bluuebunny/crossref_metadata_2025 huggingface dataset:
Retinal cross talk in the mammalian visual system
Authors: Tang Xiaolan , Tzekov Radouil , Passaglia Christopher L.
Published: March 2016

The existence and functional relevance of efferent optic nerve fibers in mammals have long been debated. While anatomical evidence for cortico-retinal and retino-retinal projections is substantial, physiological evidence is lacking, as efferent fibers are few in number and are severed in studies of excised retinal tissue. Here we show that interocular connections contribute to retinal bioelectrical activity in adult mammals. Full-field flash electroretinograms (ERGs) were recorded from one or both eyes of Brown-Norway rats under dark-adapted ( n = 16) and light-adapted ( n = 11) conditions. Flashes were confined to each eye by an opaque tube that blocked stray light. Monocular flashes evoked a small (5–15 μV) signal in the nonilluminated eye, which was named “crossed ERG” (xERG). The xERG began under dark-adapted conditions with a positive (xP1) wave that peaked at 70–90 ms and ended with slower negative (xN1) and positive (xP2) waves from 200 to 400 ms. xN1 was absent under light-adapted conditions. Injection of tetrodotoxin in either eye ( n = 15) eliminated the xERG. Intraocular pressure elevation of the illuminated eye ( n = 6) had the same effect. The treatments also altered the ERG b-wave in both eyes, and the alterations correlated with xERG disappearance. Optic nerve stimulation ( n = 3) elicited a biphasic compound action potential in the nonstimulated nerve with 10- to 13-ms latency, implying that the xERG comes from slow-conducting (W type) fibers. Monocular dye application ( n = 7) confirmed the presence of retino-retinal ganglion cells in adult rats. We conclude that mammalian eyes communicate directly with each other via a handful of optic nerve fibers. The cross talk alters retinal activity in rats, and perhaps other animals.
Epstein-Barr Virus Infection in Transplant Recipients: Sumary of a Workshop on Surveillance, Prevention and Treatment
Authors: Allen Upton , Alfieri Caroline , Preiksaitis Jutta , Humar Atul , Moore Dorothy , Tapiero Bruce , Tellier Raymond , Green Michael , Davies Dele , Hébert Diane , Weitzman Sheila , Petric Martin , Jacobson Kevan ,   Canadian PTLD Workshop Group #x2013; 1999
Published: March 2016

Diseases caused by the Epstein-Barr virus are of great significance among organ transplant recipients. One of these diseases, post-transplant lymphoproliferative disease, is a major complication among organ transplant recipients. Management of this entity is problematic due to the difficulties with laboratory surveillance, diagnosis, prevention and treatment. A group of Canadian and American experts was assembled to discuss these aspects of Epstein-Barr virus diseases in Canadian organ transplant recipients. This report summarizes the relevant background literature and levels of evidence in relation to the outcomes of the deliberations and recommendations by the expert panel.
Characterization and Alignment of Carbon Nanofibers under Shear Force in Microchannel
Authors: Yang Jinshan , Dong Shaoming , Webster David , Gilmore John , Xu Chengying
Published: March 2016

This work presents a novel method to align CNFs by using shear forces in microchannels. Effect of two different microchannel sizes (1 mm × 0.1 mm and 1 mm × 0.2 mm) on CNFs alignment is investigated. SEM images of CNFs preform display significant alignment by both microchannels, which can be interpreted using a second-order alignment tensor and a manual angle meter. In the second-order alignment tensor description, an elongated ellipse can signify high degree of alignment in the direction of the major axis. When the microchannel size is 1 mm × 0.2 mm, the lengths of major and minor axes of the ellipse are 0.982 to 0.018. An angle meter manually shows that 85% of the CNFs are aligned in the direction between 60° and 90° when the microchannel is 1 mm × 0.2 mm. Both methods can demonstrate that better alignment of CNFs can be obtained using the 1 mm × 0.2 mm microchannel.
Tensile and Compressive Properties of Woven Kenaf/Glass Sandwich Hybrid Composites
Authors: Sharba Mohaiman J. , Leman Z. , Sultan M. T. H. , Ishak M. R. , Hanim M. A. Azmah
Published: March 2016

Monotonic (tensile and compression) properties of woven kenaf/glass reinforced unsaturated polyester sandwich hybrid composites have been experimentally investigated. Five types of composites laminates were fabricated using a combination of hand lay-up and cold press techniques, postcured for two hours at 80°C and left for 48 hours at room temperature. The hybrid composites contained fixed six layers of glass as a shell, three on each side, whereas the number of core kenaf layers was changed in three stages to get S1, S2, and S3 hybrid composites. Composites specimens with pure glass and kenaf were also fabricated for comparison. It was found that one kenaf layer replaced about 20% of total fiber weight fraction of the composite; this leads to reducing the density of final hybrid composite by 13%. Besides, in mechanical properties perspective, there are less than 1% reduction in compression strength and 40% in tensile strength when compared to pure glass composite. Generally, the results revealed that the best performance was observed in S1, which showed a good balance of all mechanical properties determined in this work.
Zinc Electrode Morphology Evolution in High Energy Density Nickel-Zinc Batteries
Authors: Payer Gizem , Ebil Özgenç
Published: March 2016

Prismatic Nickel-Zinc (NiZn) batteries with energy densities higher than 100 Wh kg−1were prepared using Zn electrodes with different initial morphologies. The effect of initial morphology of zinc electrode on battery capacity was investigated. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) reveal that initial morphology of zinc electrode changes drastically after a few charge/discharge cycles regardless of initial ZnO powder used. ZnO electrodes prepared using ZnO powders synthesized from ZnCl2and Zn(NO3)2lead to average battery energy densities ranging between 92 Wh kg−1and 109 Wh kg−1while using conventional ZnO powder leads to a higher energy density, 118 Wh kg−1. Average discharge capacities of zinc electrodes vary between 270 and 345 mA g−1, much lower than reported values for nano ZnO powders in literature. Higher electrode surface area or higher electrode discharge capacity does not necessarily translate to higher battery energy density.
Inhibition of Intestinalα-Glucosidase and Glucose Absorption by Feruloylated Arabinoxylan Mono- and Oligosaccharides from Corn Bran and Wheat Aleurone
Authors: Malunga Lovemore Nkhata , Eck Peter , Beta Trust
Published: March 2016

The effect of feruloylated arabinoxylan mono- and oligosaccharides (FAXmo) on mammalianα-glucosidase and glucose transporters was investigated using human Caco-2 cells, rat intestinal acetone powder, andXenopus laevisoocytes. The isolated FAXmo from wheat aleurone and corn bran were identified to have degree of polymerization (DP) of 4 and 1, respectively, by HPLC-MS. Both FAXmo extracts were effective inhibitors of sucrase and maltase functions of theα-glucosidase. The IC50 for FAXmo extracts on Caco-2 cells and rat intestinalα-glucosidase was 1.03–1.65 mg/mL and 2.6–6.5 mg/mL, respectively. Similarly, glucose uptake in Caco-2 cells was inhibited up to 40%. The inhibitory effect of FAXmo was dependent on their ferulic acid (FA) content (R= 0.95). Sodium independent glucose transporter 2 (GLUT2) activity was completely inhibited by FAXmo in oocytes injected to express GLUT2. Our results suggest that ferulic acid and feruloylated arabinoxylan mono-/oligosaccharides have potential for use in diabetes management.
Spectral Residual Model for Rural Residential Region Extraction from GF-1 Satellite Images
Authors: Li Shaodan , Tang Hong , Yang Xin
Published: March 2016

Visual attention is an attractive technique to derive important and prominent information from a scene in natural pictures. As a visual attention approach, spectral residual (SR) model is adapted to extract the residential regions from GF-1 satellite images in this paper. Specifically, we analyzed the impact of both different combinations of GF-1 satellite image bands and threshold algorithms on rural residential region detection. In addition, the adapted approach is compared with related visual attention methods in terms of both quantitative and qualitative detection effectiveness. Experimental results showed that the SR model coupled withred,green,andbluebands in GF-1 images and Otsu threshold algorithm achieved the best results and is suitable to quickly extract rural residential regions from GF-1 images.
Ag/AgCl Loaded Bi2WO6Composite: A Plasmonic Z-Scheme Visible Light-Responsive Photocatalyst
Authors: Meng Xiangchao , Zhang Zisheng
Published: March 2016

Hierarchical flower-like Bi2WO6was successfully synthesized by facile hydrothermal method at low pH. And Ag/AgCl was loaded by photoreduction on its surface. As-prepared photocatalysts were characterized by various techniques. Bi2WO6was successfully synthesized at a size of 2-3 μm. Depositing Ag/AgCl did not destroy the crystal structure, and both Ag+and metallic Ag0were found. The band gap of the composite was 2.57 eV, which indicates that visible light could be the activating irradiation. In the photocatalytic activity test, the composite with 10 wt% Ag/AgCl boasted the highest removal efficiency (almost 100%) in 45 min. The significant enhancement can be attributed to the surface plasmon resonance (SPR) effect and the establishment of heterostructures between Ag/AgCl and Bi2WO6. A possible mechanism of photocatalytic oxidation in the presence of Ag/AgCl-Bi2WO6was proposed. This work sheds light on the potential applications of plasmonic metals in photocatalysis to enhance their activities.
Study of the Convergence in State Estimators for LTI Systems with Event Detection
Authors: Posada Juan C. , Betancur Manuel J. , Moreno Jaime A. , Guerra Rubén D. , Tamayo Martin A.
Published: March 2016

The methods frequently used to estimate the state of an LTI system require that the precise value of the output variable is known at all times, or at equidistant sampling times. In LTI systems, in which the output signal is measured through binary sensors (detectors), the traditional way of state observers design is not applicable even though the system has a complete observability matrix. This type of state observers design is known as passive. It is necessary, then, to introduce a new state estimation technique, which allows reckoning the state from the information of the variable’s crossing through a detector’s action threshold (switch). This paper seeks, therefore, to study the convergence in this type of estimators in finite time, allowing establishing, theoretically, whether some family of the proposed models can be estimated in a convergent way through the use of the estimation technique based on events.
Polychromatic Iterative Statistical Material Image Reconstruction for Photon-Counting Computed Tomography
Authors: Weidinger Thomas , Buzug Thorsten M. , Flohr Thomas , Kappler Steffen , Stierstorfer Karl
Published: March 2016

This work proposes a dedicated statistical algorithm to perform a direct reconstruction of material-decomposed images from data acquired with photon-counting detectors (PCDs) in computed tomography. It is based on local approximations (surrogates) of the negative logarithmic Poisson probability function. Exploiting the convexity of this function allows for parallel updates of all image pixels. Parallel updates can compensate for the rather slow convergence that is intrinsic to statistical algorithms. We investigate the accuracy of the algorithm for ideal photon-counting detectors. Complementarily, we apply the algorithm to simulation data of a realistic PCD with its spectral resolution limited by K-escape, charge sharing, and pulse-pileup. For data from both an ideal and realistic PCD, the proposed algorithm is able to correct beam-hardening artifacts and quantitatively determine the material fractions of the chosen basis materials. Via regularization we were able to achieve a reduction of image noise for the realistic PCD that is up to 90% lower compared to material images form a linear, image-based material decomposition using FBP images. Additionally, we find a dependence of the algorithms convergence speed on the threshold selection within the PCD.
Rhythmic Oscillations of Excitatory Bursting Hodkin-Huxley Neuronal Network with Synaptic Learning
Authors: Shi Qi , Han Fang , Wang Zhijie , Li Caiyun
Published: March 2016

Rhythmic oscillations of neuronal network are actually kind of synchronous behaviors, which play an important role in neural systems. In this paper, the properties of excitement degree and oscillation frequency of excitatory bursting Hodkin-Huxley neuronal network which incorporates a synaptic learning rule are studied. The effects of coupling strength, synaptic learning rate, and other parameters of chemical synapses, such as synaptic delay and decay time constant, are explored, respectively. It is found that the increase of the coupling strength can weaken the extent of excitement, whereas increasing the synaptic learning rate makes the network more excited in a certain range; along with the increasing of the delay time and the decay time constant, the excitement degree increases at the beginning, then decreases, and keeps stable. It is also found that, along with the increase of the synaptic learning rate, the coupling strength, the delay time, and the decay time constant, the oscillation frequency of the network decreases monotonically.
Coal and Gangue Underground Pneumatic Separation Effect Evaluation Influenced by Different Airflow Directions
Authors: Zheng Kehong , Du Changlong , Li Jianping , Qiu Bingjing
Published: March 2016

Coal and gangue underground pneumatic separation is of key importance for green mining. Two kinds of arrangement schemes for high-pressure value used in pneumatic separation system are proposed in this study. Pneumatic separation effects are examined under different arrangement of high-pressure value. Here, theoretical pneumatic separation distance formulas of mineral particles affected by different airflow directions are derived and validated by a series of numerical simulations and orthogonal experiments. In the following analysis, the effects of gangue diameter (d), conveyor velocity (v0), and the height difference between conveyor belt and air nozzle (hp) are mainly considered. The numerical simulation and experimental results indicate that pneumatic separation effects under the condition ofuandv0being in the opposite direction will be better than that ofuandv0being in the same direction. The pneumatic separation distanceΔSshows a decreasing trend with the increasing of the three factors. The study also shows that gangue diameter has the most significant influence on separation distance, followed by conveyor velocityv0and height differencehp.
Diverse Molecular Genotypes ofMycobacterium tuberculosisComplex Isolates Circulating in the Free State, South Africa
Authors: Van der Spoel van Dijk Anneke , Makhoahle Pakiso M. , Rigouts Leen , Baba Kamaldeen
Published: March 2016

Tuberculosis is a serious public health concern especially in Africa and Asia. Studies describing strain diversity are lacking in the Free State region of South Africa. The aim of the study was to describe the diversity ofMycobacterium tuberculosis(M. tuberculosis) strain families in the Free State province of South Africa. A total of 86M. tuberculosisisolates were genotyped using spoligotyping. A 12-locus mycobacterial interspersed repetitive units-variable-number tandem repeats (MIRU-VNTRs) typing was used to further characterize the resulting spoligotyping clusters. SITVITWEB identified 49 different patterns with allocation to six lineages including Latin-American-Mediterranean (LAM) (18 isolates), T (14 isolates), Beijing (five isolates), S (six isolates), Haarlem (one isolate), and X (five isolates), while 37 (43.0%) orphans were identified. Eight clusters included 37 isolates with identical spoligotypes (2 to 13/cluster). MIRU-VNTR typing further differentiated three spoligotyping clusters: SIT1/Beijing/MIT17, SIT33/LAM3/MIT213, and confirmed one SIT34/S/MIT311. In addition, SpolDB3/RIM assignment of the orphan strains resulted in a further 10 LAM and 13 T families. In total, LAM (28 isolates) and T (27 isolates) cause 63% of the individual cases of MTB in our study. The Free State has a highly diverse TB population with LAM being predominant. Further studies with inclusion of multidrug-resistant strains with larger sample size are warranted.
SIRT1: A Novel Target for the Treatment of Muscular Dystrophies
Authors: Kuno Atsushi , Horio Yoshiyuki
Published: March 2016

Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and is caused by mutations in the gene that encodes the cytoskeletal protein dystrophin. The treatment for DMD is limited to glucocorticoids, which are associated with multiple side effects. Thus, the identification of novel therapeutic targets is urgently needed. SIRT1 is an NAD+‐dependent histone/protein deacetylase that plays roles in diverse cellular processes, including stress resistance and cell survival. Studies have shown that SIRT1 activation provides beneficial effects in the dystrophin‐deficient mdx mouse, a model of DMD. SIRT1 activation leads to the attenuation of oxidative stress and inflammation, a shift from the fast to slow myofiber phenotype, and the suppression of tissue fibrosis. Although further research is needed to clarify the molecular mechanisms underlying the protective role of SIRT1 in mdx mice, we propose SIRT1 as a novel therapeutic target for patients with muscular dystrophies.
Management of Ocular Siderosis: Visual Outcome and Electroretinographic Changes
Authors: Kannan Naresh B. , Adenuga Olukorede O. , Rajan Renu P. , Ramasamy Kim
Published: March 2016

Purpose.Ocular siderosis (OS) is a sight threatening complication of retained iron-containing Intraocular Foreign Body (IOFB). Successful localization of the IOFB and timely removal are crucial to its management. The purpose of this study was to review the presentation, management, and outcome of OS at our institution.Methods. A retrospective case series of eyes with OS that underwent IOFB removal from January 2009 to March 2015 at our institution.Results. OS was seen in 9 eyes of 9 patients during the study period. There were 8 males and 1 female with an age range of 31.6 years. An IOFB was in all the eyes. The most common features of siderosis were cataract and pigmentary retinopathy seen in 6 (67%) and 4 (44%) eyes, respectively. Electroretinogram (ERG) readings were reduced in the 9 eyes. The IOFB was removed by pars plana vitrectomy in all the cases with improvement in ERG amplitudes occurring postoperatively in 7 (78%) eyes.Conclusion.A retained iron-containing IOFB can manifest itself after several years with features of OS. A careful clinical and radiologic evaluation is imperative in patients with history suggestive of penetrating ocular injury to rule out retained or occult IOFB and thus prevent this catastrophic condition.
Observer-Based Event-Triggered Control for Switched Systems with Time-Varying Delay and Norm-Bounded Disturbance
Authors: Ma Guoqi , Qin Linlin , Liu Xinghua , Wu Gang
Published: March 2016

This paper is concerned with the problem of observed-based event-triggered control for switched linear systems with time-varying delay and exogenous disturbance. First by employing a state observer, an observer-based event-triggered controller is designed to guarantee the finite-time boundedness and finite-time stabilization of the resulting dynamic augmented closed-loop system. Then based on the Lyapunov-like function method and the average dwell time technique, some sufficient conditions are given to ensure the finite-time boundedness and finite-time stabilization, respectively. Furthermore, the lower bound of the minimum interevent interval is proved to be positive, which thus excludes the Zeno behavior of sampling. A numerical example is finally exploited to verify the effectiveness and potential of the achieved control scheme.
Effects ofStreptococcus bovisIsolated from Bovine Rumen on the Fermentation Characteristics and Nutritive Value of Tanzania Grass Silage
Authors: Zanine Anderson de Moura , Bonelli Emerson Alencar , Souza Alexandre Lima de , Ferreira Daniele de Jesus , Santos Edson Mauro , Ribeiro Marinaldo Divino , Geron Luiz Juliano Valério , Pinho Ricardo Martins Araujo
Published: March 2016

This study aimed to evaluate the effects ofStreptococcus bovison the fermentation characteristics and nutritive value of Tanzania grass silage. Tanzania grass was chopped and left untreated (U) or treated withStreptococcus bovisJB1 at 1 × 106colony-forming units per gram (cfu/g) of fresh forage orStreptococcus bovisHC5 at 1 × 106 cfu/g of fresh forage and packed into sixtuplicate laboratory silos. The largest number of enterobacteria, molds and yeast (M&Y) occurred in untreated silages and the smallest populations of enterobacteria and M&Y and the largest numbers of lactic acid bacteria (LAB), at 9.81 and 9.87 log cfu/g, were observed inStreptococcus bovisJB1 and HC5, respectively (P<0.05). Silages treated with JB1 and HC5 had lower (P<0.05) silage pHs and concentrations of ammoniacal nitrogen (NH3-N) than untreated silages. The application ofStreptococcus bovisJB1 and HC5 resulted in fewer losses through gases and effluents (P<0.05), which resulted in greater dry matter recovery (DMR) and crude protein recovery (CPR) (P<0.05).Streptococcus bovisJB1 and HC5 improved the fermentative profile and increased the concentration of crude protein and DMR and CPR in Tanzania grass silage.
Leakage Characteristics of Dual-Cannula Fenestrated Tracheostomy Tubes during Positive Pressure Ventilation: A Bench Study
Authors: Berlet Thomas , Marchon Mathias
Published: March 2016

This study compared the leakage characteristics of different types of dual-cannula fenestrated tracheostomy tubes during positive pressure ventilation. Fenestrated Portex® Blue Line Ultra®, TRACOE® twist, or Rüsch® Traceofix® tracheostomy tubes equipped with nonfenestrated inner cannulas were tested in a tracheostomy-lung simulator. Transfenestration pressures and transfenestration leakage rates were measured during positive pressure ventilation. The impact of different ventilation modes, airway pressures, temperatures, and simulated static lung compliance settings on leakage characteristics was assessed. We observed substantial differences in transfenestration pressures and transfenestration leakage rates. The leakage rates of the best performing tubes were <3.5% of the delivered minute volume. At body temperature, the leakage rates of these tracheostomy tubes were <1%. The tracheal tube design was the main factor that determined the leakage characteristics. Careful tracheostomy tube selection permits the use of fenestrated tracheostomy tubes in patients receiving positive pressure ventilation immediately after stoma formation and minimises the risk of complications caused by transfenestration gas leakage, for example, subcutaneous emphysema.
Selection Criteria and Current Issues in Liver Transplantation for Hepatocellular Carcinoma
Authors: Kaido Toshimi
Published: March 2016

Liver transplantation (LT) is an ideal treatment for hepatocellular carcinoma (HCC) because it not only resects HCCs but it also replaces the underlying damaged liver with normal tissue. However, the selection criteria are still a matter of debate. After the introduction of the Milan criteria, some expanded criteria focusing on tumor size and number have been proposed. In addition, new expanded criteria considering tumor biology have been proposed using tumor markers and 18F-fluorodeoxyglucose positron emission tomography. This review summarizes the selection criteria in LT for HCC and introduces current issues focusing on the treatment for hepatitis C virus infection and the significance of sarcopenia in this field.
National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma
Authors: Chow Pierce K. H. , Choo Su Pin , Ng David C. E. , Lo Richard H. G. , Wang Michael L. C. , Toh Han Chong , Tai David W. M. , Goh Brian K. P. , Wong Jen San , Tay Kiang Hiong , Goh Anthony S. W. , Yan Sean X. , Loke Kelvin S. H. , Thang Sue Ping , Gogna Apoorva , Too Chow Wei , Irani Farah Gillian , Leong Sum , Lim Kiat Hon , Thng Choon Hua
Published: March 2016

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26th September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data.
The Promise of Epigenetics. Has It Delivered New Insights?
Authors: Cho Judy H.
Published: March 2016

Enrichment of GWAS signals within cell-specific enhancers defines cellular subsets most associated to IBD and highlights the critical role of epigenetics in IBD. We review the central role of the interleukin 23 (IL-23) pathway in cellular plasticity, mechanisms which are significantly mediated by epigenetic regulation of master transcription factors of various CD4+ T-cell subsets. Present studies need to be complemented by a deeper understanding of intestine-specific gene expression and epigenetics, especially in mononuclear phagocytes, given their enormous plasticity, and tissue-dependent function. A deeper understanding and application of epigenetics may impact and guide early treatment and ultimately, disease prevention in IBD.
Environment and Genes: What Is the Interaction?
Authors: Blumberg Richard S.
Published: March 2016

Inflammatory bowel disease (IBD) results from a continuum of complex interactions between a quartet of host-derived and external elements that involve various aspects of the intestinal microbiota, the immune system that is centered around the intestinal epithelial cell barrier, the genetic composition of the host and specific environmental factors. Recent studies into the complexity of these arrangements increasingly support the syndromic nature of this disorder and involve a wide range of interacting biologic pathways that affect innate immunity, adaptive immunity, endoplasmic reticulum stress and autophagy as well as metabolic pathways associated with cellular homeostasis. It is further likely that all of the aforementioned host factors including the microbiota, which is as much a part of ourselves as is any organ system, are under the influence of yet-to-be-understood environmental factors that predispose to and precipitate IBD. Notwithstanding the importance of genetic predisposition, these environmental influences are no doubt central to disease pathogenesis in light of the rapid emergence of IBD throughout the world and assumption of disease in migrating populations from low to high risk environments. It can thus be anticipated that environmental factors that modify the risk for development of IBD have the common attribute of affecting the relationship between the commensal microbiota and the immune system in a manner that intersects with the functionally relevant immuno-genetic pathways, and potentially modifies them through epigenetic effects, in a manner that are uniquely operative within a particular syndromic context of IBD and occur sequentially and in a reiterative fashion, perhaps beginning in early life.
Links of Autophagy Dysfunction to Inflammatory Bowel Disease Onset
Authors: El-Khider Faris , McDonald Christine
Published: March 2016

Introduction: Autophagy is a cellular stress response that plays key roles in physiological processes, such as adaptation to starvation, degradation of aberrant proteins or organelles, anti-microbial defense, protein secretion, and innate and adaptive immunity. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including inflammatory bowel disease (IBD). Genetic studies have identified multiple IBD-associated risk loci that include genes required for autophagy, and several lines of evidence demonstrate that autophagy is impaired in IBD patients. How dysfunctional autophagy contributes to IBD onset is currently under investigation by researchers. Key Messages: Dysfunctional autophagy has been identified to play a role in IBD pathogenesis by altering processes that include (1) intracellular bacterial killing, (2) anti-microbial peptide secretion by Paneth cells, (3) pro-inflammatory cytokine production by macrophages, (4) antigen presentation by dendritic cells, (5) goblet cell function, and (6) the endoplasmic reticulum stress response in enterocytes. The overall effect of dysregulation of these processes varies by cell type, stimulus, as well as cellular context. Manipulation of the autophagic pathway may provide a new avenue in the search for effective therapies for IBD. Conclusion: Autophagy plays multiple roles in IBD pathogenesis. A better understanding of the role of autophagy in IBD patients may provide better subclassification of IBD phenotypes and novel approaches to disease management.
Hygiene Hypothesis: Is the Evidence the Same All Over the World?
Authors: Leong Rupert W. , Mitrev Nikola , Ko Yanna
Published: March 2016

Background: The hygiene hypothesis refers to where modern living conditions are responsible for the increasing incidences of immune-related diseases including the development of inflammatory bowel diseases (IBD). Improved hygiene may result in decreased enteric microbiota diversity and dysbiosis, which may be responsible for the development of IBD. Key Messages: The rising incidence of IBD is well documented in developing regions of the world, in accordance with the hygiene hypothesis. What is unknown, however, is whether the hygiene hypothesis is applicable all over the world. Hygiene cannot be easily measured and proxy markers need to be used. These include regional data such as a country's gross domestic product or an individual's affluence or exposure to infection risk factors. A comparative case-control study of Caucasian Australian IBD subjects versus migrants from the Middle East to Australia identified that environmental risk factors are different in the 2 populations. Among Australian Caucasians, hygiene-related environmental risk factors are no longer relevant in the development of IBD. Given the country's high affluence, there has been high hygienic standard for several generations. However, migrants from less affluent countries exposed to hygiene-related environmental factors are at increased risks of developing IBD, especially in the second generation migrants born in the affluent country. Divergent risk factors include the use of antibiotics in childhood increasing the risk of IBD in developed societies but being a risk factor for developing IBD in migrants. In India, risk factors associated with infections were found to be positively associated with the development of ulcerative colitis, rather than protective. Conclusions: The hygiene hypothesis is not applicable to all populations worldwide, being most relevant in societies undergoing increasing affluence or following migration from less to more affluent countries. This review examines data from around the world that link the hygiene hypothesis with the development of IBD and in particular the divergent results arising from data from affluent countries versus less-affluent countries.
Dendritic Cell-T-Cell Circuitry in Health and Changes in Inflammatory Bowel Disease and Its Treatment
Authors: Knight Stella C.
Published: March 2016

Background: Dendritic, antigen-presenting cells (DCs) determine not only whether lymphocytes produce different types of immune response but also tissue-homing profiles of lymphocytes they stimulate. For example, in health, mucosal DC stimulate T cells focused to home to the mucosa; DC/T-cell circuitry thus targets immune responses to specific tissue locations. Therapies being introduced for inflammatory bowel disease (IBD) include antibodies to gut-homing molecules such as α4β7 (Vedolizumab) used ostensibly to block gut-homing lymphocytes. However, such lymphocytes are dependent on the tissue specificity of DC that stimulated them. Key Messages: In health, blood DCs have the potential to home to multiple tissues including gut (α4β7+) and skin (CLA+). DCs have become gut-specific within the intestinal microenvironment stimulated partially by local retinoid to express α4β7 (mucosal homing marker) and/or CCR9 (ileal homing marker) in the absence of skin-specific indicators. They spread veiled extensions, sample their environment, acquire/process antigens, produce cytokines and initiate innate immunity. Myeloid DC also traffic to draining lymph nodes where compartmentalization of adaptive immune responses is determined by DCs from the site of antigen exposure which dictate the homing profiles of lymphocytes they stimulate. In IBD, site and activity of disease are reflected in changes in homing/activation of gut DCs and T-cells they stimulate and also, in greater gut specificity and activation of blood DC. Homing potential of DC can be modulated toward mucosa or skin by vitamins A and D, respectively. Infliximab or interleukin-6 can divert homing profiles toward skin, perhaps predisposing to skin involvement in IBD. Probiotic bacteria or their products can also change homing profiles of gut DC toward skin homing and away from gut. Conclusions: In conclusion, development of gut focused inflammation and its treatment relies on changes in DC tissue specificity; therefore, removal or diversion of gut-homing DC as well as T-cells is likely to be critical in prevention of gut-focused inflammation in IBD.
Calprotectin or Lactoferrin: Do They Help
Authors: Wright Emily K.
Published: March 2016

Background: The diagnosis and monitoring of inflammatory bowel disease (IBD) has traditionally relied on clinical assessment, serum markers of inflammation and endoscopic examination. Fecal biomarkers such as calprotectin (FC) and lactoferrin (FL) are predominantly derived from neutrophils, are easily detectable in the feces and are now established as valuable markers of intestinal inflammation. In recent years, a ‘treat to target' concept has emerged for the management of IBD. Adequate control of inflammation in IBD at a biochemical level is quickly becoming an important target in IBD management. Key Messages: Fecal biomarkers have been shown to be significantly and consistently increased in both adult and pediatric patients with IBD versus those without IBD. Fecal biomarkers are therefore useful in determining those patients with gastrointestinal symptoms who are likely to benefit from colonoscopy versus those in whom colonoscopy is likely to be normal. Fecal biomarkers correlate significantly with endoscopic disease in both Crohn's disease and ulcerative colitis. Suggested cutoffs for FC for endoscopically active disease in IBD range from 50 to 280 μg/g. Fecal biomarkers reflect the success of treatment intensification and can help predict clinical relapse. Both FC and FL are accurate in the detection of postoperative endoscopic recurrence of Crohn's disease, and FC may be clinically useful in predicting those patients with acute severe ulcerative colitis who may progress to colectomy. There are limitations to these fecal tests including a false positive rate and intra-individual variability. Conclusions: This review focuses on the role of fecal biomarkers in the diagnosis, monitoring and management of IBD and how best to interpret results. We will discuss the emerging role of these biomarkers in the IBD management landscape including FC-guided drug dosing and the development of home-based testing and e-health applications. Fecal biomarker results must always be interpreted in a clinical context. Endoscopic assessment remains the gold standard for diagnosis and monitoring of IBD.
When to Start Immunomodulators in Inflammatory Bowel Disease?
Authors: Sharara Ala I.
Published: March 2016

Background: Immunomodulators (IMMs), including thiopurines (TPs) and methotrexate (MTX), are commonly used in the treatment of inflammatory bowel disease (IBD). Key Messages: In ulcerative colitis (UC), TPs have modest steroid-sparing effects and established efficacy in maintenance of remission. The role of MTX in UC is unclear but current evidence suggests no benefit over placebo. In Crohn's disease (CD), MTX is not effective for induction but has a modest steroid-sparing effect and is superior to placebo in maintenance of remission in responders. The addition of MTX to infliximab reduces immunogenicity and boosts infliximab levels but does not improve outcomes in active CD. TPs are not effective for induction of remission in CD but have proven steroid-sparing effects and modest efficacy in maintenance of remission and prevention of postoperative recurrence. Although effective in pediatric CD, recent evidence has questioned the benefit of early TPs in newly diagnosed adult CD. The addition of TPs to infliximab reduces immunogenicity and inflammatory markers, leads to higher infliximab levels and improves outcomes in patients with early disease. However, the benefit of continued TP therapy in this setting is unclear and should be weighed against possible side effects including an increased risk of opportunistic infections, lymphoma and non-melanoma skin cancer. Conclusions: IMMs are an important therapeutic option in IBD particularly in non-severe steroid-dependent disease and for maintenance of remission. Combination with anti-TNF agents is an important emerging option as part of a treat-to-target strategy but further research regarding patient selection, long-term use and de-escalation options is needed.
Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place?
Authors: Khanna Reena , Mosli Mahmoud H. , Feagan Brian G.
Published: March 2016

Background: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. Key Messages: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the α4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the α4β7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. Conclusions: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve.
The Future of IBD Therapy: Where Are We and Where Should We Go Next?
Authors: Mao Ren , Hu Pin-Jin
Published: March 2016

Background: The advent of biologic agents opens up a new era for the treatment of inflammatory bowel disease (IBD). In this era, the treatment goal has evolved from the traditional goal of clinical remission to a combination of clinical remission, laboratory normalization and mucosal healing, designated as ‘complete deep remission'. Such complete deep remission comprises a more ambitious disease control strategy that is believed to probably modify the natural course of IBD. Key Messages: To achieve this goal, optimization of current strategy and introduction of novel therapies have gained significant interest. In this concise review, we aim to provide an overview of the current status and future direction of IBD treatment. Specifically, we will describe the application of personalized therapy, development of new biologics, intestinal microbiome manipulation and out-of-the-box agents for IBD. Conclusions: More evidence is still desirable to better optimize the current treatment and apply novel biologics. Personalized medicine has the potential to optimize efficacy, decrease the risk of adverse events and minimize costs and should be proposed as a standard of care for the management of IBD.
The p.Gly61Glu Mutation in CYP1B1 Affects the Extracellular Matrix in Glaucoma Patients
Authors: Safari Iman , Suri Fatemeh , Haji-Seyed-Javadi Ramona , Yazdani Shahin , Elahi Elahe
Published: March 2016

Purpose: The aim of this work was to assess the possible effects of CYP1B1 mutations on the extracellular matrix (ECM) in glaucoma patients. CYP1B1 mutations are the cause of disease in a notable fraction of primary congenital glaucoma (PCG) patients and in a smaller fraction of primary open angle glaucoma (POAG) patients. Methods: The study was performed on a glaucoma family with the common homozygous p.Gly61Glu CYP1B1 mutation. The father was affected with POAG and three siblings had PCG. Microscopy was performed on the skin of the father and one son, as well as controls. Immunohistochemical studies were done using anti-CYP1B1 and anti-fibrillin-1 antibodies. Fibrillin-1 served as a marker for the ECM, and electron microscopy was also performed. Results: CYP1B1 expression patterns were the same in the patients and controls. However, microfibrils that are associated with fibrillin-1 were less abundant and more fragmented in both patients. Electron microscopy showed disturbed collagen fibers only in the PCG patient. Conclusions: The p.Gly61Glu mutation in CYP1B1 affects the ECM structure. This implies that the ECM of the trabecular meshwork may also be disrupted in a manner that affects aqueous humor flow resulting in increased intraocular pressure and contributing to the glaucoma phenotype.
Risk Factors for Acute Kidney Injury after Cardiovascular Surgery: Evidence from 2,157 Cases and 49,777 Controls - A Meta-Analysis
Authors: Yi Qian , Li Ke , Jian Zhao , Xiao Ying-Bin , Chen Lin , Zhang Yao , Ma Rui-Yan
Published: March 2016

Purpose: Cardiovascular surgery-associated acute kidney injury (AKI-CS) contributes to mortality and morbidity. However, risk factors accelerating its development are unclear. We identified risk factors for AKI-CS in patients with cardiopulmonary bypass in the hospital surgical intensive care unit to predict and minimize renal complication in future cardiac surgery. Methods: We analyzed data from 14 case-control studies published prior to June 2014 and indexed in Science Citation Index, PubMed, and other databases to determine the major risk factors for AKI-CS. Results: Analyzed risk factors were divided into three groups: preoperative, intraoperative and postoperative. Preoperative factors included: age (OR, 4.87; 95% CI, 3.50-6.24), NYHA class III/IV (OR, 2.53; 95% CI, 1.32-4.86), hypertension (OR, 1.68; 95% CI, 1.44-1.97), preoperative creatinine (OR, 0.66; 95% CI, 0.18-1.14), peripheral vascular disease (OR, 1.31 95% CI, 1.09-1.57), respiratory system disease (OR, 1.29; 95% CI, 1.10-1.50), diabetes mellitus (OR, 1.52; 95% CI, 1.07-2.16), and cerebrovascular disease (OR, 2.13; 95% CI, 1.11-4.09). Intraoperative factors were: cardiopulmonary bypass time (OR, 33.78; 95% CI, 23.15-44.41), aortic clamping time (OR, 13.24; 95% CI, 7.78-18.69), use of intra-aortic balloon pump (OR, 4.44; 95% CI, 2.37-8.30), and type of surgery (OR, 1.01; 95% CI, 0.43-2.39). Postoperative factors were: infection (OR, 3.58; 95% CI, 1.43-8.97), redo operation (OR, 2.57; 95% CI, 1.75-3.78), emergency surgery (OR, 4.76; 95% CI, 3.05-7.43), and low cardiac output (OR, 2.30; 95% CI, 1.05-5.04). Conclusions: Our results support that preoperative, intraoperative, and postoperative factors are associated with AKI-CS. Ejection fraction, BMI, acute myocardial infarction, type of surgery, and congestive heart failure were not absolutely associated with AKI.
Practice of the Treatment of Milk Allergy in the UK: A National Audit
Authors: Luyt David , Krishnan M. Thirumala , Huber Pia , Clark Andrew
Published: March 2016

Background: The management of cow's milk allergy (CMA) includes initial dairy exclusion with suitable dietary substitution, diagnostic challenges where indicated, and supervised re-introduction as the condition resolves. Information on clinician practice is limited. We audited the current practice of clinicians in the UK to evaluate adherence to international guidelines. Methods: An online questionnaire was sent to all clinicians whose practice included children identified on the national allergy society website. One hundred and sixty questionnaires were sent and 116 (73%) responded. Results: Skin prick tests were more commonly used than serum-specific IgE as diagnostic tests. Respective proportions selecting amino acid formulas (AAF) or extensively hydrolysed formulas (EHF) in severe versus mild/moderate presentations were 78 and 40% versus 20 and 88%; soya formula was the first choice in 8.6 and 24%. The criteria for selection of AAF as the first choice were predominantly severe IgE-mediated and non-IgE-mediated reactions, failure to thrive and if infants refused EHF. Oral challenges might be used to diagnose CMA in 69%, whereas nearly 90% performed challenges to assess tolerance. Most of these were open challenges, more commonly with fresh milk (90%) than baked milk (60%). Home baked milk challenges were frequently considered (70%), although only after consideration of the clinical scenario. Practice did not vary with experience. Conclusions: Current practice amongst UK clinicians of the management of CMA is broadly in line with current guidance, particularly the positioning of hypoallergenic milks as substitute milk choices. A notable deviation was the use of home baked milk challenges or re-introduction.