Dual pH and microbial-sensitive galactosylated polymeric nanocargoes for multi-level targeting to combat ulcerative colitis

Ulcerative colitis(UC)is a type of inflammatory bowel disease characterized by inflammation,ulcers and irritation of the mucosal lining.Oral drug delivery in UC encounters challenges because of multifaceted barriers.Dexamethasone-loaded galactosylated-PLGA/Eudragit S100/pullulan nanocargoes(Dexa-GP/ES/Pu NCs)have been developed with a dual stimuli-sensitive coating responsive to both colonic pH and microbiota,and an underneath galactosylated-PLGA core(GP).The galactose ligand of the GP preferentially binds to the macrophage galactose type-lectin-C(MGL-2)surface receptor.Therefore,both stimuli and ligand-mediated targeting facilitate nanocargoes to deliver Dexa specifically to the colon with enhanced macrophage uptake.Modified emulsion method coupled with a solvent evaporation coating technique was employed to prepare Dexa-GP/ES/Pu NCs.The nanocargoes were tested using in vitro,ex vivo techniques and dextran sodium sulfate(DSS)induced UC model.Prepared nanocargoes had desired physicochemical properties,drug release,cell uptake and cellular viability.Investigations using a DSS-colitis model showed high localization and mitigation of colitis with downregulation of NF-ĸB and COX-2,and restoration of clinical,histopathological,biochemical indices,antioxidant balance,microbial alterations,FTIR spectra,and epithelial junctions’integrity.Thus,Dexa-GP/ES/Pu NCs found to be biocompatible nanocargoes capable of delivering drugs to the inflamed colon with unique targeting properties for prolonged duration.

恩施市志留系地层斜坡灾变智能化预测

由于滑坡发生时间的不确定性及发生物理过程的非线性,决定了滑坡灾害预测研究的趋势是确定特定区域、特定条件下不稳定斜坡体演变成为滑坡的可能性,以及这些不稳定斜坡体空间分布规律的预测研究。以鄂西恩施市志留系地层潜在不稳定斜坡为研究对象,建立了基于GIS和人工智能神经网络的适用于研究区志留系地层斜坡灾变空间预测的技术路线及方法:从数据采集、空间数据库建立、评价指标体系建立、智能化预测模块设计、斜坡灾变智能化预测系统集成等方面进行了深入研究,得到了研究区内在将来外界营力作用下可能演变成为滑坡的不稳定斜坡区空间的分布情况,并利用遥感数据结合野外实地调查对成果进行了验证。证明了计算机智能化理论与GIS技术结合应用于斜坡灾变空间预测分析的科学性、可行性以及可靠性。

Role of the receptor for advanced glycation end products in hepatic fibrosis

AIM:To study the role of advanced glycation end products(AGE)and their specifi c receptor(RAGE)in the pathogenesis of liver fi brogenesis.METHODS:In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells(HSC)were measured after stimulation with the two RAGE ligands,advanced glycation end product-bovine serum albumin(AGE-BSA)and Nε-(carboxymethyl)lysine(CML)-BSA,or with tumor necrosis factor-α(TNF-α).In vivo RAGE expression was examined in models of hepatic fi brosis induced by bile duct ligation or thioacetamide.The effects of AGE-BSA and CML-BSA on HSC proliferation,signal transduction and profi brogenic gene expression were studied in vitro.RESULTS:In hepatic fibrosis,RAGE expression was enhanced in activated HSC,and also in endothelial cells,inflammatory cells and activated bile duct epithelia.HSC expressed RAGE which was upregulated after stimulation with AGE-BSA,CML-BSA,and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation,apoptosis,fibrogenic signal transduction and fibrosis-or fibrolysis-related gene expression,except for marginal upregulation of procollagen α1(Ⅰ)mRNA by AGE-BSA.CONCLUSION:Despite upregulation of RAGE in activated HSC,RAGE stimulation by AGE does not alter their fibrogenic activation.Therefore,RAGE does not contribute directly to hepatic fibrogenesis.

Differential diagnosis in inflammatory bowel disease colitis:State of the art and future perspectives

Distinction between Crohn's disease of the colonrectum and ulcerative colitis or inflammatory bowel disease(IBD) type unclassified can be of pivotal importance for a tailored clinical management,as each entity often involves specific therapeutic strategies and prognosis.Nonetheless,no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations.Hence,we have performed a literature search to address the problem of differential diagnosis in IBD colitis,revised current and emerging diagnostic tools and refined disease classification strategies.Nowadays,the differential diagnosis is an untangled issue,and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis.This topic is receiving emerging attention,as medical therapies,surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients.The optimization of standard diagnostic approaches based on clinical features,biomarkers,radiology,endoscopy and histopathology appears to provide only marginal benefits.Conversely,emerging diagnostic techniques in the field of gastrointestinal endoscopy,molecular pathology,genetics,epigenetics,metabolomics and proteomics have already shown promising results.Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD,better reflecting diverse disease behaviors based on specific pathogenic pathways.

New endoscopic approaches in IBD

Recent advances in endoscopic imaging techniques have revolutionized the diagnostic approach of patients with inflammatory bowel disease(IBD).New,emerging endoscopic imaging techniques visualized a plethora of new mucosal details even at the cellular and subcellular level.This review offers an overview about new endoscopic techniques,including chromoendoscopy,magnification endoscopy,spectroscopy,confocal laser endomicroscopy and endocytoscopy in the face of IBD.

Cancer risk in IBD: How to diagnose and how to manage DALM and ALM

The risk of developing neoplasia leading to colorectal cancer is significantly increased in ulcerative colitis (UC) and most likely in Crohn's disease. Several endoscopic surveillance strategies have been implemented to identify these lesions. The main issue is that colitisassociated neoplasms often occurs in flat mucosa, often being detected on taking random biopsies rather than by identification of these lesions via endoscopic imaging. The standard diagnostic procedure in long lasting UC is to take four biopsies every 10 cm. Image enhancement methods, such as chromoendoscopy and virtual histology using endomicroscopy, have greatly im- proved neoplasia detection rates and may contribute toreduced random biopsies by taking targeted "smart" biopsies. Chromoendoscopy may effectively be performed by experienced endoscopists for routine screening of UC patients. By contrast, endomicroscopy is often only available in selected specialized endoscopic centers. Importantly, advanced endoscopic imaging has the poten- tial to increase the detection rate of neoplasia whereas the interplay between endoscopic experience and interpretation of histological biopsy evaluation allows the physician to make a proper diagnosis and to find the appropriate therapeutic approach. Colitis-associated intraepithelial neoplasms may occur in flat mucosa of endoscopically normal appearance or may arise as dysplasia-associated lesion or mass (DALM), which may be indistinguishable from sporadic adenomas in healthy or non-colitis mucosa [adenoma-like mass (ALM)]. The aim of this review was to summarize endoscopic and histological characteristics of DALM and ALM in the context of therapeutic procedures.

Probe based confocal laser endomicroscopy of the pancreatobiliary system

AIM:To review applications of confocal laser endomicroscopy(CLE) in pancreatobiliary lesions and studies that assessed training and interpretation of images. METHODS: A computerized literature search was performed using OVID MEDLINE, EMBASE, Cochrane library, and the ISI Web of Knowledge from 1980 to October 2014. We also searched abstracts from major meetings that included the Digestive Disease Week, Canadian Digestive Disease Week and the United European Gastroenterology Week using a combination of controlled vocabulary and text words related to p CLE, confocal, endomicroscopy, probe-based confocal laser endomicroscopy, and bile duct to identify reports of trials. In addition, recursive searches and crossreferencing was performed, and manual searches of articles identified after the initial search was also completed. We included fully published articles and those in abstract form. Given the relatively recent introduction of CLE we included randomized trials and cohort studies.R E S U LT S : In the evaluation of indeterminate pancreatobiliary strictures CLE with ERCP compared to ERCP alone can increase the detection of cancerous strictures with a sensitivity of(98% vs 45%) andhas a negative predictive value(97% vs 69%), but decreased the specificity(67% vs 100%) and the positive predictive value(71% vs 100%) when compared to index pathology. Modifications in the classification systems in indeterminate biliary strictures have increased the specificity of p CLE from 67% to 73%. In pancreatic cystic lesions there is a need to develop similar systems to interpret and characterize lesions based on CLE images obtained. The presence of superficial vascular network predicts serous cystadenomas accurately. Also training in acquiring and interpretation of images is feasible in those without any prior knowledge in CLE in a relatively simple manner and computer-aided diagnosis software is a promising innovation. CONCLUSION: The role of p CLE in the evaluation of pancreatobiliary disorders might be better suited for those with an intermediate and low probability.

Simulation of Fluid Flow in a Channel Induced by Three Types of Fin-Like Motion

One of many interesting research activities in biofluidmechanics is dedicated to investigations of locomotion in water. Some of propulsion mechanisms observed in the underwater world are used in the development process of underwater autonomic vehicles （AUV）. In order to characterise several solutions according to their manoeuvrability, influence on the surrounding fluid and energetic efficiency, a detailed analysis of fin-like movement is indispensable. In the current paper an analysis of undulatory, oscillatory and combined fin-like movements by means of numerical simulation is carried out. The conservation equation of mass and the conservation equation of momentum axe solved with the Finite Volume Method （FWM） by use of the software CFX-10.0. The undulatory and oscillatory fin movements axe modelled with an equation that is implemented within an additional subroutine and joined with the main solver. N carried out in the computational domain, in which one fin is fixed in a flow-through water duct. Simulations axe carded out in the range of the Re number up to 105. The results show significant influence of applied fin motion on the velocity distribution in the surrounding fluid.

Insights into Theranostic Properties of Titanium Dioxide for Nanomedicine

Titanium dioxide(TiO2)nanostructures exhibit a broad range of theranostic properties that make them attractive for biomedical applications.TiO2 nanostructures promise to improve current theranostic strategies by leveraging the enhanced quantum confinement,thermal conversion,specific surface area,and surface activity.This review highlights certain important aspects of fabrication strategies,which are employed to generate multifunctional TiO2 nanostructures,while outlining post-fabrication techniques with an emphasis on their suitability for nanomedicine.The biodistribution,toxicity,biocompatibility,cellular adhesion,and endocytosis of these nanostructures,when exposed to biological microenvironments,are examined in regard to their geometry,size,and surface chemistry.The final section focuses on recent biomedical applications of TiO2 nanostructures,specifically evaluating therapeutic delivery,photodynamic and sonodynamic therapy,bioimaging,biosensing,tissue regeneration,as well as chronic wound healing.

Gonadal damage and options for fertility preservation in female and male cancer survivors

It is estimated that in 2010, 1 in every 250 adults will be a childhood cancer survivor. Today, oncological surgery, radiotherapy and chemotherapy achieve relatively high rates of remission and long-term survival, yet are often detrimental to fertility. Quality of life is increasingly important to long-term survivors of cancer, and one of the major quality-of-life issues is the ability to produce and raise normal children. Developments in the near future in the emerging field of fertility preservation in cancer survivors promise to be very exciting. This article reviews the published literature, discusses the effects of cancer treatment on fertility and presents the options available today thanks to advances in assisted-reproduction technology for maintaining fertility in male and female patients undergoing this type of treatment. The various diagnostic methods of assessing the fertility potential and the efficacy of in vitro fertilization （IVF） after cancer treatment are also presented.

Grapefruit-seed extract attenuates ethanol-and stress-induced gastric lesions via activation of prostaglandin, nitric oxide and sensory nerve pathways

AIM: Grapefruit-seed extract (GSE) containing flavonoids, possesses antibacterial and antioxidative properties but whether it influences the gastric defense mechanism and gastroprotection against ethanol- and stress-induced gastric lesions remains unknown. METHODS: We compared the effects of GSE on gastric mucosal lesions induced in rats by topical application of 100% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without (A) inhibition of cyclooxygenase (COX)-1 activity by indomethacin and rofecoxib, the selective COX-2 inhibitor, (B) suppression of NO-synthase with L-NNA (20 mg/kg ip), and (C) inactivation by capsaicin (125 mg/kg sc) of sensory nerves with or without intragastric (ig) pretreatment with GSE applied 30 min prior to ethanol or WRS. One hour after ethanol and 3.5 h after the end of WRS, the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was assessed by H2-gas clearance technique and plasma gastrin levels and the gastric mucosal generation of PGE2, superoxide dismutase (SOD) activity and malonyldialdehyde (MDA) concentration, as an index of lipid peroxidation were determined. RESULTS: Ethanol and WRS caused gastric lesions accompanied by the significant fall in the GBF and SOD activity and the rise in the mucosal MDA content. Pretreatment with GSE (8-64 mg/kg i g) dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) was 25 and 36 mg/kg, respectively, and this protective effect was similar to that obtained with methyl PGE2 analog (5 μg/kg i g). GSE significantly raised the GBF, mucosal generation of PGE2, SOD activity and plasma gastrin levels while attenuating MDA content. Inhibition of PGE2 generation with indomethacin or rofecoxib and suppression of NO synthase by L-NNA or capsaicin denervation reversed the GSE-induced protection and the accompanying hyperemia. Co-treatment of exogenous calcitonine gene-related peptide (CGRP) with GSE restored the protection and accompanying hyperemic effects of GSE in rats with capsaicin denervation. CONCLUSION: GSE exerts a potent gastroprotective activity against ethanol and WRS-induced gastric lesions via an increase in endogenous PG generation, suppression of lipid peroxidation and hyperemia possibly mediated by NO and CGRP released from sensory nerves.

Advanced endoscopic imaging to improve adenoma detection

Advanced endoscopic imaging is revolutionizing our way on how to diagnose and treat colorectal lesions. Within recent years a variety of modern endoscopic imaging techniques was introduced to improve adenoma detection rates. Those include high-definition imaging, dye-less chromoendoscopy techniques and novel, highly flexible endoscopes, some of themequipped with balloons or multiple lenses in order to improve adenoma detection rates. In this review we will focus on the newest developments in the field of colonoscopic imaging to improve adenoma detection rates. Described techniques include high-definition imaging, optical chromoendoscopy techniques, virtual chromoendoscopy techniques, the Third Eye Retroscope and other retroviewing devices, the G-EYE endoscope and the Full Spectrum Endoscopy-system.

Poor agreement between endoscopists and gastrointestinal pathologists for the interpretation of probe-based confocal laser endomicroscopy findings

AIM:To compare the interpretation of probe-based confocal laser endomicroscopy(p CLE)findings between endoscopists and gastrointestinal(GI)-pathologists.METHODS:All p CLE procedures were undertaken and the endoscopist rendered assessment.The same p CLE videos were then viewed offline by an expert GI pathologist.Histopathology was considered the gold standard for definitive diagnosis.The sensitivity,specificity and accuracy for diagnosis of dysplastic/neoplastic GI lesions and interobserver agreement between endoscopists and experienced gastrointestinal pathologist for p CLE findings were analyzed.RESULTS:Of the 66 included patients,40(60.6%)had lesions in the esophagus,7(10.6%)in the stomach,15(22.7%)in the biliary tract,3(4.5%)in the ampulla and 1(1.5%)in the colon.The overall sensitivity,specificity and accuracy for diagnosing dysplastic/neoplastic lesions using p CLE were higher for endoscopists than pathologist at 87.0%vs 69.6%,80.0%vs 40.0%and 84.8%vs 60.6%(P=0.0003),respectively.Area under the ROC curve(AUC)was greater for endoscopists than the pathologist(0.83 vs 0.55,P=0.0001).Overall agreement between endoscopists and pathologist was moderate for all GI lesions(K=0.43;95%CI:0.26-0.61),luminal lesions(K=0.40;95%CI:0.20-0.60)and those of dysplastic/neoplastic pathology(K=0.55;95%CI:0.37-0.72),the agreement was poor for benign(K=0.13;95%CI:-0.097-0.36)and pancreaticobiliary lesions(K=0.19;95%CI:-0.26-0.63).CONCLUSION:There is a wide discrepancy in the interpretation of p CLE findings between endoscopists and pathologist,particularly for benign and malignant pancreaticobiliary lesions.Further studies are needed to identify the cause of this poor agreement.

Context Dependent Auditory Thresholds Determined by Brainstem Audiometry and Prepulse Inhibition in Mongolian Gerbils

Information on hearing thresholds is not always reliable as differences in these thresholds have been described even for the same species. This may partially be due to different methods used by different labs. A frequently used approach to obtain an estimate of hearing threshold is the electrophysiological recording of auditory brainstem responses (ABR). They are usually recorded under deep anesthesia and represent the auditory evoked far-field potentials at various levels in the central auditory pathway. Alternatively, several behavioral approaches are employed. These commonly use operant or classical conditioning to determine hearing thresholds. A potential disadvantage of these methods is that any sound conditioning may in principle alter auditory perception and therefore auditory thresholds. To exclude this type of methodological bias a prepulse inhibition (PPI) paradigm can be used where an audiogram can be determined without any kind of pre-training. Here we compare the threshold estimates obtained by two different ABR and PPI measurements where stimuli are presented in different contexts, either randomly or non-randomly, to test for a possible effect of auditory sensitization. In addition we test the effect of a frequency specific acoustic trauma on the audiograms obtained with both methods. In general we find behaviorally determined audiograms to be significantly lower in absolute thresh- old compared to ABR measurements. Furthermore non-randomized presentation context of the stimuli generally results in audiograms with 10 to 15 dB lower thresholds than pseudo-randomized presentation. Finally, the amount of threshold loss induced by acoustic trauma is similar for all methods tested.

In vivo detection of mucosal healing-involved histiocytes by confocal laser endomicroscopy

Histiocytes have a pivotal role in wound repair and intestinal epithelial recovery-the most important goal to sustain gut functionality.Yet,an in vivo description of colonic histiocytes by confocal laser endomicroscopy(CLE) is missing.Here,we report the case of a 45-yearsold male patient who was referred to our clinic with weight loss and a history of two consecutive Clostridium difficile colitis episodes,the latter cured 3 wk before present admission.Stool microbiology was negative.Conventional colonoscopy showed atrophy and a light mucosal oedema in the distal colon.During on-going endoscopy,we performed a fluorescein-aided CLE which revealed large polygonal(histiocytes-like) cells with copious cytoplasm and large nuclei in the lamina propria of the sigmoid colon as well as regenerative epithelial changes.Histopathological assessment of biopsies from the same areas confirmed the endomicroscopical findings:Periodic acid-Schiff-and CD68-positive foamy histiocytes in the colonic lamina propria and an advanced epithelial recovery.Since stool microbiology was repeatedly negative and polymerase chain reaction-analysis from colonic biopsies could not detect any mRNA for Thropheryma whippleii and common pathogens,we interpreted this particular setting as a mucosal healing process after consecutive Clostridium difficile infections.In conclusion,by describing these colonic histiocytes,we highlight the clinical usefulness of CLE in describing the entity of histiocytes in vivo and in real-time during the process of post-infectious mucosal healing in the colon.

Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases

Guanylate-binding proteins(GBPs) are interferonstimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma(CRC) and inflammatory bowel diseases(IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong antiangiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton.

Beyond white light endoscopy: The role of optical biopsy in inflammatory bowel disease

In this review,we will discuss the use of two optical biopsy modalities in inflammatory bowel disease(IBD).The two techniques reviewed here are confocal laser endomicroscopy and endocytoscopy.We will describe the technical performance of the procedure,discuss the clinical indications for optical biopsy in IBD,and highlight active research areas with respect to the pathogenesis of IBD.Clinical indications for optical biopsies in IBD include assessment of mucosal inflammation,dysplasia detection and evaluation of cell shedding for disease relapse.Research application in the area of barrier dysfunction will also be discussed.

Traceable long range scanning tunneling microscopy

Dimensionally correct and directly traceable measurement is not feasible with conventional scanning tunneling microscopy (STMs) due to severe hysteresis and non-linearity of the commonly applied piezo tube scanners and the very short range. By integrating a custom made probing system based on tunneling current measurement into a commercially available and laser-interferometrically position controlled positioning system, an STM with a principal measuring

Histopathological confirmation of similar intramucosal distribution of fluorescein in both intravenous administration and local mucosal application for probebased confocal laser endomicroscopy of the normal stomach

Probe-based confocal laser endomicroscopy(p CLE) is capable of acquiring in vivo magnified cross-section images of the gastric mucosa. Intravenous injection of fluorescein sodium is used for confocal imaging. However, it is still under debate if local administration of the dye to the mucosa is also effective for confocal imaging as it is not yet clear if topical application also reveals the intramucosal distribution of fluorescein. The objective of this study was to evaluate the intramucosal distribution of fluorescein sodium after topical application and to compare the distribution to the conventional intravenous injection used for confocal imaging. p CLE of the stomach uninfected with Helicobacter pylori was performed in a healthy male employing intravenous administration and local mucosal application of fluorescein. The mucosa of the lower gastric body was biopsied 1 min and 5 min after intravenous administration or local mucosal application of fluorescein, and the distribution of fluorescein in the biopsy samples was examined histologically. Green fluorescence was already observed in the cytoplasm of fundic glandular cells in the biopsied deep mucosa 1 min after local mucosal application of fluorescein. It was also observed in the foveolar lumen and inter-foveolar lamina propria, although it was noted at only a few sites. In the tissue biopsied 5 min after the local mucosal application of fluorescein, green fluorescence was more frequently noted in the cytoplasm of fundic glandular cells than in that 1 min after the local mucosal application of fluorescein, although obvious green fluorescence was not identified in the foveolar lumen or inter-foveolar lamina propria. The distribution of intravenously administered fluorescein in the cytoplasm of fundic glandular cells was also clearly observed similarly to that after local mucosal application of fluorescein. Green fluorescence in more cells was observed in many cells 5 min after intravenous administration compared with that after 1 min. The presence of fluorescein in the mucosa was observed within a short time after local mucosal application of fluorescein, suggesting that pC LE images similarly to those after intravenous fluorescein administration can be acquired by local mucosal application of fluorescein.

An easy approach to assess the susceptibility of a landslide by utilizing simple raster overlay methods: A case study on Huangtupo landslide(P.R. China)

Semi qualitative index based methods using rankings and ratings are commonly used in susceptibility estimations over a wide area. However, generalized ranking and ratings are not applicable for one single landslide. This paper gives an easy and transferable approach to a susceptibility assessment of Huangtupo landslide(P.R. China), using raster addition without taking account for ranking and ratings. Slope, aspect, curvature, location and drainage buffer distance raster data sets have been obtained out of open source digital elevation models using ESRI's Arc GIS. These conditioning factor raster data sets have been translated into raster data sets including simple yes or no criteria, referring to triggering or not. Subsequently they have been added by raster math to acquire a simple raster overlay map.After that this map is compared to initial displacement measurements, obtained by using a ground based synthetic aperture radar device. Acquired data is recalculated to a raster data set using the same spatial extent, to provide the possibility of comparison of the two raster data sets. The results reveal, that 76.35% of all measured movements occur in areas where raster cells include three or more conditioning factors, indicating that easy raster math operations can lead to satisfying results in local scale.