Publication date: Available online 24 July 2017
Source:Allergologia et Immunopathologia
Author(s): R. Kalmarzi, P. Ataee, Gh. Homagostar, M. Tagik, E. Ghaderi, W. Kooti
IntroductionFood allergy refers to abnormal reactions of the body caused by an immune system response to food. This study was conducted aiming to investigate allergy to food allergens in children with food allergies.Materials and methodsThis study was conducted as a cross-sectional one on 304 children aged six months to seven years with food allergies admitted to the tertiary referral hospital in Kurdistan Province – Iran, during 2014–2015. All the patients were examined for skin prick test using 49 allergens. Finally, the obtained data were analysed using SPSS15 and chi-square and t tests.ResultsThe highest percentage of occurrence of bump reaction (wheal) and redness (flare) was due to the consumption of fish, eggs, tomatoes, and cocoa. Moreover, the lowest rate of wheal and flare was caused by exposure to allergens like latex, tea, malt, and wheat flour. The reaction most created due to the consumption of foods was flare which was higher among under three-year-olds group (p<0.05), and between the sexes, girls showed the most common allergic reactions (p<0.05).ConclusionSince food allergy has a high prevalence in children, it should be considered with great interest. Considering that avoiding food allergens is the first step in the treatment of food allergies, the present study may be a useful guide in this regard.
http://ift.tt/2tVg7BO
Δευτέρα 24 Ιουλίου 2017
Evaluation of the frequency of food allergens based on skin prick test in children in Kurdistan Province – Iran
A machine learning approach for real-time modelling of tissue deformation in image-guided neurosurgery
Source:Artificial Intelligence in Medicine
Author(s): Michele Tonutti, Gauthier Gras, Guang-Zhong Yang
ObjectivesAccurate reconstruction and visualisation of soft tissue deformation in real time is crucial in image-guided surgery, particularly in augmented reality (AR) applications. Current deformation models are characterised by a trade-off between accuracy and computational speed. We propose an approach to derive a patient-specific deformation model for brain pathologies by combining the results of pre-computed finite element method (FEM) simulations with machine learning algorithms. The models can be computed instantaneously and offer an accuracy comparable to FEM models.MethodA brain tumour is used as the subject of the deformation model. Load-driven FEM simulations are performed on a tetrahedral brain mesh afflicted by a tumour. Forces of varying magnitudes, positions, and inclination angles are applied onto the brain's surface. Two machine learning algorithms—artificial neural networks (ANNs) and support vector regression (SVR)—are employed to derive a model that can predict the resulting deformation for each node in the tumour's mesh.ResultsThe tumour deformation can be predicted in real time given relevant information about the geometry of the anatomy and the load, all of which can be measured instantly during a surgical operation. The models can predict the position of the nodes with errors below 0.3mm, beyond the general threshold of surgical accuracy and suitable for high fidelity AR systems. The SVR models perform better than the ANN's, with positional errors for SVR models reaching under 0.2mm.ConclusionsThe results represent an improvement over existing deformation models for real time applications, providing smaller errors and high patient-specificity. The proposed approach addresses the current needs of image-guided surgical systems and has the potential to be employed to model the deformation of any type of soft tissue.
http://ift.tt/2vErost
A New Preprocessing Parameter Estimation based on Geodesic Active Contour Model for Automatic Vestibular Neuritis Diagnosis
Publication date: Available online 23 July 2017
Source:Artificial Intelligence in Medicine
Author(s): Amine Ben Slama, Aymen Mouelhi, Hanene Sahli, Sondes Manoubi, Chiraz Mbarek, Hedi Trabelsi, Farhat Fnaiech, Mounir Sayadi
The diagnostic of the vestibular neuritis (VN) presents many difficulties to traditional assessment methods This paper deals with a fully automatic VN diagnostic system based on nystagmus parameter estimation using a pupil detection algorithm. A geodesic active contour model is implemented to find an accurate segmentation region of the pupil. Hence, the novelty of the proposed algorithm is to speed up the standard segmentation by using a specific mask located on the region of interest. This allows a drastically computing time reduction and a great performance and accuracy of the obtained results. After using this fast segmentation algorithm, the obtained estimated parameters are represented in temporal and frequency settings. A useful principal component analysis (PCA) selection procedure is then applied to obtain a reduced number of estimated parameters which are used to train a multi neural network (MNN). Experimental results on 90 eye movement videos show the effectiveness and the accuracy of the proposed estimation algorithm versus previous work.
Graphical abstract
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Gaussian Process Classification of Superparamagnetic Relaxometry Data: Phantom Study
Source:Artificial Intelligence in Medicine
Author(s): Javad Sovizi, Kelsey B. Mathieu, Sara L. Thrower, Wolfgang Stefan, John D. Hazle, David Fuentes
MotivationSuperparamagnetic relaxometry (SPMR) is an emerging technology that holds potential for use in early cancer detection. Measurement of the magnetic field after the excitation of cancer-bound superparamagnetic iron oxide nanoparticles (SPIONs) enables the reconstruction of SPIONs spatial distribution and hence tumor detection. However, image reconstruction often requires solving an ill-posed inverse problem that is computationally challenging and sensitive to measurement uncertainty. Moreover, an additional image processing module is required to automatically detect and localize the tumor in the reconstructed image.ObjectiveOur goal is to examine the use of data-driven machine learning technique to detect a weak signal induced by a small cluster of SPIONs (surrogate tumor) in presence of background signal and measurement uncertainty. We aim to investigate the performance of both data-driven and image reconstruction models to characterize situations that one can replace the computationally-challenging reconstruction technique by the data-driven model.MethodsWe utilize Gaussian process (GP) classification model and a physics-based image reconstruction method, tailored to SPMR datasets that are obtained from (i) in silico simulations designed based on mouse cancer models and (ii) phantom experiments using MagSense system (Imagion Biosystems, Inc.). We investigate the performance of the GP classifier against the reconstruction technique, for different levels of measurement noise, different scenarios of SPIONs distribution, and different concentrations of SPIONs at the surrogate tumor.ResultsIn our in silico source detection analysis, we were able to achieve high sensitivity results using GP model that outperformed the ImR model for various choices of SPIONs concentration at the surrogate tumor and measurement noise levels. Moreover, in our phantom studies we were able to detect the surrogate tumor phantoms with 5% and 7.3% of the total used SPIONs, surrounded by 9 low-concentration phantoms with accuracies of 87.5% and 96.4%, respectively.ConclusionsThe GP framework provides acceptable classification accuracies when dealing with in silico and phantom SPMR datasets and can outperform an image reconstruction method for binary classification of SPMR data.
http://ift.tt/2usyMbK
Cold-induced retrotransposition of fish LINEs
Source:Journal of Genetics and Genomics
Author(s): Shue Chen, Mengchao Yu, Xu Chu, Wenhao Li, Xiujuan Yin, Liangbiao Chen
Classes of retrotransposons constitute a large portion of metazoan genome. There have been cases reported that genomic abundance of retrotransposons is correlated with the severity of low environmental temperatures. However, the molecular mechanisms underlying such correlation are unknown. We show here by cell transfection assays that retrotransposition of a long interspersed nuclear element (LINE) from an Antarctic notothenioid fish Dissostichus mawsoni (dmL1) could be activated by low temperature exposure, causing increased dmL1 copies in the host cell genome. The cold-induced dmL1 propagation was demonstrated to be mediated by the mitogen-activated protein kinases (MAPK)/p38 signalling pathway, which is activated by accumulation of reactive oxygen species (ROS) in cold-stressed conditions. Surprisingly, dmL1 transfected cells showed an increase in the number of viable cells after prolonged cold exposures than non-transfected cells. Features of cold inducibility of dmL1 were recapitulated in LINEs of zebrafish origin both in cultured cell lines and tissues, suggesting existence of a common cold-induced LINE amplification in fishes. The findings revealed an important function of LINEs in temperature adaptation and provided insights into the MAPK/p38 stress responsive pathway that shapes LINE composition in fishes facing cold stresses.
http://ift.tt/2vUR8A1
Value of post-therapy 177Lu PSMA images for accurate interpretation of therapy response with 68Ga-PSMA PET/CT
Publication date: Available online 24 July 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): M. Tuncel, T. Telli
A 54-year-old man with progressive prostate cancer underwent a 68Ga-PSMA-PET/CT, which showed lymph node and bone metastases. After 2-cycles of 177Lu-PSMA therapy, the repeated 68Ga-PSMA PET/CT showed decreased radiotracer uptake in lymph node and bones metastases, but there were new lesions which may be compatible with progression or tumour sink-effect. A review of 177Lu-PSMA-therapy images revealed that new lesions in the second PET/CT were the metastatic lesions that progressed after the first PET/CT, and subsequently showed a good response. The patient received additional cycles of 177Lu-PSMA therapy, and the disease regressed further, with a PSA of 0.06ng/mL. Response evaluation of new therapeutic diagnostics (theranostic) agents needs a review of not only diagnostic PET/CT images, but also post-therapy images and laboratory results.
http://ift.tt/2tylfwo
Hallazgo incidental de captación focal del colon en estudios 18F-FDG PET/TC
Publication date: Available online 24 July 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): L. Servente, V. Gigirey, M. García Fontes, O. Alonso
ObjetivosEvaluar la frecuencia de la captación focal de colon como observación incidental en estudios 18F-FDG PET/TC. Correlacionar dicho hallazgo con resultados histopatológicos.Material y métodosSe analizaron de forma sistemática 30 estudios en los que se constató captación focal del colon de un total de 3.176 PET/TC con 18F-FDG. Se excluyeron pacientes con neoplasia colorrectal conocida. Se consignó el valor del SUV máximo (SUVm) y el hallazgo morfológico de la TC. Los estudios fueron informados por un médico radiólogo y un médico nuclear. Los hallazgos fueron correlacionados con la endoscopia y la anatomía patológica.ResultadosDe los 30 pacientes con lesiones focales hipermetabólicas del colon (0,94%), 15 eran hombres y 15 mujeres con edades comprendidas entre los 27 y 73 años (media 55 años). Los motivos de realización de la PET/TC fueron: cáncer broncopulmonar (4), cáncer de mama (4), tumor de origen desconocido (4), melanoma (3), carcinoma renal (3), neoplasia de cuello uterino (2), adenocarcinoma de ovario (2) y otros (8). Se realizaron 23 fibrocolonoscopias (FCC): 10 pacientes (43,4%) presentaron lesiones malignas, 6 pacientes (26,1%) lesiones premalignas y en 7 pacientes (30,4%) no se identificó ninguna lesión o esta fue benigna. En 7 pacientes no se hizo endoscopia por diversos motivos (rechazo del paciente para realizar el estudio, enfermedad oncológica avanzada). Se correlacionó con valores de SUVm y no se encontraron diferencias estadísticamente significativas entre lesiones malignas-premalignas y las lesiones benignas.ConclusionesLa captación focal en colon de 18F-FDG tiene relevancia clínica sobre todo asociada a lesión morfológica en TC, puede tratarse de un segundo tumor o una lesión premaligna. Se recomienda que todas las captaciones focales del colon sean valoradas con endoscopia, tengan o no alteraciones en TC.ObjectivesTo assess the frequency of focal colonic uptake as an incidental observation in 18F-FDG PET/CT studies, and to correlate this finding with histopathological results.Material and methodsOut of a total of 3,176 PET/CT studies with 18F-FDG systematic analysis was carried out on 30 studies in which colonic focal uptake was observed. Patients with known colorectal neoplasia were excluded. The maximum standardised uptake values (SUVm) and the morphological findings provided by the CT were recorded. The studies were reported by a radiologist and a nuclear medicine doctor. The findings were compared with endoscopy and pathology findings.ResultsOf the 30 patients with focal hypermetabolic lesions of the colon (0.94%), 15 were men and 15 were women with ages between 27 and 73 (mean 55 years). The reasons for PET/CT were bronchopulmonary cancer (4), breast cancer (4), tumour of unknown origin (4), melanoma (3), renal carcinoma (3), cervical neoplasia (2), adenocarcinoma of ovary (2), and others (8). Of the 23 colonoscopies performed, 10 patients (43.4%) had malignant lesions, 6 (26.1%) had pre-malignant lesions, and in 7 patients (30.4%) no lesion was identified or was benign. No endoscopy was performed on 7 patients for various reasons (patient refusal to perform the study, advanced oncological disease). An analysis was performed with the SUVm, with no statistically significant differences being found between malignant-premalignant lesions and benign lesions.ConclusionsFocal uptake in the colon of 18F-FDG has clinical relevance, and is mainly associated with morphological lesions in CT. It should be evaluated, as it may be a second tumour or a pre-malignant lesion. It is recommended that all focal uptakes of the colon be evaluated with endoscopy.
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Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma
http://ift.tt/2eJgdL8
Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma
http://ift.tt/2eJgdL8
Bioactive polysaccharide from edible Dictyophora spp.: Extraction, purification, structural features and bioactivities
Publication date: Available online 24 July 2017
Source:Bioactive Carbohydrates and Dietary Fibre
Author(s): Yuxiao Wang, Xiaodan Shi, Junyi Yin, Shaoping Nie
Dictyophora indusiata and many other Dictyophora mushrooms distribute widely around the world. They have long been used as edible mushroom in China. Owing to the outstanding healthy benefits, various bioactive substances from Dictyophora indusiata, including polysaccharide, amino acid, vitamin and protein, have been studied in recent years. Polysaccharide is one of the most important substances reported through out years. This review outlines recent progress on the extraction, purification, structural features and biological activities of polysaccharide from Dictyophora indusiata.
http://ift.tt/2tyoUdI
PMab-52: Specific and Sensitive Monoclonal Antibody Against Cat Podoplanin for Immunohistochemistry
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy , Vol. 0, No. 0.
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Inter and intraexaminer reliability in identifying and classifying myofascial trigger points in shoulder muscles
Publication date: Available online 24 July 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): José Diego Sales do Nascimento, Francisco Alburquerque-Sendín, Lorena Passos Vigolvino, Wandemberg Fortunato de Oliveira, Catarina de Oliveira Sousa
ObjectiveTo determine inter and intraexaminer reliability of examiners without clinical experience in identifying and classifying MTPs in the shoulder muscles of subjects asymptomatic and symptomatic for unilateral SIS.DesignWithin-day inter and intraexaminer reliability study.SettingPhysical Therapy Department of a University.ParticipantsFifty-two subjects participated in the study, 26 symptomatic (SG) and 26 asymptomatic (AG) for unilateral SIS.InterventionsTwo examiners, without experience for assessment MTPs, independent and blind to the clinical conditions of the subjects, assessed bilaterally the presence of MTPs (present or absent) in six shoulder muscles and classified them (latent or active) on the affected side of the SG. Each examiner performed the same assessment twice in the same day.Main Outcome MeasuresThe reliability was calculated through Percentage Agreement (PA), Prevalence and Bias Adjusted Kappa Statistics (PABAK), and weighted Kappa (IKw).ResultsIntraexaminer reliability in identifying MTPs for the SG and AG was moderate to perfect (PABAK: 0.46-1 and 0.60-1, respectively). Interexaminer reliability was between moderate and almost perfect in the two groups (PABAK: 0.46-0.92), except for the muscles of the SG, which were below these values. With respect to MTP classification, intraexaminer reliability was moderate to high for the most muscles, but interexaminer reliability was moderate for only one muscle (IKw=0.45), and between weak and reasonable for the rest (IKw: 0.06 -0.31).ConclusionsIntraexaminer reliability is acceptable in clinical practice to identify and classify MTPs. However, interexaminer reliability proved to be reliable only to identify MTPs, with the symptomatic side exhibiting lower values of reliability.
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Modification of spastic stretch reflexes at the elbow by flexion synergy expression in individuals with chronic hemiparetic stroke
Publication date: Available online 24 July 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Jacob G. McPherson, Arno H.A. Stienen, Justin M. Drogos, Julius P.A. Dewald
ObjectiveTo systematically characterize the impact of flexion synergy expression on the manifestation of elbow flexor stretch reflexes post-stroke, and to relate these findings to elbow flexor stretch reflexes in individuals without neurological injury.DesignControlled cohort study.SettingAcademic medical center.ParticipantsTen individuals with chronic hemiparetic stroke and a convenience sample of 10 individuals without neurological or musculoskeletal injury.InterventionsParticipants with stroke were interfaced with a robotic device that precisely manipulated flexion synergy expression (by regulating shoulder abduction loading) while it delivered controlled elbow extension perturbations over a wide range of velocities. This device was also used to elicit elbow flexor stretch reflexes during volitional elbow flexor activation, both in the cohort of individuals with stroke and in a control cohort. In both cases, the amplitude of volitional elbow flexor pre-activation was matched to that generated involuntarily during flexion synergy expression.Outcome measuresThe amplitude of short and long latency stretch reflexes in the biceps brachii, assessed by electromyography, and expressed as a function of background muscle activation and stretch velocity.ResultsIncreased shoulder abduction loading potentiated elbow flexor stretch reflexes via flexion synergy expression in the paretic arm. Compared to stretch reflexes in individuals without neurological injury, paretic reflexes were larger at rest but were approximately equal to control muscles at matched levels of pre-activation.ConclusionsBecause flexion synergy expression modifies stretch reflexes in involved muscles, interventions that reduce flexion synergy expression may confer the added benefit of reducing spasticity during functional use of the arm.
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Prognostic role of Nectin-4 expression in luminal B (HER2 negative) breast cancer
Publication date: Available online 24 July 2017
Source:Pathology - Research and Practice
Author(s): Jasmina Rajc, Damir Gugić, Irena Fröhlich, Ksenija Marjanović, Boris Dumenčić
Nectins are Ca2+-independent immunoglobulin (Ig) superfamily proteins that participate in the organization of epithelial and endothelial junctions and regulate several cellular activities including the entry of some viruses. Nectin-4 has recently been shown as a metastasis-associated protein in several cancers. In the following study, we have evaluated the expression of Nectin-4 inthe luminal B HER2 negative subtype breast cancer. The study group consisted of 147 patients presenting with primary unilateral breast carcinoma with no evidence of distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry and the results were correlated with the clinical data using Kaplan–Meier curves, univariate and multivariate stepwise proportional-hazard analysis (Cox model).Nectin-4 overexpression was significantly correlated with the tumour size (p<0.05; Fisher's Exact Test), also Nectin-4 expression was negatively associated with overall survival, disease free survival and distant relapse free survival with the same significance (p<0,001; Kaplan-Meier, Cox model). We did not find statistically significant correlation between Nectin-4 and age, ER, PR, age, lymph node metastasis, tumour differentiation, histologicalsubtype and Ki-67proliferation index.We suggest that Nectin-4 is a relevant prognostic factor and a therapeutic target in luminalB (HER2 negative) breast cancer.
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Editorial Board
Publication date: August 2017
Source:Pathology - Research and Practice, Volume 213, Issue 8
http://ift.tt/2uswg5r
Nuclear maspin expression: a biomarker for budding assessment in colorectal cancer specimens
Publication date: Available online 24 July 2017
Source:Pathology - Research and Practice
Author(s): Laura Banias, Simona Gurzu, Zsolt Kovacs, Tivadar Bara, Tivadar Bara, Ioan Jung
AimTo evaluate the maspin expression in colorectal carcinomas (CRC) and its possible role in quantification of the tumor budding.MethodsThe tumor budding was prospectively quantified in 49 consecutive cases of patients that underwent surgical resection for CRC. The cases were divided in two groups: group A (n=23) − low budding (<5 tumor buds per high microscopic field) and group B (n=26) − high budding CRCs (≥5 buds). Maspin expression was evaluated in the tumor core and the buds from the hot spot area in 44 of the microsatellite stable adenocarcinomas. Its expression was quantified as negative, cytoplasmic only, nuclear only or mixed expression (cytoplasm and nucleus).ResultsCompared with group A, a higher pT (p <0.0001) and pN stage (p=0.0001) and infiltrating aspect at macroscopic evaluation (p=0.0081) was identified in group B. No correlation between the maspin expression in the tumore core and the budding grade was noted (p=0.14). Compared with the tumor core, the cytoplasm to nuclear translocation of maspin was more frequently observed in cases from group B than A (n=0.0063).ConclusionFor the colorectal carcinomas, the infiltrative aspect at macroscopic evaluation and nuclear maspin in the buds might be used as indicators of risk for lymph node metastases. Maspin nuclear expression in the buds may be helpful for a proper budding assessment and may serve as a negative prognostic factor.
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Efficacy of new natural biomodification agents from Anacardiaceae extracts on dentin collagen cross-linking
Publication date: Available online 24 July 2017
Source:Dental Materials
Author(s): M.A. Moreira, N.O. Souza, R.S. Sousa, D.Q. Freitas, M.V. Lemos, D.M. De Paula, F.J.N. Maia, D. Lomonaco, S.E. Mazzetto, V.P. Feitosa
ObjectivesSeveral polyphenols from renewable sources were surveyed for dentin biomodification. However, phenols from cashew nut shell liquid (CNSL, Anacardium occidentale) and from Aroeira (Myracrodruon urundeuva) extract have never been evaluated. The present investigation aimed to compare the dentin collagen crosslinking (biomodification) effectiveness of polyphenols from Aroeira stem bark extract, proanthocyanidins (PACs) from grape-seed extract (Vitis vinifera), cardol and cardanol from CNSL after clinically relevant treatment for one minute.MethodsThree-point bending test was used to obtain the elastic modulus of fully demineralized dentin beams before and after biomodification, whilst color change and mass variation were evaluated after four weeks water biodegradation. Color aspect was assessed by optical images after biodegradation whereas collagen cross-linking was investigated by micro-Raman spectroscopy. Statistical analysis was performed with repeated-measures two way ANOVA and Tukey's test (p<0.05).ResultsThe increase in elastic modulus after biomodification was in the order cardol>cardanol>aroeira=PACs with cardol solution achieving mean 338.2% increase. The mass increase after biomodification followed the same order aforementioned. Nevertheless, after four weeks aging, more hydrophobic agent (cardanol) induced the highest resistance against water biodegradation. Aroeira and cardol attained intermediate outcomes whereas PACs provided the lower resistance. Tannin-based agents (Aroeira and PACs) stained the specimens in dark brown color. No color alteration was observed with cardol and cardanol treatments. All four agents achieved crosslinking in micro-Raman after one minute application.SignificanceIn conclusion, major components of CNSL yield overall best dentin biomodification outcomes when applied for one minute without staining the dentin collagen.
Graphical abstract
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The interrelationship of microstructure and hardness of human coronal dentin using reference point indentation technique and micro-Raman spectroscopy
Source:Dental Materials
Author(s): Rasoul Seyedmahmoud, Jacob D. McGuire, Yong Wang, Ganesh Thiagarajan, Mary P. Walker
ObjectivesThe aim of this paper is to determine the interrelationship between the microstructure – in terms of chemical composition and crystallinity – to the microhardness of coronal dentin.MethodsDentin microhardness was tested by a novel reference point indenter and compared to the traditional Knoop hardness method. Micro-Raman spectroscopy was used to determine the chemical composition and crystallinity of dentin.ResultsFrom the occlusal groove to the border of the coronal pulp chamber, dentin hardness decreased from superficial dentin (SD) to deep dentin (DD). Mineral/organic matrix ratios (phosphate/CH and phosphate/amide I) also decreased from SD to DD; however, this change was significant (P<0.05) in the phosphate/amide I ratio only. The phosphate/carbonate ratio decreased significantly by varying position from SD to DD. The degree of the crystallinity, as measured by the full width at half maximum (FWHM) of the peak at 960cm−1, decreased significantly going from superficial to deep dentin.SignificanceFor the first time, the interrelationship between the microstructure and the mechanical properties of coronal dentin was determined by using the novel reference point indentation technique and micro-Raman spectroscopy. We hypothesize that the decrease in hardness from superficial to deep dentin can potentially be explained by decreased mineral content and increased carbonate content, which is also associated with decreased crystallinity. Collectively, there is a positive association between dentin hardness and mineral content and a negative association between dentin hardness and carbonate content.
http://ift.tt/2txEmGT
Stress-responsive HILPDA is necessary for thermoregulation during fasting
Hypoxia-Inducible Lipid-Droplet Associated protein (HILPDA) has been shown to localize to lipid droplets in nutrient responsive cell types such as hepatocytes and adipocytes. However, its role in the control of whole-body homeostasis is not known. We sought to measure cell-intrinsic and systemic stress responses in a mouse strain harboring whole body Hilpda deficiency. We generated a genetically engineered mouse model of whole body HILPDA deficiency by replacing the coding HILPDA exon with Luciferase. We subjected the knockout animals to environmental stresses and measured whole-animal metabolic and behavioral parameters. Brown adipocyte precursors were isolated and differentiated in vitro to quantify the impact of HILPDA ablation in lipid storage and mobilization in these cells. HILPDA knockout animals are viable and fertile, but show reduced ambulatory activity and oxygen consumption at regular housing conditions. Acclimatization at thermoneutral conditions abolished the phenotypic differences observed at 22°C. When fasted, HILPDA KO mice are unable to maintain body temperature and become hypothermic at 22°C, without apparent abnormalities in blood chemistry parameters or tissue triglyceride content. HILPDA expression was upregulated during adipocyte differentiation and activation in vitro, however, it was not required for lipid droplet formation in brown adipocytes. We conclude that HILPDA is necessary for efficient fuel utilization suggesting a homeostatic role for Hilpda in sub-optimal environments.
http://ift.tt/2uslEDD
Naringenin Ameliorates Behavioral Dysfunction and Neurological Deficits in a d-Galactose-Induced Aging Mouse Model Through Activation of PI3K/Akt/Nrf2 Pathway
Rejuvenation Research , Vol. 0, No. 0.
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Physical Activity and Cognitive Function of Long-Distance Walkers: Studying Four Days Marches Participants
Rejuvenation Research , Vol. 0, No. 0.
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Genomic Medicine in Cardiovascular Fellowship Training.
http://ift.tt/2vUo37V
Age-Related Autonomous Aldosteronism.
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Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label).
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A Novel [alpha]-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure.
http://ift.tt/2vUTtuU
Calcitonin Gene-Related Peptide Receptor Agonism: A Double-Edged Sword?.
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Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence From Mouse and Human Studies.
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Transcatheter Therapy for Mitral Regurgitation Clinical Challenges and Potential Solutions.
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Health Resource Implications of Heart Failure Hospitalizations in Younger Patients Compared With Older Patients.
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Response by Obokata and Borlaug to Letter Regarding Article, "Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study".
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Response by Chatterjee et al to Letter Regarding Article, "Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates From Mendelian Randomization".
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Soft Tissue Sarcomas of the Extremities: Surgical Margins Can Be Close as Long as the Resected Tumor Has No Ink on It
AbstractBackground.Soft tissue sarcomas (STS) arising in the extremities pose a therapeutic challenge due to concerns of functional morbidity. Resections with negative margins are the mainstay of therapy, but the prognostic significance of surgical margins remains controversial. The purpose of this study was to determine the prognostic impact of surgical margins and clear margin widths in patients with STS of the extremities.Materials and Methods.We assessed the relationship between local recurrence‐free (LRFS), disease‐specific (DSS), and metastasis‐free survival (MFS) and potential prognostic factors retrospectively in a consecutive series of 643 patients treated at our institution between 1996 and 2016. Potential prognostic factors were assessed using univariate and multivariate analyses.Results.The median follow‐up time after primary diagnosis was 5.4 years (95% confidence interval [CI]: 4.8–6.0). The five‐year estimates of the DSS, LRFS, and MFS rates in the entire cohort were 85.3% (95% CI: 81.6–88.3), 65.3% (95% CI: 60.8–69.5) and 78.0% (95% CI: 74.1–81.4), respectively. Histological grade and the quality of surgical margins were independent prognostic factors of all three survival endpoints (LRFS, DSS, MFS) in multivariate analyses. Within the R0 subgroup, univariate and multivariate analyses of categorized (≤1 mm vs. 1–5 mm vs. >5 mm) and non‐categorized margin widths revealed that close and wide negative margins led to similar outcomes. Adjuvant radiation improved local control independently, but not DSS and MFS.Conclusion.Microscopically negative margins were associated with better LRFS, DSS, and MFS regardless of whether adjuvant radiation was applied. Here, surgical margins can be close as long as the resected tumor has no ink on it.Implications for Practice.In the present retrospective analysis of 643 patients with primary soft issue sarcomas of the extremities, surgical margins could be identified as independent predictors of local recurrence‐free, disease‐specific, and metastasis‐free survival. Given the diminished outcome of patients left with positive margins, surgical efforts should aim to achieve microscopically negative margins whenever feasible. It is noteworthy that only the quality of surgical margins, but not the negative margin width attained, had an influence on the prognosis. Our findings suggest that surgical margins can be close as long as the resected tumor has no ink on it.
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Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy
Metabolic Syndrome and Related Disorders , Vol. 0, No. 0.
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The immunopathology of dengue and Zika virus infections
Abigail Culshaw | Juthathip Mongkolsapaya | Gavin R Screaton
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Germinal center enhancement by extended antigen availability
Kimberly M Cirelli | Shane Crotty
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Acute toxicity of chlorpyrifos and carbosulfan to glochidia of the freshwater mussel Hyriopsis bialata Simpson, 1900
Abstract
The acute toxicity of carbosulfan and chlorpyrifos in formulated pesticides to glochidia (larvae) of the freshwater mussel (Hyriopsis bialata Simpson, 1900) was evaluated under static conditions in moderately hard dechlorinated tap water. Measured pesticide concentrations were 26 to 34% lower than nominal concentrations; therefore, all results are expressed in terms of measured active ingredient. Carbosulfan was relatively non-toxic to the mussel larvae with median effective concentrations (EC50) of carbosulfan at 24 and 48 h greater than 0.10 mg/L. The EC50s of chlorpyrifos at 24 and 48 h were 0.083 and 0.078 mg/L, respectively (measured concentrations). The 48-h EC50 of a combined exposure to a mixture of chlorpyrifos and carbosulfan at a constant ratio of 2.9:1 was 0.0142:0.049 mg CP:CB/L. In a separate experiment, the effect of water hardness on carbosulfan, chlorpyrifos, or a combined exposure was assessed using glochidia exposed to either soft, moderately hard, or hard reconstituted water. There was no effect of water hardness on the survival of glochidia after 24- or 48-h exposure to carbosulfan. The chlorpyrifos 48-h EC50s in soft water, moderately hard water, and hard water were 0.18, 0.11, and 0.16 mg/L, respectively. The data indicate that the lowest water hardness resulted in the highest survival of glochidia, whereas an increase to moderate water hardness resulted in significantly decreased survival of glochidia (F = 15.5, P < 0.05). The EC50s of a combined exposure at 48 h in soft water, moderately hard water, and hard water were 0.124:0.044, 0.132:0.047, and 0.064:0.022 mg CP:CB/L, respectively. The data indicate that the combined toxicity was lowest at low and moderate water hardness, whereas an increase to high water hardness resulted in a significantly decreased survival of glochidia. After 48 h, the toxicity of the combined chlorpyrifos and carbosulfan exposure in soft and hard water was greater than that of chlorpyrifos alone.
http://ift.tt/2v23Z70
Market segmentation and industry overcapacity considering input resources and environmental costs through the lens of governmental intervention
Abstract
The problems with China's regional industrial overcapacity are often influenced by local governments. This study constructs a framework that includes the resource and environmental costs to analyze overcapacity using the non-radial direction distance function and the price method to measure industrial capacity utilization and market segmentation in 29 provinces in China from 2002 to 2014. The empirical analysis of the spatial panel econometric model shows that (1) the industrial capacity utilization in China's provinces has a ladder-type distribution with a gradual decrease from east to west and there is a severe overcapacity in the traditional heavy industry areas; (2) local government intervention has serious negative effects on regional industry utilization and factor market segmentation more significantly inhibits the utilization rate of regional industry than commodity market segmentation; (3) economic openness improves the utilization rate of industrial capacity while the internet penetration rate and regional environmental management investment have no significant impact; and(4) a higher degree of openness and active private economic development have a positive spatial spillover effect, while there is a significant negative spatial spillover effect from local government intervention and industrial structure sophistication. This paper includes the impact of resources and the environment in overcapacity evaluations, which should guide sustainable development in emerging economies.
http://ift.tt/2vU78SP
Escherichia coli maltose-binding protein (MBP) activates mouse Th1 through TLR2-mediated MyD88-dependent pathway and TLR4-mediated TRIF-dependent pathway
Publication date: September 2017
Source:International Immunopharmacology, Volume 50
Author(s): GuoMu Liu, YiXin Zhang, NanNan Zhang, WeiHua Ni, Jing Jie, LiNa Jiang, GuiXiang Tai
MBP (maltose-binding protein) is a component of Escherichia coli. Our previous study found that MBP directly induces the activation of Th1 (T helper type 1), but the molecular mechanism remains unclear. In the present study, CD4+T cells were purified from the spleens of normal mice using antibody-coated immunomagnetic beads by negative selection. CD4+T cells activated with a CD3/CD28 antibody were stimulated with MBP. The results indicated that MBP elevated IFN-γ mRNA levels in activated CD4+T cells and promoted IFN-γ production from activated CD4+T cells. To explore TLR2/TLR4 signaling involved in the mechanism of MBP-induced activation of Th1, we further detected downstream molecules of TLR2/TLR4 signaling. We found that MBP increased the mRNA levels of MyD88, TRAF6, TRIF and TRAF3 expressed in CD4+T cells. The results suggested that downstream molecules of TLR2/TLR4 signaling may be involved in MBP-induced activation of CD4+T cells. Furthermore, MyD88, TRIF, TRAF3 and TRAF6 expressed in activated CD4+T cells blocked with anti-TLR2 antibody or anti-TLR4 antibody followed by treatment with MBP were detected via RT-PCR and western blotting, respectively. MBP decreased the production of IFN-γ in CD4+T cells in the presence of anti-TLR2, accompanied by the down-regulated expression of MyD88 and TRAF6. However, MBP increased the production of IFN-γ in CD4+T cells in the presence of anti-TLR4 antibody accompanied by the up-regulated expression of MyD88 and the down-regulated expression of TRIF, TRAF6 and TRAF3. The results suggested that the MyD88-dependent pathway of TLR2 and TRIF-dependent pathway are involved in the mechanism of Th1 activation induced by MBP. Our study has contributed to the clarification of the molecular mechanism of MBP-induced activation of CD4+T cells.
http://ift.tt/2uRwNPg
Effects of BPF on steroid hormone homeostasis and gene expression in the hypothalamic–pituitary–gonadal axis of zebrafish
Abstract
Bisphenol F (BPF) has been frequently detected in various environmental compartments, and previous studies found that BPF exhibits similar estrogenic and anti-androgenic effects on the mammalian endocrine system to those of bisphenol A (BPA). However, the potential disrupting effects of BPF on aquatic organisms and the underling disrupting mechanisms have not been investigated. In this study, the potential disrupting mechanisms of BPF on the hypothalamic–pituitary–gonadal (HPG) axis and liver were probed by employing the OECD 21-day short-term fecundity assay in zebrafish. The results show that BPF exposure (1 mg/L) impaired the reproductive function of zebrafish, as exemplified by alterations to testicular and ovarian histology of the treated zebrafish. Homogenate testosterone (T) levels in male zebrafish decreased in a concentration-dependent manner, and 17β-estradiol (E2) levels increased significantly when fish were exposed to 0.1 and 1 mg/L BPF. The real-time polymerase chain reaction was performed to examine gene expression in the HPG axis and liver. Hepatic vitellogenin expression was significantly upregulated in males, suggesting that BPF possesses estrogenic activity. The disturbed hormone balance was enhanced by the significant changes in gene expression along the HPG axis. These alterations suggest that BPF leads to adverse effects on the endocrine system of teleost fish, and that these effects were more prominent in males than in females.
http://ift.tt/2vD8dPA
Evaluation of colour temperatures in the cultivation of Dunaliella salina and Nannochloropsis oculata in the production of lipids and carbohydrates
Abstract
The production of biofuels from microalgae is a promising and sustainable alternative. Its production is determined by the content of lipids and carbohydrates, which is different for each microalgae species and is affected by environmental factors, being lighting one of the principal determining their biochemical composition. The colour temperature (electromagnetic radiation and light spectrum) is a determining factor for the production of lipids and carbohydrates in microalgae. The aim of this assay was to evaluate the effect of three colour temperatures (6500, 10,000 and 20,000 °K) on the biomass (cel mL−1), biomass production and productivity (g L−1 and g L−1 day−1), lipid and carbohydrate content (%), lipid and carbohydrate production and productivity (mg L−1 and mg L−1 day−1), composition and content of fatty acids (%) in two microalgae species: Dunaliella salina and Nannochloropsis oculata. The highest cell density was observed for N. oculata in stationary phase in the control (83.93 × 106 cel mL−1). However, higher lipid content was obtained in D. salina in stationary phase at 10,000 °K (80%), while N. oculata showed 67% at 6500 °K. The highest carbohydrate content was 25% in stationary phase for D. salina at 20,000 °K. Regarding the production of lipids, D. salina reached a maximum of 523 mg L−1 in exponential phase at 6500 and 10,000 °K. The highest carbohydrate production was 38 mg L−1 for D. salina in exponential phase at 20,000 °K. In both microalgae, 15 different fatty acids were identified; the most abundant was palmitic acid with 35.8% for N. oculata in stationary phase at 10,000 °K, while D. salina showed 67% of polyunsaturated fatty acids in exponential phase at 6500 °K. In conclusion, the ideal colour temperature for microalgae culture to obtain biofuels should be based on the biomolecule of interest, being necessary to individually evaluate for each species.
http://ift.tt/2urk9p1
Influence of orientation, glazing proportion and zone aspect ratio on the thermal performance of buildings during the winter period
Abstract
The objective of this study is to assess the effect of orientation, glazing proportion and aspect ratio of building zones on heat fluxes through their surfaces, under specific environmental conditions. The investigation is carried out for thermally-insulated building zones with a varying facade orientation corresponding to each cardinal point, during the winter period in the northern Greek region. For this purpose, three glazing-to-facade ratios (GR) are taken into account; along with the glazing ratio the influence of the glazing U value is also considered. Regarding the impact of the fenestration layout geometry, five different building aspect ratio profiles are examined. Thermal fluxes are assessed for two different indoor temperature settings, while the operation of the heating unit is assumed to be continuous. The transient thermal analysis with its mathematical formulation and solution are based on the thermal-network modelling approach, while the solar heat gain through glazing relies on the sunlit-pattern approach; in this way, the stricken by the solar rays glazing area is projected onto any interior surfaces to form the so called "sunlit" areas. As the orientation, glazing proportion and aspect ratio of the building zone vary, so do the sizes and shapes of the illuminated "sunlit" areas. Accordingly, the delivered into the zone direct solar energy and its diffused and ground reflected components can be determined. The adopted methodology provides a more accurate determination of solar heat gain with respect to glazing proportion and orientation as well as zone aspect ratio. With regard to surface orientation, glazing proportion and aspect ratio, computer results demonstrate the improvement of the thermal performance for a building zone with a south oriented glazing surface, as well as the deterioration for the other surface orientations; relative increases/decreases in the energy fluxes of a rectangular shaped building zone compared to a square-shaped building zone can reach up to 50%/100%.
http://ift.tt/2vDaLNS
Geochemical fractionation and pollution assessment of Zn, Cu, and Fe in surface sediments from Shadegan Wildlife Refuge, southwest of Iran
Abstract
This research focuses on the fractionation and distribution patterns of heavy metals (Zn, Cu, and Fe) in surficial sediments collected from Shadegan Wildlife Refuge, the biggest wetland in southern part of Iran, to provide an overall classification for the sources of metals in the study area using a sequential extraction method. For this purpose, a four-step sequential extraction technique was applied to define the partitioning of the metals into different geochemical phases of the sediment. The results illustrated that the average total level of Zn, Cu, and Fe in surface sediments were 55.20 ± 16.04, 22.86 ± 5.68, and 25,979.01 ± 6917.91 μg/g dw, respectively. On the average, the chemical partitioning of all metals in most stations was in the order of residual >oxidizable-organic > acid-reducible > exchangeable. In the same way, the results of calculated geochemical indices revealed that Cu, Zn, and Fe concentrations are mainly influenced by lithogenic origins. Compared with consensus-based SQGs, Cu was likely to result in occasionally harmful biological effects on the biota.
http://ift.tt/2urtD3U
Pb-induced changes in roots of two cultivated rice cultivars grown in lead-contaminated soil mediated by smoke
Abstract
Nowadays, public concerns regarding deleterious effect of lead (Pb) is on rise due to its abundance and toxic effect on plants and other living organisms. In plants, it has no noticeable biological importance but can cause various morphological, physiological, and biochemical malfunctions. To evaluate the remediating potential of plant-derived smoke (Cymbopogon jwarancusa), a pot culture experiment was designed to investigate the physiological, biochemical, metabolic, and antioxidant parameters of roots in lead (0 (control), 500, 1000, and 1500 ppm)-contaminated soil. Under dark condition, seeds were primed in smoke solution with two dilutions (1:500 and 1:1000) for 24 h. With an increasing concentration of Pb stress, fresh and dry weight and total nitrogen and protein contents decreased significantly while an increase was observed in smoke-treated seed. With increasing Pb stress level, metabolites (i.e., proline, total soluble sugar, total soluble protein, glycine betaine), and antioxidants (i.e., superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, malonyldialdehyde, and H2O2), contents of roots were increased in non-treated (without smoke treatment) samples, whereas comparatively, a low level of alteration in aforementioned metabolites and antioxidative parameters was observed in the seeds treated with smoke solution. These results suggest a positive role of smoke in alleviating lead-induced changes in roots of two cultivated cultivars of rice grown in Pb-contaminated soil.
http://ift.tt/2urPmsw
Short-duration hydrothermal fermentation of food waste: preparation of soil conditioner for amending organic-matter-impoverished arable soils
Abstract
Soil conditioners can be used to compensate for the insufficient soil nutrition and organic matter (OM) of arable soils. However, the traditional preparation method for soil conditioners is lengthy and requires facilities that occupy large tracts of land. In this study, a short-duration hydrothermal fermentation (SHF) method was developed for the preparation of soil conditioners from food waste. The SHF method required only 18 h to produce soil conditioners with physicochemical characteristics that were similar to those of soil conditioners obtained through traditional fermentation (TF), which takes 20 days to complete. Inoculation and dynamic SHF significantly affected the distribution of different molecular weight fractions in the prepared soil conditioners. The results of spectral analysis revealed that a large amount of soluble microbial byproducts and carbohydrate C formed in the SHF soil conditioner. This effect indicated that the SHF soil conditioner supplied not only immediately available nutrients, which can stimulate the growth of soil microbial communities, but also provided sustained-release nutrients for the long-term cultivation of crops on OM-impoverished soils. Cyanobacteria were present in the SHF soil conditioner at a relative abundance of 6.29%, which was 28.6 and 314.5 times those in the raw material and TF soil conditioner, respectively. Amending OM-impoverished soil with the SHF soil conditioner enhanced the carbon pool management index of the resulting SHF soil by 1.50 and 1.12 times those of unfertilized soil and TF soil, respectively. These results indicated that the SHF soil exhibited a high capacity to supply nutrients for crop growth.
http://ift.tt/2vCRJHb
Top Reviewers
Source:American Journal of Otolaryngology, Volume 38, Issue 4
http://ift.tt/2gYwBb7
Is there still a place for skin graft in giant congenital melanocytic nevus?
Abstract
Background
Congenital melanocytic nevi (CMN) has an incidence of 1–2% in newborns. These lesions can be categorized according to size, namely small, medium, large, and giant. Complete surgical excision is the main line of treatment with reconstruction by serial excision, tissue expansion, local flaps, Integra with skin graft, and skin grafting. Other modalities include curettage, dermabrasion, and laser. The aim of this article was to express the versatility of skin grafts for management of giant nevus.
Methods
All cases with lesions that cannot be closed primarily were included. Patients were 12 females and 4 males. Their ages ranged between 4 months and 22 years. All cases were excised and covered with skin graft.
Results
Full-thickness skin graft was used in combination with split-thickness sheet graft in four cases. All these cases were in the face. The average area of excised nevus was 225.5 cm2. No signs of malignancy were observed in any of the excised nevi. No recurrence was observed in this series.
Conclusions
Surgical and nonsurgical modalities are variable tools for management of giant congenital nevus. No doubt, skin graft is a good option for management of giant nevus.
Level of Evidence: IV, therapeutic study.
http://ift.tt/2uTEjZB
Outcomes of office-based temporomandibular joint arthroscopy: a 5-year retrospective study
Temporomandibular joint (TMJ) arthroscopy is a minimally invasive surgical approach for intra-articular TMJ diseases. Office-based arthroscopy using the smallest TMJ scope allows for good visualization, as well as the ability to lavage the joint in an office setting. This study aimed to assess the efficacy of an office-based TMJ arthroscopic technique. A retrospective evaluation of 363 patients with a TMJ disorder was performed. These patients underwent office-based arthroscopy using the OnPoint 1.2mm Scope System (Biomet Microfixation, Jacksonville, FL, USA) in Florida, USA, from July 2007.
http://ift.tt/2uuqJcN
Unilateral blindness after orthognathic surgery: hypotensive anaesthesia is not the primary cause
Perioperative vision loss in non-ocular surgery represents a rare but devastating complication and multiple causes have been proposed. Any portion of the visual system may be involved and several authors have tried to relate that complication with deliberate hypotension anaesthetic technique, used to control intraoperative bleeding. We report a patient operated for orthognathism who suffered unilateral blindness. After review of similar cases, we can state that the transmission of forces generated during Le fort I osteotomy is related to the complication.
http://ift.tt/2uuGn7Y
Three-dimensional aesthetic assessment of class II patients before and after orthognathic surgery and its association with quantitative surgical changes
The aim of this study was to compare evaluations of the aesthetic outcome of class II orthognathic patients, as performed by observers with varying expertise using three-dimensional (3D) facial images, and to examine the relationship of aesthetic ratings in relation to quantitative surgical changes. Pre- and postoperative 3D facial images of 20 surgically treated class II patients (13 female, 7 male) were assessed for aesthetics by orthodontists, maxillofacial surgeons, and laypeople. Attractiveness ratings for the lips, chin, and overall facial aesthetics were evaluated on a 5-point Likert scale.
http://ift.tt/2uROCOh
External carotid artery sacrifice in the treatment of infantile haemangiopericytoma in a neonate
Haemangiopericytoma of the head and neck (HN-HPC) is a rare neoplasm occurring in children. The rarity of the tumour poses a diagnostic and therapeutic challenge. Despite protocols that recommend the use of chemotherapy prior to surgery, no treatment standard has yet been proposed. This article reports the case of a 5-month-old infant with a rapidly growing, giant life-threatening HN-HPC that was treated successfully by two-stage surgery without adjuvant chemotherapy.
http://ift.tt/2uuGmRs
Restoration of Sleep Architecture after Maxillomandibular Advancement: Success Beyond the Apnea–Hypopnea Index
While effects of maxillomandibular advancement (MMA) on respiratory parameters for patients with obstructive sleep apnea (OSA) are well described, effects on sleep architecture before and after MMA are not. A retrospective cohort analysis on sleep architecture was examined in 10 OSA patients who underwent MMA surgery between July 2013 and November 2014, and had prespecified complete polysomnography (PSG) datasets. Sleep stages were examined relative to a Western European population-based control group.
http://ift.tt/2uRovag
Phasic activity and the importance of irregular breathing
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
http://ift.tt/2vUugRi
Predictors of insomnia onset in adolescents in Japan
The objective of this study was to clarify the incidence rate and predictive factors of insomnia in Japanese junior and senior high school students.
http://ift.tt/2v1KgEK
Periodic Neck Myoclonus During Sleep
Neck myoclonus is a sleep-related movement characterized by sudden myoclonic flexion or version of the head that usually occurs as a single event in REM sleep [1]. It is commonly found in healthy people without sleep complaints [2] and its clinical significance is unknown.
http://ift.tt/2vU4gWd
Reply by authors: Sleep apnea awareness among Latin-Americans
Cherrez Ojeda et al have previously reported low levels of awareness and knowledge of obstructive sleep apnea (OSA) among Latin-Americans. In their sample of 135 respondents, only 12% had high levels of awareness of obstructive sleep apnea (OSA) while only 10% had advanced knowledge of sleep apnea [1]. This is in keeping with our recent study, where we reported that 13% of respondents could correctly define OSA [2]. These findings are significant in view of the fact that there has been a high prevalence of undiagnosed OSA in both Latin America and Singapore [3, 4].
http://ift.tt/2v1zqib
Omalizumab Treatment in Chronic Inducible Urticaria: A Systematic Review of Published Evidence
Omalizumab, a recombinant anti-IgE antibody, effectively treats chronic spontaneous urticaria. Evidence is lacking in chronic inducible urticarias (CIndUs), which are frequently H1-antihistamine resistant.
http://ift.tt/2gXpKyT
Sputum autoantibodies in severe eosinophilic asthma
We report a novel concept of an autoimmune inflammation localised to the airways of severe eosinophilic asthmatics. This is possibly steroid-insensitive, contributing to disease severity, and necessitates identification of these patients for appropriate therapeutic strategies. (35 words)
http://ift.tt/2eJoe2x
Eye gaze and pupillary response in Angelman syndrome
Source:Research in Developmental Disabilities, Volume 68
Author(s): Michael P. Hong, Janna L. Guilfoyle, Lindsey N. Mooney, Logan K. Wink, Ernest V. Pedapati, Rebecca C. Shaffer, John A. Sweeney, Craig A. Erickson
BackgroundAngelman syndrome (AS) is a rare neurological disorder characterized by severe developmental disability, communication impairment, elevated seizure risk, and motor system abnormalities.AimsThe aims of this study were to determine the feasibility of social scene eye tracking and pupillometry measures in individuals with AS and to compare the performance of AS participants to individuals with idiopathic Autism Spectrum Disorder (ASD) and typically developing controls (TDC).Methods and proceduresIndividuals with AS and age- and gender- matched controls completed a social eye tracking paradigm. Neurobehavioral characterization of AS participants was completed via a battery of psychological testing and caregiver behavioral evaluations.Outcomes and resultsEight of seventeen recruited AS participants completed the eye tracking paradigm. Compared to TDC, AS subjects demonstrated significantly less preference for social scenes than geometric shapes. Additionally, AS subjects showed less pupil dilation, compared to TDC, when viewing social scenes versus geometric shapes. There was no statistically significant difference found between AS and ASD subjects in either social eye tracking or pupillometry.Conclusions and implicationsThe use of eye tracking and pupillometry may represent an innovative measure for quantifying AS-associated impairments in social salience.
http://ift.tt/2twGtdX
Evaluation of transient-evoked otoacoustic emissions in a healthy 1–10 year pediatric cohort in Sub-Saharan Africa
Transient-evoked otoacoustic emissions (TEOAEs) monitor cochlear function. High pass rates have been reported for industrialized countries. Pass rates in low and middle income countries such as Sub-Saharan Africa are rare, essentially lower and available for children up to 4 years of age and frequently based on hospital recruitments.This study aims at providing additional TEOAE pass rates of a healthy Sub-Saharan cohort aged 1–10 years with data from Gabon, Ghana and Kenya. Potentially confounding factors (recruitment site, age) are taken into consideration.
http://ift.tt/2gXlFe3
The comorbidity burden of patients with cluster headache: a population-based study
Evidence is limited regarding the comorbidity burden of patients with cluster headache (CH). We aimed to characterize comorbid conditions in a cohort of CH patients diagnosed by headache experts, using electro...
http://ift.tt/2urJUpr
OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study
OnabotulinumtoxinA has proven its efficacy in reducing the number of headache days in chronic migraine (CM) patients. The usual paradigm includes 31 pericranial injection sites with low dose (5 U) per site. Th...
http://ift.tt/2urDl6f
Perceived stress in patients with migraine: a case-control study
Perceived stress is the most common trigger for migraine. The objective of this study was to examine the clinical significance of perceived stress in migraine patients.
http://ift.tt/2vCJsDd
Isolation of limonoid compound (Hamisonine) from endophytic fungi Penicillium oxalicum LA-1 (KX622790) of Limonia acidissima L. for its larvicidal efficacy against LF vector, Culex quinquefasciatus (Diptera: Culicidae )
Abstract
Upon screening for novel and potential biocompounds with larvicidal activities, we successfully isolated hamisonine (HMSN) a limonoid compound from endophytic fungi Penicillium oxalicum LA-1 of Limonia acidissima. The extracted compound structure was elucidated by spectral studies such as UV-vis spectroscopy, thin-layer chromatography, FTIR, LC-ESI-MS, 1H NMR, and 13C NMR upon comparing with the spectral data available in the literature. Further, the isolated HMSN was tested against III and IV instar Culex quinquefasciatus larvae. The outcome of this study clearly emphasize that the extracted compound HMSN possesses a stupendous larvicidal activity in a dose-dependent manner with the LC50 and LC90 values of 1.779 and 7.685 ppm against III instar larvae and 3.031 and 28.498 ppm against IV instar larvae of C. quinquefasciatus, respectively. Interestingly, the histological studies evidently showing the damage of peritrophic membrane and epithelial cells of testing mosquito larvae.
http://ift.tt/2tw2iub
Activation of Complement by Pigment Epithelium-Derived Factor in Rheumatoid Arthritis [INNATE IMMUNITY AND INFLAMMATION]
The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium–derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family. Using ELISA, we confirmed the presence of various amounts of complexes between PEDF and C4d in the SF from 30 RA patients, whereas none were detected in SF from control subjects. Correlation analyses suggested that, in arthritis patients, C4d–PEDF complexes found in sera arise from the joints, as well as from other tissues, and levels of the complexes did not differ in sera of RA patients and healthy controls. When immobilized, recombinant PEDF expressed in eukaryotic cells activated the classical complement pathway but not the alternative or lectin pathways. C1q protein was demonstrated to bind immobilized PEDF, and PEDF was shown to bind to immobilized C1q, in particular its head regions, which are known to interact with other activators of the classical pathway. Our results call for further investigation into the role of PEDF in inflammatory processes in the joint, which, in combination with classical complement activation, appears to be part of a (patho-)physiologic response.
http://ift.tt/2gY00Ct
Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis [INNATE IMMUNITY AND INFLAMMATION]
von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic ADAMTS13 deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the AP of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release, and complement activation.
http://ift.tt/2gXW3xJ
Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death [TRANSPLANTATION]
Nucleotide-binding oligomerization domain (Nod)–containing proteins Nod1 and Nod2 play important roles in the innate immune response to pathogenic microbes, but mounting data suggest these pattern recognition receptors might also play key roles in adaptive immune responses. Targeting Nod1 and Nod2 signaling pathways in T cells is likely to provide a new strategy to modify inflammation in a variety of disease states, particularly those that depend on Ag-induced T cell activation. To better understand how Nod1 and Nod2 proteins contribute to adaptive immunity, this study investigated their role in alloantigen-induced T cell activation and asked whether their absence might impact in vivo alloresponses using a severe acute graft versus host disease model. The study provided several important observations. We found that the simultaneous absence of Nod1 and Nod2 primed T cells for activation-induced cell death. T cells from Nod1 x 2–/– mice rapidly underwent cell death upon exposure to alloantigen. The Nod1 x 2–/– T cells had sustained p53 expression that was associated with downregulation of its negative regulator MDM2. In vivo, mice transplanted with an inoculum containing Nod1 x 2–/– T cells were protected from severe graft versus host disease. The results show that the simultaneous absence of Nod1 and Nod2 is associated with accelerated T cell death upon alloantigen encounter, suggesting these proteins might provide new targets to ameliorate T cell responses in a variety of inflammatory states, including those associated with bone marrow or solid organ transplantation.
http://ift.tt/2gXVLa7
Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis [INNATE IMMUNITY AND INFLAMMATION]
Inflammatory processes play a key role in pathophysiology of many neurologic diseases/trauma, but the effect of immune cells and factors on neurotransplantation strategies remains unclear. We hypothesized that cellular and humoral components of innate immunity alter fate and migration of human neural stem cells (hNSC). In these experiments, conditioned media collected from polymorphonuclear leukocytes (PMN) selectively increased hNSC astrogliogenesis and promoted cell migration in vitro. PMN were shown to generate C1q and C3a; exposure of hNSC to PMN-synthesized concentrations of these complement proteins promoted astrogliogenesis and cell migration. Furthermore, in vitro, Abs directed against C1q and C3a reversed the fate and migration effects observed. In a proof-of-concept in vivo experiment, blockade of C1q and C3a transiently altered hNSC migration and reversed astroglial fate after spinal cord injury. Collectively, these data suggest that modulation of the innate/humoral inflammatory microenvironment may impact the potential of cell-based therapies for recovery and repair following CNS pathology.
http://ift.tt/2gXW1G7
Menin Controls the Memory Th2 Cell Function by Maintaining the Epigenetic Integrity of Th2 Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
Posttranslational modifications of histones are well-established epigenetic modifications that play an important role in gene expression and regulation. These modifications are partly mediated by the Trithorax group (TrxG) complex, which regulates the induction or maintenance of gene transcription. We investigated the role of Menin, a component of the TrxG complex, in the acquisition and maintenance of Th2 cell identity using T cell–specific Menin-deficient mice. Our gene expression analysis revealed that Menin was involved in the maintenance of the high expression of the previously identified Th2-specific genes rather than the induction of these genes. This result suggests that Menin plays a role in the maintenance of Th2 cell identity. Menin directly bound to the Gata3 gene locus, and this Menin-Gata3 axis appeared to form a core unit of the Th2-specific gene regulatory network. Consistent with the phenotype of Menin-deficient Th2 cells observed in vitro, Menin deficiency resulted in the attenuation of effector Th2 cell–induced airway inflammation. In addition, in memory Th2 (mTh2) cells, Menin was found to play an important role in the maintenance of the expression of Th2-specific genes, including Gata3, Il4, and Il13. Consequently, Menin-deficient mTh2 cells showed an impaired ability to recruit eosinophils to the lung, resulting in the attenuation of mTh2 cell–induced airway inflammation. This study confirmed the critical role of Menin in Th2 cell–mediated immune responses.
http://ift.tt/2gXVRhZ
Immune Cell Dynamics in Rhesus Macaques Infected with a Brazilian Strain of Zika Virus [INFECTIOUS DISEASE AND HOST RESPONSE]
Zika virus (ZIKV) is a mosquito-borne and sexually transmitted flavivirus that is associated with fetal CNS-damaging malformations during pregnancy in humans. This study documents the viral kinetics and immune responses in rhesus macaques infected with a clinical ZIKV Brazilian isolate. We evaluated the viral kinetics and immune responses induced after an i.v. infection with a Brazilian ZIKV clinical isolate (HS-2015-BA-01) in rhesus macaques for up to 142 d. ZIKV-specific Ab-secreting cells, germinal center reactions, and monocyte, dendritic cell, NK, and T cell frequencies were monitored. ZIKV loads were readily detected in plasma (until day 5 or 7), semen and urine (until days 7 and 14), and saliva (until day 42), but the viremia was rapidly controlled. No detectable clinical manifestations were observed. However, lymph node hyperplasia was clearly visible postviremia but was associated with low frequencies of ZIKV-specific Ab-secreting cells in lymph nodes and bone marrow, correlating with low Ab titers. CD14+/CD16– monocytes and myeloid CD11chi dendritic cells decreased in blood, whereas NK and T cell numbers were only marginally altered during the course of the study. ZIKV infection caused a significant lymphoid tissue activation but limited induction of ZIKV-specific B cells, suggesting that these parameters need to be considered for ZIKV vaccine design.
http://ift.tt/2gXW4Sj
Dietary Salt Exacerbates Experimental Colitis [INNATE IMMUNITY AND INFLAMMATION]
The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10–deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10–deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium. This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD.
http://ift.tt/2gXW2Kb
Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation [INNATE IMMUNITY AND INFLAMMATION]
Asthma is a complex disease that is promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation; however, it is unclear whether lipid mediators, such as cysteinyl leukotrienes (CysLTs), which are present in asthma, could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. In this article, we show that airway challenges with the parent CysLT, leukotriene C4 (LTC4), given in combination with low-dose IL-33 to naive wild-type mice, led to synergistic increases in airway Th2 cytokines, eosinophilia, and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R, and candidate leukotriene E4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R, because CysLT1R–/– mice, but not CysLT2R–/– mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R–/– mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata. Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses.
http://ift.tt/2gXVZht
Activation of Mouse Tcrb: Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1 [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR β (Tcrb) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites. An outstanding issue in understanding T cell gene expression programs is whether RUNX1 and ETS1 have independent functions in enhancer activation that can be dissected from cooperative binding. We now show that RUNX1 is sufficient to activate the endogenous mouse Eβ element and its neighboring 25 kb region by independently tethering this TF without coincidental ETS1 binding. Moreover, RUNX1 is sufficient for long-range promoter-Eβ looping, nucleosome clearance, and robust transcription throughout the Tcrb recombination center, spanning both DβJβ clusters. We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding, can compensate for the loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of recombination center promoters.
http://ift.tt/2gXVTq7
Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease [MUCOSAL IMMUNOLOGY]
Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg+) mice to SHS from postnatal day (PND) 3–21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed Scnn1b-Tg+ (FA-Tg+) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed Scnn1b-Tg+ (SHS-Tg+) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg+ mice exhibited marked mucus obstruction and Th2 responses, SHS-Tg+ mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, Th2 responses, and delayed bacterial clearance in SHS-Tg+ mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg+ mice, the SHS-Tg+ mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished Th2 response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.
http://ift.tt/2gXDHNd
A diagnostically difficult case of a cellular pleural fluid: Morphology, immunohistochemistry, and fluorescence in situ hybridization study
CytoJournal 2017 14(1):18-18
http://ift.tt/2urg845
Interobserver reproducibility of the Paris system for reporting urinary cytology
CytoJournal 2017 14(1):17-17
Background: The Paris System for Reporting Urinary Cytology represents a significant improvement in classification of urinary specimens. The system acknowledges the difficulty in cytologically diagnosing low-grade urothelial carcinomas and has developed categories to deal with this issue. The system uses six categories: unsatisfactory, negative for high-grade urothelial carcinoma (NHGUC), atypical urothelial cells, suspicious for high-grade urothelial carcinoma, high-grade urothelial carcinoma, other malignancies and a seventh subcategory (low-grade urothelial neoplasm). Methods: Three hundred and fifty-seven urine specimens were independently reviewed by four cytopathologists unaware of the previous diagnoses. Each cytopathologist rendered a diagnosis according to the Paris System categories. Agreement was assessed using absolute agreement and weighted chance-corrected agreement (kappa). Disagreements were classified as low impact and high impact based on the potential impact of a misclassification on clinical management. Results: The average absolute agreement was 65% with an average expected agreement of 44%. The average chance-corrected agreement (kappa) was 0.32. Nine hundred and ninety-nine of 1902 comparisons between rater pairs were in agreement, but 12% of comparisons differed by two or more categories for the category NHGUC. Approximately 15% of the disagreements were classified as high clinical impact. Conclusions: Our findings indicated that the scheme recommended by the Paris System shows adequate precision for the category NHGUC, but the other categories demonstrated unacceptable interobserver variability. This low level of diagnostic precision may negatively impact the applicability of the Paris System for widespread clinical application.
http://ift.tt/2vCZ4qw
Inflammasome and Fas-Mediated IL-1{beta} Contributes to Th17/Th1 Cell Induction in Pathogenic Bacterial Infection In Vivo [INNATE IMMUNITY AND INFLAMMATION]
CD4+ Th cells play crucial roles in orchestrating immune responses against pathogenic microbes, after differentiating into effector subsets. Recent research has revealed the importance of IFN- and IL-17 double-producing CD4+ Th cells, termed Th17/Th1 cells, in the induction of autoimmune and inflammatory diseases. In addition, Th17/Th1 cells are involved in the regulation of infection caused by the intracellular bacterium Mycobacterium tuberculosis in humans. However, the precise mechanism of Th17/Th1 induction during pathogen infection is unclear. In this study, we showed that the inflammasome and Fas-dependent IL-1β induces Th17/Th1 cells in mice, in response to infection with the pathogenic intracellular bacterium Listeria monocytogenes. In the spleens of infected wild-type mice, Th17/Th1 cells were induced, and expressed T-bet and Rort. In Pycard–/– mice, which lack the adaptor molecule of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain), Th17/Th1 induction was abolished. In addition, the Fas-mediated IL-1β production was required for Th17/Th1 induction during bacterial infection: Th17/Th1 induction was abolished in Fas–/– mice, whereas supplementation with recombinant IL-1β restored Th17/Th1 induction via IL-1 receptor 1 (IL-1R1), and rescued the mortality of Fas–/– mice infected with Listeria. IL-1R1, but not apoptosis-associated speck-like protein containing a caspase recruitment domain or Fas on T cells, was required for Th17/Th1 induction, indicating that IL-1β stimulates IL-1R1 on T cells for Th17/Th1 induction. These results indicate that IL-1β, produced by the inflammasome and Fas-dependent mechanisms, contributes cooperatively to the Th17/Th1 induction during bacterial infection. This study provides a deeper understanding of the molecular mechanisms underlying Th17/Th1 induction during pathogenic microbial infections in vivo.
http://ift.tt/2eJ7UyO
Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice [INNATE IMMUNITY AND INFLAMMATION]
During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN-α/β) are induced in inflammatory conditions associated with increased alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-α/β receptor is required for inflammation-induced alloimmunization. Additionally, mitochondrial antiviral signaling protein–mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic-polycytidylic acid–induced IFN-α/β production and alloimmunization. We further report that IFN-α, in the absence of an adjuvant, is sufficient to induce RBC alloimmunization. These findings raise the possibility that patients with IFN-α/β–mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies.
http://ift.tt/2eJ8gFG
Here, There, and Anywhere? Arguments for and against the Physical Plasma Cell Survival Niche [BRIEF REVIEWS]
To maintain Ab titers, individual plasma cells must survive for extended periods, perhaps even for the life of the host. Although it is clear that plasma cell survival requires cell extrinsic signals, the nature and source of these signals remains open for debate. It is commonly postulated that plasma cells only gain access to these signals within specialized regulatory microenvironments, or niches, in the bone marrow or in the gut. In this review we discuss current concepts and information surrounding plasma cell survival niches, and consider two opposing models to explain long-term serologic immunity.
http://ift.tt/2eJ8BIs
Deficiency of Phosphatidylinositol 3-Kinase {delta} Signaling Leads to Diminished Numbers of Regulatory T Cells and Increased Neutrophil Activity Resulting in Mortality Due to Endotoxic Shock [INNATE IMMUNITY AND INFLAMMATION]
Despite decades of clinical and biomedical research, the pathogenesis of sepsis and its spectrum of diseases (severe sepsis and septic shock), which are leading causes of death in intensive care units, are still poorly understood. In this article, we show that signaling via the p110 isoform of PI3K is critical for survival in experimental sepsis. Mice with an inactive knock-in mutation in the p110 gene (p110D910A) succumbed acutely to nonlethal dose LPS challenge. The susceptibility of p110D910A mice to LPS was associated with increased neutrophil numbers and activities in the tissues, due in part to delayed apoptosis resulting mostly from inherent reduced regulatory T cell (Treg) numbers. Adoptive transfer of wild-type or p110D910A Tregs abrogated exaggerated neutrophil activity, increased neutrophil apoptosis, and rescued p110D910A mice from mortality after LPS challenge. We confirmed the clinical relevance of these findings by showing that human Tregs also regulate neutrophil function and survival. Collectively, our results show that PI3K is essential for survival during sepsis. In addition, our data highlight the importance of Tregs in regulating the pathogenesis of sepsis and septic shock via their effects on neutrophil survival and function, and provide evidence of regulation of innate immunity by cells of the adaptive immune system.
http://ift.tt/2eJ8cWs
Cutting Edge: Eosinophils Undergo Caspase-1-Mediated Pyroptosis in Response to Necrotic Liver Cells [CUTTING EDGE]
Many chronic liver disorders are characterized by dysregulated immune responses and hepatocyte death. We used an in vivo model to study the immune response to necrotic liver injury and found that necrotic liver cells induced eosinophil recruitment. Necrotic liver induced eosinophil IL-1β and IL-18 secretion, degranulation, and cell death. Caspase-1 inhibitors blocked all of these responses. Caspase-1–mediated cell death with accompanying cytokine release is the hallmark of a novel form of cell death termed pyroptosis. To confirm this response in a disease model, we isolated eosinophils from the livers of Schistosoma mansoni–infected mice. S. mansoni eggs lodge in the hepatic sinusoids of infected mice, resulting in hepatocyte death, inflammation, and progressive liver fibrosis. This response is typified by massive eosinophilia, and we were able to confirm pyroptosis in the infiltrating eosinophils. This demonstrated that pyroptosis is a cellular pathway used by eosinophils in response to large-scale hepatic cell death.
http://ift.tt/2gXWfgr
IFN-{gamma}-Expressing Th17 Cells Are Required for Development of Severe Ocular Surface Autoimmunity [MUCOSAL IMMUNOLOGY]
Th17 cells are critical effectors mediating the ocular surface autoimmunity in dry eye disease (DED). Increased IFN- has also been implicated in DED; however, it remains unclear to what extent Th1 cells contribute to DED pathogenesis. In this study, we investigated the cellular source of IFN- and assessed its contribution to corneal epitheliopathy in DED mice. We discovered a significant IL-17A+IFN-+ (Th17/1) population and determined that these cells are derived from Th17 precursors. Adoptive transfer of Th17/1, but not Th1, cells confers the disease to naive recipients as effectively as do Th17 cells alone. DED-induced IL-12 and IL-23 are required for in vivo transition of pathogenic Th17 cells to IFN- producers. Furthermore, using IFN-–deficient Th17 cells, we demonstrate the disease-amplifying role of Th17-derived IFN- in DED pathogenesis. These results clearly demonstrate that Th17 cells mediate ocular surface autoimmunity through both IL-17A and IFN-.
http://ift.tt/2eJ27t3
Activation of Human Basophils by A549 Lung Epithelial Cells Reveals a Novel IgE-Dependent Response Independent of Allergen [ALLERGY AND OTHER HYPERSENSITIVITIES]
Evidence for epithelial cell (EC)–derived cytokines (e.g., thymic stromal lymphopoietin [TSLP]) activating human basophils remains controversial. We therefore hypothesize that ECs can directly activate basophils via cell-to-cell interaction. Basophils in medium alone or with IL-3 ± anti-IgE were coincubated with TSLP, IL-33, or IL-25. Analogous experiments cocultured basophils (1–72 h) directly with EC lines. Supernatants were tested for mediators and cytokines. Abs targeting receptors were tested for neutralizing effects. Lactic acid (pH 3.9) treatment combined with passive sensitization tested the role of IgE. Overall, IL-33 augmented IL-13 secretion from basophils cotreated with IL-3, with minimal effects on histamine and IL-4. Conversely, basophils (but not mast cells) released histamine and marked levels of IL-4/IL-13 (10-fold) when cocultured with A549 EC and IL-3, without exogenous allergen or IgE cross-linking stimuli. The inability to detect IL-33 or TSLP, or to neutralize their activity, suggested a unique mode of basophil activation by A549 EC. Half-maximal rates for histamine (4 h) and IL-4 (5 h) secretion were slower than observed with standard IgE-dependent activation. Ig stripping combined with passive sensitization ± omalizumab showed a dependency for basophil-bound IgE, substantiated by a requirement for cell-to-cell contact, aggregation, and FcRI-dependent signaling. A yet unidentified IgE-binding lectin associated with A549 EC is implicated after discovering that LacNAc suppressed basophil activation in cocultures. These findings point to a lectin-dependent activation of basophil requiring IgE but independent of allergen or secreted cytokine. Pending further investigation, we predict this unique mode of activation is linked to inflammatory conditions whereby IgE-dependent activation of basophils occurs despite the absence of any known allergen.
http://ift.tt/2eIKV7d
Involvement of NK Cells in IL-28B-Mediated Immunity against Influenza Virus Infection [INNATE IMMUNITY AND INFLAMMATION]
IL-28B is a member of the newly discovered type III IFN family and exhibits unique antiviral properties compared with other family members. NK cells play a critical role in defending against viruses; however, little is known about the role of IL-28B in NK cell function. In a mouse model of influenza A virus (mouse adapted influenza A/PR/8/34 strain) infection, long-term overexpression of IL-28B induced by hepatocyte-specific gene delivery exerted a strong antiviral effect in the presence of NK cells. In IL-28B–overexpressing wild-type mice, the percentages and absolute numbers of NK cells in the spleen, liver, and lung were markedly increased, with higher proliferation and accelerated NK cell maturation based on phenotypes staining with CD11b and CD27 or CD11b and KLRG1. Furthermore, the effect of IL-28B on NK cells was macrophage dependent, as confirmed in an in vitro coculture assay and in in vivo macrophage- or alveolar macrophage–depletion experiments. Transwell studies demonstrated that CFSE-labeled NK cell proliferation was driven, in a dose-dependent manner, by unknown soluble factor(s) secreted by IL-28B–stimulated alveolar macrophages, without requiring direct cell–cell contact. An understanding of the NK cell–promoting features of IL-28B will facilitate future clinical application of this cytokine.
http://ift.tt/2eJ8jBm
Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice [INNATE IMMUNITY AND INFLAMMATION]
Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.
http://ift.tt/2eIKMkb
Caveolin-1 Influences LFA-1 Redistribution upon TCR Stimulation in CD8 T Cells [ANTIGEN RECOGNITION AND RESPONSES]
TCR stimulation by peptide–MHC complexes on APCs requires precise reorganization of molecules into the area of cellular contact to form an immunological synapse from where T cell signaling is initiated. Caveolin (Cav)1, a widely expressed transmembrane protein, is involved in the regulation of membrane composition, cellular polarity and trafficking, and the organization of signal transduction pathways. The presence of Cav1 protein in T cells was identified only recently, and its function in this context is not well understood. We show that Cav1-knockout CD8 T cells have a reduction in membrane cholesterol and sphingomyelin, and upon TCR triggering they exhibit altered morphology and polarity, with reduced effector function compared with Cav1 wild-type CD8 T cells. In particular, redistribution of the β2 integrin LFA-1 to the immunological synapse is compromised in Cav1-knockout T cells, as is the ability of LFA-1 to form high-avidity interactions with ICAM-1. Our results identify a role for Cav1 in membrane organization and β2 integrin function in primary CD8 T cells.
http://ift.tt/2eJ8wo8
Suppression of Lipopolysaccharide-Induced Inflammatory Response by Fragments from Serum Amyloid A [INNATE IMMUNITY AND INFLAMMATION]
Serum amyloid A (SAA) is known as an acute-phase protein and a biomarker for inflammatory diseases. Published studies have shown that SAA possesses proinflammatory cytokine-like activity and is chemotactic for phagocytes, but the structural basis for these activities remains unidentified. In this article, we report that truncated SAA1 proteins lacking N- and C-terminal sequences exhibit reduced proinflammatory activity and strongly suppress LPS-induced expression of IL-1β, IL-6, and TNF-α in macrophages. A truncated SAA1 containing aa 11–58 was examined further and found to facilitate p38 MAPK phosphorylation while reducing LPS-stimulated phosphorylation of ERK and JNK. In LPS-challenged mice, aa 11–58 reduced the severity of acute lung injury, with significantly less neutrophil infiltration in the lungs and attenuated pulmonary expression of IL-1β, IL-6, and TNF-α. Coadministration of aa 11–58 markedly improved mouse survival in response to a lethal dose of LPS. A potent induction of IL-10 was observed in a TLR2-dependent, but TLR4-independent, manner in macrophages stimulated with aa 11–58. However, the aa 11–58 fragment of SAA1 was unable to induce chemotaxis or calcium flux through formyl peptide receptor 2. These results indicate that the N- and C-terminal sequences contain structural determinants for the proinflammatory and chemotactic activities of SAA1, and their removal switches SAA1 to an anti-inflammatory role. Given that proteolytic processing of SAA is associated with the pathological changes in several diseases, including secondary amyloidosis, our findings may shed light on the structure–function relationship of SAA1 with respect to its role in inflammation.
http://ift.tt/2eIqFCF
B Cell-Extrinsic Myd88 and Fcer1g Negatively Regulate Autoreactive and Normal B Cell Immune Responses [ANTIGEN RECOGNITION AND RESPONSES]
MyD88 and FcR common -chain (Fcer1g, FcR) elicit proinflammatory responses to exogenous Ags. Deletion of these receptors in autoimmune models has generally led to reduced overall disease. In B cells, Myd88 is required for anti-DNA and anti-RNA autoantibody responses, whereas Fcer1g is not expressed in these cells. The roles of these receptors in myeloid cells during B cell autoimmune activation remain less clear. To investigate the roles of Myd88 and Fcer1g in non-B cells, we transferred anti–self-IgG (rheumatoid factor) B cells and their physiologic target Ag, anti-chromatin Ab, into mice lacking Fcer1g, Myd88, or both and studied the extrafollicular plasmablast response. Surprisingly, we found a markedly higher and more prolonged response in the absence of either molecule; this effect was accentuated in doubly deficient recipients, with a 40-fold increase compared with wild-type recipients at day 10. This enhancement was dependent on CD40L, indicating that Myd88 and FcR, presumably on myeloid APCs, were required to downregulate T cell help for the extrafollicular response. To extend the generality, we then investigated a classic T cell–dependent response to (4-hydroxy-3-nitrophenyl)acetyl conjugated to chicken globulin and found a similar effect. Thus, these results reveal novel regulatory roles in the B cell response for receptors that are typically proinflammatory.
http://ift.tt/2gXBIbI
Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
The T cell repertoire is a function of thymic V(D)J rearrangement and of peripheral selection. The mature repertoire embodies TCR sequences that are important for survival and can identify important structural aspects of the TCR. Analysis of the circulating TCRBV19 CD8 T cell repertoire showed that a majority of NDN-encoded CDR3 amino acid motifs start at CDR3 position four, well within the V region. Rearrangement at this position indicates that the DNA hairpin loop is not opened at the position adjacent to the recombination signal sequence, but rather is trimmed back three or more bases. In this article, we show that the rearrangement frequency distribution within the V region reveals selection on CDR3 position four. The selection is already established in single-positive CD8 thymocytes. Crystal structures reveal a possible basis for this selection due to the location of this residue in a bend that positions the remaining portion of CDR3 to interact with the peptide and MHC. Examination of other TCRBV families also shows selection for rearrangement within the V region of a number of genes and for CD8 and CD4 cells. The exact profile of rearrangement within the V region appears to be V gene specific. The frequent observation of side chains associated with turn motifs at CDR3 positions three and four fits with the structural need for a bend. The data are discussed in terms of the generation of a structural turn motif, the rearrangement mechanism, and selection of the repertoire on the peptide and MHC.
http://ift.tt/2eJ29Bb