinical MRI research study.

http://ift.tt/2g1zwze

Diffusion-Weighted Genitourinary Imaging

Publication date: Available online 5 December 2016
Source:Radiologic Clinics of North America
Author(s): Martin H. Maurer, Kirsi Hannele Härmä, Harriet Thoeny

Teaser

This review article aims to provide an overview on of diffusion-weighted MR imaging (DW-MR imaging) in the urogenital tract. Compared with conventional cross-sectional imaging methods, the additional value of DW-MR imaging in the detection and further characterization of benign and malignant lesions of the kidneys, bladder, prostate, and pelvic lymph nodes is discussed as well as the role of DW-MR imaging in the evaluation of treatment response.


http://ift.tt/2gZ02pY

Imaging in Urolithiasis

Publication date: Available online 5 December 2016
Source:Radiologic Clinics of North America
Author(s): William R. Masch, Kevin C. Cronin, Dushyant V. Sahani, Avinash Kambadakone

Teaser

Imaging plays an important role in the diagnosis of urolithiasis as well as its pre-treatment planning and post-treatment follow-up. Proper imaging technique is essential to provide appropriate clinical care to affected patients. This article reviews the clinically relevant imaging findings most likely to influence management decisions.


http://ift.tt/2haMD0W

Prostate MR Imaging

Publication date: Available online 4 December 2016
Source:Radiologic Clinics of North America
Author(s): Hiram Shaish, Samir S. Taneja, Andrew B. Rosenkrantz

Teaser

Improvements in prostate MR imaging techniques and the introduction of MR imaging-targeted biopsies have had central roles in prostate cancer (PCa) management. The role of MR imaging has progressed from largely staging patients with biopsy-proven PCa to detecting, characterizing, and guiding the biopsy of suspected PCa. These diagnostic advances, combined with improved therapeutic interventions, have led to a more sophisticated and individually tailored approach to patients' unique PCa profile. This review discusses the MR imaging, a standardized reporting scheme, and the role of fusion-targeted prostate biopsy.


http://ift.tt/2gYUH1T

Image-Guided Renal Interventions

Publication date: Available online 4 December 2016
Source:Radiologic Clinics of North America
Author(s): Sharath K. Bhagavatula, Paul B. Shyn

Teaser

Image-guided renal biopsies have an increasing role in clinical practice. Renal mass and renal parenchymal biopsy indications, techniques, and other clinical considerations are reviewed in this article. Image-guided renal mass ablation shows significant promise and increasing clinical utility as more studies demonstrate its safety and efficacy. Renal mass ablation indications, techniques, and other considerations are also reviewed.


http://ift.tt/2gZ261m

Complement and sepsis-induced heart dysfunction

Publication date: Available online 5 December 2016
Source:Molecular Immunology
Author(s): Fatemeh Fattahi, Peter A. Ward
It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after "recovery" from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. Use of a neutralizing antibody to C5a largely attenuates cardiac dysfunction and other adverse events developing during sepsis. The molecular basis for cardiac dysfunctions is linked to generation of C5a and its interaction with C5a receptors present on surfaces of cardiomyocytes (CMs). It is established that C5a interactions with C5a receptors leads to significant reductions involving faulty contractility and relaxation in CMs. In addition, C5a interactions with C5a receptors on CMs results in reductions in Na⁺/K⁺-ATPase in CMs. This ATPase is essential for intact action potentials in CMs. The enzymatic activity and protein for this ATPase were strikingly reduced in CMs during sepsis by unknown mechanisms. In addition, C5a interactions with C5aRs also caused reductions in CM homeostatic proteins that regulate cytosolic [Ca²⁺]i in CMs: sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) and Na⁺/Ca²⁺ exchanger (NCX). In the absence of C5a receptors, defects in SERCA2 and NCX in CMs after sepsis are strikingly attenuated. These observations suggest new strategies to protect the heart from dysfunction developing during sepsis.



http://ift.tt/2g1eOzq

Editorial Board/ Publication Information

Publication date: December 2016
Source:Molecular Immunology, Volume 80





http://ift.tt/2h7vmBP

Cutting Out the Middle Man in Light-Hormone Interactions

Publication date: 5 December 2016
Source:Developmental Cell, Volume 39, Issue 5
Author(s): Anna N. Stepanova, Jose M. Alonso
In this issue of Developmental Cell, Shi et al. (2016a) show that red-light-activated phytochrome B interacts with transcriptional regulators of ethylene signaling, EIN3/EIL1, triggering their degradation by bringing the F-box proteins EBF1 and 2 to the complex. These findings provide a paradigm for crosstalk between light and hormone signaling pathways.

Teaser

In this issue of Developmental Cell, Shi et al. (2016a) show that red-light-activated phytochrome B interacts with transcriptional regulators of ethylene signaling, EIN3/EIL1, triggering their degradation by bringing the F-box proteins EBF1 and 2 to the complex. These findings provide a paradigm for crosstalk between light and hormone signaling pathways.


http://ift.tt/2gIBNhC

Interphase Positioning of Centromeres Sets Up Spindle Assembly

Publication date: 5 December 2016
Source:Developmental Cell, Volume 39, Issue 5
Author(s): Hironori Funabiki
It has been known for many years that centromeres cluster at the spindle pole body in fission yeast. In this issue of Developmental Cell, Fernández-Álvarez et al. (2016) reveal that the functional significance of clustering is to promote spindle assembly by modulating nuclear envelope integrity at the onset of mitosis.

Teaser

It has been known for many years that centromeres cluster at the spindle pole body in fission yeast. In this issue of Developmental Cell, Fernández-Álvarez et al. (2016) reveal that the functional significance of clustering is to promote spindle assembly by modulating nuclear envelope integrity at the onset of mitosis.


http://ift.tt/2guTJcR

Long Oskar Controls Mitochondrial Inheritance in Drosophila melanogaster

Publication date: 5 December 2016
Source:Developmental Cell, Volume 39, Issue 5
Author(s): Thomas Ryan Hurd, Beate Herrmann, Julia Sauerwald, Justina Sanny, Markus Grosch, Ruth Lehmann
Inherited mtDNA mutations cause severe human disease. In most species, mitochondria are inherited maternally through mechanisms that are poorly understood. Genes that specifically control the inheritance of mitochondria in the germline are unknown. Here, we show that the long isoform of the protein Oskar regulates the maternal inheritance of mitochondria in Drosophila melanogaster. We show that, during oogenesis, mitochondria accumulate at the oocyte posterior, concurrent with the bulk streaming and churning of the oocyte cytoplasm. Long Oskar traps and maintains mitochondria at the posterior at the site of primordial germ cell (PGC) formation through an actin-dependent mechanism. Mutating long oskar strongly reduces the number of mtDNA molecules inherited by PGCs. Therefore, Long Oskar ensures germline transmission of mitochondria to the next generation. These results provide molecular insight into how mitochondria are passed from mother to offspring, as well as how they are positioned and asymmetrically partitioned within polarized cells.

Graphical abstract

Teaser

Mitochondria are inherited maternally through poorly understood mechanisms. Hurd et al. show that the long isoform of Oskar protein specifically controls mitochondrial germline inheritance in Drosophila melanogaster. Through an actin-dependent mechanism, Long Oskar traps mitochondria where the cells that give rise to the next generation form, ensuring efficient mtDNA inheritance.


http://ift.tt/2gZKRzb

Examining Topological Domain Influence on Enhancer Function

Publication date: 5 December 2016
Source:Developmental Cell, Volume 39, Issue 5
Author(s): Robert A. Beagrie, Ana Pombo
Enhancers regulate the expression of target genes across large genomic distances, but it is unclear how recently discovered topological domains affect this regulation. Reporting in this issue of Developmental Cell, Symmons et al. (2016) show that the endogenous Shh topological domain promotes functional interactions between Shh and its remote enhancer.

Teaser

Enhancers regulate the expression of target genes across large genomic distances, but it is unclear how recently discovered topological domains affect this regulation. Reporting in this issue of Developmental Cell, Symmons et al. (2016) show that the endogenous Shh topological domain promotes functional interactions between Shh and its remote enhancer.


http://ift.tt/2gZP8Td

Basal Cell-Extracellular Matrix Adhesion Regulates Force Transmission during Tissue Morphogenesis

Publication date: 5 December 2016
Source:Developmental Cell, Volume 39, Issue 5
Author(s): Katharine Goodwin, Stephanie J. Ellis, Emily Lostchuck, Teresa Zulueta-Coarasa, Rodrigo Fernandez-Gonzalez, Guy Tanentzapf
Tissue morphogenesis requires force-generating mechanisms to organize cells into complex structures. Although many such mechanisms have been characterized, we know little about how forces are integrated across developing tissues. We provide evidence that integrin-mediated cell-extracellular matrix (ECM) adhesion modulates the transmission of apically generated tension during dorsal closure (DC) in Drosophila. Integrin-containing adhesive structures resembling focal adhesions were identified on the basal surface of the amnioserosa (AS), an extraembryonic epithelium essential for DC. Genetic modulation of integrin-mediated adhesion results in defective DC. Quantitative image analysis and laser ablation experiments reveal that basal cell-ECM adhesions provide resistance to apical cell displacements and force transmission between neighboring cells in the AS. Finally, we provide evidence for integrin-dependent force transmission to the AS substrate. Overall, we find that integrins regulate force transmission within and between cells, thereby playing an essential role in transmitting tension in developing tissues.

Graphical abstract

Teaser

Goodwin, Ellis et al. identify integrin-containing focal adhesion-like structures on the basal amnioserosa surface that act as tethers, anchoring the apical cell surface to the substrate. These basal adhesions are required for dorsal closure, where they modulate apical surface force transmission and may resist large-scale cell displacements during tissue contraction.


http://ift.tt/2h7oHrn

Complement and sepsis-induced heart dysfunction

Publication date: Available online 5 December 2016
Source:Molecular Immunology
Author(s): Fatemeh Fattahi, Peter A. Ward
It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after "recovery" from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. Use of a neutralizing antibody to C5a largely attenuates cardiac dysfunction and other adverse events developing during sepsis. The molecular basis for cardiac dysfunctions is linked to generation of C5a and its interaction with C5a receptors present on surfaces of cardiomyocytes (CMs). It is established that C5a interactions with C5a receptors leads to significant reductions involving faulty contractility and relaxation in CMs. In addition, C5a interactions with C5a receptors on CMs results in reductions in Na⁺/K⁺-ATPase in CMs. This ATPase is essential for intact action potentials in CMs. The enzymatic activity and protein for this ATPase were strikingly reduced in CMs during sepsis by unknown mechanisms. In addition, C5a interactions with C5aRs also caused reductions in CM homeostatic proteins that regulate cytosolic [Ca²⁺]i in CMs: sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) and Na⁺/Ca²⁺ exchanger (NCX). In the absence of C5a receptors, defects in SERCA2 and NCX in CMs after sepsis are strikingly attenuated. These observations suggest new strategies to protect the heart from dysfunction developing during sepsis.



http://ift.tt/2g1eOzq

Editorial Board/ Publication Information

Publication date: December 2016
Source:Molecular Immunology, Volume 80





http://ift.tt/2h7vmBP

UVB irradiation induces rapid changes in galanin, substance P and c-fos immunoreactivity in rat dorsal root ganglia and spinal cord.

Publication date: Available online 5 December 2016
Source:Peptides
Author(s): Leila Etemadi, Lina M.E. Pettersson, Nils Danielsen
Recent studies have shown that UVB irradiation induces primary and secondary hyperalgesia in rats and humans peaking about 24hrs after UVB exposure. In the present study we investigated the changes in galanin, substance P and c-fos immunoreactivity in rat DRG and spinal cord at the L5 level 2–96hrs after UVB irradiation. UVB irradiation of the heel area in rats almost increased the skin blood flow two-fold 24hrs after irradiation as measured by laser Doppler technique. UVB irradiation induced a significant reduction of the proportion of galanin positive DRG neurons for all time points, except at 12hrs. In the spinal cord, UVB irradiation induced increased immunoreactivity for galanin in the dorsal horn, the area around the central canal and interestingly also in the lateral spinal nucleus 12–96hrs after exposure. For substance P the proportion of substance P positive neurons was unchanged but UVB irradiation induced increased substance P immunoreactivity in the dorsal part of the spinal cord 48hrs after irradiation. UVB irradiation also induced c-fos immunoreactivity in the dorsal horn and the area around the central canal 24 and 48hrs after exposure. This translational model of UVB irradiation will induce rapid changes of neuropeptides implicated in nociceptive signaling in areas known to be of importance for nociception in a time frame, about 24hrs after exposure, where also neurophysiological alteration have been described in humans and rats.



http://ift.tt/2guYp2e

Dataset of the absorption, emission and excitation spectra and fluorescence intensity graphs of fluorescent cyanine dyes for the quantification of low amounts of dsDNA

Publication date: February 2017
Source:Data in Brief, Volume 10
Author(s): Brigitte Bruijns, Roald Tiggelaar, Han Gardeniers
This article describes data related to a research article entitled "Fluorescent cyanine dyes for the quantification of low amounts of dsDNA" (B. Bruijns, R. Tiggelaar, J. Gardeniers, 2016) [1]. Six cyanine dsDNA dyes - EvaGreen, SYBR Green, PicoGreen, AccuClear, AccuBlue NextGen and YOYO-1 – are investigated and in this article the absorption spectra, as well as excitation and emission spectra, for all six researched cyanine dyes are given, all recorded under exactly identical experimental conditions. The intensity graphs, with the relative fluorescence in the presence of low amounts of dsDNA, are also provided.



http://ift.tt/2gYEpWJ

Large reductions in urban black carbon concentrations in the United States between 1965 and 2000

Publication date: February 2017
Source:Atmospheric Environment, Volume 151
Author(s): Thomas W. Kirchstetter, Chelsea V. Preble, Odelle L. Hadley, Tami C. Bond, Joshua S. Apte
Long-term pollutant concentration trends can be useful for evaluating air quality effects of emission controls and historical transitions in energy sources. We employed archival records of coefficient of haze (COH), a now-retired measure of light-absorbing particulate matter, to re-construct historical black carbon (BC) concentrations at urban locations in the United States (U.S.). The following relationship between COH and BC was determined by reinstating into service COH monitors beside aethalometers for two years in Vallejo and one year in San Jose, California: BC (μg m⁻³) = 6.7COH + 0.1, R² = 0.9. Estimated BC concentrations in ten states stretching from the East to West Coast decreased markedly between 1965 and 1980: 5-fold in Illinois, Ohio, and Virginia, 4-fold in Missouri, and 2.5-fold in Pennsylvania. Over the period from the mid-1960s to the early 2000s, annual average BC concentrations in New Jersey and California decreased from 13 to 2 μg m⁻³ and 4 to 1 μg m⁻³, respectively, despite concurrent increases in fossil fuel consumption from 1.6 to 2.1 EJ (EJ = 10¹⁸ J) in New Jersey and 4.2 to 6.4 EJ in California. New Jersey's greater reliance on BC-producing heavy fuel oils and coal in the 1960s and early 1970s and subsequent transition to cleaner fuels explains why the decrease was larger in New Jersey than California. Patterns in seasonal and weekly BC concentrations and energy consumption trends together indicate that reducing wintertime emissions – namely substituting natural gas and electricity for heavy fuel oil in the residential sector – and decreasing emissions from diesel vehicles contributed to lower ambient BC concentrations. Over the period of study, declining concentrations of BC, a potent and short-lived climate warming pollutant, contrast increasing fossil fuel carbon dioxide (CO2) emissions in the U.S. Declining BC emissions may have had the benefit of mitigating some atmospheric warming driven by increased CO2 emissions with complementary health benefits.



http://ift.tt/2h6QLv0

Effect of travel restriction on PM10 concentrations in Naples: One year of experience

Publication date: February 2017
Source:Atmospheric Environment, Volume 151
Author(s): Giuliano Polichetti
The PM10 is an ubiquitarian and most common pollutant in the world, especially in the Western countries, and it is responsible onset of many pathologies from cancer to cardiorespiratory diseases and human reproduction, on the pregnant women and birth outcomes, in addition to recently has been associated with metabolic diseases (like diabetes). In the light of this scenario, the city of Naples decided in 2010, attempting to reduce PM10 concentrations, to establish a travel restriction for the cars over the city to time slots and on alternate days. We have analyzed the PM10 data from eight monitoring stations dislocated on the city ground. The period of analysis was a year, from July 2010 to July 2011. The results were not absolutely close to expectations, having practically demonstrated that there is no statistically significant difference between the days and hours when the travel restriction was active and those where no have the travel restriction. In conclusion, the travel restriction at time slots and alternate days as structured in the city of Naples seems have not significant improvement of air quality but should need further studies to obtain more reliable data.

Graphical abstract

http://ift.tt/2gZfJ2J

Exposure assessment models for elemental components of particulate matter in an urban environment: A comparison of regression and random forest approaches

Publication date: February 2017
Source:Atmospheric Environment, Volume 151
Author(s): Cole Brokamp, Roman Jandarov, M.B. Rao, Grace LeMasters, Patrick Ryan
Exposure assessment for elemental components of particulate matter (PM) using land use modeling is a complex problem due to the high spatial and temporal variations in pollutant concentrations at the local scale. Land use regression (LUR) models may fail to capture complex interactions and non-linear relationships between pollutant concentrations and land use variables. The increasing availability of big spatial data and machine learning methods present an opportunity for improvement in PM exposure assessment models. In this manuscript, our objective was to develop a novel land use random forest (LURF) model and compare its accuracy and precision to a LUR model for elemental components of PM in the urban city of Cincinnati, Ohio. PM smaller than 2.5 μm (PM2.5) and eleven elemental components were measured at 24 sampling stations from the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS). Over 50 different predictors associated with transportation, physical features, community socioeconomic characteristics, greenspace, land cover, and emission point sources were used to construct LUR and LURF models. Cross validation was used to quantify and compare model performance. LURF and LUR models were created for aluminum (Al), copper (Cu), iron (Fe), potassium (K), manganese (Mn), nickel (Ni), lead (Pb), sulfur (S), silicon (Si), vanadium (V), zinc (Zn), and total PM2.5 in the CCAAPS study area. LURF utilized a more diverse and greater number of predictors than LUR and LURF models for Al, K, Mn, Pb, Si, Zn, TRAP, and PM2.5 all showed a decrease in fractional predictive error of at least 5% compared to their LUR models. LURF models for Al, Cu, Fe, K, Mn, Pb, Si, Zn, TRAP, and PM2.5 all had a cross validated fractional predictive error less than 30%. Furthermore, LUR models showed a differential exposure assessment bias and had a higher prediction error variance. Random forest and other machine learning methods may provide more accurate exposure assessment.



http://ift.tt/2gZbMuW

Heparin-hyaluronic acid hydrogel for efficient cellular activities of 3D encapsulated adipose derived stem cells

Publication date: Available online 5 December 2016
Source:Acta Biomaterialia
Author(s): Kihak Gwon, Eunsol Kim, Giyoong Tae
We have developed stem cell-responsive, heparin-hyaluronic acid (Hep-HA) hydrogel, crosslinked by thiolated heparin (Hep-SH) and methacrylated hyaluronic acid (HA-MA) via visible light mediated, thiol-ene reaction. Physical properties of the hydrogel (gelation time, storage modulus, and swelling ratio) were tunable by adjusting light intensity, initiator/polymer concentration, and precursor pH. Culture of human adipose derived mesenchymal stem cells (ADSCs) using this hydrogel was characterized and compared with the control hydrogels including Hep-PEG hydrogel, PEG-HA hydrogel. Sufficient initial adhesion and continuous proliferation of ADSCs in 2D were observed on both heparin-containing hydrogels (Hep-HA and Hep-PEG hydrogel) in contrast to no adhesion of ADSCs on PEG-HA hydrogel. On the other hand, in the case of 3D culture of encapsulated ADSCs, efficient cellular activities such as spreading, proliferation, migration, and differentiation of ADSCs were only observed in soft Hep-HA hydrogel compared to Hep-PEG or PEG-HA hydrogel with the similar modulus. The upregulated expressions of hyaluronidases in ADSCs encapsulated in Hep-HA hydrogel compared to the control hydrogels and effective degradation of the hydrogel by hyaluronidase imply that the degradation of hydrogel was necessary for 3D cellular activities. Thus, Hep-HA hydrogel, where heparin acts as a binding domain for ADSCs and HA acts as a degradation site by cell secreted enzymes, was efficient for 3D culture of human ADSCs without any additional modification using biological/chemical molecules.[Statement of Significance]Stem cell-responsive hydrogel composed of heparin and hyaluronic acid was prepared by visible light-mediated thiol-ene reaction. Without additional modification using functional peptides for cell adhesion and matrix degradation, ADSCs encapsulated in this hydrogel showed efficient cellular activities such as spreading, proliferation, migration, and differentiation of ADSCs whereas control hydrogels missing heparin or hyaluronic acid could not support cellular activities in 3D. In this hydrogel, heparin mainly acts as a binding domain for stem cells and hyaluronic acid mainly acts as a degradation site by ADSC secreted enzymes, but interrelated synergistic functions of heparin and HA were observed. Therefore, we speculate that this hydrogel can serve as a promising carrier for stem cell based therapy and various tissue engineering applications.



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Selective recruitment of non-classical monocytes promotes skeletal muscle repair

Publication date: February 2017
Source:Biomaterials, Volume 117
Author(s): Cheryl L. San Emeterio, Claire E. Olingy, Yihsuan Chu, Edward A. Botchwey
Regeneration of traumatic defects in skeletal muscle requires the synchronized behavior of multiple cells that participate in repair. The inflammatory cascade that is rapidly initiated after injury serves as a powerful node at which to guide the progression of healing and influence tissue repair. Here, we examine the role that myeloid cells play in the healing of traumatic skeletal muscle injury, and leverage their pro-regenerative functions using local delivery of the immunomodulatory small molecule FTY720. We demonstrate that increasing the frequency of non-classical monocytes in inflamed muscle coincides with increased numbers of CD206+ alternatively activated macrophages. Animals treated with immunomodulatory materials had greater defect closure and more vascularization in the acute phases of injury. In the later stages of repair, during which parenchymal tissue growth occurs, we observed improved regeneration of muscle fibers and decreased fibrotic tissue following localization of pro-regenerative inflammation. These results highlight non-classical monocytes as a novel therapeutic target to improve the regenerative outcome after traumatic skeletal muscle injury.



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Harnessing cancer cell metabolism for theranostic applications using metabolic glycoengineering of sialic acid in breast cancer as a pioneering example

Publication date: February 2017
Source:Biomaterials, Volume 116
Author(s): Haitham A. Badr, Dina M.M. AlSadek, Motawa E. El-Houseini, Christopher T. Saeui, Mohit P. Mathew, Kevin J. Yarema, Hafiz Ahmed
Abnormal cell surface display of sialic acids – a family of unusual 9-carbon sugars - is widely recognized as distinguishing feature of many types of cancer. Sialoglycans, however, typically cannot be identified with sufficiently high reproducibility and sensitivity to serve as clinically accepted biomarkers and similarly, almost all efforts to exploit cancer-specific differences in sialylation signatures for therapy remain in early stage development. In this report we provide an overview of important facets of glycosylation that contribute to cancer in general with a focus on breast cancer as an example of malignant disease characterized by aberrant sialylation. We then describe how cancer cells experience nutrient deprivation during oncogenesis and discuss how the resulting metabolic reprogramming, which endows breast cancer cells with the ability to obtain nutrients during scarcity, constitutes an "Achilles' heel" that we believe can be exploited by metabolic glycoengineering (MGE) strategies to develop new diagnostic methods and therapeutic approaches. In particular, we hypothesize that adaptations made by breast cancer cells that allow them to efficiently scavenge sialic acid during times of nutrient deprivation renders them vulnerable to MGE, which refers to the use of exogenously-supplied, non-natural monosaccharide analogues to modulate targeted aspects of glycosylation in living cells and animals. In specific, once non-natural sialosides are incorporated into the cancer "sialome" they can be exploited as epitopes for immunotherapy or as chemical tags for targeted delivery of imaging or therapeutic agents selectively to tumors.



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Editorial board

Publication date: January 2017
Source:Biomaterials, Volume 115





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A Possible Association of Diindolylmethane with Pulmonary Embolism and Deep Venous Thrombosis

Introduction. 3,3′-Diindolylmethane is available as a supplement in the United States for "cancer prevention" and "augmentation of physical fitness." A derivative of indole-3-carbinol found in plants, diindolylmethane, binds to receptors associated with the sex steroid pathways and has unclear effects on estrogen and androgen physiology. We present a patient who had been taking diindolylmethane and developed right lower extremity deep venous thrombosis and bilateral pulmonary embolism. Case Presentation. A 65-year-old man presented with swelling, erythema, and warmth of his right lower extremity for three to four weeks. He had been taking diindolylmethane one tablet daily for three to four months. Risk factors for venous thromboembolism included tobacco use, personal history of possible pulmonary embolism, body mass index, and age. Imaging studies found extensive deep venous thrombosis in his right lower extremity and bilateral pulmonary embolism with probable right middle lobe infarction. Follow-up imaging showed chronic deep venous thrombosis in his right lower extremity. Discussion. As suggested in this single case, patients who take diindolylmethane may be at greater risk for venous thromboembolism. Further reports and studies are necessary in order to elucidate this possible association. Clinicians should question patients about supplements in the setting of venous thromboembolism.

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Toward Connecting Metabolism to the Exocytotic Site

Publication date: Available online 5 December 2016
Source:Trends in Cell Biology
Author(s): Mourad Ferdaoussi, Patrick E. MacDonald
Within cells the regulated exocytosis of secretory granules controls multiple physiological functions, including endocrine hormone secretion. Release of the glucose-regulating hormone insulin from pancreatic islet β cells is critical for whole-body metabolic homeostasis. Impaired insulin secretion appears early in the progression to type 2 diabetes (T2D). Key mechanisms that control the β-cell exocytotic response, mediating the long-known but little understood metabolic amplification of insulin secretion, are becoming clearer. Recent insights indicate a convergence of metabolism-driven signals, such as lipid-derived messengers and redox-dependent deSUMOylation, at the plasma membrane to augment Ca²⁺-dependent insulin exocytosis. These pathways have important implications for the metabolic control of hormone secretion, for the functional compensation that occurs in obesity, and for impaired insulin secretion in diabetes.



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Bax and Bak Pores: Are We Closing the Circle?

Publication date: Available online 5 December 2016
Source:Trends in Cell Biology
Author(s): Katia Cosentino, Ana J. García-Sáez
Bax and its homolog Bak are key regulators of the mitochondrial pathway of apoptosis. On cell stress Bax and Bak accumulate at distinct foci on the mitochondrial surface where they undergo a conformational change, oligomerize, and mediate cytochrome c release, leading to cell death. The molecular mechanisms of Bax and Bak assembly and mitochondrial permeabilization have remained a longstanding question in the field. Recent structural and biophysical studies at several length scales have shed light on key aspects of Bax and Bak function that have shifted how we think this process occurs. These discoveries reveal an unexpected molecular mechanism in which Bax (and likely Bak) dimers assemble into oligomers with an even number of molecules that fully or partially delineate pores of different sizes to permeabilize the mitochondrial outer membrane (MOM) during apoptosis.



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Assessing the value of mepolizumab for severe eosinophilic asthma: a cost-effectiveness analysis

Publication date: Available online 4 December 2016
Source:Annals of Allergy, Asthma & Immunology
Author(s): Melanie D. Whittington, R. Brett McQueen, Daniel A. Ollendorf, Jeffrey A. Tice, Richard H. Chapman, Steven D. Pearson, Jonathan D. Campbell
BackgroundAdding mepolizumab to standard treatment with inhaled corticosteroids and controller medications could decrease asthma exacerbations and use of long-term oral steroids in patients with severe disease and increased eosinophils; however, mepolizumab is costly and its cost effectiveness is unknown.ObjectiveTo estimate the cost effectiveness of mepolizumab.MethodsA Markov model was used to determine the incremental cost per quality-adjusted life year (QALY) gained for mepolizumab plus standard of care (SoC) and for SoC alone. The population, adults with severe eosinophilic asthma, was modeled for a lifetime time horizon. A responder scenario analysis was conducted to determine the cost effectiveness for a cohort able to achieve and maintain asthma control.ResultsOver a lifetime treatment horizon, 23.96 exacerbations were averted per patient receiving mepolizumab plus SoC. Avoidance of exacerbations and decrease in long-term oral steroid use resulted in more than $18,000 in cost offsets among those receiving mepolizumab, but treatment costs increased by more than $600,000. Treatment with mepolizumab plus SoC vs SoC alone resulted in a cost-effectiveness estimate of $386,000 per QALY. To achieve cost effectiveness of approximately $150,000 per QALY, mepolizumab would require a more than 60% price discount. At current pricing, treating a responder cohort yielded cost-effectiveness estimates near $160,000 per QALY.ConclusionThe estimated cost effectiveness of mepolizumab exceeds value thresholds. Achieving these thresholds would require significant discounts from the current list price. Alternatively, treatment limited to responders improves the cost effectiveness toward, but remains still slightly above, these thresholds. Payers interested in improving the efficiency of health care resources should consider negotiations of the mepolizumab price and ways to predict and assess the response to mepolizumab.



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Perceptually salient spectrotemporal modulations for recognition of sustained musical instruments

Modulation Power Spectra include dimensions of spectral and temporal modulation that contribute significantly to the perception of musical instrument timbres. Nevertheless, it remains unknown whether each instrument's identity is characterized by specific regions in this representation. A recognition task was applied to tuba, trombone, cello, saxophone, and clarinet sounds resynthesized with filtered spectrotemporal modulations. The most relevant parts of this representation for instrument identification were determined for each instrument. In addition, instruments that were confused with each other led to non-overlapping spectrotemporal modulation regions, suggesting that musical instrument timbres are characterized by specific spectrotemporal modulations.

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Analysis of the Outcomes in Central Venous Access Port Implantation Performed by Residents via the Internal Jugular Vein and Subclavian Vein

Publication date: Available online 5 December 2016
Source:Journal of Surgical Education
Author(s): Hajime Matsushima, Tomohiko Adachi, Toru Iwata, Takashi Hamada, Hiroki Moriuchi, Manpei Yamashita, Tomoo Kitajima, Hitoshi Okubo, Susumu Eguchi
ObjectiveThe central venous access port (CVAP) has played an important role in the safe administration of chemotherapy and parenteral nutrition. The aim of the present study was to clarify the optimal access vein for CVAP implantation when performed by residents rather than attending surgeons.MethodsA consecutive cases of CVAP implantation via the subclavian vein (SV) using a landmark-guided technique or via the internal jugular vein (JV) using an ultrasound-guided technique were divided into 2 groups according to whether the intervention was performed by a resident or an attending surgeon. Early and late complications were compared retrospectively between the 2 groups, and the outcomes of the CVAPs were compared between those implanted via the SV and those implanted via the JV in resident group.ResultsA total of 207 cases of CVAP implantation were performed. Overall, 114 implantations were performed by residents, and another 93 implantations were performed by attending surgeons. Early complications were seen more frequently in the resident group (6.1%) than in the attending-surgeon group (1.1%), but the difference was not significant. No differences in operating time or late complications were observed between the 2 groups. In the resident group, CVAP implantations via the JV using the ultrasound-guided technique were associated with a shorter operating time compared with the SV approach.ConclusionsResidents can perform CVAP implantations safely using both the SV and JV approaches. However, the JV approach using an ultrasound-guided technique can be performed in less time than the SV approach.



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Modular Training for Robot-Assisted Radical Prostatectomy: Where to Begin?

Publication date: Available online 5 December 2016
Source:Journal of Surgical Education
Author(s): Catherine Lovegrove, Kamran Ahmed, Giacomo Novara, Khurshid Guru, Alex Mottrie, Ben Challacombe, Henk Van der Poel, James Peabody, Prokar Dasgupta
ObjectiveEffective training is paramount for patient safety. Modular training entails advancing through surgical steps of increasing difficulty. This study aimed to construct a modular training pathway for use in robot-assisted radical prostatectomy (RARP). It aims to identify the sequence of procedural steps that are learnt before surgeons are able to perform a full procedure without an intervention from mentor.DesignThis is a multi-institutional, prospective, observational, longitudinal study. We used a validated training tool (RARP Score). Data regarding surgeons' stage of training and progress were collected for analysis. A modular training pathway was constructed with consensus on the level of difficulty and evaluation of individual steps. We identified and recorded the sequence of steps performed by fellows during their learning curves.Setting and ParticipantsWe included 15 urology fellows from UK, Europe, and Australia.ResultsA total of 15 surgeons were assessed by mentors in 425 RARP cases over 8 months (range: 7-79) across 15 international centers. There were substantial differences in the sequence of RARP steps according to the chronology of the procedure, difficulty level, and the order in which surgeons actually learned steps.Steps were not attempted in chronological order. The greater the difficulty, the later the cohort first undertook the step (p = 0.021). The cohort undertook steps of difficulty level I at median case number 1. Steps of difficulty levels II, III, and IV showed more variation in median case number of the first attempt.We recommend that, in the operating theater, steps be learned in order of increasing difficulty. A new modular training route has been designed. This incorporates the steps of RARP with the following order of priority: difficulty level > median case number of first attempt > most frequently undertaken in surgical training.ConclusionsAn evidence-based modular training pathway has been developed that facilitates a safe introduction to RARP for novice surgeons.



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Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1
Author(s): Pablo Penaloza MacMaster, Jennifer L. Shields, Quazim A. Alayo, Crystal Cabral, Jessica Jimenez, Jade Mondesir, Abishek Chandrashekar, Joseph M. Cabral, Matthew Lim, M. Justin Iampietro, Nicholas M. Provine, Christine A. Bricault, Michael Seaman, Klaus Orlinger, Andreas Aspoeck, Gerhard Fuhrmann, Anders E. Lilja, Thomas Monath, Bastien Mangeat, Daniel D. Pinschewer, Dan H. Barouch
An important focus in vaccine research is the design of vaccine vectors with low seroprevalence and high immunogenicity. Replication-incompetent lymphocytic choriomeningitis virus (rLCMV) vectors do not elicit vector-neutralizing antibody responses, and homologous prime-boost regimens with rLCMV vectors induce boostable and protective T cell responses to model antigens in mice. However, cellular and humoral immune responses following homologous rLCMV vaccine regimens have not been rigorously evaluated in non-human primates (NHPs). To test whether rLCMV vectors constitute an effective vaccine platform in NHPs, we developed rLCMV vectors expressing SIVmac239 Env and Gag antigens and assessed their immunogenicity in mice and cynomolgus macaques. Immunization with rLCMV vaccine vectors expressing SIV Env and Gag was effective at generating SIV-specific T cell and antibody responses in both mice and NHPs. Epitope mapping using SIV Env in C57BL/6 mice demonstrated that rLCMV vectors induced sustained poly-functional responses to both dominant and subdominant epitopes. Our results suggest the potential of rLCMV vectors as vaccine candidates. Future SIV challenge experiments in rhesus macaques will be needed to assess immune protection by these vaccine vectors.



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The recombinant N-terminal domain of spike proteins is a potential vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) infection

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1
Author(s): Lan Jiaming, Yao Yanfeng, Deng Yao, Hu Yawei, Bao Linlin, Huang Baoying, Yan Jinghua, George F. Gao, Qin Chuan, Tan Wenjie
The persistent public health threat of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) highlights the need for an effective MERS-CoV vaccine. Previous studies have focused mainly on the receptor-binding domain (RBD) on the spike protein of MERS-CoV. Herein, we investigated the immunogenicity and protective potential of the recombinant N-terminal domain (rNTD) of spike proteins as a vaccine candidate. BALB/c mice vaccinated with 5 or 10μg of rNTD protein demonstrated a significant humoral immune response (serum IgG and neutralizing activity). Additionally, according to the enzyme-linked immunospot, intracellular cytokine staining, and cytometric bead array assays, significant and functional T-cell immunity was induced by 10μg of the rNTD vaccination with aluminum and CpG adjuvant. Furthermore, rNTD-immunized mice showed reduced lung abnormalities in a MERS-CoV-challenge mouse model transfected with an adenoviral vector expressing human DPP4, showing protection consistent with that found with rRBD vaccination. These data show that rNTD induced potent cellular immunity and antigen-specific neutralizing antibodies in mice and that it demonstrated protective capacity against a viral challenge, indicating that rNTD is a vaccine candidate against MERS-CoV infection.



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Comparative analysis of influenza A(H3N2) virus hemagglutinin specific IgG subclass and IgA responses in children and adults after influenza vaccination

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1
Author(s): Alessandro Manenti, Sarah M. Tete, Kristin G.-I. Mohn, Åsne Jul-Larsen, Elena Gianchecchi, Emanuele Montomoli, Karl A. Brokstad, Rebecca J. Cox
Two different influenza vaccines are generally used in many countries; trivalent live attenuated influenza vaccine (LAIV3) and trivalent inactivated influenza vaccine (IIV3). Studies comparing the antibody response to IIV3 and LAIV3 commonly investigate the seroprotective response by hemagglutination-inhibition (HI) assay. However, there is limited data regarding comparative analysis of IgG subclass and IgA responses induced by LAIV3 and IIV3.Fifteen children <5years received 2 doses of LAIV3 while 14 children aged 10–17years received one dose. In addition, 15 adults were vaccinated with either intranasal LAIV3 or intramuscular IIV3. We analyzed the H3N2 humoral responses by HI assay and the hemagglutinin (HA) specific IgG1, IgG2, IgG3, IgG4 and IgA1 responses by ELISA. Furthermore, we investigated the avidity of induced IgG antibodies.Pre-existing seroprotective HI antibodies were present in adults (73%) previously vaccinated with IIV3. Vaccination resulted in a significant increase in HI titers in all groups, except LAIV3 vaccinated adults. Furthermore, a negative correlation between age and HI titers in LAIV3 vaccinated subjects was observed post-vaccination. LAIV3 in children and IIV3 in adults induced HA-specific IgG1, low IgG3 but no IgG2 or IgG4. Moreover, significant IgA1 responses were only induced in children. Interestingly, IIV3 and LAIV3 induced IgG antibodies with comparable and significantly augmented avidity post-vaccination in children and adults.Our results suggest that age and/or exposure history play a significant role in determining the antibody response.Clinical trial registry: ClinicalTrials.gov NCT01003288 and NCT01866540



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Editorial Board/Aims and Scope

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1





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ViroSpot microneutralization assay for antigenic characterization of human influenza viruses

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1
Author(s): Carel A. van Baalen, Rienk E. Jeeninga, Germaine H.W.M. Penders, Brenda van Gent, Ruud van Beek, Marion P.G. Koopmans, Guus F. Rimmelzwaan
The hemagglutination inhibition (HI) assay has been used for the antigenic characterization of influenza viruses for decades. However, the majority of recent seasonal influenza A viruses of the H3N2 subtype has lost the capacity to agglutinate erythrocytes of various species. The hemagglutination (HA) activity of other A(H3N2) strains is generally sensitive to the action of the neuraminidase inhibitor oseltamivir, which indicates that the neuraminidase and not the hemagglutinin is responsible for the HA activity. These findings complicate the antigenic characterization and selection of A(H3N2) vaccine strains, calling for alternative antigenic characterization assays. Here we describe the development and use of the ViroSpot microneutralization (MN) assay as a reliable and robust alternative for the HI assay. Serum neutralization of influenza A(H3N2) reference virus strains and epidemic isolates was determined by automated readout of immunostained cell monolayers, in a format designed to minimize the influence of infectious virus doses on serum neutralization titers. Neutralization of infection was largely independent from rates of viral replication and cell-to-cell transmission, facilitating the comparison of different virus isolates. Other advantages of the ViroSpot MN assay include its relative insensitivity to variation in test dose of infectious virus, automated capture and analyses of residual infection patterns, and compatibility with standardized large scale analyses. Using this assay, a number of epidemic influenza A(H3N2) strains that failed to agglutinate erythrocytes, were readily characterized antigenically.



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Humoral and cellular response after varicella vaccination in VZV IgG seronegative kidney transplant candidates

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1
Author(s): Marcia M.L. Kho, Joke M. Zuijderwijk, Annemiek A. van der Eijk, Ronella de Kuiper, Marieken J. Boer-Verschragen, Willem Weimar, Nicole M. van Besouw
BackgroundIn immunocompromised patients, primary infection with VZV may have a disastrous clinical course. Vaccination of VZV-seronegative patients on the waiting list for renal transplantation may prevent severe disease. However, the immunologic response of end-stage renal disease patients to peptide vaccines is far from optimal. Our question was whether end-stage renal disease patients with undetectable VZV-IgG levels were able to mount an adequate humoral and cellular response to a live attenuated varicella vaccine.MethodsKidney transplant candidates with undetectable VZV levels were vaccinated twice with a live attenuated varicella vaccine at an interval of 6weeks. VZV IgG levels were analysed till 2years after vaccination. The VZV-specific T-cell reactivity was determined prior to vaccination and after transplantation.ResultsSeventy-seven percent (40/52) of the vaccinees reached positive VZV-IgG levels after vaccination (responders). Eighty-two percent (9/11) showed an increase in VZV-specific CD4⁺ memory T-cells (both central and effector memory cells). The percentage VZV-specific CD8⁺ memory T-cells did not increase. None of the non-responders suffered from primary VZV after transplantation. No severe vaccine-related adverse events were reported, only spontaneously resolving local skin irritation.ConclusionThe live attenuated varicella vaccine evokes positive VZV IgG-levels and VZV-specific memory T-cells in VZV-seronegative potential kidney transplant candidates.



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Challenges to estimating vaccine impact using hospitalization data

Publication date: 3 January 2017
Source:Vaccine, Volume 35, Issue 1
Author(s): Cynthia Schuck-Paim, Robert J. Taylor, Lone Simonsen, Roger Lustig, Esra Kürüm, Christian A.W. Bruhn, Daniel M. Weinberger
Because the real-world impact of new vaccines cannot be known before they are implemented in national programs, post-implementation studies at the population level are critical. Studies based on analysis of hospitalization rates of vaccine-preventable outcomes are typically used for this purpose. However, estimates of vaccine impact based on hospitalization data are particularly prone to confounding, as hospitalization rates are tightly linked to changes in the quality, access and use of the healthcare system, which often occur simultaneously with introduction of new vaccines. Here we illustrate how changes in healthcare delivery coincident with vaccine introduction can influence estimates of vaccine impact, using as an example reductions in infant pneumonia hospitalizations after introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) in Brazil. To this end, we explore the effect of changes in several metrics of quality and access to public healthcare on trends in hospitalization rates before (2008–09) and after (2011−12) PCV10 introduction in 2010. Changes in infant pneumonia hospitalization rates following vaccine introduction were significantly associated with concomitant changes in hospital capacity and the fraction of the population using public hospitals. Importantly, reduction of pneumonia hospitalization rates after PCV10 were also associated with the expansion of outpatient services in several Brazilian states, falling more sharply where primary care coverage and the number of health units offering basic and emergency care increased more. We show that adjustments for unrelated (non-vaccine) trends commonly employed by impact studies, such as use of single control outcomes, are not always sufficient for accurate impact assessment. We discuss several ways to identify and overcome such biases, including sensitivity analyses using different denominators to calculate hospitalizations rates and methods that track changes in the outpatient setting. Employing these practices can improve the accuracy of vaccine impact estimates, particularly in evolving healthcare settings typical of low- and middle-income countries.



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Idiopathic eruptive macular pigmentation with papillomatosis

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Electrophysiology in Fisher syndrome

Publication date: January 2017
Source:Clinical Neurophysiology, Volume 128, Issue 1
Author(s): Satoshi Kuwabara, Yukari Sekiguchi, Sonoko Misawa
Fisher syndrome (FS), a variant of Guillain–Barré syndrome (GBS), is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. The lesion sites for these unique clinical features include the oculomotor nerves and group 1a neurons in the dorsal root ganglion, and the presence of FS is determined by the expression of ganglioside GQ1b in the human nervous system. Neurophysiological findings suggest that ataxia and areflexia are due to an impaired proprioceptive afferent system. Typically, the soleus H-reflex is absent and a body-sway analysis using posturography shows a 1-Hz peak, which indicates proprioception dysfunction. Sensory nerve action potentials and somatosensory-evoked potentials are abnormal in approximately 30% of FS patients, indicating the occasional involvement of cutaneous (group 2) afferents. During the disease course, approximately 15% of FS patients suffer an overlap of axonal GBS with nerve conduction abnormalities that reflect axonal dysfunction. This review summarizes electrophysiological abnormalities and their clinical significance in FS.



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Sleep-related modifications of EEG connectivity in the sensory-motor networks in Huntington Disease: An eLORETA Study and Review of the Literature

Publication date: Available online 5 December 2016
Source:Clinical Neurophysiology
Author(s): Carla Piano, Claudio Imperatori, Anna Losurdo, Anna Rita Bentivoglio, Pietro Cortelli, Giacomo Della Marca
ObjectiveTo evaluate EEG functional connectivity in the sensory-motor network, during wake and sleep, in patients with Huntington Disease (HD).Methods23 patients with HD and 23 age- and sex-matched healthy controls were enrolled. EEG connectivity analysis was performed by means of exact Low Resolution Electric Tomography (eLORETA).ResultsIn wake, HD patients showed an increase of delta lagged phase synchronization (T= 3.60; p< 0.05) among Broadman's Areas (BA) 6-8 bilaterally; right BA 6-8 and right BA 1-2-3; left BA 1-2-3 and left BA 4. In NREM, HD patients showed an increase of delta lagged phase synchronization (T= 3.56; p< 0.05) among left BA 1-2-3 and right BA 6-8. In REM, HD patients showed an increase of lagged phase synchronization (T= 3.60; p< 0.05) among the BA 6-8 bilaterally (delta band); left BA 1-2-3 and right BA 1-2-3 (theta); left BA 1-2-3 and right BA 4 (theta); left BA 1-2-3 and right BA 1-2-3 (alpha).ConclusionsOur results may reflect an abnormal function of the motor areas or an effort to counterbalance the pathological motor output. Significance. Our results may help to understand the pathophysiology of sleep-related movement disorders in Huntington's Disease, and to define therapeutically strategies.



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Issue Information

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Efficacy of the Individual Components of a Tinnitus Management Protocol

Tinnitus is a perception of sound in the ears or head in the absence of an actual physical sound. Tinnitus represents one of the most common and distressing otologic problems, and it can cause various somatic and psychological disorders that interfere with the quality of life (Yetiser et al., 2002). Approximately 12 million individuals in the United States have been diagnosed with tinnitus, of which ~1 million have severe tinnitus interfering with their daily activities (Meikle, 1997; Tyler & Baker, 1983). Various treatment methods from medications to electrical stimulation to alternative medicine have been investigated, but all have limited efficacy at present. These treatments are generally aimed at reducing or eliminating the tinnitus perception, and have been largely unsuccessful in that goal.

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Growth inhibitory effect of Scrophularia oxysepala extract on mouse mammary carcinoma 4T1 cells in vitro and in vivo systems

Publication date: Available online 4 December 2016
Source:Biomedicine & Pharmacotherapy
Author(s): Pooneh Chokhachi Baradaran, Ali Mohammadi, Behzad Mansoori, Sepideh Chokhachi Baradaran, Behzad Baradaran
IntroductionMedical plants have been intensively studied as a source of antitumor compounds. In the present study, we determine the effect of Scrophularia oxysepala on triggering apoptosis and diminishing growth, size and weight of the tumor in the allograft model of Balb/c mice.Material & methodsThe cytotoxic effects of Scrophularia oxysepala extract on 4T1 cells were studied using MTT (3-[4,5-dimethyl-2-thiazolyl]-2, 5 diphenyl tetrazolium bromide) assay and Trypan blue staining. DNA fragmentation assay was done for apoptosis detection. After the establishment of tumor in Balb/c mice, two groups of mice were received the extract at two doses of 50 and 100mg/kg respectively using intraperitoneal injection once every two days for 28 days. In order to assess the induction of apoptosis in cancer cells, the TUNEL assay was carried out in tumoral tissues. Moreover, the Ki67 test was used to evaluate tumor proliferation.ResultsAccording to the findings, the Scrophularia oxysepala extract inhibited cell growth. In vivo results showed that tumor size in mice treated with the extract was significantly reduced. The weight of tumor mass in treated mice after resection was less than the control group. According to the TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay results, the herbal extract induced apoptosis in tumoral cells. Ki67 test also demonstrated that administration of the extract suppressed the growth of tumor cells.ConclusionOur data well approved the anti-proliferative effect of Scrophularia oxysepala extract, and clearly showed that, the plant extract can decrease the growth of breast cancer cells in tumor mass. Thus it may represent an ideal therapeutic tool for breast cancer.



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Paraoxonase 3 promotes cell proliferation and metastasis by PI3K/Akt in oral squamous cell carcinoma

Publication date: Available online 4 December 2016
Source:Biomedicine & Pharmacotherapy
Author(s): Lili Zhu, Yiyin Shen, Wei Sun
Paraoxonase 3 (PON3) is an oncogene in cancer, however, little is known about the mechanisms and roles of PON3 in oral squamous cell carcinoma (OSCC), which is the aim of our study. We found that the expression of PON3 was up-regulated in OSCC samples and cell lines. PON3 was associated with accelerating cell proliferation, cell cycle, migration and invasion in OSCC cells. Further research showed that PON3 was regulated by PI3K/Akt pathway. We also found that AP-1 was an important transcriptional factor regulating PON3 expression in OSCC. The study elucidates that PI3K/Akt pathway up-regulated the expression of PON3 in OSCC by AP-1.



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Investigation for role of tissue factor and blood coagulation system in severe acute pancreatitis and associated liver injury

Publication date: Available online 4 December 2016
Source:Biomedicine & Pharmacotherapy
Author(s): Zhi-Bing Ou, Chun-Mu Miao, Ming-Xin Ye, Ding-Pei Xing, Kun He, Pei-Zhi Li, Rong-Tao Zhu, Jian-Ping Gong
This study aims to investigate the molecular mechanisms underlying the pathogenesis of severe acute pancreatitis (SAP) and SAP-associated liver injury, we performed an association analysis of the functions of tissue factor (TF) and blood coagulation system in both SAP patients and mouse SAP model. Our results showed that serum TF and tissue factor-microparticle (TF-MP) levels were highly up-regulated in both SAP patients and SAP mouse model, which was accompanied by the dysfunction of blood coagulation system. Besides, TF expression was also highly up-regulated in the Kupffer cells (KCs) of SAP mouse model. After inhibiting KCs in SAP mouse model, the amelioration of blood coagulation system functions was associated with the decrease in serum TF and TF-MPs levels, and the reduction of SAP-associated liver injury was associated with the decrease of TF expression in KCs. In conclusion, the dis-regulated TF expression and associated dysfunction of blood coagulation system are critical factors for the pathogenesis of SAP and SAP-associated liver injury. TF may serve as a potential and effective target for treating SAP and SAP-associated liver injury.



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Dicranostiga leptopodu (Maxim.) Fedde extracts attenuated CCl4-induced acute liver damage in mice through increasing anti-oxidative enzyme activity to improve mitochondrial function

Publication date: Available online 4 December 2016
Source:Biomedicine & Pharmacotherapy
Author(s): Deping Tang, Fang Wang, Jinzhou Tang, Aihong Mao, Shiqi Liao, Qin Wang
Dicranostiga Leptodu (Maxim.) fedde (DLF), a poppy plant, has been reported have many benefits and medicinal properties, including free radicals scavenging and detoxifying. However, the protective effect of DLF extracts against carbon tetrachloride (CCl4)-induced damage in mice liver has not been elucidated. Here, we demonstrated that DLF extracts attenuated CCl4-induced liver damage in mice through increasing anti-oxidative enzyme activity to improve mitochondrial function. In this study, the mice liver damage evoked by CCl4 was marked by morphology changes, significant rise in lipid peroxidation, as well as alterations of mitochondrial respiratory function. Interestingly, pretreatment with DLF extracts attenuated CCl4-induced morphological damage and increasing of lipid peroxidation in mice liver. Additionally, DLF extracts improved mitochondrial function by preventing the disruption of respiratory chain and suppression of mitochondrial Na⁺K⁺-ATPase and Ca²⁺-ATPase activity. Furthermore, administration with DLF extracts elevated superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels and maintained the balance of redox status. This results showed that toxic protection effect of DLF extracts on mice liver is mediated by improving mitochondrial respiratory function and keeping the balance of redox status, which suggesting that DLF extracts could be used as potential toxic protection agent for the liver against hepatotoxic agent.



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Eupafolin nanoparticle improves acute renal injury induced by LPS through inhibiting ROS and inflammation

Publication date: Available online 4 December 2016
Source:Biomedicine & Pharmacotherapy
Author(s): Hao Zhang, Ming-Kun Chen, Ke Li, Cheng Hu, Min-Hua Lu, Jie Situ
Acute renal injury is a common severe clinical syndrome, occurring in many clinical situations. It is necessary to explore effective drugs to treat it. Eupafolin is a flavonoid compound, derived from Phyla nodiflora, which has been previously reported to possess a variety of pharmacological activities, including anti-inflammatory and antioxidant effects. However, it is known little about how it works in acute renal injury. Also, eupafolin is characterized by skin penetration and poor water solubility, limiting its clinical applications. Thus, we synthesized an eupafolin nanoparticle delivery system. We found that eupafolin nanoparticle could address the physicochemical defects of raw eupafolin and increase water solubility without any toxicity to normal renal cells via reducing particle size. Eupafolin nanoparticle attenuated LPS-induced acute renal injury in mice through inhibiting oxidative stress and inflammation accompanied with up-regulated SOD activity and down-regulated pro-inflammatory cytokines. Additionally, inactivation of NF-κB and MAPKs of p38, ERK1/2 and JNK signaling pathways was a main molecular mechanism by which eupafolin nanoparticle improved renal injury. Together, eupafolin nanoparticle exhibits effective anti-oxidant and anti-inflammatory activities, which could be used as a potential drug to ameliorate acute renal injury clinically.



http://ift.tt/2gXACvr

Photoactivated hypericin increases the expression of SOD-2 and makes MCF-7 cells resistant to photodynamic therapy

Publication date: Available online 5 December 2016
Source:Biomedicine & Pharmacotherapy
Author(s): Patrícia Kimáková, Peter Solár, Barbora Fecková, Veronika Sačková, Zuzana Solárová, Lenka Ilkovičová, Martin Kello
Photoactivated hypericin increased production of reactive oxygen species in human breast adenocarcinoma MCF-7 as well as in MDA-MB-231 cells 1h after photodynamic therapy. On the other hand, reactive oxygen species dropped 3h after photodynamic therapy with hypericin, but only in MCF-7 cells, whereas in MDA-MB-231 cells remained elevated. The difference in the dynamics of reactive oxygen species after hypericin activation was related to increased activity of SOD-2 in MCF-7 cells compared to MDA-MB-231 cells. Indeed, photodynamic therapy with hypericin significantly increased SOD-2 activity in MCF-7 cells, but only slightly in MDA-MB-231 cells. In this regard, SOD-2 activity correlated well with enhanced both mRNA expression as well as SOD-2 protein level in MCF-7 cells. The role of SOD-2 in the resistance of MCF-7 cells to photodynamic therapy with hypericin was monitored using SOD-2 inhibitor - 2-methoxyestradiol. Interestingly, the combination of photodynamic therapy with hypericin and methoxyestradiol sensitized MCF-7 cells to photodynamic therapy and significantly reduced its clonogenic ability. Furthermore, methoxyestradiol potentiated the activation of caspase 3/7 and apoptosis induced by photodynamic therapy with hypericin.



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Decoding hand gestures from primary somatosensory cortex using high-density ECoG

Publication date: Available online 5 December 2016
Source:NeuroImage
Author(s): Mariana P. Branco, Zachary V. Freudenburg, Erik J. Aarnoutse, Martin G. Bleichner, Mariska J. Vansteensel, Nick F. Ramsey
Electrocorticography (ECoG) based Brain-Computer Interfaces (BCIs) have been proposed as a way to restore and replace motor function or communication in severely paralyzed people. To date, most motor-based BCIs have either focused on the sensorimotor cortex as a whole or on the primary motor cortex (M1) as a source of signals for this purpose. Still, target areas for BCI are not confined to M1, and more brain regions may provide suitable BCI control signals. A logical candidate is the primary somatosensory cortex (S1), which not only shares similar somatotopic organization to M1, but also has been suggested to have a role beyond sensory feedback during movement execution. Here, we investigated whether four complex hand gestures, taken from the American sign language alphabet, can be decoded exclusively from S1 using both spatial and temporal information. For decoding, we used the signal recorded from a small patch of cortex with subdural high-density (HD) grids in five patients with intractable epilepsy. Notably, we introduce a new method of trial alignment based on the increase of the electrophysiological response, which virtually eliminates the confounding effects of systematic and non-systematic temporal differences within and between gestures execution. Results show that S1 classification scores are high (76%), similar to those obtained from M1 (74%) and sensorimotor cortex as a whole (85%), and significantly above chance level (25%). We conclude that S1 offers characteristic spatiotemporal neuronal activation patterns that are discriminative between gestures, and that it is possible to decode gestures with high accuracy from a very small patch of cortex using subdurally implanted HD grids. The feasibility of decoding hand gestures using HD-ECoG grids encourages further investigation of implantable BCI systems for direct interaction between the brain and external devices with multiple degrees of freedom.



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Physiological Adaptations to Sugar Intake: New Paradigms from Drosophila melanogaster

Publication date: Available online 5 December 2016
Source:Trends in Endocrinology & Metabolism
Author(s): Wen-bin Alfred Chng, Ville Hietakangas, Bruno Lemaitre
Sugars are important energy sources, but high sugar intake poses a metabolic challenge and leads to diseases. Drosophila melanogaster is a generalist fruit breeder that encounters high levels of dietary sugars in its natural habitat. Consequently, Drosophila displays adaptive responses to dietary sugars, including highly conserved and unique metabolic adaptations not described in mammals. Carbohydrate homeostasis is maintained by a network comprising intracellular energy sensors, transcriptional regulators, and hormonal and neuronal mechanisms that together coordinate animal behavior, gut function, and metabolic flux. Here we give an overview of the physiological responses associated with sugar intake and discuss some of the emerging themes and applications of the Drosophila model in understanding sugar sensing and carbohydrate metabolism.



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