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Background/objectives: Obesity increases colorectal cancer (CRC) risk. However, the effects of weight loss on CRC risk are unclear. Epigenetic mechanisms involving microRNAs that lead to dysregulated gene expression may mediate the effects of obesity and weight loss on CRC risk. We examined the effects of obesity and weight loss following Roux-en-Y gastric bypass (RYGB) on microRNA expression in the human rectal mucosa., Subjects/methods: We collected rectal mucosal biopsies from obese patients (n = 22) listed for RYGB and age- and sex-matched healthy non-obese Controls (n = 20), at baseline and six months post-surgery. We quantified microRNA expression in rectal mucosal biopsies using Next Generation Sequencing and bioinformatics analysis to investigate the likely functional consequences of these epigenetic changes., Results: Compared with non-obese individuals, obese individuals showed differential expression of 112 microRNAs (p < 0.05). At six-months post-RYGB, when mean body mass had fallen by 27 kg, 60 microRNAs were differentially expressed, compared with baseline (p < 0.05). The expression of 36 microRNAs differed significantly between both i) obese and non-obese individuals and ii) obese individuals pre- and post-RYGB. Quantitative polymerase chain reaction (qPCR) demonstrated that expression of miR-31 and miR-215 was significantly (p < 0.05) higher, 143-fold and 15-fold respectively, in obese than in non-obese individuals. Weight loss, following RYGB, reduced expression of miR-31 and miR-215 to levels comparable with Controls. These differentially expressed microRNAs are implicated in pathways linked with inflammation, obesity and cancer., Conclusion: Our findings show, for the first time, that obesity is associated with dysregulated microRNA expression in the human rectal mucosa. Further, surgically-induced weight loss may normalise microRNA expression in this tissue., (© 2021. The Author(s).)

Background: In mucosal barrier interfaces, flexible responses of gene expression to long-term environmental changes allow adaptation and fine-tuning for the balance of host defense and uncontrolled not-resolving inflammation. Epigenetic modifications of the chromatin confer plasticity to the genetic information and give insight into how tissues use the genetic information to adapt to environmental factors. The oral mucosa is particularly exposed to environmental stressors such as a variable microbiota. Likewise, persistent oral inflammation is the most important intrinsic risk factor for the oral inflammatory disease periodontitis and has strong potential to alter DNA-methylation patterns. The aim of the current study was to identify epigenetic changes of the oral masticatory mucosa in response to long-term inflammation that resulted in periodontitis., Methods and Results: Genome-wide CpG methylation of both inflamed and clinically uninflamed solid gingival tissue biopsies of 60 periodontitis cases was analyzed using the Infinium MethylationEPIC BeadChip. We validated and performed cell-type deconvolution for infiltrated immune cells using the EpiDish algorithm. Effect sizes of DMPs in gingival epithelial and fibroblast cells were estimated and adjusted for confounding factors using our recently developed "intercept-method". In the current EWAS, we identified various genes that showed significantly different methylation between periodontitis-inflamed and uninflamed oral mucosa in periodontitis patients. The strongest differences were observed for genes with roles in wound healing (ROBO2, PTP4A3), cell adhesion (LPXN) and innate immune response (CCL26, DNAJC1, BPI). Enrichment analyses implied a role of epigenetic changes for vesicle trafficking gene sets., Conclusions: Our results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense., (© 2021. The Author(s).)

Background: We aimed to elucidate the risk of metastatic recurrence after endoscopic resection (ER) without additional treatment for esophageal squamous cell carcinomas (ESCCs) with tumor invasion into the muscularis mucosa (pT1a-MM) or submucosa (T1b-SM)., Methods: We retrospectively enrolled patients with pT1a-MM/pT1b-SM ESCC after ER at 21 institutions in Japan between 2006 and 2017. We compared metastatic recurrence between patients with and without additional treatment, stratified into category A (pT1a-MM with negative lymphovascular invasion [LVI] and vertical margin [VM]), B (tumor invasion into the submucosa ≤ 200 µm [pT1b-SM1] with negative LVI and VM), and C (others). Subsequently, using multivariate Cox analysis, we evaluated risk factors for metastatic recurrence after ER without additional treatment., Results: We enrolled 593 patients, and metastatic recurrence occurred in 38 patients. Metastatic recurrence after additional treatment was significantly lower than that after no additional treatment in category C (9.1% vs. 23.6% in 5 years, p = 0.001), whereas no significant difference was noted in categories A (0.0% vs. 2.6%) and B (0.0% vs. 4.3%). In patients without additional treatment after ER, risk factors for metastatic recurrence were lymphatic invasion (hazard ratio [HR], 5.61), positive VM (HR, 4.55), and tumor invasion into the submucosa > 200 μm (HR, 3.25), and, but near half of the patients with metastatic recurrence had no further recurrence after salvage treatment, resulting in excellent 5-year disease-specific survival in categories A (99.6%) and B (100.0%)., Conclusions: Closed follow-up with no additional treatment may be an acceptable option after ER in pT1a-MM/pT1b-SM1 ESCC with negative LVI and VM., (© 2021. Japanese Society of Gastroenterology.)

A device that can easily measure electrical impedance might be a helpful tool for investigating the pathophysiology of gastroesophageal reflux disease. The first aim of this study was to validate our newly developed bioelectrical admittance measurement (BAM) through in vitro experimentation. The second aim was to investigate whether evaluation of BAM by this measurement differed between patients with heartburn according to their response to proton pump inhibitor (PPI) therapy. Caco-2 cell monolayers and three-dimensional tissues were examined by BAM using a frequency response analyzer. BAM was also used to measure the impedance through cell layers. Subsequently, BAM was performed during endoscopy in 41 patients experiencing heartburn without esophageal mucosal breaks. After 2-wk administration of 20-mg rabeprazole twice daily, patient responses to PPI were classified as "good" or "poor" according to their clinical course. In each patient, histological alterations and gene expression levels of inflammation mediators and tight junction proteins were evaluated. Impedance profiles indicated that monolayer Caco-2 cells on top of eight-layered normal human dermal fibroblasts had the highest magnitude of impedance over the range of frequencies. In vivo results revealed that patients with good responses to PPI displayed significantly higher admittance. Severity of low-grade inflammation was significantly associated with esophageal wall admittance. Moreover, esophageal wall admittance may be more closely related to basal zone hyperplasia than dilatation of intercellular spaces. Thus, BAM may be able to detect abnormalities in the subepithelial layer of the esophagus. NEW & NOTEWORTHY Bioelectrical admittance measurement is a new method to evaluate esophageal mucosal permeability vertically during upper gastrointestinal endoscopy. Measurement of low-grade inflammation of the esophageal mucosa with electrical conductivity shows promise in assessing proton pump inhibitor responsiveness in patients with gastroesophageal reflux disease. As various gastrointestinal diseases are associated with changes in mucosal permeability, bioelectrical admittance measurement is expected to be clinically applied to therapeutic decision-making for these diseases in the future.

Purpose: Chronic intermittent hypoxia (IH) plays a pivotal role in the consequences of obstructive sleep apnea (OSA). It has been demonstrated that IH impairs nasomaxillary complex growth to reduce nasal airway cavity size in rodent models. Although turbinate dysfunction with inflammatory mucosal hypertrophy is related to OSA, the role of IH in turbinate hypertrophy with inflammation-driven fibrosis is unknown. Here, we aimed to clarify the pathogenesis of inflammatory mucosal hypertrophy and epithelial-mesenchymal transition (EMT) in the nasal turbinate under IH., Methods: Seven-week-old male Sprague-Dawley rats were exposed to IH (4% O 2 to 21% O 2 with 0% CO 2 ) at a rate of 20 cycles/h., Results: Hypertrophy of the turbinate mucosa occurred after 3 weeks, with the turbinate mucosa of the experimental group becoming significantly thicker than in the control group. Immunostaining showed that IH increased the expression of TGFβ and N-cadherin and decreased E-cadherin expression in the turbinate mucosa. Quantitative PCR analysis demonstrated that IH enhanced the expression of not only the inflammatory markers Tnf-a, Il-1b, and Nos2 but also the EMT markers Tgf-b1, Col1a1, and Postn., Conclusions: Collectively, these results suggest that IH induced turbinate hypertrophy via upregulation of gene expression related to inflammation and EMT in the nasal mucosa.

Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms and in biofilm-dispersed form. It is therefore of major importance in understanding homeostatic and altered host-microorganism interactions to consider not only the planktonic lifestyle, but also biofilms and biofilm-dispersed forms. In this Review, we discuss the natural organization of microorganisms at gastrointestinal surfaces, stratification of microbiota taxonomy, biogeographical localization and trans-kingdom interactions occurring within the biofilm habitat. We also discuss existing models used to study biofilms. We assess the contribution of the host-mucosa biofilm relationship to gut homeostasis and to diseases. In addition, we describe how host factors can shape the organization, structure and composition of mucosal biofilms, and how biofilms themselves are implicated in a variety of homeostatic and pathological processes in the gut. Future studies characterizing biofilm nature, physical properties, composition and intrinsic communication could shed new light on gut physiology and lead to potential novel therapeutic options for gastrointestinal diseases.

Lactation insufficiency is variously defined and includes the inability to produce milk, not producing enough milk to exclusively meet infant growth requirements, and pathological interruption of lactation (e.g., mastitis). Of women with intent-to-breastfeed, lactation insufficiency has been estimated to affect 38%-44% of newly postpartum women, likely contributing to the nearly 60% of infants that are not breastfed according to the World Health Organization's guidelines. To date, research and clinical practice aimed at improving feeding outcomes have focused on hospital lactation support and education, with laudable results. However, researchers' reports of recent rodent studies concerning fundamental lactation biology have suggested that the underlying pathologies of lactation insufficiency may be more nuanced than is currently appreciated. In this article, we identify mucosal biology of the breast and lactation-specific liver biology as two under-researched aspects of lactation physiology. Specifically, we argue that further scientific inquiry into reproductive state-dependent regulation of immunity in the human breast will reveal insights into novel immune based requirements for healthy lactation. Additionally, our synthesis of the literature supports the hypothesis that the liver is an essential player in lactation-highlighting the potential that pathologies of the liver may also be associated with lactation insufficiency. More research into these biologic underpinnings of lactation is anticipated to provide new avenues to understand and treat lactation insufficiency.

Treatment of esophageal and extraesophageal reflux syndromes is mainly focused on inhibiting the secretion of hydrochloric acid. In spite of the high efficacy of proton pump inhibitors, approx. 30-60% of GERD patients experience daily symptoms. Beside acid reflux, other factors such as abnormal esophageal peristalsis, visceral hypersensitivity, ineffective esophageal clearance mechanisms, and impaired mucosal barrier also play an important role in generating GERD symptoms. An additional therapeutic proposition is a procedure aimed at improving the defense mechanisms of esophageal mucosa rather than inhibiting the damage-inducing factors. The preparation consisting of hyaluronic acid (HA), chondroitin sulfate (SC) and poloxamer 407 protects against harmful factors (hydrochloric acid, pepsin) and accelerates mucosal healing and regeneration, constituting a substantial element of monotherapy or add-on therapy in patients with gastroesophageal reflux disease.

Background: Transient receptor potential vanilloid 4 (TRPV4) is activated by stretch (mechanical), warm temperature, some epoxyeicosatrienoic acids, and lipopolysaccharide. TRPV4 is expressed throughout the gastrointestinal epithelia and its activation induces adenosine triphosphate (ATP) exocytosis that is involved in visceral hypersensitivity. As an ATP transporter, vesicular nucleotide transporter (VNUT) mediates ATP storage in secretory vesicles and ATP release via exocytosis upon stimulation., Summary: TRPV4 is sensitized under inflammatory conditions by a variety of factors, including proteases and serotonin, whereas methylation-dependent silencing of TRPV4 expression is associated with various pathophysiological conditions. Gastrointestinal epithelia also release ATP in response to hypo-osmolality or acid through molecular mechanisms that remain unclear. These synergistically released ATP could be involved in visceral hypersensitivity. Low concentrations of the first generation bisphosphate, clodronate, were recently reported to inhibit VNUT activity and thus clodronate may be a safe and potent therapeutic option to treat visceral pain. Key Messages: This review focuses on: (1) ATP and TRPV4 activities in gastrointestinal epithelia; (2) factors that could modulate TRPV4 activity in gastrointestinal epithelia; and (3) the inhibition of VNUT as a potential novel therapeutic strategy for functional gastrointestinal disorders., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background: Heat stroke is a life-threatening syndrome that is characterized by its severe clinical symptoms, rapid progression, and high rate of mortality. Recently, research has indicated that a dysfunctional intestinal epithelia barrier plays an important role in the pathophysiology of heat stroke. Protecting the intestines from heat stress had been identified as a potentially effective treatment for patients with heat stroke and may reduce the innate immune response caused by endotoxins in circulation., Objectives: The aim of this review is to discuss this key event in heat stroke and to describe the mechanism during progression., Discussion: Direct injuries and secondary impairments of the intestine induced by heat stress are discussed; recent studies that refer to intestine-specific prevention and treatment in heat stroke and heat stress-induced injuries are also summarized., Conclusions: A more detailed pathogenesis of heat stroke needs to be elucidated so that potentially effective means of treatment and prevention of heat stroke can be developed and studied., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: Mucositis is a common and therapy-limiting adverse effect of cancer treatments including radiotherapy, chemotherapy, and immunotherapy. The optimal zinc formulation, dosage, and timing of administration warrant further research as does the efficacious prevention of febrile mucositis that predisposes to febrile neutropenia., Recent Findings: Metaanalyses concluded that zinc sulfate failed to significantly reduce the incidence or severity of chemotherapy-induced oral mucositis, whereas polaprezinc was associated with a significant reduction. Three new trials were published in 2018. The first trial found that zinc sulfate reduced the incidence and severity of chemotherapy-induced oral mucositis. The second reported that polaprezinc reduced oral mucositis in pediatric patients receiving high-dose chemotherapy for hematopoietic stem cell transplantation. The third trial demonstrated efficacy for a zinc lozenge for postoperative sore throat induced by an endotracheal intubation., Summary: Zinc deficits, dietary or induced by cancer, are common in patients with cancer. Febrile mucositis may better describe the condition linking mucositis with febrile neutropenia. Febrile mucositis disrupts treatment and may be life-threatening. A paradigm shift is needed for a more comprehensive understanding of febrile mucositis. Zinc effects on the thymic immunological network and T lymphocytes during chemoradiotherapy regimens also warrant further investigation.

ntroduction: The publication describes the characteristics of the glottis in FDs objectified by OQ, measured with VSK and EGG., Aim: The aim of the study was to objectify glottal function in different types of FDs. The scope was to use open quotients gained from various mucosal wave imaging techniques for differential diagnosis of FDs., Material and Method: The study included 204 individuals. In the study, each patient underwent otolaryngological and phoniatric examination. LVS, EGG and VSK were conducted, their results were recorded and stored using an EndoSTROB-DX- -Xion GmbH (Berlin) device with DIVAS software., Results: All patients with FDs had abnormalities in LVS. A statistical analysis showed differences in LVS characteristics according to the type of FD. The mean value of OQVSK was 0.521 in the control group and 0.565 in the study group (P &lt; 0.05). Significant differences were found between patients with hypofunctional - 0.584 and hyperfunctional dysphonia - 0.55. The QOQEGG mean value in patients with FDs was 0.581 and in the control group 0.549 (P &lt; 0.01). There were statistically significant differences between groups of patients with hyper- and hypofunctional dysphonias. Medians amounted to 0.574 and 0.604, respectively. Authors observed different relations of OQ with the type of FD. They decided to introduce a new parameter, illustrating the proportion of QOQEGG/OQVSK., Conclusions: Videostrobokymographic and electroglottographic open quotients differentiate euphony from dysphony. The value of OQVSK and QOQEGG and their proportion varies depending on different types of functional dysphonias. The OQVSK and QOQEGG should be included in the diagnostic algorithm of voice.

Ultrafast laser ablation may provide a treatment for vocal fold (VF) scarring. Optical properties of VFs must be known prior to clinical implementation to select appropriate laser surgery conditions. We present scattering lengths of epithelium ℓs  ,  ep, superficial lamina propria ℓs  ,  SLP, and ablation thresholds Fth of human and canine VF tissues. Our experimental approach involves an image-guided, laser-ablation-based method that allows for simultaneous determination of ℓs and Fth in these multilayered tissues. Studying eight canine samples, we found ℓs  ,  ep  =  75.3  ±  5.7  μm, ℓs  ,  SLP  =  26.1  ±  1.2  μm, Fth  ,  ep  =  1.58  ±  0.06  J  /  cm2, and Fth  ,  SLP  =  1.55  ±  0.17  J  /  cm2. Studying five human samples, we found ℓs  ,  ep  =  42.8  ±  3.3  μm and Fth  ,  ep  =  1.66  ±  0.10  J  /  cm2. We studied the effects of cumulative pulse overlap on ablation threshold and found no significant variations beyond 12 overlapping pulses. Interestingly, our studies about the effect of sample storage on the scattering properties of porcine VF show a 60% increase in ℓs  ,  ep for fresh porcine VF when compared to the same sample stored in isotonic solution. These results provide guidelines for clinical implementation by enabling selection of optimal laser surgery parameters for subsurface ablation of VF tissues.

Background: The Eustachian tube is a collapsible upper respiratory airway that is periodically opened to maintain a healthy middle ear. Young children, <10 years old, exhibit reduced Eustachian tube opening efficiency and are at risk for developing middle ear infections. Although these infections increase mucosal adhesion, it is not known how adhesion forces alters the biomechanics of Eustachian tube opening in young children. This study uses computational techniques to investigate how increased mucosal adhesion alters Eustachian tube function in young children., Methods: Multi-scale finite element models were used to simulate the muscle-assisted opening of the Eustachian tube in healthy adults and young children. Airflow during opening was quantified as a function of adhesion strength, muscle forces and tissue mechanics., Findings: Although Eustachian tube function was sensitive to increased mucosal adhesion in both adults and children, young children developed Eustachian tube dysfunction at significantly lower values of mucosal adhesion. Specifically, the critical adhesion value was 2 orders of magnitude lower in young children as compared to healthy adults. Although increased adhesion did not alter the sensitivity of Eustachian tube function to tensor and levator veli palatini muscles forces, increased adhesion in young children did reduced the sensitivity of Eustachian tube function to changes in cartilage and mucosal tissue stiffness., Interpretations: These results indicate that increased mucosal adhesion can significantly alter the biomechanical mechanisms of Eustachian tube function in young children and that clinical assessment of adhesion levels may be important in therapy selection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Mucous membrane pemphigoid (MMP) is a group of chronic autoimmune sub-epithelial blistering disorders, which mostly affect the oral mucosa and the conjunctiva. MMP is very diverse in terms of both the clinical and immunological features (IgG and IgA autoantibodies may react with different antigens). MMP can be induced by infections and medication, including ophthalmologic medication, which may lead to the development of eye lesions. In contrast, a vegetating variant of MMP is extremely rare. Here, we report an MMP case that demonstrated unusual clinical features, that is, pyogenic granulomas on the conjunctivae and extensive vegetating erosions on the skin of intertriginous regions. All these lesions were considered to be induced by unconventional medication containing arsenic., (© 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: Reliable prognosticators for T1 bladder cancer (T1BC) are urgently needed., Objective: To compare the prognostic value of 2 substage systems for T1BC in patients treated by transurethral resection (TUR) and adjuvant bacillus Calmette-Guérin therapy., Design, Setting, and Participants: The slides of 601 primary T1BCs from four institutes were reviewed by 2 uropathologists and substaged according to 2 classifications: metric substage according to T1 microinvasive (T1m-lamina propria invasion <0.5mm) and T1 extensive invasive (pT1e-invasion ≥ 0.5mm), and according to invasion of the muscularis mucosae (MM) (T1a-invasion above or into MM/T1b)., Outcome Measurements and Statistical Analysis: Multivariable analyses for progression-free (PFS) and cancer-specific survival (CSS) were performed including substage, size, multiplicity, carcinoma in situ, sex, age, WHO-grade 1973, and WHO-grade 2004 as variables., Results: Median follow-up was 5.9 years (interquartile range: 3.3-9.0). Progression to T2BC was observed in 148 (25%) patients and 94 (16%) died of BC. The MM was not present at the invasion front in 135 (22%) of tumors. Slides were substaged as follows: 213 T1m and 388 T1e and 281 T1a and 320 T1b. On multivariable analysis, T1m/e substage and WHO 1973 grade were the strongest prognosticators for PFS (hazard ratio [HR] = 3.8 and HR = 1.8) and CSS (HR = 2.7 and HR = 2.6), respectively. Other prognostic factors for CSS were age (HR = 1.03), and tumor size (HR = 1.8). Substage according to MM-invasion was not significant. Our study was limited by its retrospective design and that standard re-TUR was not performed if TUR was macroscopically complete and muscularis propria was present in resected specimens., Conclusions: Metric substaging of T1BC was possible in all cases of 601 T1BC patients and it was a strong independent prognosticator of both PFS and CSS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose of Review: In this review, we discuss current diagnostic testing modalities for both gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) and then introduce mucosal impedance (MI), a novel technology that measures epithelial integrity in real time during endoscopy. We describe the advantages and disadvantages of MI as compared with traditional diagnostic testing., Recent Findings: We review studies that demonstrate that GERD and EoE have distinct MI patterns, and that physicians can accurately diagnose and distinguish the two during endoscopy with minimal time added to the procedure. We also review studies showing that MI has the capability to assess treatment response in both GERD and EoE and that it can be used to diagnose GERD in patients with extraesophageal reflux symptoms. Mucosal impedance testing is a major advancement in the diagnosis of GERD and EoE. Future studies are planned to assess whether MI can be used as a treatment endpoint in EoE and whether it can be used to predict response to anti-reflux surgery.

Aims: Mounting evidence indicates that a variety of factors released from the urothelium or suburothelium can modulate smooth muscle activity. Although the relationship between the mucosa and smooth muscle has been investigated, little is known about the pathophysiologic changes in detrusor-mucosa interactions in neurogenic bladders. The goal of the study was to determine the impact of the mucosa on evoked responses in spinal cord injured (SCI) bladders., Methods: Urinary bladders were obtained from 6wk SCI rats or age-matched uninjured controls. Ex vivo isometric tension studies were performed and muscarinic receptor expression was measured in bladder tissue with and without mucosa., Results: The magnitude and area of nerve evoked responses in SCI tissue with mucosa was higher than without mucosa. The duration and decay time of nerve-evoked responses were longer in SCI than control tissue irrespective of the mucosa. The level of the muscarinic M 2 receptor was decreased in the mucosa of SCI bladders., Conclusions: Detrusor-mucosa interactions are substantially altered in the neurogenic bladder. After spinal cord injury, an excitatory modulation of smooth muscle contraction by the mucosa emerges, and could be targeted via intravesical treatment in the context of neurogenic bladder dysfunction., (© 2018 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.)

In this study, we describe a novel insight about the use of bone marrow-derived mesenchymal stem cells (BM-MSCs) for fallopian tube (FT) regeneration. Seventy rats' tubes were involved in this study and divided into 4 groups: control (15), ethanol injured (20), mesenchymal stem cell (MSC)-recipient without injury (15), and MSC recipient after injury (20). The BM-MSCs were isolated from male rats, and their incorporation into the tissues was confirmed by the detection of Sry gene in MSC-recipient rats using RT-PCR. Histological and immunohistological sections of the 4 groups were comparably evaluated. We found that direct injection of ethanol into FT caused structural impairment, which was restored largely after receiving MSCs. We have revealed for the first time that prominin 1 (Prom1, stem cell marker) was expressed in the fimbriated distal tubal end. The MSC transplantation caused (1) significant increase in the tissue level and immunoexpresstion of Prom1 ( P < .001 and P = .017, respectively) and vascular endothelial growth factor (VEGF; vasculogenic marker; P < .001 and P = .004, respectively), (2) significant increase in the immunoexpresstion of proliferating cell nuclear antigen (PCNA; proliferation marker; P < .001), and (3) significant decrease in the immunoexpresstion of caspase 3 (CASP-3; apoptotic marker; P < .001) compared to the injured tissues. In conclusion, MSCs could exhibit its restorative effect on FT through their ability to (1) activate the resident stem cells in the distal tubal end, (2) mediate the expression of VEGF and PCNA, and (3) influence tissue apoptosis. This study laid the foundation for assessing the contribution of stem cells in the distal tubal end in direct repair of the tube when required to assist reproduction.

Background: Bloodstream infections (BSIs) are a leading cause of morbidity and mortality in children undergoing hematopoietic stem cell transplant (HSCT). Indwelling central venous catheters (CVCs) increase risk for BSIs, yet mucosal barrier injury-associated laboratory-confirmed bloodstream infection (MBI-LCBI) may also occur due to translocation of pathogenic organisms from the gastrointestinal tract into the bloodstream. The purpose of this study was to determine the association between stool organisms and BSIs in children with CVCs who underwent HSCT., Methods: We performed a retrospective analysis of 78 children who received allogeneic HSCT over 3 years (2012-2014). Surveillance stool cultures were analyzed pre- and post-HSCT to assess correlations between organisms isolated from stool and CVC cultures., Results: Twenty-four of 78 children experienced 31 BSIs. Fifteen (48%) of these isolates were identified in stool within 30 days of the positive blood culture, and 11 (36%) isolates met criteria for MBI-LCBI., Conclusions: Mucosal barrier injury leads to translocation of pathogenic organisms into the bloodstream and accounts for a significant number of BSIs in children undergoing HSCT. Nursing assessment of mucosal changes during HSCT and interventions to preserve intact mucosa are essential to prevent MBI-LCBI.

Objective: Introduction: Chronic inflammatory diseases of the mucous membranes of the nose, paranasal sinuses, and pharynx are the most common pathology of the upper airways. Pathological processes develop more often in the maxillary and ethmoidal sinuses than in the frontal ones; however, the clinical course of frontitis is more severe. Fundamental understanding of the specific structure of frontal sinuses is crucial in the awareness of the precursors of the onset and development of its pathology, the choice of methods of diagnostics and treatment. The aim: The paper was aimed at the analysis of the publications on current data related to the structure and functions of the human frontal sinus and its structural components. Materials and methods: The bibliosemantic method has been used during the study. Findings of the current research works on the study of the human frontal sinus have been analyzed., Results: Review: The resulting analysis shows that despite the significant amount of research works devoted to the study of the structure and functions of the frontal sinus, the morphofunctional features of its mucosa and the state of local immune protection remained unknown for a long time., Conclusion: Conclusions: The resulting literature review showed that the study of the morphofunctional properties of the frontal sinus is relevant to date that is reflected in the number of research works, elucidating its topographoanatomical, histological, physiological and immunohistochemical features.

Sexual transmission of HIV requires exposure to the virus and infection of activated mucosal immune cells, specifically CD4 + T cells or dendritic cells. The foreskin is a major site of viral entry in heterosexual transmission of HIV. Although the probability of acquiring HIV from a sexual encounter is low, the risk varies even after adjusting for known HIV risk factors. The genital microbiome may account for some of the variability in risk by interacting with the host immune system to trigger inflammatory responses that mediate the infection of mucosal immune cells. We conducted a case-control study of uncircumcised participants nested within a randomized-controlled trial of male circumcision in Rakai, Uganda. Using penile (coronal sulcus) swabs collected by study personnel at trial enrollment, we characterized the penile microbiome by sequencing and real-time PCR and cytokine levels by electrochemiluminescence assays. The absolute abundances of penile anaerobes at enrollment were associated with later risk of HIV seroconversion, with a 10-fold increase in Prevotella , Dialister , Finegoldia , and Peptoniphilus increasing the odds of HIV acquisition by 54 to 63%, after controlling for other known HIV risk factors. Increased abundances of anaerobic bacteria were also correlated with increased cytokines, including interleukin-8, which can trigger an inflammatory response that recruits susceptible immune cells, suggesting a mechanism underlying the increased risk. These same anaerobic genera can be shared between heterosexual partners and are associated with increased HIV acquisition in women, pointing to anaerobic dysbiosis in the genital microbiome and an accompanying inflammatory response as a novel, independent, and transmissible risk factor for HIV infection. IMPORTANCE We found that uncircumcised men who became infected by HIV during a 2-year clinical trial had higher levels of penile anaerobes than uncircumcised men who remained HIV negative. We also found that having higher levels of penile anaerobes was also associated with higher production of immune factors that recruit HIV target cells to the foreskin, suggesting that anaerobes may modify HIV risk by triggering inflammation. These anaerobes are known to be shared by heterosexual partners and are associated with HIV risk in women. Therefore, penile anaerobes may be a sexually transmissible risk factor for HIV, and modifying the penile microbiome could potentially reduce HIV acquisition in both men and women., (Copyright © 2017 Liu et al.)

Background: Proton pump inhibitors and laparoscopic anti-reflux surgery (LARS) offer long-term symptom control to patients with gastro-oesophageal reflux disease (GERD)., Aim: To evaluate the process of 'normalisation' of the squamous epithelium morphology of the distal oesophagus on these therapies., Methods: In the LOTUS trial, 554 patients with chronic GERD were randomised to receive either esomeprazole (20-40 mg daily) or LARS. After 5 years, 372 patients remained in the study (esomeprazole, 192; LARS, 180). Biopsies were taken at the Z-line and 2 cm above, at baseline, 1, 3 and 5 years. A severity score was calculated based on: papillae elongation, basal cell hyperplasia, intercellular space dilatations and eosinophilic infiltration. The epithelial proliferative activity was assessed by Ki-67 immunohistochemistry., Results: A gradual improvement in all variables over 5 years was noted in both groups, at both the Z-line and 2 cm above. The severity score decreased from baseline at each subsequent time point in both groups (P < 0.001, all comparisons), attaining a normal level by 5 years. Corresponding decreases in Ki-67 expression were observed (P < 0.001, all comparisons). No significant differences were found between esomeprazole treatment and LARS. Neither baseline severity score nor Ki-67 expression predicted the risk of treatment failure., Conclusions: Five years of treatment is generally required before squamous epithelial cell morphology and proliferation are 'normalised' in patients with chronic GERD, despite endoscopic and symptomatic disease control. Control of the acid component of the refluxate seems to play the predominant role in restoring tissue morphology., (© 2017 John Wiley & Sons Ltd.)

Structural characteristics of the vaginal mucosa in stress incontinence and its correction by IncontiLase technology were studied. Studies of vaginal biopsy specimens before the exposure showed degenerative and atrophic changes in the stratified squamous epithelium, disorganization of fibrillar structures of the intercellular matrix, and microcirculatory disorders. Studies after Er:YAG laser exposure showed signs of neocollagenogenesis and elastogenesis, foci of neoangiogenesis, reduction of epithelial degeneration and atrophy, and an increase of the fibroblast population. Morphometry showed that the volume density of blood capillaries and the thickness of the epithelial layer increased by 61.1 and 64.5%, respectively. The use of IncontiLase technology in stress incontinence led to structural reorganization of the vaginal mucosa, improving its morphology and function and alleviating the symptoms of incontinence.

Background and Aims: Regulatory Foxp3 + CD4 + T cells [Tregs] have been implicated in the control of colitis in T-cell transfer models, yet their ability to regulate colitis induced by innate immunity and the impact of gut inflammation on their fate and function have been poorly documented., Methods: Colitis was induced by dextran sodium sulphate in DEREG transgenic mice. Tregs ablation and transfer experiments showd that Tregs could limit the severity of colitis in B6 mice., Results: Gut inflammation resulted in increased number of Tregs in mesenteric lymph nodes [MLN] and colon lamina propria [LP], although their frequency decreased due to massive concomitant leukocyte infiltration. This coincided at both sites with a dramatic increase in Ki67 + Tregs which retained proliferative capacity. Gut inflammation resulted in enhanced suppressive function of Tregs in colon lamina propria and neuropillin-1 - [NRP1 - ] Treg in MLN. Real-time polymerase chain reaction analysis and flow cytometry [using IL10-egfp-reporter mice] showed that compared with NRP1 + Treg, NRP1 - Treg express higher levels of IL-10 transcripts and were enriched in IL10-expressing cells both in the steady state and during colitis. Moreover, Treg conversion in vivo from from naïve CD4 + T cells or Treg precursors was impaired in colitic mice. Finally, gut inflammation caused a decrease in intestinal dendritic cells, affecting both CD103 + CD11b + and CD103 + CD11b - subsets and affected their Treg conversion capacity., Conclusions: Together, our data indicate that non-specific colon inflammation triggers proliferation and suppressive function of Tregs in the lamina propria and MLN, but impairs their de novo conversion from CD4 + T cells by intestinal dendritic cells., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The internal face of the detrusor smooth muscle wall of the urinary bladder is covered by a mucosa, separating muscle from the hostile environment of urine. However, the mucosa is more than a very low permeability structure and offers a sensory function that monitors the extent of bladder filling and composition of the urine. The mucosa may be considered as a single functional structure and comprises a tight epithelial layer under which is a basement membrane and lamina propria. The latter region itself is a complex of afferent nerves, blood vessels, interstitial cells and in some species including human beings a muscularis mucosae. Stress on the bladder wall through physical or chemical stressors elicits release of chemicals, such as ATP, acetylcholine, prostaglandins and nitric oxide that modulate the activity of either afferent nerves or the muscular components of the bladder wall. The release and responses are graded so that the mucosa forms a dynamic sensory structure, and there is evidence that the gain of this system is increased in pathologies such as overactive bladder and bladder pain syndrome. This system therefore potentially provides a number of drug targets against these conditions, once a number of fundamental questions are answered. These include how is mediator release regulated; what are the intermediate roles of interstitial cells that surround afferent nerves and blood vessels; and what is the mode of communication between urothelium and muscle - by diffusion of mediators or by cell-to-cell communication?, (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

A customized mechanical tester that slices thin, soft samples was used to measure the fracture toughness of vocal fold tissue. Porcine vocal fold lamina propria was subjected to quasi-static, guillotine-like tests at three equally distanced regions along the anterior-posterior direction. The central one-third where high-velocity collisions between vocal folds occur was found to have the maximum fracture toughness. In contrast, the anterior one-third featured a lower toughness. Fracture toughness can be indicative of the risk of benign and malignant lesions in vocal fold tissue., (Copyright © 2016 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Mucous membrane pemphigoid (MMP) is a subtype of autoimmune subepidermal blistering diseases characterized by autoantibodies to structural components of the hemidesmosome primarily affecting mucous membranes. Inflammation-related progressive scarring can lead to serious complications, including blindness, and the disease may be associated with malignancy. Conventional immunosuppressive treatment is often insufficiently effective and limited due to side effects, warranting new therapeutic options ideally targeting both inflammation and extensively recalcitrant cicatrization. Heat shock protein 90 (Hsp90) is a cell stress-inducible chaperone required for the function of a large number of client proteins, and its pharmacological inhibition has proven to be effective and relatively safe in patients with cancer. Recent observations also suggest a promising role of Hsp90 as drug target in preclinical in vivo murine models of autoimmune diseases such as subepidermal bullous and fibrotic autoimmune disorders comprising epidermolysis bullosa acquisita and systemic sclerosis, respectively, which exhibit some pathophysiological features reminiscent of MMP. This article thus hypothesizes that Hsp90 blockade could represent a double-edged sword in MMP treatment by targeting pathogenic factors of inflammatory blister and fibrosis formation. Moreover, Hsp90 inhibitors could even be proclaimed as a triple-edged sword in case of an underlying malignancy. Future studies investigating the role of Hsp90 in MMP are needed to clarify whether Hsp90 inhibition could become a novel treatment approach for patients with this potentially devastating disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: The human esophageal mucosa expresses various components of the renin-angiotensin system (RAS), e.g. the main effector peptide angiotensin II (AngII). The aim of this study was to investigate the esophageal presence of angiotensin III (AngIII) and angiotensin IV (AngIV) forming enzymes and the AngIV receptor (AT4R). The aim was also to study the actions of AngIV and to look for aberrations in patients with gastroesophageal reflux disease (GERD)., Materials and Methods: Esophageal biopsies were collected from healthy volunteers (n: 19) and individuals with erosive reflux disease (n: 14). Gene transcripts and protein expression of aminopeptidase A, -B and -M, and the AT4R were investigated by reverse transcriptase polymerase chain reaction (rt-PCR), western blot (WB) and immunohistochemistry (IHC). The functional impact of AngIV was examined in an Ussing chamber., Results: Aminopeptidase A, -B and -M and the AT4R were expressed in the esophageal epithelium. The AT4R was less prominent in certain areas in the mucosa of reflux patients. AngIV influenced the esophageal epithelial ion transport. The impact was lower in patients with GERD., Conclusion: The AT4R and formation enzymes of AngIII and AngIV are present in the human esophageal epithelium. Moreover, the present results suggest that AngIV exert regulatory impact on the epithelium and that RAS is involved in mucosal aberrations associated with GERD., (© The Author(s) 2014.)

Objective: To compare two methods of neovagina construction, the Frank and McIndoe techniques, in terms of structural and biological aspects., Study Design: A total of 55 subjects were included in this retrospective study: 43 underwent the Frank technique (FT) and 12 underwent the McIndoe technique (MT). A clinical evaluation and a comparison of the structural (color, shine, presence of hair, and histology) and biological (bacteriological, pH, and hormonal determinations) features were performed. Statistical analysis was performed using the Fisher and Mann-Whitney tests., Results: The time to achieve a functional neovagina using the FT was longer than when using the MT (9.8±5.3 versus 5.8±2.9 months) (p=0.01). The neovaginal wall of the MT skin grafts was more rigid and drier, and it did not exhibit a shine in the way that the FT skin grafts did. The lining of the cavity formed by the FT in all subjects was similar to that of vaginal mucosa, whereas the lining formed by the MT persisted as a skin graft in 83.3% of the cases. The pH was lower for the FT (p<0.01), and Döderlein bacilli were present in 90% of the FT neovaginas but absent from the MT neovaginas. In the latter, flora with anaerobic bacteria was present. Hormonal cytology showed estrogen activity in 100% of the FT neovaginas, but there was no such activity in the MT neovaginas., Conclusions: Our data suggest that the FT may be clinically, structurally, and biologically superior to the MT for the creation of neovaginas and is also less costly., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Exposure to cement dust has been associated with deleterious health effects in humans. This study investigated whether residing near a cement factory increases the risk of irritations to the mucous membranes of the eyes and respiratory system. A cross sectional study was conducted in Freedom Compound, a community bordering a cement factory in Chilanga, Zambia and a control community, Bauleni, located 18 km from the cement plant. A modified American Thoracic Society questionnaire was administered to 225 and 198 respondents aged 15-59 years from Freedom and Bauleni, respectively, to capture symptoms of the irritations. Respondents from Freedom Compound, were more likely to experience the irritations; adjusted ORs 2.50 (95% CI: 1.65, 3.79), 4.36 (95% CI (2.96, 6.55)) and 1.94 (95% CI (1.19, 3.18)) for eye, nose and sinus membrane irritations respectively. Cohort panel studies to determine associations of cement emissions to mucous membrane irritations and respiratory symptoms, coupled with field characterization of the exposure are needed to assess whether the excess prevalence of symptoms of mucous membrane irritations observed in Freedom compound are due to emissions from the cement factory.

Eosinophilic esophagitis (EoE) is a chronic allergen-mediated inflammatory disease of the esophagus. This inflammation leads to feeding difficulties, failure to thrive and vomiting in young children, and causes food impaction and esophageal stricture in adolescents and adults. In the 20 years since EoE was first described, we have gained a great deal of knowledge regarding the genetic predisposition of disease, the inflammatory milieu associated with EoE and the long-term complications of chronic inflammation. Herein, we summarize the important breakthroughs in the field including both in vitro and in vivo analysis. We discuss insights that we have gained from large-scale unbiased genetic analysis, a multitude of genetically and chemically altered mouse models of EoE and most importantly, the results of clinical trials of various pharmacologic agents. Understanding these successes and failures may be the key to developing more effective therapeutic strategies.

Intestinal mucosal barrier function is the capacity of the intestine to provide adequate containment of luminal microorganisms and molecules while preserving the ability to absorb nutrients. The central element is the epithelial layer, which physically separates the lumen and the internal milieu and is in charge of vectorial transport of ions, nutrients, and other substances. The secretion of mucus-forming mucins, sIgA, and antimicrobial peptides reinforces the mucosal barrier on the extraepithelial side, while a variety of immune cells contributes to mucosal defense in the inner side. Thus, the mucosal barrier is of physical, biochemical, and immune nature. In addition, the microbiota may be viewed as part of this system because of the mutual influence occurring between the host and the luminal microorganisms. Alteration of the mucosal barrier function with accompanying increased permeability and/or bacterial translocation has been linked with a variety of conditions, including inflammatory bowel disease. Genetic and environmental factors may converge to evoke a defective function of the barrier, which in turn may lead to overt inflammation of the intestine as a result of an exacerbated immune reaction toward the microbiota. According to this hypothesis, inflammatory bowel disease may be both precipitated and treated by either stimulation or downregulation of the different elements of the mucosal barrier, with the outcome depending on timing, the cell type affected, and other factors. In this review, we cover briefly the elements of the barrier and their involvement in functional defects and the resulting phenotype.

Background & Aims: Histologic analysis is used to distinguish patients with proton pump inhibitor-responsive eosinophilia (PPI-REE) from those with eosinophilic esophagitis (EoE). It is not clear whether these entities have different etiologies. Exposure to acid reflux can impair the integrity of the esophageal mucosal. We proposed that patients with EoE and PPI-REE might have reflux-induced esophageal mucosal damage that promotes transepithelial flux of allergens. We therefore assessed the integrity of the esophageal mucosal in these patients at baseline and after PPI., Methods: We performed a prospective study of 16 patients with suspected EoE and 11 controls. Patients had dysphagia, endoscopic signs of EoE, and esophageal eosinophilia (>15 eosinophils/high-power field [eos/hpf]). All subjects underwent endoscopy at baseline; endoscopy was performed again on patients after 8 weeks of treatment with high-dose esomeprazole. After PPI treatment, patients were diagnosed with EoE (>10 eos/hpf; n = 8) or PPI-REE (≤10 eos/hpf; n = 8). We evaluated the structure (intercellular spaces) and function (electrical tissue impedance, transepithelial electrical resistance, transepithelial molecule flux) of the esophageal mucosal barrier., Results: Compared with controls, electrical tissue impedance and transepithelial electrical resistance were reduced in patients with EoE (P < .001 and P < .001, respectively) and PPI-REE (P = .01 and P = .06, respectively), enabling transepithelial small-molecule flux. PPI therapy partially restored these changes in integrity and inflammation in patients with PPI-REE, but not in those with EoE., Conclusions: The integrity of the esophageal mucosa is impaired in patients with EoE and PPI-REE, allowing transepithelial transport of small molecules. PPI therapy partially restores mucosal integrity in patients with PPI-REE, but not in those with EoE. Acid reflux might contribute to transepithelial allergen flux in patients with PPI-REE. Trialregister.nl number: NTR3480., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials., Methods: A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized., Results: The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohn's Disease (SES-CD) are indices with the most extensively described operating properties., Conclusions: Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required.

There is abundant evidence that the lower urinary tract (LUT) mucosal layer is involved both in mechanosensory functions that regulate bladder contractile activity and in urethral sensation. Changes to the mucosa can be associated with a number of bladder pathologies. For example, alterations of the urothelium and underlying lamina propria at both the molecular and structural levels have been reported in both patients and animals associated with disorders such as bladder pain syndrome and diabetic cystopathy. In contrast to the urinary bladder, much less is known about the urothelium/lamina propria of the bladder neck/proximal urethra. There are important gender differences in the outflow region both anatomically and with respect to innervation, hormonal sensitivity, and location of the external urethral sphincter. There is reasonable evidence to support the view that the mucosal signaling pathway in the proximal urethra is important for normal voiding, but it has also been speculated that the proximal urethra can initiate bladder overactivity. When dysfunctional, the proximal urethra may be an interesting target, for example, botulinum toxin injections aiming at eliminating both urgency and incontinence due to detrusor overactivity., (© 2014 Wiley Periodicals, Inc.)

Conclusion: Vestibular evoked myogenic potential (VEMP) function results can vary between individuals with different middle ear conditions. Therefore, by analyzing VEMP results after paper patching, we can predict the condition of the middle ear in chronic otitis media (COM) patients., Objectives: VEMP responses decrease with impairment of sound transmission, such as in conductive hearing loss (CHL). COM with tympanic membrane (TM) perforation is a common disorder that causes various degrees of CHL. The aim of this study was to evaluate and clarify the VEMP responses in patients with COM with different middle ear pathology., Methods: This study included 50 patients with unilateral COM with TM perforation. Initial pure-tone audiometry (PTA) and VEMP responses were recorded. After paper patching, PTA and VEMP were re-performed. Each VEMP response was compared with those of the healthy controls. Moreover, VEMP responses between pre- and post-paper patching were compared., Results: There was a positive correlation between normalizing of VEMP parameters, such as p13 and VEMP asymmetry ratio (VAR), and reduction of air-bone gap in patients with COM after paper patching. The VEMP response in patients with COM with intact ossicle and clean mucosa was more normalized compared with those in patients with COM with different middle ear conditions.

Many common inflammatory disorders are characterized by the infiltration of neutrophils across epithelial lined (mucosal) surfaces resulting in disruption of critical barrier function that protects from microbes and noxious agents. In such conditions, disease symptoms are complex but directly related to leukocyte effects on the barrier and epithelial cell function. It is now highly regarded that cellular factors such as cytokines and receptor-ligand interactions mediating adhesion of leukocytes to epithelial cells have potent effects on epithelial homeostasis, defined by coordinated proliferation, migration, differentiation, and regulated cell shedding. Certain cytokines, for example, not only alter leukocyte interactions with epithelia through changes in expression of adhesion molecules but also affect barrier function through alterations in the composition and dynamics of intercellular junctions. In particular, inflammation-induced loss of many tight junction molecules, in part, can account for dysregulated cellular proliferation, migration, survival, and barrier function. This review will highlight how neutrophils interact with epithelial cells with particular focus on adhesion molecules involved and signaling events that play roles in regulating mucosal homeostasis and pathobiology. A better understanding of these molecular events may provide new ideas for therapeutics directed at attenuating consequences of pathologic inflammation of mucosal surfaces.

BACKGROUND AND AIMS. Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function. However, the influence of acid and/or bile acids on human esophageal epithelial barrier function and the tight junction (TJ) proteins has not been fully elucidated. The aim of the study is to investigate the esophageal barrier function and TJ expression in healthy subjects and patients with GERD. The functionality of esophageal mucosa exposed to bile salt deoxycholic acid (DCA) and trypsin has been studied in vitro. MATERIAL AND METHODS. Endoscopic biopsies from healthy controls and patients with GERD-related symptom with endoscopic erosive signs, as well as esophageal mucosa taken from patients undergoing esophagectomy were evaluated in Ussing chambers and by western blot and immunohistochemistry. RESULTS. The esophageal epithelium from GERD patients had lower electrical resistance and higher epithelial currents than controls. Claudin-1 and -4 were significantly decreased in GERD patients. The bile salt DCA in the low concentration of 1.5 mM and trypsin increased the resistance and claudin-1 expression, while the higher concentration of 2.5 mM DCA and trypsin decreased the resistance and the claudin-3, -4 and E-cadherin expressions. CONCLUSION. In addition to acidic reflux, duodenal reflux components, such as bile salts and trypsin, have the potential to disrupt the esophageal barrier function, partly by modulating the TJ proteins. However, the expression of TJ is dependent on both the refluxed material as well as the concentration of the bile salt.

Background: Gastro-esophageal reflux disease (GERD) is very prevalent and has a high burden on health security system costs. Nevertheless, pathophysiology is complex and not well-understood. Several mechanisms have been proposed: decreased salivation, impaired esophageal clearance, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations (TLESRs), increased acid, and pepsin secretion, pyloric incompetence provoking duodeno-gastro-esophageal reflux of bile acids and trypsin. Independent of the relevance of each mechanism, the ultimate phenomenon is that mucosal epithelium is exposed for a longer time to agents as acid and pepsin or is in contact to luminal agents not commonly present in gastric refluxate as trypsin or bile acids. This leads to a visible damage of the epithelium (erosive esophagitis -EE) or impairing mucosal integrity without any sign of macroscopic alteration as occurs in non-erosive reflux disease (NERD). Luminal factors are not the only responsible for such impairment; more recent data indicate that endogenous factors may also play a role., Purpose: This review will update the most recent findings on the putative pathophysiological mechanisms and specially will focus on the role of esophageal mucosal integrity in GERD. Methodologies used for the evaluation of mucosal integrity, its relevance in EE and NERD, its involvement in symptoms perception and the effect of luminal and endogenous factors will be discussed., (© 2013 John Wiley & Sons Ltd.)

Objective: Patients with non-erosive reflux disease (NERD) have impaired oesophageal mucosal integrity (dilated intercellular spaces). Oesophageal mucosal integrity reflects the balance between repeated reflux damage and mucosal recovery. The relationship between mucosal integrity and acid sensitivity is unclear. Oesophageal impedance may be used for in vivo mucosal integrity measurement. We studied acid-induced changes in oesophageal mucosal integrity and acid perception in patients with heartburn., Design: 50 patients with heartburn whithout oesophagitis underwent impedance monitoring before, during and after 10 min oesophageal perfusion with neutral (pH 6.5) and acid solutions (pH 1). Symptoms and impedance were recorded during perfusion. Impedance recovery was assessed for 2 h post-perfusion in ambulatory conditions followed by 24-h impedance-pH study., Results: Reflux monitoring discriminated 20 NERD and 30 functional heartburn (FH) patients. Neutral perfusion caused impedance fall that recovered within 10 min. Acid perfusion caused impedance fall with slow recovery: 6.5 Ω/min (IQR 3.3-12.0 Ω/min). Patients with slow recovery (< 25th percentile) had lower baseline impedance (1273 Ω ± 208 Ω vs. 3220 Ω ± 275 Ω ±, p < 0.01) and more frequent acid sensitivity (10/12 vs. 4/12, p = 0.04) than those with fast (> 75th percentile) recovery. Patients with NERD had lower baseline impedance (1669 ± 182 Ω vs. 2384 ± 211 Ω, p = 0.02) and slower impedance recovery (6.0 ± 0.9 Ω/min vs. 10.7 ± 1.6 Ω/min, p = 0.03) than patients with FH., Conclusion: Impaired mucosal integrity might be the consequence of repeated reflux episodes with slow recovery. Mucosal integrity, recovery capacity and symptom perception are linked. Low basal impedance and slow recovery after acid challenge are associated with increased acid sensitivity.

Provoked vestibulodynia represents the most frequent cause of dyspareunia before menopause. Vulvodynia's pain and burning sensations are related to neuropathic pain and associated to various degrees of vulvar mucosal hypersensitivity (mostly in the vestibular area), pelvic floor muscles dysfunction, a disorder of general perception of pain and/or various complex regional pain syndromes such as fibromyalgia, glossodynia, painful bladder syndrome (interstitial cystitis)… Vaginal infections such as candidiasis and vaginosis are important trigger and risk factors. Women suffering from vulvodynia are often described as vulnerable, pessimistic, developing feelings of guilt towards their partner. They tend to be hyper vigilant to their pain and develop catastrophizing reactions (rumination, magnification and helplessness) and avoidance/escape behaviors (fear-avoidance model). Diagnosis is based on medical history, clinical examination (Q-tip test) and exclusion of vaginitis. Treatment consists of a multidisciplinary approach involving topical therapies (emollients, anesthetics, hormonotherapy if necessary), pelvic floor physiotherapy with electromyographic biofeedback, drug treatment of pain with antidepressants (amitriptyline…) or anticonvulsants (pregabaline…) and a psychosexual support., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Patients with gastroesophageal reflux disease (GERD) have impaired esophageal mucosal integrity. Measurement of the mucosal integrity is complex and time-consuming. Electrical tissue impedance spectroscopy (ETIS) is a device that measures impedance of tissue in vivo during endoscopy. In this study, we aimed to validate ETIS as a measure of esophageal mucosal integrity., Methods: Electrical tissue impedance spectroscopy measurements were performed during upper endoscopy in 12 GERD patients and 11 healthy controls after cessation of proton pump inhibition. During endoscopy biopsies of the distal esophagus were obtained for transmission electron microscopy to determine dilation of intercellular spaces (DIS) and for Ussing chamber experiments to determine transepithelial permeability and transepithelial electrical resistance., Key Results: Extracellular impedance measured in vivo by ETIS was significantly lower in GERD patients compared to controls [mean (SD) 5621 (3299) Ω.m and 8834 (2542) Ω.m, respectively, P < 0.05]. We found a strong inverse relation between extracellular impedance determined by ETIS and DIS (r = -0.76, P < 0.05), and between extracellular resistance in vivo and transepithelial permeability of esophageal biopsies (r = -0.65, P < 0.01)., Conclusions & Inferences: Electrical tissue impedance spectroscopy is a new tool that can be used to evaluate esophageal mucosal integrity changes during endoscopy., (© 2013 John Wiley & Sons Ltd.)

Impairment of Eustachian tube function has been observed after hyperbaric oxygen treatment as well as after diving on oxygen used as breathing gas. The aim of the present study was to evaluate the influence of hyperbaric oxygen exposure on Eustachian tube ventilatory function and airflow characteristics of the nose. Six police task force divers performing two consecutive dives within a regular training schedule on oxygen were examined. Middle ear impedance, and nasal airflow velocities before and after diving as well as on the morning after the dive day were measured. Middle ear impedance decreased overnight in comparison to pre-dive values (P = 0.027) as well as compared to the value after the first dive (P = 0.032). Rhinoflowmetry did not reveal any changes of nasal airflow velocities related to the dives. Furthermore, no association between middle ear impedance and nasal airflow velocities was found. An impairment of Eustachian tube ventilatory function was obtained after hyperbaric oxygen exposure during dives employing oxygen as breathing gas. This impairment, however, was not associated with altered airflow characteristics of divers' noses. Thus, it seems unlikely that hyperbaric oxygen exerts an effect on the nasal mucosa similar to that on the Eustachian tube mucosa.

Irritable bowel syndrome (IBS), non-erosive reflux disorder (NERD), and functional dyspepsia (FD) are best classified as immuno-neuronal disorders of the mucosa or functional mucosal syndromes (FMS). Each appears to be clinically reversible using high potency sucralfate (HPS). In FMS of the GI tract, postprandial nausea, altered motility, discordant peristalsis, vomiting, diarrhea, and hyperalgesia are the clinical expressions of a mucosal imbalance between pro-inflammatory cytokines of up-regulated intra-epithelial lymphocytes (IELs) and feedback anti-inflammatory cytokines tasked with moderating the antigenic response of IELs. Normal functioning GI tract requires an operative balance between pro-inflammatory and anti-inflammatrory cytokines, a balance governed by locally expressed growth factors. The surface concentration of sucralfate can be enhanced 7-23-fold by suspending it in a select concentration of cations and multi-dentate cationic chelators. Increased surface concentration of sucralfate facilitates novel dose effects which include efficient activation of growth factors, quiescence of gated-nociceptor firing and resultant restoration of normal GI function., (Published by Elsevier Ltd.)

Background: Ulceration of the oesophageal squamous mucosa (ulcerative oesophagitis) is a pathological manifestation of gastro-oesophageal reflux disease, and is a major risk factor for the development of Barrett's oesophagus. Barrett's oesophagus is characterised by replacement of reflux-damaged oesophageal squamous epithelium with a columnar intestinal-like epithelium. We previously reported discovery of microRNAs that are differentially expressed between oesophageal squamous mucosa and Barrett's oesophagus mucosa. Now, to better understand early steps in the initiation of Barrett's oesophagus, we assessed the expression, location and function of these microRNAs in oesophageal squamous mucosa from individuals with ulcerative oesophagitis., Methods: Quantitative real-time PCR was used to compare miR-21, 143, 145, 194, 203, 205 and 215 expression levels in oesophageal mucosa from individuals without pathological gastro-oesophageal reflux to individuals with ulcerative oesophagitis. Correlations between microRNA expression and messenger RNA differentiation markers BMP-4, CK8 and CK14 were analyzed. The cellular localisation of microRNAs within the oesophageal mucosa was determined using in-situ hybridisation. microRNA involvement in proliferation and apoptosis was assessed following transfection of a human squamous oesophageal mucosal cell line (Het-1A)., Results: miR-143, miR-145 and miR-205 levels were significantly higher in gastro-oesophageal reflux compared with controls. Elevated miR-143 expression correlated with BMP-4 and CK8 expression, and elevated miR-205 expression correlated negatively with CK14 expression. Endogenous miR-143, miR-145 and miR-205 expression was localised to the basal layer of the oesophageal epithelium. Transfection of miR-143, 145 and 205 mimics into Het-1A cells resulted in increased apoptosis and decreased proliferation., Conclusions: Elevated miR-143, miR-145 and miR-205 expression was observed in oesophageal squamous mucosa of individuals with ulcerative oesophagitis. These miRNAs localised to the basal layer of the oesophageal epithelium. They reduced proliferation and increased apoptosis, and may play roles in regulating epithelial restoration in response to injury caused by gastro-oesophageal reflux.