Neutrophils and the Inflammatory Tissue Microenvironment in the Mucosa

PubMed Central

Campbell, Eric L.; Kao, Daniel J.; Colgan, Sean P.

2016-01-01

The interaction of neutrophils (PMNs) and epithelial cells are requisite lines of communication during mucosal inflammatory responses. Consequences of such interactions often determine endpoint organ function, and for this reason, much interest has developed around defining the constituents of the tissue microenvironment of inflammatory lesions. Physiologic in vitro and in vivo models have aided in discovery of components that define the basic inflammatory machinery that mold the inflammatory tissue microenvironment. Here, we will review the recent literature related to the contribution of PMNs to molding of the tissue microenvironment, with an emphasis on the gastrointestinal (GI) tract. We focus on endogenous pathways for promoting tissue homeostasis and the molecular determinants of neutrophil-epithelial cell interactions during ongoing inflammation. These recent studies highlight the dynamic nature of these pathways and lend insight into the complexity of treating mucosal inflammation. PMID:27558331

Oral and intestinal mucositis - causes and possible treatments.

PubMed

Duncan, M; Grant, G

2003-11-01

Chemotherapy and radiotherapy, whilst highly effective in the treatment of neoplasia, can also cause damage to healthy tissue. In particular, the alimentary tract may be badly affected. Severe inflammation, lesioning and ulceration can occur. Patients may experience intense pain, nausea and gastro-enteritis. They are also highly susceptible to infection. The disorder (mucositis) is a dose-limiting toxicity of therapy and affects around 500 000 patients world-wide annually. Oral and intestinal mucositis is multi-factorial in nature. The disruption or loss of rapidly dividing epithelial progenitor cells is a trigger for the onset of the disorder. However, the actual dysfunction that manifests and its severity and duration are greatly influenced by changes in other cell populations, immune responses and the effects of oral/gut flora. This complexity has hampered the development of effective palliative or preventative measures. Recent studies have concentrated on the use of bioactive/growth factors, hormones or interleukins to modify epithelial metabolism and reduce the susceptibility of the tract to mucositis. Some of these treatments appear to have considerable potential and are at present under clinical evaluation. This overview deals with the cellular changes and host responses that may lead to the development of mucositis of the oral cavity and gastrointestinal tract, and the potential of existing and novel palliative measures to limit or prevent the disorder. Presently available treatments do not prevent mucositis, but can limit its severity if used in combination. Poor oral health and existing epithelial damage predispose patients to mucositis. The elimination of dental problems or the minimization of existing damage to the alimentary tract, prior to the commencement of therapy, lowers their susceptibility. Measures that reduce the flora of the tract, before therapy, can also be helpful. Increased production of free radicals and the induction of inflammation are early events in the onset of mucositis. Prophylactic administration of scavengers or anti-inflammatories can partially counteract or limit some of these therapy-mediated effects, as can the use of cryotherapy. The regular use of mouthwashes, mouth coatings, antibiotics and analgesics is essential, prior to and during loss and ablation of the epithelial layer. Granulocyte-macrophage colony-stimulating factor/granulocyte colony-stimulating factor or the use of laser light therapy may aid restitution and repair. Glutamine supplements may be beneficial in the repair/recovery phase.

AIDS-related Kaposi sarcoma: findings on thallium-201 scintigraphy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, V.W.; Rosen, M.P.; Baum, A.

1988-12-01

No simple, noninvasive method is available for evaluating extracutaneous Kaposi sarcoma in AIDS patients or for following the tumor's response to treatment. We report our preliminary experience with thallium-201 scintigraphy in nine AIDS patients with proved Kaposi sarcoma. Eight of the nine had abnormal uptake of the radionuclide in skin, lymph nodes, oral cavity, vagina, and lungs. Only four of the nine had cutaneous Kaposi sarcoma at the time of scanning. All cutaneous and mucosal lesions were thallium avid. Two of the six patients with thallium-avid nodes underwent nodal biopsy. Both biopsies confirmed the diagnosis of Kaposi sarcoma. Cutaneous Kaposimore » sarcoma developed later in one of these patients, showing the efficacy of thallium scintigraphy for the early detection of extracutaneous lesions. These preliminary results show thallium avidity in Kaposi sarcoma involving the skin and various extracutaneous sites (lymph nodes, lung, mucosa, and vagina). Thallium scintigraphy is a potentially useful procedure for detecting extracutaneous Kaposi sarcoma in AIDS patients.« less

Vaccine-induced, simian immunodeficiency virus-specific CD8+ T cells reduce virus replication but do not protect from simian immunodeficiency virus disease progression.

PubMed

Engram, Jessica C; Dunham, Richard M; Makedonas, George; Vanderford, Thomas H; Sumpter, Beth; Klatt, Nichole R; Ratcliffe, Sarah J; Garg, Seema; Paiardini, Mirko; McQuoid, Monica; Altman, John D; Staprans, Silvija I; Betts, Michael R; Garber, David A; Feinberg, Mark B; Silvestri, Guido

2009-07-01

Our limited understanding of the interaction between primate lentiviruses and the host immune system complicates the design of an effective HIV/AIDS vaccine. To identify immunological correlates of protection from SIV disease progression, we immunized two groups of five rhesus macaques (RMs) with either modified vaccinia Ankara (MVA) or MVADeltaudg vectors that expressed SIVmac239 Gag and Tat. Both vectors raised a SIV-specific CD8(+) T cell response, with a magnitude that was greater in mucosal tissues than in peripheral blood. After challenge with SIVmac239, all vaccinated RMs showed mucosal and systemic CD8(+) T cell recall responses that appeared faster and were of greater magnitude than those in five unvaccinated control animals. All vaccinated RMs showed a approximately 1-log lower peak and early set-point SIV viral load than the unvaccinated animals, and then, by 8 wk postchallenge, exhibited levels of viremia similar to the controls. We observed a significant direct correlation between the magnitude of postchallenge SIV-specific CD8(+) T cell responses and SIV viral load. However, vaccinated RMs showed no protection from either systemic or mucosal CD4(+) T cell depletion and no improved survival. The observation that vaccine-induced, SIV-specific CD8(+) T cells that partially control SIVmac239 virus replication fail to protect from immunological or clinical progression of SIV infection underscores both the complexity of AIDS pathogenesis and the challenges of properly assessing the efficacy of candidate AIDS vaccines.

Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers.

PubMed

Loke, P'ng; Favre, David; Hunt, Peter W; Leung, Jacqueline M; Kanwar, Bittoo; Martin, Jeffrey N; Deeks, Steven G; McCune, Joseph M

2010-04-15

HIV "controllers" are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have correlated results from polychromatic flow cytometry and oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV(+) persons with high viral loads and progressive disease ("noncontrollers"). Paired peripheral blood and rectosigmoid biopsies were analyzed from 9 controllers and 11 noncontrollers. Several cellular immune parameters were found to be concordant between the 2 compartments. Compared with noncontrollers, the mucosal tissues of controllers had similar levels of effector T cells and fewer regulatory T cells (Tregs). Using principal component analysis to correlate immunologic parameters with gene expression profiles, transcripts were identified that accurately distinguished between controllers and noncontrollers. Direct 2-way comparison also revealed genes that are significantly different in their expression between controllers and noncontrollers, all of which had reduced expression in controllers. In addition to providing an approach that integrates flow cytometry datasets with transcriptional profiling analysis, these results underscore the importance of the sustained inflammatory response that attends progressive HIV disease.

Novel vaccine development strategies for inducing mucosal immunity

PubMed Central

Fujkuyama, Yoshiko; Tokuhara, Daisuke; Kataoka, Kosuke; Gilbert, Rebekah S; McGhee, Jerry R; Yuki, Yoshikazu; Kiyono, Hiroshi; Fujihashi, Kohtaro

2012-01-01

To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed. PMID:22380827

Dendritic cell-targeting DNA-based mucosal adjuvants for the development of mucosal vaccines

PubMed Central

Kataoka, Kosuke; Fujihashi, Kohtaro

2009-01-01

In order to establish effective mucosal immunity against various mucosal pathogens, vaccines must be delivered via the mucosal route and contain effective adjuvant(s). Since mucosal adjuvants can simply mix with the antigen, it is relatively easy to adapt them for different types of vaccine development. Even in simple admixture vaccines, the adjuvant itself must be prepared without any complications. Thus, CpG oligodeoxynucleotides or plasmids encoding certain cDNA(s) would be potent mucosal adjuvant candidates when compared with other substances that can be used as mucosal adjuvants. The strategy of a DNA-based mucosal adjuvant facilitates the targeting of mucosal dendritic cells, and thus is an effective and safe approach. It would also provide great flexibility for the development of effective vaccines for various mucosal pathogens. PMID:19722892

Unexpected High Digestion Rate of Cooked Starch by the Ct-Maltase-Glucoamylase Small Intestine Mucosal α-Glucosidase Subunit

PubMed Central

Lin, Amy Hui-Mei; Nichols, Buford L.; Quezada-Calvillo, Roberto; Avery, Stephen E.; Sim, Lyann; Rose, David R.; Naim, Hassan Y.; Hamaker, Bruce R.

2012-01-01

For starch digestion to glucose, two luminal α-amylases and four gut mucosal α-glucosidase subunits are employed. The aim of this research was to investigate, for the first time, direct digestion capability of individual mucosal α-glucosidases on cooked (gelatinized) starch. Gelatinized normal maize starch was digested with N- and C-terminal subunits of recombinant mammalian maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) of varying amounts and digestion periods. Without the aid of α-amylase, Ct-MGAM demonstrated an unexpected rapid and high digestion degree near 80%, while other subunits showed 20 to 30% digestion. These findings suggest that Ct-MGAM assists α-amylase in digesting starch molecules and potentially may compensate for developmental or pathological amylase deficiencies. PMID:22563462

Unexpected high digestion rate of cooked starch by the Ct-maltase-glucoamylase small intestine mucosal α-glucosidase subunit.

PubMed

Lin, Amy Hui-Mei; Nichols, Buford L; Quezada-Calvillo, Roberto; Avery, Stephen E; Sim, Lyann; Rose, David R; Naim, Hassan Y; Hamaker, Bruce R

2012-01-01

For starch digestion to glucose, two luminal α-amylases and four gut mucosal α-glucosidase subunits are employed. The aim of this research was to investigate, for the first time, direct digestion capability of individual mucosal α-glucosidases on cooked (gelatinized) starch. Gelatinized normal maize starch was digested with N- and C-terminal subunits of recombinant mammalian maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) of varying amounts and digestion periods. Without the aid of α-amylase, Ct-MGAM demonstrated an unexpected rapid and high digestion degree near 80%, while other subunits showed 20 to 30% digestion. These findings suggest that Ct-MGAM assists α-amylase in digesting starch molecules and potentially may compensate for developmental or pathological amylase deficiencies.

Mucosal vaccines: a paradigm shift in the development of mucosal adjuvants and delivery vehicles.

PubMed

Srivastava, Atul; Gowda, Devegowda Vishakante; Madhunapantula, SubbaRao V; Shinde, Chetan G; Iyer, Meenakshi

2015-04-01

Mucosal immune responses are the first-line defensive mechanisms against a variety of infections. Therefore, immunizations of mucosal surfaces from which majority of infectious agents make their entry, helps to protect the body against infections. Hence, vaccinization of mucosal surfaces by using mucosal vaccines provides the basis for generating protective immunity both in the mucosal and systemic immune compartments. Mucosal vaccines offer several advantages over parenteral immunization. For example, (i) ease of administration; (ii) non-invasiveness; (iii) high-patient compliance; and (iv) suitability for mass vaccination. Despite these benefits, to date, only very few mucosal vaccines have been developed using whole microorganisms and approved for use in humans. This is due to various challenges associated with the development of an effective mucosal vaccine that can work against a variety of infections, and various problems concerned with the safe delivery of developed vaccine. For instance, protein antigen alone is not just sufficient enough for the optimal delivery of antigen(s) mucosally. Hence, efforts have been made to develop better prophylactic and therapeutic vaccines for improved mucosal Th1 and Th2 immune responses using an efficient and safe immunostimulatory molecule and novel delivery carriers. Therefore, in this review, we have made an attempt to cover the recent advancements in the development of adjuvants and delivery carriers for safe and effective mucosal vaccine production. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Plasma and Mucosal Immunoglobulin M, Immunoglobulin A, and Immunoglobulin G Responses to the Vibrio cholerae O1 Protein Immunome in Adults With Cholera in Bangladesh.

PubMed

Charles, Richelle C; Nakajima, Rie; Liang, Li; Jasinskas, Al; Berger, Amanda; Leung, Daniel T; Kelly, Meagan; Xu, Peng; Kovác, Pavol; Giffen, Samantha R; Harbison, James D; Chowdhury, Fahima; Khan, Ashraful I; Calderwood, Stephen B; Bhuiyan, Taufiqur Rahman; Harris, Jason B; Felgner, Philip L; Qadri, Firdausi; Ryan, Edward T

2017-07-01

Cholera is a severe dehydrating illness of humans caused by toxigenic strains of Vibrio cholerae O1 or O139. Identification of immunogenic V. cholerae antigens could lead to a better understanding of protective immunity in human cholera. We probed microarrays containing 3652 V. cholerae antigens with plasma and antibody-in-lymphocyte supernatant (ALS, a surrogate marker of mucosal immune responses) from patients with severe cholera caused by V. cholerae O1 in Bangladesh and age-, sex-, and ABO-matched Bangladeshi controls. We validated a subset of identified antigens using enzyme-linked immunosorbent assay. Overall, we identified 608 immunoreactive V. cholerae antigens in our screening, 59 of which had higher immunoreactivity in convalescent compared with acute-stage or healthy control samples (34 in plasma, 39 in mucosal ALS; 13 in both sample sets). Identified antigens included cholera toxin B and A subunits, V. cholerae O-specific polysaccharide and lipopolysaccharide, toxin coregulated pilus A, sialidase, hemolysin A, flagellins (FlaB, FlaC, and FlaD), phosphoenolpyruvate-protein phosphotransferase, and diaminobutyrate-2-oxoglutarate aminotransferase. This study is the first antibody profiling of the mucosal and systemic antibody responses to the nearly complete V. cholerae O1 protein immunome; it has identified antigens that may aid in the development of an improved cholera vaccine. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Effect of Clinically Relevant CAD/CAM Zirconia Polishing on Gingival Fibroblast Proliferation and Focal Adhesions

PubMed Central

Fischer, Nicholas G.; Wong, Jeffrey; Cerutis, D. Roselyn

2017-01-01

Mucosal seal formation around dental abutments is critical to the successful integration of dental implants into the human oral cavity. No information exists for how clinically relevant polishing procedures for computer-aided design and computer-aided manufactured (CAD/CAM) zirconia abutments affects cellular responses important to mucosal seal formation. CAD/CAM zirconia was divided into four groups for clinically relevant polishing utilizing commercial polishing heads: control, coarse, coarse plus medium, and coarse plus medium plus fine. Surfaces were analyzed with scanning electron microscopy (SEM), atomic force microscopy (AFM), and optical profilometry (OP). Subsequently, human gingival fibroblasts (HGFs) were seeded onto the zirconia surfaces. Proliferation was measured via a quantitative SEM technique and focal adhesion kinase (FAK) phosphorylation status was measured by an enzyme-linked immunosorbent assay (ELISA). Results showed an increase in proliferation on all polished surfaces as compared to the control. Phosphorylation of FAK at tyrosine 397 (Y397) was up-modulated on the control surfaces. The associated cell adaptation is discussed. In all cases, FAK phosphorylation was greater at 24 h than 48 h. These results suggest that clinicians should be mindful of the effects of abutment polishing methodology, as this may have an impact on early mucosal seal formation. PMID:29186907

Evaluation of mast cells, eosinophils, blood capillaries in oral lichen planus and oral lichenoid mucositis.

PubMed

Reddy, D Santhosh; Sivapathasundharam, B; Saraswathi, T R; SriRam, G

2012-01-01

Mast cells are granule containing secretory cells present in oral mucosal and connective tissue environment. Oral lichen planus and oral lichenoid lesions are commonly occurring oral diseases and have some similarity clinically and histologically. Both are characterized by an extensive sub epithelial infiltrate of T cells, together with mast cells, eosinophils and blood capillaries. In this study mast cell and eosinophil densities along with number of blood capillaries were studied to find out if they could aid in histopathological distinction between oral lichen planus and lichenoid mucositis. To enumerate mast cells and compare the status of Mast Cells (Intact or Degranulated) in Lichen planus, Lichenoid mucositis and normal buccal mucosa in tissue sections stained with Toluidine Blue, and also to enumerate Eosinophils and blood capillaries in tissue sections stained with H and E. The study group included 30 cases each of oral lichen planus and oral lichenoid mucositis. 10 cases of clinically normal oral buccal mucosa formed the control group. All the sections were stained with Toluidine blue and H and E separately. Histopathological analysis was done using binocular light microscope equipped with square ocular grid to standardize the field of evaluation. The result of the study showed. · Significant increase in number of mast cells in oral lichen planus and oral lichenoid mucositis compared to normal buccal mucosa. · Significant increase of intact mast cells suepithelially within the inflammatory cell infiltrate in oral lichen planus compared to oral lichenoid mucositis. · Significant increase of degranulated mast cells in oral lichenoid mucositis to oral lichen planus, and increase in number of eosinophil densities in oral lichenoid mucositis compared to oral lichen planus. · Significant increase in number of capillaries in oral lichenoid mucositis compared to oral lichen planus. The findings of increased number of intact mast cells sub epithelially in oral lichen planus to oral lichenoid mucositis and increase in number of degranulated mast cells as well as capillaries subepithelially in oral lichenoid mucositis to oral lichen planus can be used as reliable criteria for histologic distinction between these two lesions. The increase of eosinophils in oral lichenoid mucositis to oral lichen planus could be used as adjunct histologic criterion in the diagnosis of oral lichenoid mucositis.

Dermoscopic appearance of an amelanotic mucosal melanoma

PubMed Central

Blum, Andreas; Beck-Zoul, Ulrike; Held, Laura; Haase, Sylvie

2016-01-01

Background Hypomelanotic or amelanotic melanomas are challenging to identify, especially at mucosal sites. The dermoscopic clues to the diagnosis of mucosal melanomas have been reported to be structureless zones with the presence of blue, gray, or white colors. Case A female in her seventies noted a new lesion on the inside of her right labia that first appeared two months prior. Her past medical history was significant for rheumatoid arthritis requiring ongoing treatment with methotrexate for 20 years and adalimumab for 10 years. After no response to two weeks of local treatment for suspected herpes simplex infection, her gynecologist performed a skin biopsy. Based on the histopathological diagnosis of an amelanotic melanoma (Breslow thickness of 1.3 mm) the patient was referred to dermatology for further assessment. Polarized dermoscopy revealed a distinct asymmetric, sharply demarcated homogenous white papule (4 × 5 mm) as well as polymorphous vessels. Conclusion Dermoscopy may aid in the diagnosis of amelanotic mucosal melanomas. Our case revealed a structureless white area and polymorphous vessels. Additional clues to the diagnosis were the advanced age of the patient and the clinical presentation of a new lesion. PMID:27867742

Neutrophil-derived JAML Inhibits Repair of Intestinal Epithelial Injury During Acute Inflammation

PubMed Central

Weber, Dominique A.; Sumagin, Ronen; McCall, Ingrid C.; Leoni, Giovanna; Neumann, Philipp A.; Andargachew, Rakieb; Brazil, Jennifer C.; Medina-Contreras, Oscar; Denning, Timothy L.; Nusrat, Asma; Parkos, Charles A.

2014-01-01

Neutrophil transepithelial migration (TEM) during acute inflammation is associated with mucosal injury. Using models of acute mucosal injury in-vitro and in-vivo, we describe a new mechanism by which neutrophils infiltrating the intestinal mucosa disrupt epithelial homeostasis. We report that junctional adhesion molecule-like protein (JAML) is cleaved from neutrophil surface by zinc-metalloproteases during TEM. Neutrophil-derived soluble JAML bound to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) resulting in compromised barrier and inhibition of wound repair, through decreased epithelial proliferation. The deleterious effects of JAML on barrier and wound repair were reversed with an anti-JAML mAb that inhibits JAML-CAR binding. Thus, JAML released from transmigrating neutrophils across inflamed epithelia can promote recruitment of leukocytes and aid in clearance of invading microorganisms. However, sustained release of JAML under pathologic conditions associated with persistence of large numbers of infiltrated neutrophil would compromise intestinal barrier and inhibit mucosal healing. Targeting JAML-CAR interactions may thus improve mucosal healing responses under conditions of dysregulated neutrophil recruitment. PMID:24621992

Riga-Fede-like disease in an AIDS patient.

PubMed

Cunha, Vanessa Santos; Rocha Zanol, Jorge David; Sprinz, Eduardo

2007-12-01

Riga-Fede disease is a benign and ulcerative process that occurs as a result of repetitive trauma of the oral mucosal surfaces by the teeth. The authors describe here a case of a 40-year-old man in rescue therapy for advanced AIDS with a 2-month history of an ulcerated area on the dorsal surface of his tongue, which was histopathologically consistent with Riga-Fede disease. This case report is unique because it is the first time that this lesion has been reported in an AIDS patient, and Riga-Fede disease should be included in the differential diagnosis of a tongue ulcer in these populations.

Simultaneous approach using systemic, mucosal and transcutaneous routes of immunization for development of protective HIV-1 vaccines.

PubMed

Belyakov, I M; Ahlers, J D

2011-01-01

Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4(+) and CD8(+) T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4(+) and CD8(+) responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4(+) and CD8(+) CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8(+) CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti-viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection.

New generation of oral mucosal vaccines targeting dendritic cells

PubMed Central

Owen, Jennifer L.; Sahay, Bikash; Mohamadzadeh, Mansour

2013-01-01

As most infectious organisms gain entry at mucosal surfaces, there is a great deal of interest in developing vaccines that elicit effective mucosal immune responses against pathogen challenge. Targeted vaccination is one of the most effective methods available to prevent and control infectious diseases. Mucosal vaccines can offer lower costs, better accessibility, needle free delivery, and a higher capacity for mass immunizations during pandemics. Both local mucosal immunity and robust systemic responses can be achieved through mucosal vaccination. Recent progress in understanding the molecular and cellular components of the mucosal immune system have allowed for the development of a novel mucosal vaccine platform utilizing specific dendritic cell-targeting peptides and orally administered lactobacilli to elicit efficient antigen specific immune responses against infections, including B. anthracis in experimental models of disease. PMID:23835515

New generation of oral mucosal vaccines targeting dendritic cells.

PubMed

Owen, Jennifer L; Sahay, Bikash; Mohamadzadeh, Mansour

2013-12-01

As most infectious organisms gain entry at mucosal surfaces, there is a great deal of interest in developing vaccines that elicit effective mucosal immune responses against pathogen challenge. Targeted vaccination is one of the most effective methods available to prevent and control infectious diseases. Mucosal vaccines can offer lower costs, better accessibility, needle free delivery, and a higher capacity for mass immunizations during pandemics. Both local mucosal immunity and robust systemic responses can be achieved through mucosal vaccination. Recent progress in understanding the molecular and cellular components of the mucosal immune system have allowed for the development of a novel mucosal vaccine platform utilizing specific dendritic cell-targeting peptides and orally administered lactobacilli to elicit efficient antigen specific immune responses against infections, including Bacillus anthracis in experimental models of disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Antibodies and Their Receptors: Different Potential Roles in Mucosal Defense

PubMed Central

Horton, Rachel E.; Vidarsson, Gestur

2013-01-01

Over recent years it has become increasingly apparent that mucosal antibodies are not only restricted to the IgM and IgA isotypes, but that also other isotypes and particularly IgG can be found in significant quantities at some mucosal surfaces, such as in the genital tract. Their role is more complex than traditionally believed with, among other things, the discovery of novel function of mucosal immunoglobulin receptors. A thorough knowledge in the source and function and mucosal immunoglobulins is particularly important in development of vaccines providing mucosal immunity, and also in the current climate of microbicide development, to combat major world health issues such as HIV. We present here a comprehensive review of human antibody mediated mucosal immunity. PMID:23882268

Dark Agouti rat model of chemotherapy-induced mucositis: establishment and current state of the art.

PubMed

Vanhoecke, Barbara; Bateman, Emma; Mayo, Bronwen; Vanlancker, Eline; Stringer, Andrea; Thorpe, Daniel; Keefe, Dorothy

2015-06-01

Mucositis is a major oncological problem. The entire gastrointestinal and genitourinary tract and also other mucosal surfaces can be affected in recipients of radiotherapy, and/or chemotherapy. Major progress has been made in recent years in understanding the mechanisms of oral and small intestinal mucositis, which appears to be more prominent than colonic damage. This progress is largely due to the development of representative laboratory animal models of mucositis. This review focuses on the development and establishment of the Dark Agouti rat mammary adenocarcinoma model by the Mucositis Research Group of the University of Adelaide over the past 20 years to characterize the mechanisms underlying methotrexate-, 5-fluorouracil-, and irinotecan-induced mucositis. It also aims to summarize the results from studies using different animal model systems to identify new molecular and cellular markers of mucositis. © 2015 by the Society for Experimental Biology and Medicine.

Mucosal secretion changes during radiotherapy in the oral cavity.

PubMed

Aziz, Luaay; Ebenfelt, Anders

2007-09-01

Mucositis in the oral cavity is a serious complication during radiation therapy for head and neck cancer, causing local discomfort and pain. In severe cases, hospitalization and interruption of radiotherapy may be necessary. The pathogenesis of this mucositis is not clear. With the purpose of getting more understanding of the pathogenesis of the mucositis, we examined the mucosal secretion from ten patients during radiotherapy with an imprint technique. In the secretion we studied the cellular composition and cellular function. In eight of ten treated patients the numbers of granulocytes increased in the secretion after 2 weeks of radiation therapy. The granulocytes, however, did not show any signs of phagocytosis. The patients all developed mucositis. We propose that the granulocytes in the secretion might play an important role in the development of mucositis during radiotherapy.

Development of plant-based mucosal vaccines against widespread infectious diseases.

PubMed

Salyaev, Rurick K; Rigano, Maria Manuela; Rekoslavskaya, Natalya I

2010-08-01

Mucosal vaccination is a perspective for the control of infectious diseases, since it is capable of inducing humoral and cell-mediated responses. In addition, the delivery of vaccines to mucosal surfaces makes immunization practice safe and acceptable, and eliminates needle-associated risks. Transgenic plants can be used as bioreactors for the production of mucosally delivered protective antigens. This technology shows great promise to simplify and decrease the cost of vaccine delivery. Herein, we review the development of mucosally administered vaccines expressed in transgenic plants. In particular, we evaluate the advantages and disadvantages of using plants for the production of mucosal vaccines against widespread infectious diseases such as HIV, hepatitis B and TB.

Mucositis care in acute leukemia and non-Hodgkin lymphoma patients undergoing high-dose chemotherapy.

PubMed

Martinez, José Manuel; Pereira, Dulcineia; Chacim, Sérgio; Mesquita, Edgar; Sousa, Inês; Martins, Ângelo; Azevedo, Teresa; Mariz, José Mário

2014-09-01

This study intends to provide new insights into the incidence and care of mucositis by the epidemiological characterization of patients with hematological malignancy treated at our institution. It also aims to understand the effectiveness of several treatments used. This is a longitudinal observational single-center study-convenience sample-which includes malignant hematologic inpatients submitted to high-dose CT from February to August 2012. We registered epidemiological data, diagnosis, oral mucositis daily questionnaire (OMDQ), World Health Organization (WHO) oral toxicity scale, and supportive medications used for mucositis. We evaluated 30 patients who had 73 episodes of hospitalization, having recorded the development of mucositis in 21.9 % (n = 16) episodes (22 patients with acute leukemia (AL) and 8 patients with non-Hodgkin lymphoma (NHL)). Grades 3-4 mucositis was reported in 4.1 % of the total episodes. The results of OMDQ showed some limitations in the quality of life, of patients with mucositis, related with the ability to eat and drink due to mouth pain (p < 0.001). In patients with NHL and AL, neutropenia entails an increased risk of mucositis (p < 0.001). Patients who did not initiate early prophylaxis with conservative measures developed mucositis earlier (p < 0.05). The incidence of mucositis is high, being reported mainly in AL patients, with limitations in quality of life. Grade 4 neutropenia increases mucositis risk. Early prophylaxis with basic oral care may delay mucositis. Further studies are crucial to characterize mucositis epidemiology, physiopathology, and its management.

Prevention of oral mucositis due to 5-fluorouracil treatment with oral cryotherapy.

PubMed

Baydar, Mustafa; Dikilitas, Mustafa; Sevinc, Alper; Aydogdu, Ismet

2005-08-01

One of the most common and important side effects of 5-fluorouracil (5-FU) is mucositis with ulcerations in the oral cavity. We investigated the effects of local cryotherapy on mucositis incidence administrated durng 5-FU treatment. In a total of 99 courses, 5-FU and folinic acid combination chemotherapy was given to 40 patients. In our study, we considered every course as a single case, and cryotherapy was given to the same patient in one course but not given in the next. While mucositis developed in 6.7% of the courses given with cryotherapy, this ratio was 38.9% in courses given without cryotherapy. In the logistic regression analysis, development of mucositis had been found to correlate only with cryotherapy. Odds ratio (OR) = 11.5; in the 95% confidence interval (CI) = 3.2 - 41.9; (p = 0.001). Results of initial studies evaluating the effects of cryotherapy in preventing mucositis due to 5-FU based chemotherapy regimens were promising. We concluded that oral cooling prevents 5-FU induced mucositis. This effective prophylactic treatment should be used in patients who are at increased risk for developing 5-FU induced mucositis.

Prevention of oral mucositis due to 5-fluorouracil treatment with oral cryotherapy.

PubMed Central

Baydar, Mustafa; Dikilitas, Mustafa; Sevinc, Alper; Aydogdu, Ismet

2005-01-01

INTRODUCTION: One of the most common and important side effects of 5-fluorouracil (5-FU) is mucositis with ulcerations in the oral cavity. We investigated the effects of local cryotherapy on mucositis incidence administrated durng 5-FU treatment. METHODS: In a total of 99 courses, 5-FU and folinic acid combination chemotherapy was given to 40 patients. In our study, we considered every course as a single case, and cryotherapy was given to the same patient in one course but not given in the next. RESULTS: While mucositis developed in 6.7% of the courses given with cryotherapy, this ratio was 38.9% in courses given without cryotherapy. In the logistic regression analysis, development of mucositis had been found to correlate only with cryotherapy. Odds ratio (OR) = 11.5; in the 95% confidence interval (CI) = 3.2 - 41.9; (p = 0.001). DISCUSSION: Results of initial studies evaluating the effects of cryotherapy in preventing mucositis due to 5-FU based chemotherapy regimens were promising. We concluded that oral cooling prevents 5-FU induced mucositis. This effective prophylactic treatment should be used in patients who are at increased risk for developing 5-FU induced mucositis. PMID:16173332

Recent advances in microparticle and nanoparticle delivery vehicles for mucosal vaccination.

PubMed

McNeela, E A; Lavelle, E C

2012-01-01

The great potential of mucosal vaccination is widely accepted but progress in the clinical development of subunit mucosal vaccines has been disappointing. Of the available approaches, the use of polymer-based microparticles is attractive because these delivery vehicles can be specifically tailored for vaccines and they offer the potential for integration of adjuvant. Here we address recent developments in the use of particulates as mucosal vaccines and the potential of novel targeting strategies, formulation approaches and adjuvant combinations to enhance the efficacy of particle-based mucosal vaccines. This review discusses the current status of mucosal vaccines based on particles and highlights several of the strategies that are currently under investigation for improving their immunogenicity. These include enhancing the stability of formulations in the luminal environment, increasing uptake by specifically targeting particles to mucosal inductive sites, and augmenting immunogenicity through co-formulation with immunostimulatory agents.

Quantification of oral palatine Langerhans cells in HIV/AIDS associated oral Kaposi sarcoma with and without oral candidiasis.

PubMed

Jivan, Vibha; Meer, Shabnum

2016-01-01

Langerhans cells (LCs) are effective antigen-presenting cells that function as "custodians" of mucosa, modifying the immune system to pathogen entry, and tolerance to self-antigen and commensal microbes. A reduction in number of LCs in human immunodeficiency virus (HIV)-positive individuals may predispose to local mucosal infections. To quantitatively determine the number of oral mucosal LCs in HIV/acquired immunodeficiency syndrome HIV/acquired immunodeficiency syndrome (AIDS) associated oral Kaposi sarcoma (KS) with/without oral candidiasis (OC) and to define in situ interrelationships between the cells, OC, and HIV infection. Thirty-two periodic acid-Schiff. (PAS) stained histologic sections of palatal HIV/AIDS associated KS with intact oral epithelium were examined for Candida and divided into two groups: . (1) KS coinfected with Candida and. (2) KS noninfected with Candida. Sections were immunohistochemically stained with CD1a. The standard length of surface epithelium was measured and number of positively stained LCs counted per unit length. Control cases included non-Candida infected palatal mucosa overlying pleomorphic adenoma. (PA) and oral mucosa infected with Candida in otherwise healthy individuals. LC number per unit length of surface epithelium was statistically significantly greatest in uninfected PA mucosa and lowest in KS coinfected with Candida (P = 0.0001). A statistically significant difference was also noted between uninfected PA mucosa and non-Candida infected KS (P = 0.0014), in KS coinfected with Candida and non-infected KS (P = 0.0035), between OC and PA (P = 0.0001), and OC and KS coinfected with Candida (P = 0.0247). LC numbers are significantly reduced in oral tissues of HIV/AIDS infected patients by Candida infection when compared to oral tissues without.

The mucosal immune system: From dentistry to vaccine development

PubMed Central

KIYONO, Hiroshi; AZEGAMI, Tatsuhiko

2015-01-01

The oral cavity is the beginning of the aero-digestive tract, which is covered by mucosal epithelium continuously under the threat of invasion of pathogens, it is thus protected by the mucosal immune system. In the early phase of our scientific efforts for the demonstration of mucosal immune system, dental science was one of major driving forces due to their foreseeability to use oral immunity for the control of oral diseases. The mucosal immune system is divided functionally into, but interconnected inductive and effector sites. Intestinal Peyer’s patches (PPs) are an inductive site containing antigen-sampling M cells and immunocompetent cells required to initiate antigen-specific immune responses. At effector sites, PP-originated antigen-specific IgA B cells become plasma cells to produce polymeric IgA and form secretory IgA by binding to poly-Ig receptor expressed on epithelial cells for protective immunity. The development of new-generation mucosal vaccines, including the rice-based oral vaccine MucoRice, on the basis of the coordinated mucosal immune system is a promising strategy for the control of mucosal infectious diseases. PMID:26460320

Microneedle and mucosal delivery of influenza vaccines

PubMed Central

Kang, Sang-Moo; Song, Jae-Min; Kim, Yeu-Chun

2017-01-01

In recent years with the threat of pandemic influenza and other public health needs, alternative vaccination methods other than intramuscular immunization have received great attention. The skin and mucosal surfaces are attractive sites probably because of both non-invasive access to the vaccine delivery and unique immunological responses. Intradermal vaccines using a microinjection system (BD Soluvia) and intranasal vaccines (FluMist) are licensed. As a new vaccination method, solid microneedles have been developed using a simple device that may be suitable for self-administration. Because coated micorneedle influenza vaccines are administered in the solid state, developing formulations maintaining the stability of influenza vaccines is an important issue to be considered. Marketable microneedle devices and clinical trials remain to be developed. Other alternative mucosal routes such as oral and intranasal delivery systems are also attractive for inducing cross protective mucosal immunity but effective non-live mucosal vaccines remain to be developed. PMID:22697052

Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome

PubMed Central

Handley, Scott; Thackray, Larissa B.; Zhao, Guoyan; Presti, Rachel; Miller, Andrew; Droit, Lindsay; Abbink, Peter; Maxfield, Lori F.; Kambal, Amal; Duan, Erning; Stanley, Kelly; Kramer, Joshua; Macri, Sheila C.; Permar, Sallie R.; Schmitz, Joern E.; Mansfield, Keith; Brenchley, Jason M.; Veazey, Ronald S.; Stappenbeck, Thaddeus S.; Wang, David; Barouch, Dan H.; Virgin, Herbert W.

2012-01-01

SUMMARY Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used next generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not non-pathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis. PMID:23063120

Lactobacillus brevis CD2 lozenges prevent oral mucositis in patients undergoing high dose chemotherapy followed by haematopoietic stem cell transplantation

PubMed Central

Sharma, Atul; Tilak, TVSVGK; Bakhshi, Sameer; Raina, Vinod; Kumar, Lalit; Chaudhary, Surendra Pal; Sahoo, Ranjit Kumar; Gupta, Ritu; Thulkar, Sanjay

2016-01-01

Background Oral mucositis is a common inflammatory complication in patients undergoing high-dose chemotherapy and radiation followed by haematopoietic stem cell transplantation (HSCT). Lactobacillus brevis CD2 has been proven efficacious in preventing chemoradiotherapy-induced oral mucositis in squamous cell carcinoma of head and neck. Methods This phase II study aimed to evaluate the safety and efficacy of L. brevis CD2 lozenges in preventing oral mucositis in patients undergoing HSCT. Eligible patients received four to six lozenges of L. brevis CD2 per day, beginning from 4 to 7 days before initiation of chemotherapy and continuing until resolution of mucositis or till day +24. Results Of 31 patients enrolled, 7 (22.6%) patients did not develop any mucositis, 6 (19.4%) patients developed grade 1, 12 (38.7%) patients developed grade 2, 4 (12.9%) and 2 (6.5%) patients developed grade 3 and grade 4 mucositis, respectively. Median time to onset and for resolution of mucositis were 6 days and 8 days, respectively. No adverse events were reported with usage of study drug. However, one patient died of Klebsiella sepsis. Conclusion Promising results from the study encourage the use of L. brevis CD2 lozenges as a supportive care treatment option; however, a randomised, double-blind, multicentric trial in a larger population is warranted. Trials registration number NCT01480011 at https://www.clinicaltrials.gov/ (Registered on Nov 04, 2011). PMID:28848667

Biology and Mucosal Immunity to Myxozoans

PubMed Central

Gómez, Daniela; Bartholomew, Jerri; Sunyer, J. Oriol

2014-01-01

Myxozoans are among the most abundant parasites in nature. Their life cycles involve two hosts: an invertebrate, usually an annelid, and a vertebrate, usually a fish. They affect fish species in their natural habitats but also constitute a menace for fish aquaculture. Using different strategies they are able to parasitize and cause damage in multiple organs, including mucosal tissues, which they use also as portals of entry. In fish, the main mucosal sites include the intestine, skin and gills. Recently the finding of a specific mucosal immunoglobulin in teleost (IgT), analogous to mammalian IgA, and the capacity of fish to develop a specific mucosal immune response against different pathogens, has highlighted the importance of studying immune responses at mucosal sites. In this review, we describe the major biological characteristics of myxozoan parasites and present the data available regarding immune responses for species that infect mucosal sites. As models for mucosal immunity we review the responses to Enteromyxum spp. and Ceratomyxa shasta, both of which parasitize the intestine. The immune response at the skin and gills is also described, as these mucosal tissues are used by myxozoans as attaching surfaces and portal of entry, and some species also parasitize these sites. Finally, the development of immunoprophylactic strategies is discussed. PMID:23994774

The Prevalence and Investigation of Risk Factors of Oral Mucositis in a Pediatric Oncology Inpatient Population; a Prospective Study.

PubMed

Allen, Gabrielle; Logan, Richard; Revesz, Tom; Keefe, Dorothy; Gue, Sam

2018-01-01

Oral mucositis can be a frequent and severe complication of chemotherapy in children. It can result in pain, infection, depression, prolonged admission, treatment delays, increase in patient morbidity, and increased costs. To record the prevalence and severity of oral mucositis among inpatients and explore the relationship of risks factors and the development of oral mucositis. During an 18-month period 643 clinical inpatient assessments were completed on 73 children who were admitted and had received chemotherapy in the last 14 days. There were 43 episodes of oral mucositis in 31 children; 42.5% of the inpatient population. World Health Organization assessment identified 32.6% of episodes were grade 1, 34.9% grade 2, 14.0% grade 3, and 18.6% grade 4. Analysis revealed significant associations between patient diagnosis (P<0.0001), chemotherapy cycles (P<0.0001), day 8 and 9 of the chemotherapy cycle (P<0.05), and neutropenia (P<0.0001) and oral mucositis. Children had increased length of admission with increasing severity of oral mucositis (P=0.0005). The prevalence of oral mucositis was 42.5% among inpatients and admission length was increased with increasing severity. Patient diagnosis, chemotherapy treatment block, day of chemotherapy cycle, and neutropenic status were shown to influence the risk of developing oral mucositis.

Effect of topical honey on limitation of radiation-induced oral mucositis: an intervention study.

PubMed

Khanal, B; Baliga, M; Uppal, N

2010-12-01

Radiation therapy for oral carcinoma is therapeutically useful in dose of at least 6000 cGy but causes mucositis that severely interferes with oral function. The literature indicates that honey appears to promote wound healing, so the authors investigated whether its anti-inflammatory properties might limit the severity of radiation-induced oral mucositis. A single-blinded, randomized, controlled clinical trial was carried out to compare the mucositis-limiting qualities of honey with lignocaine. A visual assessment scale permitted scoring of degrees of mucositis and statistical evaluation of the results was performed using the χ(2) test. Only 1 of 20 patients in the honey group developed intolerable oral mucositis compared with the lignocaine group, indicating that honey is strongly protective (RR=0.067) against the development of mucositis. The proportion of patients with intolerable oral mucositis was lower in the honey group and this was statistically significant (p=0.000). Honey applied topically to the oral mucosa of patients undergoing radiation therapy appears to provide a distinct benefit by limiting the severity of mucositis. Honey is readily available, affordable and well accepted by patients making it useful for improving the quality of life in irradiated patients. Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

In vitro and ex vivo evaluation of polymeric nanoparticles for vaginal and rectal delivery of the anti-HIV drug dapivirine.

PubMed

das Neves, José; Araújo, Francisca; Andrade, Fernanda; Michiels, Johan; Ariën, Kevin K; Vanham, Guido; Amiji, Mansoor; Bahia, Maria Fernanda; Sarmento, Bruno

2013-07-01

Prevention strategies such as the development of microbicides are thought to be valuable in the fight against HIV/AIDS. Despite recent achievements, there is still a long road ahead in the field, particularly at the level of drug formulation. Drug nanocarriers based on polymers may be useful in enhancing local drug delivery while limiting systemic exposure. We prepared differently surface-engineered poly(ε-caprolactone) (PCL) nanoparticles (NPs) and tested their ability to modulate the permeability and retention of dapivirine in cell monolayers and pig vaginal and rectal mucosa. NPs coated with poly(ethylene oxide) (PEO) were shown able to reduce permeability across monolayers/tissues, while modification of nanosystems with cetyl trimethylammonium bromide (CTAB) enhanced transport. In the case of coating NPs with sodium lauryl sulfate (SLS), dapivirine permeability was unchanged. All NPs increased monolayer/tissue drug retention as compared to unformulated dapivirine. This fact was associated, at least partially, to the ability of NPs to be taken up by cells or penetrate mucosal tissue. Cell and tissue toxicity was also affected differently by NPs: PEO modification decreased the in vitro (but not ex vivo) toxicity of dapivirine, while higher toxicity was generally observed for NPs coated with SLS or CTAB. Overall, presented results support that PCL nanoparticles are capable of modulating drug permeability and retention in cell monolayers and mucosal tissues relevant for vaginal and rectal delivery of microbicides. In particular, PEO-modified dapivirine-loaded PCL NPs may be advantageous in increasing drug residence at epithelial cell lines/mucosal tissues, which may potentially increase the efficacy of microbicide drugs.

Patients' Characteristics, Histopathological Findings, and Tumor Stage in Different Types of Malignant Melanoma: A Retrospective Multicenter Study.

PubMed

Farahmand, Ali-Mohammad; Ehsani, Amir-Hoshang; Mirzaei, Mojtaba; Mohsenian, Maryam; Ghanadan, Alireza

2017-05-01

Cutaneous malignant melanoma (CMM) is currently the most fatal of skin cancers accounting for 50000 deaths annually. Five distinct melanomas are described histopathologically: superficial spreading, lentigo maligna, nodular, acral lentiginous and mucosal melanoma. The aim of this study was to investigate the characteristics of patients with various types of malignant melanoma and evaluate histopathological findings. In this retrospective study, we obtained our data from the records of 111 patients with melanoma. Biopsied specimens were collected and re-evaluated. Demographic information and histopathological findings were noted. SPSS 16 was used for analyzing data. Chi-square and one-way ANOVA was conducted for comparing categorical and numerical variables respectively. The mean age of patients was 59.33±14.68 years old. Most common melanoma type was acral lentiginous (40.5%), followed by nodular (35.1%) and mucosal (10.8%). The highest tumor thickness was viewed in nodular melanoma followed by mucosal melanoma. The highest rate of metastasis, microsatellitosis, perineural invasion and Clark level of the invasion were reported in nodular and acral lentiginous respectively. The most frequent rate of ulceration and vascular invasion was reported in mucosal melanoma. Distribution of melanoma types varies largely in different regions. Lack of classic presentations in some types necessitate specific public education about warning signs. Histopathological and pathological characteristics in melanoma can aid in better staging and management of the tumor.

Vaccines against enteric infections for the developing world.

PubMed

Czerkinsky, Cecil; Holmgren, Jan

2015-06-19

Since the first licensure of the Sabin oral polio vaccine more than 50 years ago, only eight enteric vaccines have been licensed for four disease indications, and all are given orally. While mucosal vaccines offer programmatically attractive tools for facilitating vaccine deployment, their development remains hampered by several factors: -limited knowledge regarding the properties of the gut immune system during early life; -lack of mucosal adjuvants, limiting mucosal vaccine development to live-attenuated or killed whole virus and bacterial vaccines; -lack of correlates/surrogates of mucosal immune protection; and -limited knowledge of the factors contributing to oral vaccine underperformance in children from developing countries. There are now reasons to believe that the development of safe and effective mucosal adjuvants and of programmatically sound intervention strategies could enhance the efficacy of current and next-generation enteric vaccines, especially in lesser developed countries which are often co-endemic for enteric infections and malnutrition. These vaccines must be safe and affordable for the world's poorest, confer long-term protection and herd immunity, and must be able to contain epidemics. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Vaccines against enteric infections for the developing world

PubMed Central

Czerkinsky, Cecil; Holmgren, Jan

2015-01-01

Since the first licensure of the Sabin oral polio vaccine more than 50 years ago, only eight enteric vaccines have been licensed for four disease indications, and all are given orally. While mucosal vaccines offer programmatically attractive tools for facilitating vaccine deployment, their development remains hampered by several factors: —limited knowledge regarding the properties of the gut immune system during early life;—lack of mucosal adjuvants, limiting mucosal vaccine development to live-attenuated or killed whole virus and bacterial vaccines;—lack of correlates/surrogates of mucosal immune protection; and—limited knowledge of the factors contributing to oral vaccine underperformance in children from developing countries.There are now reasons to believe that the development of safe and effective mucosal adjuvants and of programmatically sound intervention strategies could enhance the efficacy of current and next-generation enteric vaccines, especially in lesser developed countries which are often co-endemic for enteric infections and malnutrition. These vaccines must be safe and affordable for the world's poorest, confer long-term protection and herd immunity, and must be able to contain epidemics. PMID:25964464

Mucosal Vaccine Development Based on Liposome Technology

PubMed Central

Norling, Karin; Bally, Marta; Höök, Fredrik

2016-01-01

Immune protection against infectious diseases is most effective if located at the portal of entry of the pathogen. Hence, there is an increasing demand for vaccine formulations that can induce strong protective immunity following oral, respiratory, or genital tract administration. At present, only few mucosal vaccines are found on the market, but recent technological advancements and a better understanding of the principles that govern priming of mucosal immune responses have contributed to a more optimistic view on the future of mucosal vaccines. Compared to live attenuated vaccines, subcomponent vaccines, most often protein-based, are considered safer, more stable, and less complicated to manufacture, but they require the addition of nontoxic and clinically safe adjuvants to be effective. In addition, another limiting factor is the large antigen dose that usually is required for mucosal vaccines. Therefore, the combination of mucosal adjuvants with the recent progress in nanoparticle technology provides an attractive solution to these problems. In particular, the liposome technology is ideal for combining protein antigen and adjuvant into an effective mucosal vaccine. Here, we describe and discuss recent progress in nanoparticle formulations using various types of liposomes that convey strong promise for the successful development of the next generation of mucosal vaccines. PMID:28127567

Oral mucositis in head and neck cancer: risk, biology, and management.

PubMed

Sonis, Stephen T

2013-01-01

Of the toxicities associated with conventional forms of treatment for head and neck cancers, probably none has such a consistent legacy as oral mucositis.1 Despite the fact that mucosal injury was noted as far back as Marie Curie's first forays into therapeutic radiation, an effective intervention has yet to be developed. In addition to its historic link to radiation, new therapeutic strategies including induction chemotherapy often produce mucositis, and targeted therapies appear to alter mucositis risk and its severity and course.2 The symptomatic effect of oral mucositis is profound. Disabling oral and oropharyngeal pain prevents patients from eating normally, requires opiate analgesics, and in some cases results in alteration or discontinuation of anticancer therapy.3 Furthermore, the health and economic consequences of oral mucositis are far from trivial. The incremental cost of oral mucositis in patients with head and neck cancer exceeds $17,000 (USD).4.

Pretreatment with Saccharomyces boulardii does not prevent the experimental mucositis in Swiss mice.

PubMed

Maioli, Tatiani Uceli; de Melo Silva, Brenda; Dias, Michelle Nobre; Paiva, Nivea Carolina; Cardoso, Valbert Nascimento; Fernandes, Simone Odilia; Carneiro, Cláudia Martins; Dos Santos Martins, Flaviano; de Vasconcelos Generoso, Simone

2014-04-11

The antimetabolite chemotherapy 5-Fluorouracil is one of the most commonly prescribed drugs in clinical cancer treatment. Although this drug is not specific for cancer cells and also acts on healthy cells, it can cause mucositis, a common collateral effect. Dysbiosis has also been described in 5-fluorouracil-induced mucositis and is likely to contribute to the overall development of mucositis. In light of this theory, the use of probiotics could be a helpful strategy to alleviate mucositis. So the aim of this study was evaluate the impact of the probiotic Saccharomyces boulardii in a model of mucositis. After induced of mucositis, mice from the Mucositis groups showed a decrease in food consumption (p < 0.05) and therefore had a greater weight loss (p < 0.05). The treatment with Saccharomyces boulardii did not reverse this effect (p > 0.05). Mucositis induced an increase in intestinal permeability and intestinal inflammation (p < 0.05). There were no differences in mucosal lesions, intestinal permeability and sIgA secretion (p > 0.05) in mice pretreated with S. boulardii. S. boulardii was not able to prevent the effects of experimental mucositis induced by 5- Fluorouracil.

Pretreatment with Saccharomyces boulardii does not prevent the experimental mucositis in Swiss mice

PubMed Central

2014-01-01

Background The antimetabolite chemotherapy 5-Fluorouracil is one of the most commonly prescribed drugs in clinical cancer treatment. Although this drug is not specific for cancer cells and also acts on healthy cells, it can cause mucositis, a common collateral effect. Dysbiosis has also been described in 5-fluorouracil-induced mucositis and is likely to contribute to the overall development of mucositis. In light of this theory, the use of probiotics could be a helpful strategy to alleviate mucositis. So the aim of this study was evaluate the impact of the probiotic Saccharomyces boulardii in a model of mucositis. Results After induced of mucositis, mice from the Mucositis groups showed a decrease in food consumption (p < 0.05) and therefore had a greater weight loss (p < 0.05). The treatment with Saccharomyces boulardii did not reverse this effect (p > 0.05). Mucositis induced an increase in intestinal permeability and intestinal inflammation (p < 0.05). There were no differences in mucosal lesions, intestinal permeability and sIgA secretion (p > 0.05) in mice pretreated with S. boulardii. Conclusions S. boulardii was not able to prevent the effects of experimental mucositis induced by 5- Fluorouracil. PMID:24721659

CD40L-adjuvanted DNA/modified vaccinia virus Ankara simian immunodeficiency virus SIV239 vaccine enhances SIV-specific humoral and cellular immunity and improves protection against a heterologous SIVE660 mucosal challenge.

PubMed

Kwa, Suefen; Lai, Lilin; Gangadhara, Sailaja; Siddiqui, Mariam; Pillai, Vinod B; Labranche, Celia; Yu, Tianwei; Moss, Bernard; Montefiori, David C; Robinson, Harriet L; Kozlowski, Pamela A; Amara, Rama Rao

2014-09-01

It remains a challenge to develop a successful human immunodeficiency virus (HIV) vaccine that is capable of preventing infection. Here, we utilized the benefits of CD40L, a costimulatory molecule that can stimulate both dendritic cells (DCs) and B cells, as an adjuvant for our simian immunodeficiency virus (SIV) DNA vaccine in rhesus macaques. We coexpressed the CD40L with our DNA/SIV vaccine such that the CD40L is anchored on the membrane of SIV virus-like particle (VLP). These CD40L containing SIV VLPs showed enhanced activation of DCs in vitro. We then tested the potential of DNA/SIV-CD40L vaccine to adjuvant the DNA prime of a DNA/modified vaccinia virus Ankara (MVA) vaccine in rhesus macaques. Our results demonstrated that the CD40L adjuvant enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV CD8 and CD4 T cell responses, significantly delayed the acquisition of heterologous mucosal SIV infection, and improved viral control. Notably, the CD40L adjuvant enhanced the control of viral replication in the gut at the site of challenge that was associated with lower mucosal CD8 immune activation, one of the strong predictors of disease progression. Collectively, our results highlight the benefits of CD40L adjuvant for enhancing antiviral humoral and cellular immunity, leading to enhanced protection against a pathogenic SIV. A single adjuvant that enhances both humoral and cellular immunity is rare and thus underlines the importance and practicality of CD40L as an adjuvant for vaccines against infectious diseases, including HIV-1. Despite many advances in the field of AIDS research, an effective AIDS vaccine that can prevent infection remains elusive. CD40L is a key stimulator of dendritic cells and B cells and can therefore enhance T cell and antibody responses, but its overly potent nature can lead to adverse effects unless used in small doses. In order to modulate local expression of CD40L at relatively lower levels, we expressed CD40L in a membrane-bound form, along with SIV antigens, in a nucleic acid (DNA) vector. We tested the immunogenicity and efficacy of the CD40L-adjuvanted vaccine in macaques using a heterologous mucosal SIV infection. The CD40L-adjuvanted vaccine enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV T cell responses and improved protection. These results demonstrate that VLP-membrane-bound CD40L serves as a novel adjuvant for an HIV vaccine. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Primary mucosal melanomas: a comprehensive review

PubMed Central

Mihajlovic, Marija; Vlajkovic, Slobodan; Jovanovic, Predrag; Stefanovic, Vladisav

2012-01-01

Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas. PMID:23071856

Primary mucosal melanomas: a comprehensive review.

PubMed

Mihajlovic, Marija; Vlajkovic, Slobodan; Jovanovic, Predrag; Stefanovic, Vladisav

2012-01-01

Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas.

Kindler syndrome with palmoplantar hyperhidrosis and blonde hair.

PubMed

Maheshwari, Anshul; Dhaked, Daulat Ram; Mathur, Deepak K; Bhargava, Puneet

2015-01-01

Kindler syndrome (KS) is a very rare genodermatosis characterized by acral blistering starting in infancy along with photosensitivity, progressive poikiloderma, cutaneous atrophy, and a variable degree of mucosal involvement. A large number of other cutaneous and extracutaneous features have been described, which aid in diagnosing it. Generally KS has been found to be associated with hypohidrosis/anhidrosis. We herein present a rare case of KS with unique features.

Commensal microbiome effects on mucosal immune system development in the ruminant gastrointestinal tract.

PubMed

Taschuk, Ryan; Griebel, Philip J

2012-06-01

Commensal microflora play many roles within the mammalian gastrointestinal tract (GIT) that benefit host physiology by way of direct or indirect interactions with mucosal surfaces. Commensal flora comprises members across all microbial phyla, although predominantly bacterial, with population dynamics varying with host species, genotype, and environmental factors. Little is known, however, about the complex mechanisms regulating host-commensal interactions that underlie this mutually beneficial relationship and how alterations in the microbiome may influence host development and susceptibility to infection. Research into the gut microbiome has intensified as it becomes increasingly evident that symbiont-host interactions have a significant impact on mucosal immunity and health. Furthermore, evidence that microbial populations vary significantly throughout the GIT suggest that regional differences in the microbiome may also influence immune function within distinct compartments of the GIT. Postpartum colonization of the GIT has been shown to have a direct effect on mucosal immune system development, but information is limited regarding regional effects of the microbiome on the development, activation, and maturation of the mucosal immune system. This review discusses factors influencing the colonization and establishment of the microbiome throughout the GIT of newborn calves and the evidence that regional differences in the microbiome influence mucosal immune system development and maturation. The implications of this complex interaction are also discussed in terms of possible effects on responses to enteric pathogens and vaccines.

Mucosal prior to systemic application of recombinant adenovirus boosting is more immunogenic than systemic application twice but confers similar protection against SIV-challenge in DNA vaccine-primed macaques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schulte, Reiner; Suh, You-Suk; Sauermann, Ulrike

2009-01-20

We investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by various routes in the Simian immunodeficiency virus (SIV) rhesus monkey model for AIDS. Twelve animals were immunized with SIV DNA-vectors followed by the application of a recombinant adenovirus (rAd5) expressing the same genes either intramuscularly (i.m.) or by oropharyngeal spray. The second rAd5-application was given i.m. All vaccinees plus six controls were challenged orally with SIVmac239 12 weeks post-final immunization. Both immunization strategies induced strong SIV Gag-specific IFN-{gamma} and T-cell proliferation responses and mediated a conservation of CD4{sup +} memory T-cells and a reduction of viralmore » load during peak viremia following infection. Interestingly, the mucosal group was superior to the systemic group regarding breadth and strength of SIV-specific T-cell responses and exhibited lower vector specific immune responses. Therefore, our data warrant the inclusion of mucosal vector application in a vaccination regimen which makes it less invasive and easier to apply.« less

Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis.

PubMed

Yadev, Nishant P; Murdoch, Craig; Saville, Stephen P; Thornhill, Martin H

2011-06-01

Candida albicans is a commensal organism that can be isolated from the majority of healthy individuals. However, in certain susceptible individuals C. albicans can become pathogenic leading to the mucocutaneous infection; oral candidiasis. Murine models and in vitro monolayer cultures have generated some data on the likely virulence and host factors that contribute to oral candidiasis but these models have limitations. Recently, tissue engineered oral mucosal models have been developed to mimic the normal oral mucosa but little information is available on their true representation. In this study, we assessed the histological features of three different tissue engineered oral mucosal models compared to the normal oral mucosa and analysed both cell damage and cytokine release following infection with C. albicans. Models comprised of normal oral keratinocytes and a fibroblast-containing matrix displayed more similar immunohistological and proliferation characteristics to normal mucosa, compared to models composed of an oral carcinoma cell line. Although all models were invaded and damaged by C. albicans in a similar manner, the cytokine response was much more pronounced in models containing normal keratinocytes. These data suggest that models based on normal keratinocytes atop a fibroblast-containing connective tissue will significantly aid in dissecting the molecular pathogenesis of oral candidiasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemotherapy-Induced and/or Radiation Therapy-Induced Oral Mucositis—Complicating the Treatment of Cancer

PubMed Central

Naidu, Maddireddy Umameshwar Rao; Ramana, Gogula Venkat; Rani, Pingali Usha; Mohan, Iyyapu Krishna; Suman, Avula; Roy, Priyadarshni

2004-01-01

Abstract The term mucositis is coined to describe the adverse effects of radiation and chemotherapy treatments. Mucositis is one of the most common adverse reactions encountered in radiation therapy for head and neck cancers, as well as in chemotherapy, in particular with drugs affecting DNA synthesis (S-phase-specific agents such as fluorouracil, methotrexate, and cytarabine). Mucositis may limit the patient's ability to tolerate chemotherapy or radiation therapy, and nutritional status is compromised. It may drastically affect cancer treatment as well as the patient's quality of life. The incidence and severity of mucositis will vary from patient to patient. It will also vary from treatment to treatment. It is estimated that there is 40% incidence of mucositis in patients treated with standard chemotherapy and this will not only increase with the number of treatment cycles but also with previous episodes. Similarly, patients who undergo bone marrow transplantation and who receive high doses of chemotherapy have a 76% chance of getting mucositis. Patients receiving radiation, in particular to head and neck cancers, have a 30% to 60% chance. The exact pathophysiology of development is not known, but it is thought to be divided into direct and indirect mucositis. Chemotherapy and/or radiation therapy will interfere with the normal turnover of epithelial, cells leading to mucosal injury; subsequently, it can also occur due to indirect invasion of Gram-negative bacteria and fungal species because most of the cancer drugs will cause changes in blood counts. With the advancement in cytology, a more precise mechanism has been established. With this understanding, we can select and target particular mediators responsible for the mucositis. Risk factors such as age, nutritional status, type of malignancy, and oral care during treatment will play important roles in the development of mucositis. Many treatment options are available to prevent and treat this condition, but none of them can completely prevent or treat mucositis. More and more pathological methods are being developed to understand this condition so that better therapeutic regimens can be selected. Emphasis also should be made in assessing the patient's psychologic condition, particular depressive disorders. This is important because treatment with antidepressants will not only contribute in lifting depression but also reduces pain somatization. Although mucositis is rarely life-threatening, it will interfere with treatment of cancer to a great extent. PMID:15548350

Does Long-Term Itraconazole Prophylaxis Result in In Vitro Azole Resistance in Mucosal Candida albicans Isolates from Persons with Advanced Human Immunodeficiency Virus Infection?

PubMed Central

Goldman, Mitchell; Cloud, Gretchen A.; Smedema, Melinda; LeMonte, Ann; Connolly, Patricia; McKinsey, David S.; Kauffman, Carol A.; Moskovitz, Bruce; Wheat, L. Joseph

2000-01-01

The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. Mucosal Candida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicans accounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC50) for last-episode isolates from the itraconazole group was 0.125 μg/ml compared to 0.015 μg/ml for the placebo group subjects, P = 0.0001. The MIC50 of fluconazole for the last isolates from the itraconazole group was 1.5 μg/ml compared to 0.5 μg/ml for the placebo subjects (P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P = 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole. PMID:10817713

[Therapeutic effect of rebamipide for oral mucositis associated with FEC therapy for breast cancer].

PubMed

Enami, Akiko; Masuda, Norikazu; Yamamura, Jun; Mizutani, Makiko; Yasojima, Hiroyuki; Shikata, Ayako; Masaoka, Miyuki; Takada, Seiko; Bamba, Nao; Yamamoto, Mie; Abe, Megumi; Makihara, Katsuya

2014-11-01

No guidelines for supportive drug therapy have been established for oral mucositis occurring during cancer chemotherapy. We retrospectively examined the progression of oral mucositis in 91 patients with breast cancer who received the 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 regimen between September 2007 and August 2008. Daily rebamipide was administered to patients with oral mucositis as per hospital protocol to evaluate the hypothesized preventive and mucosal protective effects of rebamipide(Mucosta®). Oral mucositis was observed in 43 patients (47%)during 4 courses of FEC. The median age of the patients was 55 years(range, 32-76 years). Of the 91 patients, 49 patients who did not receive rebamipide during the 4 FEC courses were classified as group A, 14 patients who received rebamipide before the start of FEC were classified as group B, and 28 patients who received rebamipide after developing oral mucositis were classified as group C. The incidence of oral mucositis at the start of FEC with or without rebamipide administration was observed in 5 patients in group B (36%) and 38 patients in groups A and C (49%) (p=0.3472). The mucositis grade was G1 in 4 patients and G2 in 1 patient in group B, and G1 in 20 patients and G2 plus G3 in 18 patients in groups A and C (p=0.2467). In group C, the grade decreased in 25 patients (89%) and did not occur (G0) in 17 patients (61%) during the next course, and 15 patients (54%) continued to the final course without any occurrence of mucositis. These results suggest that rebamipide is effective for the treatment of oral mucositis. Although significant differences were not observed in the groups, rebamipide has the potential to prevent development of oral mucositis and alleviate its symptoms, and seems promising as a new supportive drug therapy. We hope to verify the preventive and protective effects of rebamipide by conducting a prospective, randomized trial while treating oral mucositis with basic oral care and appropriate interventions provided by a multidisciplinary team.

Chemotherapy-induced oral mucositis and associated infections in a novel organotypic model.

PubMed

Sobue, T; Bertolini, M; Thompson, A; Peterson, D E; Diaz, P I; Dongari-Bagtzoglou, A

2018-06-01

Oral mucositis is a common side effect of cancer chemotherapy, with significant adverse impact on the delivery of anti-neoplastic treatment. There is a lack of consensus regarding the role of oral commensal microorganisms in the initiation or progression of mucositis because relevant experimental models are non-existent. The goal of this study was to develop an in vitro mucosal injury model that mimics chemotherapy-induced mucositis, where the effect of oral commensals can be studied. A novel organotypic model of chemotherapy-induced mucositis was developed based on a human oral epithelial cell line and a fibroblast-embedded collagen matrix. Treatment of organotypic constructs with 5-fluorouracil (5-FU) reproduced major histopathologic characteristics of oral mucositis, such as DNA synthesis inhibition, apoptosis and cytoplasmic vacuolation, without compromising the three-dimensional structure of the multilayer organotypic mucosa. Although structural integrity of the model was preserved, 5-FU treatment resulted in a widening of epithelial intercellular spaces, characterized by E-cadherin dissolution from adherens junctions. In a neutrophil transmigration assay we discovered that this treatment facilitated transport of neutrophils through epithelial layers. Moreover, 5-FU treatment stimulated key proinflammatory cytokines that are associated with the pathogenesis of oral mucositis. 5-FU treatment of mucosal constructs did not significantly affect fungal or bacterial biofilm growth under the conditions tested in this study; however, it exacerbated the inflammatory response to certain bacterial and fungal commensals. These findings suggest that commensals may play a role in the pathogenesis of oral mucositis by amplifying the proinflammatory signals to mucosa that is injured by cytotoxic chemotherapy. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Global issues in pediatric nutrition: AIDS.

PubMed

Ball, C S

1998-10-01

Nutrition is a final common pathway in chronic disease, and weight loss is a major manifestation of acquired immunodeficiency syndrome (AIDS). In sub-Saharan Africa, studies have shown that 25% of children with malnutrition have human immunodeficiency virus (HIV) infection, although patterns of malnutrition are indistinguishable from those who are HIV negative. Breast-feeding increases the risk of vertical transmission, and the overall risk versus benefit needs continuing careful consideration in relation to local mortality from gastroenteritis and malnutrition. Chronic diarrhea is much more common in HIV-infected children in Africa and may have a multiplicity of causes, including infection with adherent forms of Escherichia coli, protozoa, and even direct HIV infection of intestinal mucosal cells. The HIV wasting syndrome produces reduction in bioelectrical impedence, fat, lean body mass, and body cell mass, but the changes can be predicted from equations used in starvation states. Micronutrients may be important, but observed changes may be due to immune mediator activation, rather than malnutrition. Calorie supplementation is beneficial when delivered by any route, but is likely to produce the greatest positive change when CD4 counts are highest in relation to calorie intake. Paradoxically, HIV-infected children may be obese early in the disease until AIDS develops. There is an inextricable link between disease and nutritional status. In children with AIDS wasting syndrome, a low CD4 count and high viral load are likely so that effective antiviral treatment may ultimately produce the greatest improvement in health, including nutritional status.

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs

PubMed Central

Matoba, Nobuyuki; Magérus, Aude; Geyer, Brian C.; Zhang, Yunfang; Muralidharan, Mrinalini; Alfsen, Annette; Arntzen, Charles J.; Bomsel, Morgane; Mor, Tsafrir S.

2004-01-01

A vaccine that would engage the mucosal immune system against a broad range of HIV-1 subtypes and prevent epithelial transmission is highly desirable. Here we report fusing the mucosal targeting B subunit of cholera toxin to the conserved galactosylceramide-binding domain (including the ELDKWA-neutralizing epitope) of the HIV-1 gp41 envelope protein, which mediates the transcytosis of HIV-1 across the mucosal epithelia. Chimeric protein expressed in bacteria or plants assembled into oligomers that were capable of binding galactosyl-ceramide and GM1 gangliosides. Mucosal (intranasal) administration in mice of the purified chimeric protein followed by an i.p. boost resulted in transcytosis-neutralizing serum IgG and mucosal IgA responses and induced immunological memory. Plant production of mucosally targeted immunogens could be particularly useful for immunization programs in developing countries, where desirable product traits include low cost of manufacture, heat stability, and needle-free delivery. PMID:15347807

Mucosal Vaccination against Tuberculosis Using Inert Bioparticles

PubMed Central

Reljic, Rajko; Sibley, Laura; Huang, Jen-Min; Pepponi, Ilaria; Hoppe, Andreas; Hong, Huynh A.

2013-01-01

Needle-free, mucosal immunization is a highly desirable strategy for vaccination against many pathogens, especially those entering through the respiratory mucosa, such as Mycobacterium tuberculosis. Unfortunately, mucosal vaccination against tuberculosis (TB) is impeded by a lack of suitable adjuvants and/or delivery platforms that could induce a protective immune response in humans. Here, we report on a novel biotechnological approach for mucosal vaccination against TB that overcomes some of the current limitations. This is achieved by coating protective TB antigens onto the surface of inert bacterial spores, which are then delivered to the respiratory tract. Our data showed that mice immunized nasally with coated spores developed humoral and cellular immune responses and multifunctional T cells and, most importantly, presented significantly reduced bacterial loads in their lungs and spleens following pathogenic challenge. We conclude that this new vaccine delivery platform merits further development as a mucosal vaccine for TB and possibly also other respiratory pathogens. PMID:23959722

The role of Octenidol(®), Glandomed(®) and chlorhexidine mouthwash in the prevention of mucositis and in the reduction of the oropharyngeal flora: a double-blind randomized controlled trial.

PubMed

Mutters, Nico T; Neubert, Thomas R; Nieth, Rudolf; Mutters, Reinier

2015-01-01

The oropharyngeal flora is of importance for the development of oral mucositis, which is a frequent complication in oncologic practice. It also plays a role in the pathogenesis of ventilator-associated pneumonia. Mucositis is associated with significantly worse clinical and economic outcomes. The aim of our study was to assess the efficacy of Octenidol(®), Glandomed(®) and chlorhexidine mouthwash in the prevention of mucositis and reduction of the oropharyngeal flora. A prospective, double-blinded RCT including two strata was conducted between October 2008 and November 2010. Stratum i consisted of ventilated cardiothoracic surgical patients. Stratum ii consisted of medical patients with haemato-oncological malignancies requiring stem cell transplantation. The primary outcome measures were development of mucositis regarding to OMAS/WHO score and reduction of the oropharyngeal flora. Both strata showed low OMAS/WHO scores which did not differ significantly between the groups. The overall mean reduction of colony forming units was significantly higher in the Octenidol(®) group compared to the chlorhexidine and the Glandomed(®) groups. No significant differences in the development of mucositis were found, thus all solutions proved successful in the prevention of mucositis. However, Octenidol(®) was superior in the reduction of the oropharyngeal flora. Hence, the preventive effect on nosocomial infections might be higher in patients using Octenidol(®) rather than chlorhexidine or Glandomed(®).

Management of Chemoradiation-Induced Mucositis in Head and Neck Cancers With Oral Glutamine

PubMed Central

Panda, Niharika; Dash, Manoj Kumar; Mohanty, Sumita; Samantaray, Sagarika

2016-01-01

Purpose Head and neck cancers are the third most common cancers worldwide. Oral mucositis is the most common toxicity seen in patients who receive chemoradiation to treat head and neck cancer. The aim of this study was to evaluate the efficacy and safety of oral glutamine supplementation in these patients. Materials and Methods From December 2013 to December 2014, we randomly assigned to two arms 162 patients who had squamous cell carcinoma of the head and neck. Patients in arm A were given oral glutamine once per day, whereas those in arm B served as negative control subjects. All patients received radiotherapy given as 70 Gy in 35 fractions over 7 weeks with an injection of cisplatin once per week. Patients were assessed once per week to evaluate for the onset and severity of mucositis, pain, use of analgesics, and for Ryle tube feeding. Results We observed that 53.1% of patients developed mucositis toward the fifth week in the glutamine arm compared with 55.5% of patients in the control arm at the third week. None in the glutamine arm compared with 92.35% of patients in the control arm developed G3 mucositis. Rates of adverse events like pain, dysphagia, nausea, edema, and cough, as well as use of analgesics and Ryle tube feeding, were significantly lower in the glutamine arm than in the control arm. Conclusion This study highlights that the onset as well as the severity of mucositis in patients receiving glutamine was significantly delayed. None of the patients receiving glutamine developed G3 mucositis. Hence, the findings emphasize the use of oral glutamine supplementation as a feasible and affordable treatment option for mucositis in patients with head and neck cancers who are receiving chemoradiation. PMID:28717702

Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation

PubMed Central

Sung, Lillian; Robinson, Paula; Treister, Nathaniel; Baggott, Tina; Gibson, Paul; Tissing, Wim; Wiernikowski, John; Brinklow, Jennifer; Dupuis, L Lee

2017-01-01

Purpose To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0–18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). Methods The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. Results We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. Conclusions All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted. PMID:25818385

Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation.

PubMed

Sung, Lillian; Robinson, Paula; Treister, Nathaniel; Baggott, Tina; Gibson, Paul; Tissing, Wim; Wiernikowski, John; Brinklow, Jennifer; Dupuis, L Lee

2017-03-01

To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0-18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Clinical Implications of Oral Candidiasis: Host Tissue Damage and Disseminated Bacterial Disease

PubMed Central

Kong, Eric F.; Kucharíková, Sona; Peters, Brian M.; Shirtliff, Mark E.

2014-01-01

The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species Candida albicans and the bacterium Staphylococcus aureus are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV+ and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to S. aureus resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive C. albicans hyphal invasion coupled with S. aureus deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of C. albicans. Further, in contrast to previous findings, S. aureus dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal C. albicans infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals. PMID:25422264

Clinical implications of oral candidiasis: host tissue damage and disseminated bacterial disease.

PubMed

Kong, Eric F; Kucharíková, Sona; Van Dijck, Patrick; Peters, Brian M; Shirtliff, Mark E; Jabra-Rizk, Mary Ann

2015-02-01

The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species Candida albicans and the bacterium Staphylococcus aureus are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV(+) and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to S. aureus resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive C. albicans hyphal invasion coupled with S. aureus deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of C. albicans. Further, in contrast to previous findings, S. aureus dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal C. albicans infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

PubMed

Oosterom, N; Dirks, N F; Heil, S G; de Jonge, R; Tissing, W J E; Pieters, R; van den Heuvel-Eibrink, M M; Heijboer, A C; Pluijm, S M F

2018-06-19

Children with acute lymphoblastic leukemia (ALL) are at increased risk of vitamin D deficiency, which might make them more susceptible to developing adverse events. Previous studies showed that low vitamin D levels were associated with an increased inflammatory mucosal state and impaired mucosal tissue barriers. We examined the prevalence of vitamin D deficiency and studied the association between vitamin D levels and methotrexate (MTX)-induced oral mucositis in pediatric ALL. We assessed 25-hydroxyvitamin D (25(OH)D 3 ) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D 3 ) levels in 99 children with ALL before the start of 4 × 5 g/m 2 high-dose methotrexate (HD-MTX) (T0) and in 81/99 children after discontinuation of HD-MTX (T1). Two cutoff values for vitamin D deficiency exist: 25(OH)D 3 levels < 30 and < 50 nmol/L. Oral mucositis was defined as grade ≥ 3 according to the National Cancer Institute Criteria. Vitamin D deficiency occurred in respectively 8% (< 30 nmol/L) and 33% (< 50 nmol/L) of the patients at T0, and more frequently in children > 4 years of age as compared to children between 1 and 4 years of age. A decrease in 25(OH)D 3 levels during HD-MTX therapy was associated with developing severe oral mucositis (OR 1.6; 95% CI [1.1-2.4]). 25(OH)D 3 and 24,25(OH) 2 D 3 levels at T0 and the change in 24,25(OH) 2 D 3 levels during therapy were not associated with the development of severe oral mucositis. This study showed that vitamin D deficiency occurs frequently in pediatric ALL patients above the age of 4 years. A decrease in 25(OH)D 3 levels during MTX therapy was observed in children with ALL that developed severe oral mucositis.

Recombinant poxviruses as mucosal vaccine vectors.

PubMed

Gherardi, M Magdalena; Esteban, Mariano

2005-11-01

The majority of infections initiate their departure from a mucosal surface, such as Human immunodeficiency virus (HIV), a sexually transmitted virus. Therefore, the induction of mucosal immunity is a high priority in the development of vaccines against mucosal pathogens. The selection of an appropriate antigen delivery system is necessary to induce an efficient mucosal immune response. Poxvirus vectors have been the most intensively studied live recombinant vector, and numerous studies have demonstrated their ability to induce mucosal immune responses against foreign expressed antigens. Previous studies have demonstrated that recombinants based on the attenuated modified vaccinia virus Ankara (MVA) vector were effective in inducing protective responses against different respiratory viruses, such as influenza and respiratory syncytial virus, following immunization via mucosal routes. Recent studies performed in the murine and macaque models have shown that recombinant MVA (rMVA) does not only stimulate HIV-specific immunity in the genital and rectal tracts following mucosal delivery, but can also control simian/human immunodeficiency viraemia and disease progression. In addition, a prime-boost vaccination approach against tuberculosis emphasized the importance of the intranasal rMVA antigen delivery to induce protective immunity against Mycobacterium tuberculosis. The aim of this review is to summarize the studies employing recombinant poxviruses, specifically rMVA as a mucosal delivery vector. The results demonstrate that rMVAs can activate specific immune responses at mucosal surfaces, and encourage further studies to characterize and improve the MVA mucosal immunogenicity of poxvirus vectors.

Chemotherapy: the effect of oral cryotherapy on the development of mucositis.

PubMed

Karagözoğlu, Serife; Filiz Ulusoy, Mehlika

2005-07-01

The aim of this study is to investigate the effect of oral cryotherapy on the development of chemotherapy-induced mucositis in patients administered combined chemotherapy. Mucositis has been of interest to scientists for more than 20 years. Unfortunately, this has not resulted in the development of standard procedures for prevention and management. To cope with this side-effect and to prevent opportunistic infections that may emerge during treatment, attempts are taken to provide preventative and comfort measures. In this context, cryotherapy (oral cooling) has become popular as a cheap and readily applicable method in preventing the developing due the rapid infusion of chemotherapy agents, or decreasing its severity. Study involved 60 patients, 30 of whom were in the study group and 30 in the control group. Ice cubes at a size that can be moved easily in the mouth and whose corners have been smoothed in order that they will not cause irritation in the mouth has been used in oral cryotherapy in the study group. Oral chemotherapy was initiated five minutes before chemotherapy and maintained during venous infusions of etoposide (Vepesid), platinol (Cisplatin), mitomycin (Mitomycin-C) and vinblastin (Velbe) depending on the chemotherapy course. According to Patient-Judged Mucositis Grading, the rate of mucositis is 36.7% in study group and 90.0% in control group, the difference between two groups being statistically significant (P < 0.05). According to Physician-Judged Mucositis Grading, the rate of mucositis is 10.0% in the study group and 50.0% in the control group, the difference between two groups being statistically significant (P < 0.05). Oral pH values decreased in 90% of the subjects in study group, i.e. mucositis risk was reduced whereas oral pH values remained unchanged or decreased in 86.7% of the subjects in the control group, namely mucositis risk increased. The difference between study and control groups in terms of the change in pH values after chemotherapy was found to be statistically significant (P < 0.05). Our findings have demonstrated that oral cryotherapy makes an important contribution to the protection of oral health by reducing the mucositis score according to patient- and physician-judged mucositis score and by increasing oral pH values. Aggressive cancer therapy places patients at greater risk for oral complications and treatment-related consequences. Unfortunately, prevention and/or treatment of such oral sequelae have often become overlooked as priorities of the treatment team. Effective approaches for the prevention or treatment of oral mucositis have not been standardized, and vary considerably among institutions. Prophylactic measures begin with an increased emphasis on improved oral status. Oral cryotherapy, the therapeutic administration of cold, is a prophylactic measure for oral inflammation. The relevance for clinical practice will be to understand the content of mucositis; comprehensive care should focus on the prevention of this complication in the clinical practice.

Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment.

PubMed

Saadeh, Claire E

2005-04-01

Oral mucositis is a frequently encountered and potentially severe complication associated with administration of chemotherapy and radiotherapy. Although many pharmacologic interventions have been used for the prevention and treatment of oral mucositis, there is not one universally accepted strategy for its management. Most preventive and treatment strategies are based on limited, often anecdotal, clinical data. Basic oral hygiene and comprehensive patient education are important components of care for any patient with cancer at risk for development of oral mucositis. Nonpharmacologic approaches for the prevention of oral mucositis include oral cryotherapy for patients receiving chemotherapy with bolus 5-fluorouracil, and low-level laser therapy for patients undergoing hematopoietic stem cell transplantation. Chlorhexidine, amifostine, hematologic growth factors, pentoxifylline, glutamine, and several other agents have all been investigated for prevention of oral mucositis. Results have been conflicting, inconclusive, or of limited benefit. Treatment of established mucositis remains a challenge and focuses on a palliative management approach. Topical anesthetics, mixtures (also called cocktails), and mucosal coating agents have been used despite the lack of experimental evidence supporting their efficacy. Investigational agents are targeting the specific mechanisms of mucosal injury; among the most promising of these is recombinant human keratinocyte growth factor.

Multi-scale Finite Element Modeling of Eustachian Tube Function: Influence of Mucosal Adhesion

PubMed Central

Malik, J.E.; Swarts, J.D.; Ghadiali, S. N.

2017-01-01

The inability to open the collapsible Eustachian tube (ET) leads to the development of chronic Otitis Media (OM). Although mucosal inflammation during OM leads to increased mucin gene expression and elevated adhesion forces within the ET lumen, it is not known how changes in mucosal adhesion alter the biomechanical mechanisms of ET function. In this study, we developed a novel multi-scale finite element model of ET function in adults that utilizes adhesion spring elements to simulate changes in mucosal adhesion. Models were created for six adult subjects and dynamic patterns in muscle contraction were used to simulate the wave-like opening of the ET that occurs during swallowing. Results indicate that ET opening is highly sensitive to the level of mucosal adhesion and that exceeding a critical value of adhesion leads to rapid ET dysfunction. Parameter variation studies and sensitivity analysis indicate that increased mucosal adhesion alters the relative importance of several tissue biomechanical properties. For example, increases in mucosal adhesion reduced the sensitivity of ET function to tensor veli palatini muscle forces but did not alter the insensitivity of ET function to levator veli palatini muscle forces. Interestingly, although changes in cartilage stiffness did not significantly influence ET opening under low adhesion conditions, ET opening was highly sensitive to changes in cartilage stiffness under high adhesion conditions. Therefore, our multi-scale computational models indicate that changes in mucosal adhesion as would occur during inflammatory OM alter the biomechanical mechanisms of ET function. PMID:26891171

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

PubMed

Lalla, Rajesh V; Bowen, Joanne; Barasch, Andrei; Elting, Linda; Epstein, Joel; Keefe, Dorothy M; McGuire, Deborah B; Migliorati, Cesar; Nicolatou-Galitis, Ourania; Peterson, Douglas E; Raber-Durlacher, Judith E; Sonis, Stephen T; Elad, Sharon

2014-05-15

Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis. A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, in each treatment setting, was assigned a level of evidence, based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. The literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Oral mucositis: etiology, and clinical and pharmaceutical management.

PubMed

Zur, Eyal

2012-01-01

Oral mucosal damage is one of the common and worst side effects of radiotherapy and chemotherapy treatment for cancer. With prevalence between 10% and 100%, depending on the cytotoxic and/or radiotherapy regimen and patient-associated variables, this morbid condition represents a significant problem in oncology. This article addresses oral mucositis and discusses its prevalence, risk factors, clinical and economical impacts, etiology, and clinical management in view of the most recent evidence. Despite clear progress and the development of clinical guidelines on this topic, what we currently have to offer to patients to manage mucositis and oropharyngeal pain is still inadequate. This article offers two compounded preparations supported by evidence-based data to treat oral mucositis. Expansion of the knowledge of the pathogenesis of mucositis as well as a better insight into individual risk factors will provide opportunities to improve management strategies.

Immune cell populations within the duodenal mucosa of dogs with enteropathies.

PubMed

German, A J; Hall, E J; Day, M J

2001-01-01

The mucosal immune system may play a critical role in the pathogenesis of small intestinal enteropathies. The aim of the current study was to assess mucosal immune cell populations in dogs with inflammatory bowel disease (IBD), idiopathic antibiotic-responsive diarrhea (ARD), and adverse reactions to food (FR). Endoscopic biopsies were performed of the duodenum of dogs with these conditions and from a group of dogs without enteric disease. Additional control samples were collected after death from other dogs that did not have evidence of enteric disease. Immunohistochemistry and computer-aided morphometry were used to assess the distribution of immune cell subsets in both lamina propria and intestinal epithelium. Compared with controls, dogs with ARD had increased numbers of lamina propria immunoglobulin (Ig) A- plasma cells and CD4+ cells. More marked alterations were noted in dogs with IBD, with significant increases in lamina propria IgG+ plasma cells, T cells (CD3+), CD4+ cells, macrophages, and neutrophils, but with reduced mast cell numbers. Increased intraepithelial CD3+ T cells were also present in the dogs with IBD, compared with controls. However, lamina propria and epithelial populations were unaltered in dogs with FR when compared with controls. The altered mucosal immune cell populations observed in dogs with ARD or IBD may reflect an underlying immunologic pathogenesis in these disorders.

Advanced topical drug delivery system for the management of vaginal candidiasis.

PubMed

Johal, Himmat Singh; Garg, Tarun; Rath, Goutam; Goyal, Amit Kumar

2016-01-01

Vaginal candidiasis or vulvovaginal candidiasis (VC) is a common mucosal infection of vagina, mainly caused by Candida species. The major symptoms of VC are dyspareunia, pruritis, itching, soreness, vagina as well as vulvar erythema and edema. Most common risk factors that lead to the imbalance in the vaginal micro biota are the use of antibiotics, pregnancy, diabetes mellitus, immuno suppression as in AIDS or HIV patients, frequent sexual intercourse, spermicide and intra-uterine devices and vaginal douching. Various anti-fungal drugs are available for effective treatment of VC. Different conventional vaginal formulations (creams, gels, suppositories, powder, ointment, etc.) for VC are available today but have limited efficacy because of lesser residence time on vaginal epithelium due to self-cleansing action of vagina. So to overcome this problem, an extended and intimate contact with vaginal mucosa is desired; which can be accomplished by utilizing mucoadhesive polymers. Mucoadhesive polymers have an excellent binding capacity to mucosal tissues for considerable period of time. This unique property of these polymers significantly enhances retention time of different formulations on mucosal tissues. Currently, various novel formulations such as liposomes, nano- and microparticles, micro-emulsions, bio-adhesive gel and tablets are used to control and treat VC. In this review, we focused on current status of vaginal candidiasis, conventional and nanotechnology inspired formulation approaches.

Velopharyngeal mucosal surface topography in healthy subjects and subjects with obstructive sleep apnea.

PubMed

Lambeth, Christopher; Amatoury, Jason; Wang, Ziyu; Foster, Sheryl; Amis, Terence; Kairaitis, Kristina

2017-03-01

Macroscopic pharyngeal anatomical abnormalities are thought to contribute to the pathogenesis of upper airway (UA) obstruction in obstructive sleep apnea (OSA). Microscopic changes in the UA mucosal lining of OSA subjects are reported; however, the impact of these changes on UA mucosal surface topography is unknown. This study aimed to 1 ) develop methodology to measure UA mucosal surface topography, and 2 ) compare findings from healthy and OSA subjects. Ten healthy and eleven OSA subjects were studied. Awake, gated (end expiration), head and neck position controlled magnetic resonance images (MRIs) of the velopharynx (VP) were obtained. VP mucosal surfaces were segmented from axial images, and three-dimensional VP mucosal surface models were constructed. Curvature analysis of the models was used to study the VP mucosal surface topography. Principal, mean, and Gaussian curvatures were used to define surface shape composition and surface roughness of the VP mucosal surface models. Significant differences were found in the surface shape composition, with more saddle/spherical and less flat/cylindrical shapes in OSA than healthy VP mucosal surface models ( P < 0.01). OSA VP mucosal surface models were also found to have more mucosal surface roughness ( P < 0.0001) than healthy VP mucosal surface models. Our novel methodology was utilized to model the VP mucosal surface of OSA and healthy subjects. OSA subjects were found to have different VP mucosal surface topography, composed of increased irregular shapes and increased roughness. We speculate increased irregularity in VP mucosal surface may increase pharyngeal collapsibility as a consequence of friction-related pressure loss. NEW & NOTEWORTHY A new methodology was used to model the upper airway mucosal surface topography from magnetic resonance images of patients with obstructive sleep apnea and healthy adults. Curvature analysis was used to analyze the topography of the models, and a new metric was derived to describe the mucosal surface roughness. Increased roughness was found in the obstructive sleep apnea vs. healthy group, but further research is required to determine the functional effects of the measured difference on upper airway airflow mechanics. Copyright © 2017 the American Physiological Society.

Mucosal immunity and novel tuberculosis vaccine strategies: route of immunisation-determined T-cell homing to restricted lung mucosal compartments.

PubMed

Lai, Rocky; Afkhami, Sam; Haddadi, Siamak; Jeyanathan, Mangalakumari; Xing, Zhou

2015-06-01

Despite the use of bacille Calmette-Guérin (BCG) for almost a century, pulmonary tuberculosis (TB) continues to be a serious global health concern. Therefore, there has been a pressing need for the development of new booster vaccines to enhance existing BCG-induced immunity. Protection following mucosal intranasal immunisation with AdHu5Ag85A is associated with the localisation of antigen-specific T-cells to the lung airway. However, parenteral intramuscular immunisation is unable to provide protection despite the apparent presence of antigen-specific T-cells in the lung interstitium. Recent advances in intravascular staining have allowed us to reassess the previously established T-cell distribution profile and its relationship with the observed differential protection. Respiratory mucosal immunisation empowers T-cells to home to both the lung interstitium and the airway lumen, whereas intramuscular immunisation-activated T-cells are largely trapped within the pulmonary vasculature, unable to populate the lung interstitium and airway. Given the mounting evidence supporting the safety and enhanced efficacy of respiratory mucosal immunisation over the traditional parenteral immunisation route, a greater effort should be made to clinically develop respiratory mucosal-deliverable TB vaccines. Copyright ©ERS 2015.

Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines

NASA Astrophysics Data System (ADS)

Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-Ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

2010-07-01

Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (`nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy--a randomized controlled trial.

PubMed

Svanberg, Anncarin; Birgegård, Gunnar; Ohrn, Kerstin

2007-10-01

Mucositis is a major complication in myeloablative therapy, which often necessitates advanced pharmacological pain treatment, including i.v. opioids. Attempts to prevent oral mucositis have included oral cryotherapy, which has been shown to reduce mucositis, but there is a lack of knowledge concerning the effect of oral cryotherapy on opioid use by reducing the mucositis for patients treated with myeloablative therapy before bone marrow transplantation (BMT). The aim of the present study was to evaluate if oral cryotherapy could delay or alleviate the development of mucositis and thereby reduce the number of days with i.v. opioids among patients who receive myeloablative therapy before BMT. Eighty patients 18 years and older, scheduled for BMT, were included consecutively and randomised to oral cryotherapy or standard oral care. A stratified randomisation was used with regard to type of transplantation. Intensity of pain, severity of mucositis and use of opioids were recorded using pain visual analogue scale (VAS) scores, mucositis index scores and medical and nursing charts. This study showed that patients receiving oral cryotherapy had less pronounced mucositis and significantly fewer days with i.v. opioids than the control group. In the autologous setting, cryotherapy patients also needed significantly lower total dose of opioids. Oral cryotherapy is an effective and well-tolerated therapy to alleviate mucositis and consequently reduce the number of days with i.v. opioids among patients treated with myeloablative therapy before BMT.

Antibody-mediated protection against mucosal simian-human immunodeficiency virus challenge of macaques immunized with alphavirus replicon particles and boosted with trimeric envelope glycoprotein in MF59 adjuvant.

PubMed

Barnett, Susan W; Burke, Brian; Sun, Yide; Kan, Elaine; Legg, Harold; Lian, Ying; Bost, Kristen; Zhou, Fengmin; Goodsell, Amanda; Zur Megede, Jan; Polo, John; Donnelly, John; Ulmer, Jeffrey; Otten, Gillis R; Miller, Christopher J; Vajdy, Michael; Srivastava, Indresh K

2010-06-01

We have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus SHIV(SF162P4) following sequential immunization with alphavirus replicon particles (VRP) of a chimeric recombinant VEE/SIN alphavirus (derived from Venezuelan equine encephalitis virus [VEE] and the Sindbis virus [SIN]) encoding human immunodeficiency virus type 1 HIV-1(SF162) gp140DeltaV2 envelope (Env) and trimeric Env protein in MF59 adjuvant (R. Xu, I. K. Srivastava, C. E. Greer, I. Zarkikh, Z. Kraft, L. Kuller, J. M. Polo, S. W. Barnett, and L. Stamatatos, AIDS Res. Hum. Retroviruses 22:1022-1030, 2006). The protection did not require T-cell immune responses directed toward simian immunodeficiency virus (SIV) Gag. We extend those findings here to demonstrate antibody-mediated protection against mucosal challenge in macaques using prime-boost regimens incorporating both intramuscular and mucosal routes of delivery. The macaques in the vaccination groups were primed with VRP and then boosted with Env protein in MF59 adjuvant, or they were given VRP intramuscular immunizations alone and then challenged with SHIV(SF162P4) (intrarectal challenge). The results demonstrated that these vaccines were able to effectively protect the macaques to different degrees against subsequent mucosal SHIV challenge, but most noteworthy, all macaques that received the intramuscular VRP prime plus Env protein boost were completely protected. A statistically significant association was observed between the titer of virus neutralizing and binding antibodies as well as the avidity of anti-Env antibodies measured prechallenge and protection from infection. These results highlight the merit of the alphavirus replicon vector prime plus Env protein boost vaccine approach for the induction of protective antibody responses and are of particular relevance to advancing our understanding of the potential correlates of immune protection against HIV infection at a relevant mucosal portal of entry.

Effect of nanovaccine chemistry on humoral immune response kinetics and maturation

NASA Astrophysics Data System (ADS)

Haughney, Shannon L.; Ross, Kathleen A.; Boggiatto, Paola M.; Wannemuehler, Michael J.; Narasimhan, Balaji

2014-10-01

Acute respiratory infections represent a significant portion of global morbidity and mortality annually. There is a critical need for efficacious vaccines against respiratory pathogens. To vaccinate against respiratory disease, pulmonary delivery is an attractive route because it mimics the route of natural infection and can confer both mucosal and systemic immunity. We have previously demonstrated that a single dose, intranasal vaccine based on polyanhydride nanoparticles elicited a protective immune response against Yersinia pestis for at least 40 weeks after immunization with F1-V. Herein, we investigate the effect of nanoparticle chemistry and its attributes on the kinetics and maturation of the antigen-specific serum antibody response. We demonstrate that manipulation of polyanhydride nanoparticle chemistry facilitated differential kinetics of development of antibody titers, avidity, and epitope specificity. The results provide new insights into the underlying role(s) of nanoparticle chemistry in providing long-lived humoral immunity and aid in the rational design of nanovaccine formulations to induce long-lasting and mature antibody responses.Acute respiratory infections represent a significant portion of global morbidity and mortality annually. There is a critical need for efficacious vaccines against respiratory pathogens. To vaccinate against respiratory disease, pulmonary delivery is an attractive route because it mimics the route of natural infection and can confer both mucosal and systemic immunity. We have previously demonstrated that a single dose, intranasal vaccine based on polyanhydride nanoparticles elicited a protective immune response against Yersinia pestis for at least 40 weeks after immunization with F1-V. Herein, we investigate the effect of nanoparticle chemistry and its attributes on the kinetics and maturation of the antigen-specific serum antibody response. We demonstrate that manipulation of polyanhydride nanoparticle chemistry facilitated differential kinetics of development of antibody titers, avidity, and epitope specificity. The results provide new insights into the underlying role(s) of nanoparticle chemistry in providing long-lived humoral immunity and aid in the rational design of nanovaccine formulations to induce long-lasting and mature antibody responses. Electronic supplementary information (ESI) available: Fig. S1. See DOI: 10.1039/c4nr03724c

Functional and structural characteristics of secretory IgA antibodies elicited by mucosal vaccines against influenza virus.

PubMed

Suzuki, Tadaki; Ainai, Akira; Hasegawa, Hideki

2017-09-18

Mucosal tissues are major targets for pathogens. The secretions covering mucosal surfaces contain several types of molecules that protect the host from infection. Among these, mucosal immunoglobulins, including secretory IgA (S-IgA) antibodies, are the major contributor to pathogen-specific immune responses. IgA is the primary antibody class found in many external secretions and has unique structural and functional features not observed in other antibody classes. Recently, extensive efforts have been made to develop novel vaccines that induce immunity via the mucosal route. S-IgA is a key molecule that underpins the mechanism of action of these mucosal vaccines. Thus, precise characterization of S-IgA induced by mucosal vaccines is important, if the latter are to be used successfully in a clinical setting. Intensive studies identified the fundamental characteristics of S-IgA, which was first discovered almost half a century ago. However, S-IgA itself has not gained much attention of late, despite its importance to mucosal immunity; therefore, some important questions remain. This review summarizes the current understanding of the molecular characteristics of S-IgA and its role in intranasal mucosal vaccines against influenza virus infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunology of Gut Mucosal Vaccines

PubMed Central

Pasetti, Marcela F.; Simon, Jakub K.; Sztein, Marcelo B.; Levine, Myron M.

2011-01-01

Summary Understanding the mechanisms underlying the induction of immunity in the gastrointestinal mucosa following oral immunization and the cross-talk between mucosal and systemic immunity should expedite the development of vaccines to diminish the global burden caused by enteric pathogens. Identifying an immunological correlate of protection in the course of field trials of efficacy, animal models (when available), or human challenge studies is also invaluable. In industrialized country populations, live attenuated vaccines (e.g. polio, typhoid, and rotavirus) mimic natural infection and generate robust protective immune responses. In contrast, a major challenge is to understand and overcome the barriers responsible for the diminished immunogenicity and efficacy of the same enteric vaccines in underprivileged populations in developing countries. Success in developing vaccines against some enteric pathogens has heretofore been elusive (e.g. Shigella). Different types of oral vaccines can selectively or inclusively elicit mucosal secretory immunoglobulin A and serum immunoglobulin G antibodies and a variety of cell-mediated immune responses. Areas of research that require acceleration include interaction between the gut innate immune system and the stimulation of adaptive immunity, development of safe yet effective mucosal adjuvants, better understanding of homing to the mucosa of immunologically relevant cells, and elicitation of mucosal immunologic memory. This review dissects the immune responses elicited in humans by enteric vaccines. PMID:21198669

Multi-scale finite element modeling of Eustachian tube function: influence of mucosal adhesion.

PubMed

Malik, J E; Swarts, J D; Ghadiali, S N

2016-12-01

The inability to open the collapsible Eustachian tube (ET) leads to the development of chronic Otitis Media (OM). Although mucosal inflammation during OM leads to increased mucin gene expression and elevated adhesion forces within the ET lumen, it is not known how changes in mucosal adhesion alter the biomechanical mechanisms of ET function. In this study, we developed a novel multi-scale finite element model of ET function in adults that utilizes adhesion spring elements to simulate changes in mucosal adhesion. Models were created for six adult subjects, and dynamic patterns in muscle contraction were used to simulate the wave-like opening of the ET that occurs during swallowing. Results indicate that ET opening is highly sensitive to the level of mucosal adhesion and that exceeding a critical value of adhesion leads to rapid ET dysfunction. Parameter variation studies and sensitivity analysis indicate that increased mucosal adhesion alters the relative importance of several tissue biomechanical properties. For example, increases in mucosal adhesion reduced the sensitivity of ET function to tensor veli palatini muscle forces but did not alter the insensitivity of ET function to levator veli palatini muscle forces. Interestingly, although changes in cartilage stiffness did not significantly influence ET opening under low adhesion conditions, ET opening was highly sensitive to changes in cartilage stiffness under high adhesion conditions. Therefore, our multi-scale computational models indicate that changes in mucosal adhesion as would occur during inflammatory OM alter the biomechanical mechanisms of ET function. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Evaluation of the effect of cryotherapy in preventing oral mucositis associated with chemotherapy - a randomized controlled trial.

PubMed

Katrancı, Nilgün; Ovayolu, Nimet; Ovayolu, Ozlem; Sevinc, Alper

2012-09-01

The goal of this study was to assess the effect of oral cryotherapy on the development of oral mucositis related to infusion of 5-fluorouracil (5-FU) with leucovorin. This study, a randomized controlled trial with random assignments to the experimental and control groups, was conducted with cancer patients. The study included 60 patients; 30 patients in the study group were instructed to hold ice cubes in their mouth shortly before, during, and shortly after infusion of 5-FU with leucovorin, the 30 patients in the control group received routine care. Oral mucositis in the patients was evaluated at 7, 14, and 21 days after chemotherapy. For analysis of data, chi-square, Fisher's tests were used; p < 0.05 was accepted as statistically significant. In the majority of patients receiving cryotherapy, oral mucositis was not observed (Grade 0) at 7 and 14 days. Similarly, incidence of Grades 1, 2, and 3 oral mucositis in the experimental group was quite a bit lower when compared to the control group (p < 0.05). On day 21, no statistically significant difference between the experimental and control groups was determined based on the development of oral mucositis (p > 0.05). We found that oral cryotherapy has a significant contribution to the protection of oral health by reducing mucositis score according to the WHO mucositis scale, especially on the 7th and 14th days. Nurses' awareness of how cryotherapy can affect patients and options for resolving problems will enable them to provide a higher standard of individualized care. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantitative analysis of patients with celiac disease by video capsule endoscopy: A deep learning method.

PubMed

Zhou, Teng; Han, Guoqiang; Li, Bing Nan; Lin, Zhizhe; Ciaccio, Edward J; Green, Peter H; Qin, Jing

2017-06-01

Celiac disease is one of the most common diseases in the world. Capsule endoscopy is an alternative way to visualize the entire small intestine without invasiveness to the patient. It is useful to characterize celiac disease, but hours are need to manually analyze the retrospective data of a single patient. Computer-aided quantitative analysis by a deep learning method helps in alleviating the workload during analysis of the retrospective videos. Capsule endoscopy clips from 6 celiac disease patients and 5 controls were preprocessed for training. The frames with a large field of opaque extraluminal fluid or air bubbles were removed automatically by using a pre-selection algorithm. Then the frames were cropped and the intensity was corrected prior to frame rotation in the proposed new method. The GoogLeNet is trained with these frames. Then, the clips of capsule endoscopy from 5 additional celiac disease patients and 5 additional control patients are used for testing. The trained GoogLeNet was able to distinguish the frames from capsule endoscopy clips of celiac disease patients vs controls. Quantitative measurement with evaluation of the confidence was developed to assess the severity level of pathology in the subjects. Relying on the evaluation confidence, the GoogLeNet achieved 100% sensitivity and specificity for the testing set. The t-test confirmed the evaluation confidence is significant to distinguish celiac disease patients from controls. Furthermore, it is found that the evaluation confidence may also relate to the severity level of small bowel mucosal lesions. A deep convolutional neural network was established for quantitative measurement of the existence and degree of pathology throughout the small intestine, which may improve computer-aided clinical techniques to assess mucosal atrophy and other etiologies in real-time with videocapsule endoscopy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clinical assessment of oral mucositis and candidiasis compare to chemotherapic nadir in transplanted patients.

PubMed

Patussi, Cleverson; Sassi, Laurindo Moacir; Munhoz, Eduardo Ciliao; Zanicotti, Roberta Targa Stramandinoli; Schussel, Juliana Lucena

2014-01-01

Oral mucositis is a chief complication in patients undergoing hematopoietic stem cell transplantation (HSCT). It is considered a toxic inflammatory reaction that interferes with the patient's recuperation and quality of life. Oral candidiasis is a common fungal infection observed in dental practice, particularly in immunocompromised patients. The aim of this study was to evaluate the presence of oral mucositis and oral candidiasis in patients who underwent HSCT and their correlation with the chemotherapeutic nadir (lowest possible outcome). We evaluated patients with different diagnoses who underwent HSCT at the Hospital Erasto Gaertner. No chemotherapeutic nadir curves could be associated with mucositis, and patients had different presentations of mucositis. No patient developed oral candidiasis during hospitalization. Together with cell counts, we collected demographic data including age, oral hygiene, habits harmful to health, and the use of oral prostheses. It was observed that patients who smoked cigarettes before hospitalization showed less mucositis, resulting in no feeding problems or other comorbid conditions due to the effect of mucositis. However, the nadir of the chemotherapy curve, in isolation, is not a predictive tool for the appearance (or no appearance) of oral mucositis.

Changes in biochemical parameters of oral fluid in patients during the orthodontic treatment with a bracket system under the action of a developed mucosal gel with probiotic.

PubMed

Voronkova, Anna V; Smaglyuk, Lyubov V

2018-01-01

Introduction: Many research studies involving orthodontic patients focus on changes in levels of oral microbiocenosis after bracket placement. Based upon this the objective of the current study was to determine the effect of the developed mucosal gel with probiotics on the biochemical parameters of the oral fluid of patients during the orthodontic treatment with a bracket system. The aim: Aim of our study is to determine the effect of the developed mucosal gel with probiotics on the biochemical parameters of the oral fluid of patients during the orthodontic treatment with a bracket system. Materials and methods: 45 patients at the age of 18-24, with 15 people in each group (control, main and comparison group) were examined. The main group was presented by patients who, in order to prevent dysbiosis of the oral cavity during orthodontic treatment, were prescribed local use of the developed mucosal gel with probiotic. The statistical processing of the results of the study was carried out using methods of variation statistics using the EXCEL program (the standard package of Microsoft Office). Results: According to the results of biochemical studies, it was found that the use of orthodontic treatment of mucosal gel with probiotic in patients with crowded teeth contributes to the strengthening of antioxidant protection, an increase in nonspecific resistance, decrease in inflammation and normalization of microbiocenosis of the oral cavity. Conclusion: These studies indicated that the use of the developed mucosal gel with probiotic in patients with maxillofacial anomalies from the first day after fixation, as indicated by the level of biochemical markers of inflammation.

Binding of Helocobacter pyori to Human Gastric Mucose: Identification and Characterization of a Lewis b Bingind Protein.

DTIC Science & Technology

1995-06-01

putative virulence factors of H. pylori have been identified to date. These factors include a urease , flagella, a mucinase, a cytotoxin, and two adhesins...The urease is believed to aid in bacterial survival of the harsh gastric environment by generating ammonia from urea to neutralize the low pH (Segal...A Laboratory Manual. Cold Spring Harbor, New York. Cold Spring Harbor Laboratory Press. Hazell, S., A. Lee. 1986. Campylobacter pyloridis urease

Intestinal mucositis: mechanisms and management.

PubMed

Keefe, Dorothy M

2007-07-01

To describe the advances in the rapidly evolving field of intestinal (or alimentary) mucositis during the past year. Major advances have been made in both the clinical and preclinical setting, with the publication of a suite of articles regarding the pathobiology and management of mucositis, as well as several articles on important basic research in the area. The mechanism of mucositis development is now understood to be much more complex than previously thought, with an interplay of host and drug factors leading to overt damage, and variation in manifestation of that damage depending on the specific region of the gut. The MASCC/ISOO management guidelines for mucositis have been updated: a recommendation for the use of palifermin in the hematology transplant setting has been added, and a couple of previous recommendations have been revoked. This marks an important milestone in mucositis, as it is the first time a drug has been available that substantially reduces the occurrence and severity of mucositis. There is still much to be done to abolish the severe toxicity of chemotherapy and radiotherapy; however, progress is accelerating, and new targeted drugs are becoming available.

Budding off: bringing functional genomics to Candida albicans

PubMed Central

Anderson, Matthew Z.

2016-01-01

Candida species are the most prevalent human fungal pathogens, with Candida albicans being the most clinically relevant species. Candida albicans resides as a commensal of the human gastrointestinal tract but is a frequent cause of opportunistic mucosal and systemic infections. Investigation of C. albicans virulence has traditionally relied on candidate gene approaches, but recent advances in functional genomics have now facilitated global, unbiased studies of gene function. Such studies include comparative genomics (both between and within Candida species), analysis of total RNA expression, and regulation and delineation of protein–DNA interactions. Additionally, large collections of mutant strains have begun to aid systematic screening of clinically relevant phenotypes. Here, we will highlight the development of functional genomics in C. albicans and discuss the use of these approaches to addressing both commensalism and pathogenesis in this species. PMID:26424829

Microbiota and Mucosal Immunity in Amphibians

PubMed Central

Colombo, Bruno M.; Scalvenzi, Thibault; Benlamara, Sarah; Pollet, Nicolas

2015-01-01

We know that animals live in a world dominated by bacteria. In the last 20 years, we have learned that microbes are essential regulators of mucosal immunity. Bacteria, archeas, and viruses influence different aspects of mucosal development and function. Yet, the literature mainly covers findings obtained in mammals. In this review, we focus on two major themes that emerge from the comparative analysis of mammals and amphibians. These themes concern: (i) the structure and functions of lymphoid organs and immune cells in amphibians, with a focus on the gut mucosal immune system; and (ii) the characteristics of the amphibian microbiota and its influence on mucosal immunity. Lastly, we propose to use Xenopus tadpoles as an alternative small-animal model to improve the fundamental knowledge on immunological functions of gut microbiota. PMID:25821449

Phenotypes and distribution of mucosal memory B-cell populations in the SIV/SHIV Rhesus macaque model

PubMed Central

Demberg, Thorsten; Mohanram, Venkatramanan; Venzon, David; Robert-Guroff, Marjorie

2014-01-01

As vaccine-elicited antibodies have now been associated with HIV protective efficacy, a thorough understanding of mucosal and systemic B-cell development and maturation is needed. We phenotyped mucosal memory B-cells, investigated isotype expression and homing patterns, and defined plasmablasts and plasma cells at three mucosal sites (duodenum, jejunum and rectum) in rhesus macaques, the commonly used animal model for pre-clinical vaccine studies. Unlike humans, macaque mucosal memory B-cells lacked CD27 expression; only two sub-populations were present: naïve (CD21+CD27−) and tissue-like (CD21−CD27−) memory. Similar to humans, IgA was the dominant isotype expressed. The homing markers CXCR4, CCR6, CCR9 and α4β7 were differentially expressed between naïve and tissue-like memory B-cells. Mucosal plasmablasts were identified as CD19+CD20+/−HLA-DR+Ki-67+IRF4+CD138+/− and mucosal plasma cells as CD19+CD20−HLA-DR−Ki-67−IRF4+CD138+. Both populations were CD39+/−CD27−. Plasma cell phenotype was confirmed by spontaneous IgA secretion by ELISpot of positively-selected cells and J-chain expression by real-time PCR. Duodenal, jejunal and rectal samples were similar in B-cell memory phenotype, isotype expression, homing receptors and plasmablast/plasma cell distribution among the three tissues. Thus rectal biopsies adequately monitor B-cell dynamics in the gut mucosa, and provide a critical view of mucosal B-cell events associated with development of vaccine-elicited protective immune responses and SIV/SHIV pathogenesis and disease control. PMID:24814239

Streptococcus agalactiae Inhibits Candida albicans Hyphal Development and Diminishes Host Vaginal Mucosal TH17 Response.

PubMed

Yu, Xiao-Yu; Fu, Fei; Kong, Wen-Na; Xuan, Qian-Kun; Wen, Dong-Hua; Chen, Xiao-Qing; He, Yong-Ming; He, Li-Hua; Guo, Jian; Zhou, Ai-Ping; Xi, Yang-Hong; Ni, Li-Jun; Yao, Yu-Feng; Wu, Wen-Juan

2018-01-01

Streptococcus agalactiae and Candida albicans often co-colonize the female genital tract, and under certain conditions induce mucosal inflammation. The role of the interaction between the two organisms in candidal vaginitis is not known. In this study, we found that co-infection with S. agalactiae significantly attenuated the hyphal development of C. albicans , and that EFG1 -Hwp1 signal pathway of C. albicans was involved in this process. In a mouse model of vulvovaginal candidiasis (VVC), the fungal burden and the levels of pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α showed a increase on co-infection with S. agalactiae , while the level of TH17 T cells and IL-17 in the cervicovaginal lavage fluid were significantly decreased. Our results indicate that S. agalactiae inhibits C. albicans hyphal development by downregulating the expression of EFG1 -Hwp1. The interaction between S. agalactiae and C. albicans may attenuate host vaginal mucosal TH17 immunity and contribute to mucosal colonization by C. albicans .

Li-Fraumeni syndrome presenting as mucosal melanoma: Case report and treatment considerations.

PubMed

Klein, Jonah D; Kupferman, Michael E

2017-02-01

Li-Fraumeni syndrome (LFS) is a familial cancer predisposition associated with a germline mutation in TP53. Patients with LFS are at risk of developing malignancies and require comprehensive screening. We describe an index case of LFS presenting with mucosal melanoma. A 21-year-old woman presented with a left maxillary mucosal lesion and a left neck mass. Biopsies revealed metastatic mucosal melanoma, which is a pathology previously unreported in LFS families. Genetic testing revealed LFS, with a germline TP53 mutation, and pedigree analysis identified 9 first-degree and second-degree relatives with hematologic malignancies. The patient underwent a maxillectomy and left neck dissection, followed by adjuvant radiotherapy. At 30-month follow-up, there was no evidence of local, regional, or distant failure, nor did she develop a second primary tumor. This represents the first reported case of LFS associated with mucosal melanoma. Treatment considerations, specifically the risks of adjuvant therapy in LFS, are discussed. © 2016 Wiley Periodicals, Inc. Head Neck 39: E20-E22, 2017. © 2016 Wiley Periodicals, Inc.

Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates.

PubMed

Saunders, Kevin O; Santra, Sampa; Parks, Robert; Yates, Nicole L; Sutherland, Laura L; Scearce, Richard M; Balachandran, Harikrishnan; Bradley, Todd; Goodman, Derrick; Eaton, Amanda; Stanfield-Oakley, Sherry A; Tartaglia, James; Phogat, Sanjay; Pantaleo, Giuseppe; Esteban, Mariano; Gomez, Carmen E; Perdiguero, Beatriz; Jacobs, Bertram; Kibler, Karen; Korber, Bette; Montefiori, David C; Ferrari, Guido; Vandergrift, Nathan; Liao, Hua-Xin; Tomaras, Georgia D; Haynes, Barton F

2018-04-15

A preventive human immunodeficiency virus type 1 (HIV-1) vaccine is an essential part of the strategy to eradicate AIDS. A critical question is whether antibodies that do not neutralize primary isolate (tier 2) HIV-1 strains can protect from infection. In this study, we investigated the ability of an attenuated poxvirus vector (NYVAC) prime-envelope gp120 boost to elicit potentially protective antibody responses in a rhesus macaque model of mucosal simian-human immunodeficiency virus (SHIV) infection. NYVAC vector delivery of a group M consensus envelope, trivalent mosaic envelopes, or a natural clade B isolate B.1059 envelope elicited antibodies that mediated neutralization of tier 1 viruses, cellular cytotoxicity, and phagocytosis. None of the macaques made neutralizing antibodies against the tier 2 SHIV SF162P3 used for mucosal challenge. Significant protection from infection was not observed for the three groups of vaccinated macaques compared to unvaccinated macaques, although binding antibody to HIV-1 Env correlated with decreased viremia after challenge. Thus, NYVAC Env prime-gp120 boost vaccination elicited polyfunctional, nonneutralizing antibody responses with minimal protective activity against tier 2 SHIV mucosal challenge. IMPORTANCE The antibody responses that confer protection against HIV-1 infection remain unknown. Polyfunctional antibody responses correlated with time to infection in previous macaque studies. Determining the ability of vaccines to induce these types of responses is critical for understanding how to improve upon the one efficacious human HIV-1 vaccine trial completed thus far. We characterized the antibody responses induced by a NYVAC-protein vaccine and determined the protective capacity of polyfunctional antibody responses in an R5, tier 2 mucosal SHIV infection model. Copyright © 2018 American Society for Microbiology.

Dual TLR2/9 Recognition of Herpes Simplex Virus Infection Is Required for Recruitment and Activation of Monocytes and NK Cells and Restriction of Viral Dissemination to the Central Nervous System

PubMed Central

Uyangaa, Erdenebileg; Choi, Jin Young; Patil, Ajit Mahadev; Hossain, Ferdaus Mohd Altaf; Park, Sung OK; Kim, Bumseok; Kim, Koanhoi; Eo, Seong Kug

2018-01-01

The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV via an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-α and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip-DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4+ and CD8+ T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV. PMID:29760708

Dual TLR2/9 Recognition of Herpes Simplex Virus Infection Is Required for Recruitment and Activation of Monocytes and NK Cells and Restriction of Viral Dissemination to the Central Nervous System.

PubMed

Uyangaa, Erdenebileg; Choi, Jin Young; Patil, Ajit Mahadev; Hossain, Ferdaus Mohd Altaf; Park, Sung Ok; Kim, Bumseok; Kim, Koanhoi; Eo, Seong Kug

2018-01-01

The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV via an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-α and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip-DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4 + and CD8 + T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV.

Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis

PubMed Central

Manieri, Nicholas A.; Mack, Madison R.; Himmelrich, Molly D.; Worthley, Daniel L.; Hanson, Elaine M.; Eckmann, Lars; Wang, Timothy C.; Stappenbeck, Thaddeus S.

2015-01-01

Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I2 (PGI2) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair. PMID:26280574

Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis.

PubMed

Manieri, Nicholas A; Mack, Madison R; Himmelrich, Molly D; Worthley, Daniel L; Hanson, Elaine M; Eckmann, Lars; Wang, Timothy C; Stappenbeck, Thaddeus S

2015-09-01

Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I₂ (PGI₂) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair.

Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

PubMed

Chen, Joey; Seabrook, Jamie; Fulford, Adrienne; Rajakumar, Irina

2017-03-01

Background Up to 70% of patients receiving hematopoietic stem cell transplant develop oral mucositis as a side effect of high-dose melphalan conditioning chemotherapy. Oral cryotherapy has been documented to be potentially effective in reducing oral mucositis. The aim of this study was to examine the effectiveness of the cryotherapy protocol implemented within the hematopoietic stem cell transplant program. Methods A retrospective chart review was conducted of adult multiple myeloma patients who received high-dose melphalan conditioning therapy for autologous hematopoietic stem cell transplant. Primary endpoints were incidence and severity of oral mucositis. Secondary endpoints included duration of oral mucositis, duration of hospital stay, parenteral narcotics use and total parenteral nutrition use. Results One hundred and forty patients were included in the study, 70 patients in both no cryotherapy and cryotherapy groups. Both oral mucositis incidence and severity were found to be significantly lower in the cryotherapy group. Fifty (71.4%) experienced mucositis post cryotherapy compared to 67 (95.7%) in the no cryotherapy group (p < 0.001). The median oral mucositis severity, assessed using the WHO oral toxicity scale from grade 0-4, experienced in the no group was 2.5 vs. 2 in the cryotherapy group (p = 0.03). Oral mucositis duration and use of parenteral narcotics were also significantly reduced. Duration of hospital stay and use of parenteral nutrition were similar between the two groups. Conclusion The cryotherapy protocol resulted in a significantly lower incidence and severity of oral mucositis. These results provide evidence for the continued use of oral cryotherapy, an inexpensive and generally well-tolerated practice.

Innate immunity in HIV-1 infection: epithelial and non-specific host factors of mucosal immunity- a workshop report.

PubMed

Nittayananta, W; Weinberg, A; Malamud, D; Moyes, D; Webster-Cyriaque, J; Ghosh, S

2016-04-01

The interplay between HIV-1 and epithelial cells represents a critical aspect in mucosal HIV-1 transmission. Epithelial cells lining the oral cavity cover subepithelial tissues, which contain virus-susceptible host cells including CD4(+) T lymphocytes, monocytes/macrophages, and dendritic cells. Oral epithelia are among the sites of first exposure to both cell-free and cell-associated virus HIV-1 through breast-feeding and oral-genital contact. However, oral mucosa is considered to be naturally resistant to HIV-1 transmission. Oral epithelial cells have been shown to play a crucial role in innate host defense. Nevertheless, it is not clear to what degree these local innate immune factors contribute to HIV-1 resistance of the oral mucosa. This review paper addressed the following issues that were discussed at the 7th World Workshop on Oral Health and Disease in AIDS held in Hyderabad, India, during November 6-9, 2014: (i) What is the fate of HIV-1 after interactions with oral epithelial cells?; (ii) What are the keratinocyte and other anti-HIV effector oral factors, and how do they contribute to mucosal protection?; (iii) How can HIV-1 interactions with oral epithelium affect activation and populations of local immune cells?; (iv) How can HIV-1 interactions alter functions of oral epithelial cells? © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Systemic Immunization with Papillomavirus L1 Protein Completely Prevents the Development of Viral Mucosal Papillomas

NASA Astrophysics Data System (ADS)

Suzich, Joann A.; Ghim, Shin-Je; Palmer-Hill, Frances J.; White, Wendy I.; Tamura, James K.; Bell, Judith A.; Newsome, Joseph A.; Bennett Jenson, A.; Schlegel, Richard

1995-12-01

Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.

Postnatal Passive Immunization of Neonatal Macaques with a Triple Combination of Human Monoclonal Antibodies against Oral Simian-Human Immunodeficiency Virus Challenge

PubMed Central

Hofmann-Lehmann, Regina; Vlasak, Josef; Rasmussen, Robert A.; Smith, Beverly A.; Baba, Timothy W.; Liska, Vladimir; Ferrantelli, Flavia; Montefiori, David C.; McClure, Harold M.; Anderson, Daniel C.; Bernacky, Bruce J.; Rizvi, Tahir A.; Schmidt, Russell; Hill, Lori R.; Keeling, Michale E.; Katinger, Hermann; Stiegler, Gabriela; Cavacini, Lisa A.; Posner, Marshall R.; Chou, Ting-Chao; Andersen, Janet; Ruprecht, Ruth M.

2001-01-01

To develop prophylaxis against mother-to-child human immunodeficiency virus (HIV) transmission, we established a simian-human immunodeficiency virus (SHIV) infection model in neonatal macaques that mimics intrapartum mucosal virus exposure (T. W. Baba et al., AIDS Res. Hum. Retroviruses 10:351–357, 1994). Using this model, neonates were protected from mucosal SHIV-vpu+ challenge by pre- and postnatal treatment with a combination of three human neutralizing monoclonal antibodies (MAbs), F105, 2G12, and 2F5 (Baba et al., Nat. Med. 6:200–206, 2000). In the present study, we used this MAb combination only postnatally, thereby significantly reducing the quantity of antibodies necessary and rendering their potential use in humans more practical. We protected two neonates with this regimen against oral SHIV-vpu+ challenge, while four untreated control animals became persistently infected. Thus, synergistic MAbs protect when used as immunoprophylaxis without the prenatal dose. We then determined in vitro the optimal MAb combination against the more pathogenic SHIV89.6P, a chimeric virus encoding env of the primary HIV89.6. Remarkably, the most potent combination included IgG1b12, which alone does not neutralize SHIV89.6P. We administered the combination of MAbs IgG1b12, 2F5, and 2G12 postnatally to four neonates. One of the four infants remained uninfected after oral challenge with SHIV89.6P, and two infants had no or a delayed CD4+ T-cell decline. In contrast, all control animals had dramatic drops in their CD4+ T cells by 2 weeks postexposure. We conclude that our triple MAb combination partially protected against mucosal challenge with the highly pathogenic SHIV89.6P. Thus, combination immunoprophylaxis with passively administered synergistic human MAbs may play a role in the clinical prevention of mother-to-infant transmission of HIV type 1. PMID:11462019

A Multiplex Microsphere-Based Immunoassay Increases the Sensitivity of SIV-Specific Antibody Detection in Serum Samples and Mucosal Specimens Collected from Rhesus Macaques Infected with SIVmac239.

PubMed

Powell, Rebecca L R; Ouellette, Ian; Lindsay, Ross W; Parks, Christopher L; King, C Richter; McDermott, Adrian B; Morrow, Gavin

2013-06-01

Results from recent HIV-1 vaccine studies have indicated that high serum antibody (Ab) titers may not be necessary for Ab-mediated protection, and that Abs localized to mucosal sites might be critical for preventing infection. Enzyme-linked immunosorbent assay (ELISA) has been used for decades as the gold standard for Ab measurement, though recently, highly sensitive microsphere-based assays have become available, with potential utility for improved detection of Abs. In this study, we assessed the Bio-Plex(®) Suspension Array System for the detection of simian immunodeficiency virus (SIV)-specific Abs in rhesus macaques (RMs) chronically infected with SIV, whose serum or mucosal SIV-specific Ab titers were negative by ELISA. We developed a SIVmac239-specific 4-plex bead array for the simultaneous detection of Abs binding to Env, Gag, Pol, and Nef. The 4-plex assay was used to quantify SIV-specific serum IgG and rectal swab IgA titers from control (SIV-naive) and SIVmac239-infected RMs. The Bio-Plex assay specifically detected anti-SIV Abs in specimens from SIV-infected animals for all four analytes when compared to SIV-naive control samples (p≤0.04). Furthermore, in 70% of Env and 79% of Gag ELISA-negative serum samples, specific Ab was detected using the Bio-Plex assay. Similarly, 71% of Env and 48% of Gag ELISA-negative rectal swab samples were identified as positive using the Bio-Plex assay. Importantly, assay specificity (i.e., probability of true positives) was comparable to ELISA (94%-100%). The results reported here indicate that microsphere-based methods provide a substantial improvement over ELISA for the detection of Ab responses, aid in detecting specific Abs when analyzing samples containing low levels of Abs, such as during the early stages of a vaccine trial, and may be valuable in attempts to link protective efficacy of vaccines with induced Ab responses.

Rice-based mucosal vaccine as a global strategy for cold-chain- and needle-free vaccination

PubMed Central

Nochi, Tomonori; Takagi, Hidenori; Yuki, Yoshikazu; Yang, Lijun; Masumura, Takehiro; Mejima, Mio; Nakanishi, Ushio; Matsumura, Akiko; Uozumi, Akihiro; Hiroi, Takachika; Morita, Shigeto; Tanaka, Kunisuke; Takaiwa, Fumio; Kiyono, Hiroshi

2007-01-01

Capable of inducing antigen-specific immune responses in both systemic and mucosal compartments without the use of syringe and needle, mucosal vaccination is considered ideal for the global control of infectious diseases. In this study, we developed a rice-based oral vaccine expressing cholera toxin B subunit (CTB) under the control of the endosperm-specific expression promoter 2.3-kb glutelin GluB-1 with codon usage optimization for expression in rice seed. An average of 30 μg of CTB per seed was stored in the protein bodies, which are storage organelles in rice. When mucosally fed, rice seeds expressing CTB were taken up by the M cells covering the Peyer's patches and induced CTB-specific serum IgG and mucosal IgA antibodies with neutralizing activity. When expressed in rice, CTB was protected from pepsin digestion in vitro. Rice-expressed CTB also remained stable and thus maintained immunogenicity at room temperature for >1.5 years, meaning that antigen-specific mucosal immune responses were induced at much lower doses than were necessary with purified recombinant CTB. Because they require neither refrigeration (cold-chain management) nor a needle, these rice-based mucosal vaccines offer a highly practical and cost-effective strategy for orally vaccinating large populations against mucosal infections, including those that may result from an act of bioterrorism. PMID:17573530

Mucosal Vaccination Overcomes the Barrier to Recombinant Vaccinia Immunization Caused by Preexisting Poxvirus Immunity

NASA Astrophysics Data System (ADS)

Belyakov, Igor M.; Moss, Bernard; Strober, Warren; Berzofsky, Jay A.

1999-04-01

Overcoming preexisting immunity to vaccinia virus in the adult population is a key requirement for development of otherwise potent recombinant vaccinia vaccines. Based on our observation that s.c. immunization with vaccinia induces cellular and antibody immunity to vaccinia only in systemic lymphoid tissue and not in mucosal sites, we hypothesized that the mucosal immune system remains naive to vaccinia and therefore amenable to immunization with recombinant vaccinia vectors despite earlier vaccinia exposure. We show that mucosal immunization of vaccinia-immune BALB/c mice with recombinant vaccinia expressing HIV gp160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses. These responses occurred not only in mucosal but also in systemic lymphoid tissue, whereas systemic immunization was ineffective under these circumstances. In this context, intrarectal immunization was more effective than intranasal immunization. Boosting with a second dose of recombinant vaccinia was also more effective via the mucosal route. The systemic HIV-specific cytotoxic T lymphocyte response was enhanced by coadministration of IL-12 at the mucosal site. These results also demonstrate the independent compartmentalization of the mucosal versus systemic immune systems and the asymmetric trafficking of lymphocytes between them. This approach to circumvent previous vaccinia immunity may be useful for induction of protective immunity against infectious diseases and cancer in the sizable populations with preexisting immunity to vaccinia from smallpox vaccination.

Treatment of oral mucositis due to chemotherapy

PubMed Central

Bagán-Sebastián, José V

2016-01-01

Introduction The management of oral mucositis is a challenge, due to its complex biological nature. Over the last 10 years, different strategies have been developed for the management of oral mucositis caused by chemotherapy in cancer patients. Material and Methods An exhaustive search was made of the PubMed-Medline, Cochrane Library and Scopus databases, crossing the key words “oral mucositis”, “prevention” and “treatment” with the terms “chemotherapy” and “radiotherapy” by means of the boolean operators “AND” and “NOT”. A total of 268 articles were obtained, of which 96 met the inclusion criteria. Results Several interventions for the prevention of oral mucositis, such as oral hygiene protocols, amifostine, benzidamine, calcium phosphate, cryotherapy and iseganan, among others, were found to yield only limited benefits. Other studies have reported a decrease in the appearance and severity of mucositis with the use of cytoprotectors (sucralfate, oral glutamine, hyaluronic acid), growth factors, topical polyvinylpyrrolidone, and low power laser irradiation. Conclusions Very few interventions of confirmed efficacy are available for the management of oral mucositis due to chemotherapy. However, according to the reviewed literature, the use of palifermin, cryotherapy and low power laser offers benefits, reducing the incidence and severity of oral mucositis – though further studies are needed to confirm the results obtained. Key words:Chemotherapy-Induced Oral Mucositis Treatment. PMID:27034762

Novel mucosal DNA-MVA HIV vaccination in which DNA-IL-12 plus cholera toxin B subunit (CTB) cooperates to enhance cellular systemic and mucosal genital tract immunity.

PubMed

Maeto, Cynthia; Rodríguez, Ana María; Holgado, María Pía; Falivene, Juliana; Gherardi, María Magdalena

2014-01-01

Induction of local antiviral immune responses at the mucosal portal surfaces where HIV-1 and other viral pathogens are usually first encountered remains a primary goal for most vaccines against mucosally acquired viral infections. Exploring mucosal immunization regimes in order to find optimal vector combinations and also appropriate mucosal adjuvants in the HIV vaccine development is decisive. In this study we analyzed the interaction of DNA-IL-12 and cholera toxin B subunit (CTB) after their mucosal administration in DNA prime/MVA boost intranasal regimes, defining the cooperation of both adjuvants to enhance immune responses against the HIV-1 Env antigen. Our results demonstrated that nasal mucosal DNA/MVA immunization schemes can be effectively improved by the co-delivery of DNA-IL-12 plus CTB inducing elevated HIV-specific CD8 responses in spleen and more importantly in genital tract and genito-rectal draining lymph nodes. Remarkably, these CTL responses were of superior quality showing higher avidity, polyfunctionality and a broader cytokine profile. After IL-12+CTB co-delivery, the cellular responses induced showed an enhanced breadth recognizing with higher efficiency Env peptides from different subtypes. Even more, an in vivo CTL cytolytic assay demonstrated the higher specific CD8 T-cell performance after the IL-12+CTB immunization showing in an indirect manner its potential protective capacity. Improvements observed were maintained during the memory phase where we found higher proportions of specific central memory and T memory stem-like cells T-cell subpopulations. Together, our data show that DNA-IL-12 plus CTB can be effectively employed acting as mucosal adjuvants during DNA prime/MVA boost intranasal vaccinations, enhancing magnitude and quality of HIV-specific systemic and mucosal immune responses.

Commensal Streptococcus mitis is a unique vector for oral mucosal vaccination

PubMed Central

Daifalla, Nada; Cayabyab, Mark J.; Xie, Emily; Kim, Hyeun Bum; Tzipori, Saul; Stashenko, Philip; Duncan, Margaret; Campos-Neto, Antonio

2014-01-01

The development of vaccine approaches that induce mucosal and systemic immune responses is critical for the effective prevention of several infections. Here, we report on the use of the abundant human oral commensal bacterium Streptococcus mitis as a delivery vehicle for mucosal immunization. Using homologous recombination we generated a stable rS. mitis expressing a Mycobacterium tuberculosis protein (Ag85b). Oral administration of rS. mitis in gnotobiotic piglets resulted in efficient oral colonization and production of oral and systemic anti-Ag85b specific IgA and IgG antibodies. These results support that the commensal S. mitis is potentially a useful vector for mucosal vaccination. PMID:25522856

The Role of Chronic Mucosal Trauma in Oral Cancer: A Review of Literature

PubMed Central

Singhvi, Hitesh Rajendra; Malik, Akshat; Chaturvedi, Pankaj

2017-01-01

Chronic mucosal trauma resulting from sharp teeth, dentures, faulty restoration, or implants has frequently been associated with the development of oral cancer. The definitive evidence for the same is lacking. We undertook a search using the terms – dental trauma, mucosal trauma, oral cancer, squamous cell carcinoma, risk factor, potentially malignant lesion, dental factor, mechanical irritation, dental irritation, and cancer in the following electronic databases: MEDLINE, PubMed, ScienceDirect, Cochrane Database of Systematic Reviews, and Wiley InterScience. The search yielded 788 articles. Of these articles, only 22 articles described chronic mucosal trauma as risk factors for oral cancers and were considered in this review. The review shows that chronic mucosal irritation resulting from ill-fitting dentures may be considered a risk factor for the development of oral cancer, such cancers occur commonly over the lateral border of the tongue. However, no association has been proven between the duration of denture use and cancer formation. In patients without any addiction, such cancers occur more frequently in females. These cancers may present with an early nodal disease but their prognosis and outcomes have not been studied separately till now. PMID:28469336

Bilateral Superior Labial Mucosal Transposition Flaps to Correct Stenosis of the Nares Following Bilateral Rostral Maxillectomy Combined with Nasal Planum Resection in a Dog.

PubMed

Séguin, Bernard; Steinke, Julia R

2016-04-01

To describe a technique using labial mucosal flaps to correct stenosis of the nares subsequent to bilateral rostral maxillectomy and nasal planum resection. Case report Client-owned dog. A 10-year-old, neutered male Golden Retriever developed repeated stenosis of the nares, at first after bilateral rostral maxillectomy and nasal planum resection, and again after revision surgery. Bilateral, superior labial mucosal transposition flaps were created and interpolated between the nasal mucosa and skin after debridement of scar tissue. The stenosis did not recur after mucosal flap transposition and the dog returned to normal quality of life (last follow-up 25 months postoperative). Single-stage, superior labial mucosal transposition flaps can be used to correct nares stenosis subsequent to previous surgery. © Copyright 2016 by The American College of Veterinary Surgeons.

Streptococcus agalactiae Inhibits Candida albicans Hyphal Development and Diminishes Host Vaginal Mucosal TH17 Response

PubMed Central

Yu, Xiao-Yu; Fu, Fei; Kong, Wen-Na; Xuan, Qian-Kun; Wen, Dong-Hua; Chen, Xiao-Qing; He, Yong-Ming; He, Li-Hua; Guo, Jian; Zhou, Ai-Ping; Xi, Yang-Hong; Ni, Li-Jun; Yao, Yu-Feng; Wu, Wen-Juan

2018-01-01

Streptococcus agalactiae and Candida albicans often co-colonize the female genital tract, and under certain conditions induce mucosal inflammation. The role of the interaction between the two organisms in candidal vaginitis is not known. In this study, we found that co-infection with S. agalactiae significantly attenuated the hyphal development of C. albicans, and that EFG1-Hwp1 signal pathway of C. albicans was involved in this process. In a mouse model of vulvovaginal candidiasis (VVC), the fungal burden and the levels of pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α showed a increase on co-infection with S. agalactiae, while the level of TH17 T cells and IL-17 in the cervicovaginal lavage fluid were significantly decreased. Our results indicate that S. agalactiae inhibits C. albicans hyphal development by downregulating the expression of EFG1-Hwp1. The interaction between S. agalactiae and C. albicans may attenuate host vaginal mucosal TH17 immunity and contribute to mucosal colonization by C. albicans. PMID:29527193

Analyzing the value of monitoring duodenal mucosal perfusion using photoplethysmography.

PubMed

Fink, Mitchell P

2014-10-13

Photoplethysmography (PPG) is a technique that permits noninvasive measurement of changes in the volume of tissues. A novel device uses PPG to assess changes in duodenal mucosal perfusion. When tested in septic piglets, data obtained using this device correlate with the blood lactate concentration and duodenal serosal microvascular blood flow as measured with a laser Doppler flowmeter. This new PPG-based approach for continuously monitoring gut mucosal perfusion warrants further development, leading to prospective clinical trials in patients.

Budding off: bringing functional genomics to Candida albicans.

PubMed

Anderson, Matthew Z; Bennett, Richard J

2016-03-01

Candida species are the most prevalent human fungal pathogens, with Candida albicans being the most clinically relevant species. Candida albicans resides as a commensal of the human gastrointestinal tract but is a frequent cause of opportunistic mucosal and systemic infections. Investigation of C. albicans virulence has traditionally relied on candidate gene approaches, but recent advances in functional genomics have now facilitated global, unbiased studies of gene function. Such studies include comparative genomics (both between and within Candida species), analysis of total RNA expression, and regulation and delineation of protein-DNA interactions. Additionally, large collections of mutant strains have begun to aid systematic screening of clinically relevant phenotypes. Here, we will highlight the development of functional genomics in C. albicans and discuss the use of these approaches to addressing both commensalism and pathogenesis in this species. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Physiopathology and Management of Gluten-Induced Celiac Disease.

PubMed

Kumar, Jitendra; Kumar, Manoj; Pandey, Rajesh; Chauhan, Nar Singh

2017-02-01

Proline- and glutamine-rich gluten proteins are one of the major constituents of cereal dietary proteins, which are largely resistant to complete cleavage by the human gastrointestinal (GI) digestive enzymes. Partial digestion of gluten generates approximately 35 amino acids (aa) immunomodulatory peptides which activate T-cell-mediated immune system, followed by immunological inflammation of mucosa leading to the onset of celiac disease (CD). CD is an autoimmune disease associated with HLA-DQ2/DQ8 polymorphism and dysbiosis of gut microbiota. CD is either diagnosed using duodenal mucosal biopsis or serological testing for transglutaminase 2 (TG2) specific antibodies (IgA and IgG). Current therapy for CD management is gluten-free diet, while other therapies like glutenase, probiotics, immunomodulation, jamming of HLA-DQ2, inhibition of TG2, and gluten tolerance aided by gluten tolerizing vaccines are being developed. © 2017 Institute of Food Technologists®.

Irinotecan-induced mucositis: the interactions and potential role of GLP-2 analogues.

PubMed

Mayo, Bronwen J; Stringer, Andrea M; Bowen, Joanne M; Bateman, Emma H; Keefe, Dorothy M

2017-02-01

A common side effect of irinotecan administration is gastrointestinal mucositis, often manifesting as severe diarrhoea. The damage to the structure and function of the gastrointestinal tract caused by this cytotoxic agent is debilitating and often leads to alterations in patients' regimens, hospitalisation or stoppage of treatment. The purpose of this review is to identify mechanisms of irinotecan-induced intestinal damage and a potential role for GLP-2 analogues for intervention. This is a review of current literature on irinotecan-induced mucositis and GLP-2 analogues mechanisms of action. Recent studies have found alterations that appear to be crucial in the development of severe intestinal mucositis, including early apoptosis, alterations in proliferation and cell survival pathways, as well as induction of inflammatory cascades. Several studies have indicated a possible role for glucagon-like peptide-2 analogues in treating this toxicity, due to its proven intestinotrophic, anti-apoptotic and anti-inflammatory effects in other models of gastrointestinal disease. This review provides evidence as to why and how this treatment may improve mucositis through the possible molecular crosstalk that may be occurring in models of severe intestinal mucositis.

The global burden of oral diseases and risks to oral health.

PubMed Central

Petersen, Poul Erik; Bourgeois, Denis; Ogawa, Hiroshi; Estupinan-Day, Saskia; Ndiaye, Charlotte

2005-01-01

This paper outlines the burden of oral diseases worldwide and describes the influence of major sociobehavioural risk factors in oral health. Despite great improvements in the oral health of populations in several countries, global problems still persist. The burden of oral disease is particularly high for the disadvantaged and poor population groups in both developing and developed countries. Oral diseases such as dental caries, periodontal disease, tooth loss, oral mucosal lesions and oropharyngeal cancers, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related oral disease and orodental trauma are major public health problems worldwide and poor oral health has a profound effect on general health and quality of life. The diversity in oral disease patterns and development trends across countries and regions reflects distinct risk profiles and the establishment of preventive oral health care programmes. The important role of sociobehavioural and environmental factors in oral health and disease has been shown in a large number of socioepidemiological surveys. In addition to poor living conditions, the major risk factors relate to unhealthy lifestyles (i.e. poor diet, nutrition and oral hygiene and use of tobacco and alcohol), and limited availability and accessibility of oral health services. Several oral diseases are linked to noncommunicable chronic diseases primarily because of common risk factors. Moreover, general diseases often have oral manifestations (e.g. diabetes or HIV/AIDS). Worldwide strengthening of public health programmes through the implementation of effective measures for the prevention of oral disease and promotion of oral health is urgently needed. The challenges of improving oral health are particularly great in developing countries. PMID:16211157

Endoscopic evaluation of the comparative effects of acetylsalicylic acid and choline magnesium trisalicylate on human gastric and duodenal mucosa.

PubMed

Kilander, A; Dotevall, G

1983-02-01

A new salicylate product, choline magnesium trisalicylate (Trilisate tablets), and acetylsalicylic acid were compared for their local effects in equipotent doses on the gastroduodenal mucosa in a randomized, double-blind, cross-over study, using 10 healthy volunteers. After five-day periods of administration, gastroduodenoscopy was performed and photographs were obtained. All subjects given acetylsalicylic acid developed multiple mucosal lesions, but in only four subjects given choline magnesium trisalicylate were slight mucosal changes noted. Mean serum salicylate levels were similar in the two groups. Our data suggest that the risk of developing mucosal lesions is much less during treatment with choline magnesium trisalicylate than with acetylsalicylic acid.

Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3).

PubMed

Bjarnason, Georg A; Mackenzie, Robert G; Nabid, Abdenour; Hodson, Ian D; El-Sayed, Samy; Grimard, Laval; Brundage, Michael; Wright, James; Hay, John; Ganguly, Pradip; Leong, Carson; Wilson, Jane; Jordan, Richard C K; Walker, Melanie; Tu, Dongsheng; Parulekar, Wendy

2009-01-01

Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.

Prevention of gastrointestinal side-effects in paediatric oncology: what are the guidelines?

PubMed

Cheng, Karis K F

2017-06-01

Gastrointestinal side-effects, particularly with regard to alimentary tract mucositis and chemotherapy-induced nausea and vomiting (CINV), continue to be frequent and debilitating symptomatic conditions among children and adolescents receiving cytotoxic cancer therapy. Further avenues of progress for mucositis and CINV prevention in paediatric oncology setting are warranted. The current article reviews the major guidelines and literature published in 2016 pertaining to the prevention of mucositis and CINV. Considerable professional organizational efforts have been made to develop consensus-based or evidence-based guidelines that periodically update to define basic standards of mucositis and CINV prevention. There are a few published works in 2016 that may contribute to the emerging evidence on prevention of mucositis and CINV in the paediatric setting for future guideline updates. The concomitant use of 5-HT3 receptor antagonist and dexamethasone are effective to prevent acute and delayed CINV in children who are to receive highly or moderately emetogenic chemotherapy. Optimal control of acute and delayed CINV can prevent anticipatory CINV. Oral care protocols would be beneficial to prevent mucositis in children across all cancer treatment modalities. Cryotherapy or low-level light therapy may be applied to cooperative children undergoing chemotherapy or haematological stem cell transplant conditioning regimens with a high rate of mucositis.

Assessment of oral mucositis in adult and pediatric oncology patients: an evidence-based approach.

PubMed

Farrington, Michele; Cullen, Laura; Dawson, Cindy

2010-01-01

Oral mucositis is a frequent side effect of cancer treatment and can lead to delayed treatment, reduced treatment dosage, altered nutrition, dehydration, infections, xerostomia, pain, and higher healthcare costs. Mucositis is defined as "inflammatory lesions of the oral and/or gastrointestinal tract caused by high-dose cancer therapies. Alimentary tract mucositis refers to the expression of mucosal injury across the continuum of oral and gastrointestinal mucosa, from the mouth to the anus" (Peterson, Bensadoun, & Roila, 2008, p. ii122). Evidence demonstrates that oral mucositis is quite distressing for patients. In addition, the majority of oncology nurses are unaware of available guidelines related to the care of oral mucositis. A multidisciplinary Oral Mucositis Committee was formed by the University of Iowa Hospitals and Clinics to develop evidence-based prevention and treatment strategies for adult and pediatric oncology patients experiencing oral mucositis. The first step was implementing an evidence-based nursing oral assessment. The Iowa Model was used to guide this evidence-based practice initiative. The Oral Assessment Guide (OAG) is reliable and valid, feasible, and sensitive to changing conditions. The OAG was piloted on an Adult Leukemia and Bone Marrow Transplant Unit leading to modification and adaptation. The pilot evaluation found 87% of patients had an abnormal oral assessment involving all categories in the tool. Nursing questionnaires showed that staff (8/23; 35% response) felt they were able to identify at risk patients using the OAG (3.3; 1-4 scale), and the tool accurately identifies mucosal changes (2.9; 1-4 scale). A knowledge assessment found nurses correctly identified OAG components 63% of the time. Unlike results from a national survey, most University of Iowa Hospitals and Clinics nurses (63%) were aware of national guidelines for prevention and treatment of oral mucositis. Developing an evidence-based nursing policy and updating documentation systems was done before implementation occurred. Computer-based and printed educational materials were developed for nursing staff caring for oncology patients. Team members were responsible for facilitating adoption in clinical areas. After organizational roll out, the nursing assessment was documented in all patients 87% of the time, and 99% for inpatients. The highest risk population, head and neck cancer patients receiving radiation, had documentation in 88% of audited visits. Other clinics required further work. Changing the system to the electronic medical record created an additional need for integration of the evidence-based practice with housewide documentation of oral assessment being completed 60.9% of the time. Use of an evidence-based assessment is the first step in a comprehensive program to reduce a common and highly distressing side effect of cancer treatment. Nursing documentation of oral assessment is well integrated on inpatient units. Opportunities for improvement remain in ambulatory care. Multidisciplinary team collaborations to expand evidence-based assessment and research questions generated from this work will be shared.

Intratumoral Heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 Expression in Mucosal Melanoma.

PubMed

Curioni-Fontecedro, A; Pitocco, R; Schoenewolf, N L; Holzmann, D; Soldini, D; Dummer, R; Calvieri, S; Moch, H; Mihic-Probst, D; Fitsche, A

2015-01-01

Mucosal melanoma is a rare disease, which differs from its cutaneous counterpart genetically and for its clinical behaviour. Moreover this is a heterogeneous disease based on the tissue of origin. As CT7 and CT10 are highly expressed in cutaneous melanoma and are immunogenic in this disease, we analysed their expression throughout the different subtypes of mucosal melanoma and tumor development. We detected a frequent expression of CT7 in primaries and corresponding metastases (55%) as well as for CT10 (30%). This expression resulted to be heterogeneous in the same tumor specimen and moreover influenced by the tissue of origin. Our results support the role of these antigens in immunotherapy for mucosal melanoma.

Intratumoral Heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 Expression in Mucosal Melanoma

PubMed Central

Curioni-Fontecedro, A.; Pitocco, R.; Schoenewolf, N. L.; Holzmann, D.; Soldini, D.; Dummer, R.; Calvieri, S.; Moch, H.; Mihic-Probst, D.; Fitsche, A.

2015-01-01

Mucosal melanoma is a rare disease, which differs from its cutaneous counterpart genetically and for its clinical behaviour. Moreover this is a heterogeneous disease based on the tissue of origin. As CT7 and CT10 are highly expressed in cutaneous melanoma and are immunogenic in this disease, we analysed their expression throughout the different subtypes of mucosal melanoma and tumor development. We detected a frequent expression of CT7 in primaries and corresponding metastases (55%) as well as for CT10 (30%). This expression resulted to be heterogeneous in the same tumor specimen and moreover influenced by the tissue of origin. Our results support the role of these antigens in immunotherapy for mucosal melanoma. PMID:26161400

Interventions for preventing oral mucositis in patients with cancer receiving treatment: oral cryotherapy.

PubMed

Riley, Philip; Glenny, Anne-Marie; Worthington, Helen V; Littlewood, Anne; Clarkson, Jan E; McCabe, Martin G

2015-12-23

Oral mucositis is a side effect of chemotherapy, head and neck radiotherapy, and targeted therapy, affecting over 75% of high risk patients. Ulceration can lead to severe pain and difficulty eating and drinking, which may necessitate opioid analgesics, hospitalisation and nasogastric or intravenous nutrition. These complications may lead to interruptions or alterations to cancer therapy, which may reduce survival. There is also a risk of death from sepsis if pathogens enter the ulcers of immunocompromised patients. Ulcerative oral mucositis can be costly to healthcare systems, yet there are few preventive interventions proven to be beneficial. Oral cryotherapy is a low-cost, simple intervention which is unlikely to cause side-effects. It has shown promise in clinical trials and warrants an up-to-date Cochrane review to assess and summarise the international evidence. To assess the effects of oral cryotherapy for preventing oral mucositis in patients with cancer who are receiving treatment. We searched the following databases: the Cochrane Oral Health Group Trials Register (to 17 June 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 5), MEDLINE via Ovid (1946 to 17 June 2015), EMBASE via Ovid (1980 to 17 June 2015), CANCERLIT via PubMed (1950 to 17 June 2015) and CINAHL via EBSCO (1937 to 17 June 2015). We searched the US National Institutes of Health Trials Registry, and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching databases. We included parallel-design randomised controlled trials (RCTs) assessing the effects of oral cryotherapy in patients with cancer receiving treatment. We used outcomes from a published core outcome set registered on the COMET website. Two review authors independently screened the results of electronic searches, extracted data and assessed risk of bias. We contacted study authors for information where feasible. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, we reported mean differences (MD) and 95% CIs. We pooled similar studies in random-effects meta-analyses. We reported adverse effects in a narrative format. We included 14 RCTs analysing 1280 participants. The vast majority of participants did not receive radiotherapy to the head and neck, so this review primarily assesses prevention of chemotherapy-induced oral mucositis. All studies were at high risk of bias. The following results are for the main comparison: oral cryotherapy versus control (standard care or no treatment). Adults receiving fluorouracil-based (5FU) chemotherapy for solid cancersOral cryotherapy probably reduces oral mucositis of any severity (RR 0.61, 95% CI 0.52 to 0.72, 5 studies, 444 analysed, moderate quality evidence). In a population where 728 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 444 (95% CI 379 to 524). The number needed to treat to benefit one additional person (NNTB), i.e. to prevent them from developing oral mucositis, is 4 people (95% CI 3 to 5).The results were similar for moderate to severe oral mucositis (RR 0.52, 95% CI 0.41 to 0.65, 5 studies, 444 analysed, moderate quality evidence). NNTB 4 (95% CI 4 to 6).Severe oral mucositis is probably reduced (RR 0.40, 95% CI 0.27 to 0.61, 5 studies, 444 analysed, moderate quality evidence). Where 300 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 120 (95% CI 81 to 183), NNTB 6 (95% CI 5 to 9). Adults receiving high-dose melphalan-based chemotherapy before haematopoietic stem cell transplantation (HSCT)Oral cryotherapy may reduce oral mucositis of any severity (RR 0.59, 95% CI 0.35 to 1.01, 5 studies, 270 analysed, low quality evidence). Where 824 per 1000 would develop oral mucositis, oral cryotherapy would reduce this to 486 (95% CI reduced to 289 to increased to 833). The NNTB is 3, although the uncertainty surrounding the effect estimate means that the 95% CI ranges from 2 NNTB, to 111 NNTH (number needed to treat in order to harm one additional person, i.e. for one additional person to develop oral mucositis).The results were similar for moderate to severe oral mucositis (RR 0.43, 95% CI 0.17 to 1.09, 5 studies, 270 analysed, low quality evidence). NNTB 3 (95% CI 2 NNTB to 17 NNTH).Severe oral mucositis is probably reduced (RR 0.38, 95% CI 0.20 to 0.72, 5 studies, 270 analysed, moderate quality evidence). Where 427 per 1000 would develop severe oral mucositis, oral cryotherapy would reduce this to 162 (95% CI 85 to 308), NNTB 4 (95% CI 3 to 9).Oral cryotherapy was shown to be safe, with very low rates of minor adverse effects, such as headaches, chills, numbness/taste disturbance, and tooth pain. This appears to contribute to the high rates of compliance seen in the included studies.There was limited or no evidence on the secondary outcomes of this review, or on patients undergoing other chemotherapies, radiotherapy, targeted therapy, or on comparisons of oral cryotherapy with other interventions or different oral cryotherapy regimens. Therefore no further robust conclusions can be made. There was also no evidence on the effects of oral cryotherapy in children undergoing cancer treatment. We are confident that oral cryotherapy leads to large reductions in oral mucositis of all severities in adults receiving 5FU for solid cancers. We are less confident in the ability of oral cryotherapy to reduce oral mucositis in adults receiving high-dose melphalan before HSCT. Evidence suggests that it does reduce oral mucositis in these adults, but we are less certain about the size of the reduction, which could be large or small. However, we are confident that there is an appreciable reduction in severe oral mucositis in these adults.This Cochrane review includes some very recent and currently unpublished data, and strengthens international guideline statements for adults receiving the above cancer treatments.

Rebamipide gargle in preventive management of chemo-radiotherapy induced oral mucositis.

PubMed

Chaitanya, B; Pai, Keerthilatha M; Yathiraj, Prahlad H; Fernandes, Donald; Chhaparwal, Yogesh

2017-09-01

Oral mucositis is inflammation of mucosa of oral cavity which is an inevitable and acute side effect in patients undergoing chemoradiotherapy for head & neck cancer. Though many agents have been tried in prevention & treatment of oral mucositis, until date no single agent exists that is universally established to be effective. 60 Patients diagnosed with Head & Neck cancer recruited for concurrent chemo-radiotherapy were assigned in a double blind fashion into 2 groups using computer based 1:1 ratio randomization. Subjects in Group 1 were given Rebamipide gargle while subjects in Group 2 were given Placebo gargle in similar colour coded bottles to gargle 6 times/day. Subjective assessment of oral mucositis was done by Numeric Rating Scale (NRS) and objective scoring according to RTOG system. All subjects in the Group 1 reported good treatment compliance but 4 subjects in Group 2 developed burning sensation to gargle and were excluded. Onset of oral mucositis was 3.5days earlier in Group 2 (mean=11.17) as compared to Group 1 (mean=14.63). At the end of chemo-radiotherapy, severity of oral mucositis was significantly lower in Group 1 (mean=1.97) than in Group 2 (mean=2.81). Findings of this study revealed that Rebamipide gargle may be an effective means to prolong the onset of oral mucositis and may reduce the severity of oral mucositis in undergoing chemo-radiotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Isolation of HIV-1-Neutralizing Mucosal Monoclonal Antibodies from Human Colostrum

PubMed Central

Friedman, James; Alam, S. Munir; Shen, Xiaoying; Xia, Shi-Mao; Stewart, Shelley; Anasti, Kara; Pollara, Justin; Fouda, Genevieve G.; Yang, Guang; Kelsoe, Garnett; Ferrari, Guido; Tomaras, Georgia D.; Haynes, Barton F.; Liao, Hua-Xin

2012-01-01

Background Generation of potent anti-HIV antibody responses in mucosal compartments is a potential requirement of a transmission-blocking HIV vaccine. HIV-specific, functional antibody responses are present in breast milk, and these mucosal antibody responses may play a role in protection of the majority of HIV-exposed, breastfeeding infants. Therefore, characterization of HIV-specific antibodies produced by B cells in milk could guide the development of vaccines that elicit protective mucosal antibody responses. Methods We isolated B cells from colostrum of an HIV-infected lactating woman with a detectable neutralization response in milk and recombinantly produced and characterized the resulting HIV-1 Envelope (Env)-specific monoclonal antibodies (mAbs). Results The identified HIV-1 Env-specific colostrum mAbs, CH07 and CH08, represent two of the first mucosally-derived anti-HIV antibodies yet to be reported. Colostrum mAb CH07 is a highly-autoreactive, weakly-neutralizing gp140-specific mAb that binds to linear epitopes in the gp120 C5 region and gp41 fusion domain. In contrast, colostrum mAb CH08 is a nonpolyreactive CD4-inducible (CD4i) gp120-specific mAb with moderate breadth of neutralization. Conclusions These novel HIV-neutralizing mAbs isolated from a mucosal compartment provide insight into the ability of mucosal B cell populations to produce functional anti-HIV antibodies that may contribute to protection against virus acquisition at mucosal surfaces. PMID:22624058

Rehabilitative therapy of short bowel syndrome: experimental study and clinical trial.

PubMed

Li, N; Zhu, W; Guo, F; Ren, J; Li, Y; Wang, X; Li, J

2000-08-01

To investigate the effect of growth hormone on proliferative activity of the residual small intestinal mucosa after massive small intestinal resection and to evaluate the clinical efficacy of bowel rehabilitative therapy for short bowel syndrome. Small intestinal mucosa proliferative activity were compared in rats from control group (sham operation), short bowel group (80% small bowel resection) and growth hormone treatment group (80% small bowel resection + growth hormone 1 U x kg(-1) x d(-1) for 28 days) with the aid of histology image analysis, flow cytometric assay, immunohistochemistry analysis and RT-PCR assay. The nutritional status, D-xylose absorption and stool nitrogen output were observed in 9 consecutive parenteral nutrition dependent patients with short bowel syndrome after intestinal rehabilitative therapy (growth hormone 8 - 12 U x kg(-1) x d(-1) im + glutamine 0.6 g x kg(-1) x d(-1) iv + special diet) for 21 continuous days. Growth hormone administration significantly increased rat small intestinal mucosal villous height, mucosal thickness, proliferative index, and the expression of proliferating cell nuclear antigen and c-jun mRNA. Rehabilitative therapy increased the body weight, serum total protein and album in concentrations in patients. Their D-xylose absorption indices increased and fecal nitrogen losses decreased. Follow-up data showed that 6 of the 9 patients sustained on enteral nutrition. Growth hormone enhances the proliferative activity of the mucosal epithelium and bowel rehabilitative therapy may benefit the patients with short bowel syndrome.

Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bossi, Paolo, E-mail: Paolo.bossi@istitutotumori.mi.it; Bergamini, Cristiana; Miceli, Rosalba

Purpose: We assessed the presence of salivary cytokines, their modulation during chemoradiation therapy (CTRT), and their association with oral mucositis severity in patients with head and neck cancer (HNC). Methods and Materials: The present prospective observational study enrolled 55 patients with locally advanced HNC requiring CTRT. We also studied 10 healthy volunteers and 10 patients with other cancers. The salivary levels of 13 cytokines were analyzed. We constructed a cytokine predictive score of oral mucositis severity. Results: The baseline salivary cytokine levels were not associated with the severity of treatment-induced oral mucositis. The cytokine levels overall increased during treatment, especiallymore » in patients with worse mucositis. In particular, on univariable analysis, an increase of interleukin (IL)-1β (area under the curve [AUC] 0.733; P=.009), IL-6 (AUC 0.746; P=.005), and tumor necrosis factor-α (AUC 0.710; P=.005) at the third week of treatment was significantly associated with the development of severe oral mucositis. On multivariable analysis, the predictive score based on the IL-1β and IL-6 changes from baseline to week 3 was an early strong predictor of higher grade oral mucositis. Conclusions: The treatment of HNC patients with concurrent CTRT induces a significant increase in the salivary levels of IL-1β, IL-6, and tumor necrosis factor-α, all positively associated with the severity of mucosal toxicity. A greater increase of IL-1β and IL-6 3 weeks after treatment initiation is predictive of worse oral mucositis, representing a potential tool for the early identification of patients at risk.« less

Mucosal complications of modified osteo-odonto keratoprosthesis in chronic Stevens-Johnson syndrome.

PubMed

Basu, Sayan; Pillai, Vinay Sukumara; Sangwan, Virender S

2013-11-01

To describe clinical outcomes of complications afflicting the autologous oral mucous membrane graft after modified osteo-odonto keratoprosthesis surgery in chronic Stevens-Johnson syndrome (SJS). Prospective case series. This study included 30 eyes of 30 patients with SJS-induced dry keratinized ocular surfaces; the patients underwent various stages of this procedure between August 2009 and February 2012. Mucosal complications were classified as either necrosis or overgrowth. Mucosal necrosis was managed according to a predesigned algorithm based on timing (pre- and postimplantation) and location (central or peripheral) of necrosis. Cases with mucosal overgrowth underwent mucosal debulking and trimming. Mucosal necrosis developed in 15 (50%) eyes and overgrowth in 4 (13.3%) eyes. Preimplantation necrosis (n = 7) was initially managed conservatively, but 2 eyes required free labial-mucous membrane grafting for persistent corneal exposure. Free labial-mucous membrane grafting was performed in all cases of postimplantation necrosis (n = 10), but 8 eyes required additional tarsal pedicle flaps (n = 6, for peripheral necrosis) or through-the-lid revisions (n = 2, for central necrosis). Debulking and trimming effectively managed all cases of mucosal overgrowth, but 3 eyes required repeat procedures. At 24.1 ± 6.5 months postimplantation, the keratoprosthesis was retained in all eyes, and the probability of maintaining 20/60 or better vision was similar in eyes with or without mucosal necrosis (86 ± 8.8% vs 80 ± 10.3%). Mucosal complications, especially necrosis, occurred commonly following modified osteo-odonto keratoprosthesis surgery in dry keratinized post-SJS eyes. The algorithm-based management approach described in this study was successful in treating these complications, retaining the prosthesis and preserving useful vision. Copyright © 2013 Elsevier Inc. All rights reserved.

Perforating internal root resorption repaired with mineral trioxide aggregate caused complete resolution of odontogenic sinus mucositis: a case report.

PubMed

Bendyk-Szeffer, Maja; Łagocka, Ryta; Trusewicz, Matylda; Lipski, Mariusz; Buczkowska-Radlińska, Jadwiga

2015-02-01

An extensive perforating internal root resorption accompanied by apical periodontitis and odontogenic sinus mucositis was detected on preoperative cone-beam computed tomographic scans in a first maxillary molar. After the chemomechanical debridement of the root canals, calcium hydroxide was placed as a temporary dressing for 7 days. Mineral trioxide aggregate was used to fill the perforation site with the aid of a surgical microscope. At the next visit, the root with the resorption defect was filled with warm vertical compaction of gutta-percha. A control cone-beam computed tomographic scan acquired 6 months after the endodontic treatment revealed complete resolution of the sinus retention cyst. Moreover, the patient's frequent otolaryngologic disturbances ceased. The tooth was functional with satisfactory clinical and radiographic results after 12 months. Based on the results of this case, successful repair of an extensive, perforating internal resorption with mineral trioxide aggregate may lead to complete resolution of apical periodontitis and maxillary sinus retention cyst. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Modes of Action for Mucosal Vaccine Adjuvants

PubMed Central

2017-01-01

Abstract Vaccine adjuvants induce innate immune responses and the addition of adjuvants to the vaccine helps to induce protective immunity in the host. Vaccines utilizing live attenuated or killed whole pathogens usually contain endogenous adjuvants, such as bacterial cell wall products and their genomic nucleic acids, which act as pathogen-associated molecular patterns and are sufficient to induce adaptive immune responses. However, purified protein- or antigen-based vaccines, including component or recombinant vaccines, usually lose these endogenous innate immune stimulators, so the addition of an exogenous adjuvant is essential for the success of these vaccine types. Although this adjuvant requirement is mostly the same for parental and mucosal vaccines, the development of mucosal vaccine adjuvants requires the specialized consideration of adapting the adjuvants to characteristic mucosal conditions. This review provides a brief overview of mucosa-associated immune response induction processes, such as antigen uptake and dendritic cell subset-dependent antigen presentation. It also highlights several mucosal vaccine adjuvants from recent reports, particularly focusing on their modes of action. PMID:28436755

Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues

PubMed Central

Lai, Samuel K.; Wang, Ying-Ying; Hanes, Justin

2009-01-01

Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates, including conventional particle-based drug delivery systems, are efficiently trapped in human mucus layers by steric obstruction and/or adhesion. Trapped particles are typically removed from the mucosal tissue within seconds to a few hours depending on anatomical location, thereby strongly limiting the duration of sustained drug delivery locally. A number of debilitating diseases could be treated more effectively and with fewer side effects if drugs and genes could be more efficiently delivered to the underlying mucosal tissues in a controlled manner. This review first describes the tenacious mucus barrier properties that have precluded the efficient penetration of therapeutic particles. It then reviews the design and development of new mucus-penetrating particles that may avoid rapid mucus clearance mechanisms, and thereby provide targeted or sustained drug delivery for localized therapies in mucosal tissues. PMID:19133304

Modes of Action for Mucosal Vaccine Adjuvants.

PubMed

Aoshi, Taiki

Vaccine adjuvants induce innate immune responses and the addition of adjuvants to the vaccine helps to induce protective immunity in the host. Vaccines utilizing live attenuated or killed whole pathogens usually contain endogenous adjuvants, such as bacterial cell wall products and their genomic nucleic acids, which act as pathogen-associated molecular patterns and are sufficient to induce adaptive immune responses. However, purified protein- or antigen-based vaccines, including component or recombinant vaccines, usually lose these endogenous innate immune stimulators, so the addition of an exogenous adjuvant is essential for the success of these vaccine types. Although this adjuvant requirement is mostly the same for parental and mucosal vaccines, the development of mucosal vaccine adjuvants requires the specialized consideration of adapting the adjuvants to characteristic mucosal conditions. This review provides a brief overview of mucosa-associated immune response induction processes, such as antigen uptake and dendritic cell subset-dependent antigen presentation. It also highlights several mucosal vaccine adjuvants from recent reports, particularly focusing on their modes of action.

Potential prevention: Aloe vera mouthwash may reduce radiation-induced oral mucositis in head and neck cancer patients.

PubMed

Ahmadi, Amirhossein

2012-08-01

In recent years, more head and neck cancer patients have been treated with radiotherapy. Radiation-induced mucositis is a common and dose limiting toxicity of radiotherapy among patients with head and neck cancers. Patients undergoing radiation therapy for head and neck cancer are also at increased risk of developing oral candidiasis. A number of new agents applied locally or systemically to prevent or treat radiation-induced mucositis have been investigated, but there is no widely accepted prophylactic or effective treatment for mucositis. Topical Aloe vera is widely used for mild sunburn, frostbites, and scalding burns. Studies have reported the beneficial effects of Aloe gel for wound healing, mucous membrane protection, and treatment of oral ulcers, in addition to antiinflammatory, immunomudulation, antifungal, scavenging free radicals, increasing collagen formation and inhibiting collagenase. Herein the author postulates that oral Aloe vera mouthwash may not only prevent radiation-induced mucositis by its wound healing and antiinflammatory mechanism, but also may reduce oral candidiasis of patients undergoing head and neck radiotherapy due to its antifungal and immunomodulatory properties. Hence, Aloe vera mouthwash may provide an alternative agent for treating radiation-induced oral mucositis and candidiasis in patients with head and neck cancers.

Primary prevention of peri-implantitis: managing peri-implant mucositis.

PubMed

Jepsen, Søren; Berglundh, Tord; Genco, Robert; Aass, Anne Merete; Demirel, Korkud; Derks, Jan; Figuero, Elena; Giovannoli, Jean Louis; Goldstein, Moshe; Lambert, France; Ortiz-Vigon, Alberto; Polyzois, Ioannis; Salvi, Giovanni E; Schwarz, Frank; Serino, Giovanni; Tomasi, Cristiano; Zitzmann, Nicola U

2015-04-01

Over the past decades, the placement of dental implants has become a routine procedure in the oral rehabilitation of fully and partially edentulous patients. However, the number of patients/implants affected by peri-implant diseases is increasing. As there are--in contrast to periodontitis--at present no established and predictable concepts for the treatment of peri-implantitis, primary prevention is of key importance. The management of peri-implant mucositis is considered as a preventive measure for the onset of peri-implantitis. Therefore, the remit of this working group was to assess the prevalence of peri-implant diseases, as well as risks for peri-implant mucositis and to evaluate measures for the management of peri-implant mucositis. Discussions were informed by four systematic reviews on the current epidemiology of peri-implant diseases, on potential risks contributing to the development of peri-implant mucositis, and on the effect of patient and of professionally administered measures to manage peri-implant mucositis. This consensus report is based on the outcomes of these systematic reviews and on the expert opinion of the participants. Key findings included: (i) meta-analysis estimated a weighted mean prevalence for peri-implant mucositis of 43% (CI: 32-54%) and for peri-implantitis of 22% (CI: 14-30%); (ii) bleeding on probing is considered as key clinical measure to distinguish between peri-implant health and disease; (iii) lack of regular supportive therapy in patients with peri-implant mucositis was associated with increased risk for onset of peri-implantitis; (iv) whereas plaque accumulation has been established as aetiological factor, smoking was identified as modifiable patient-related and excess cement as local risk indicator for the development of peri-implant mucositis; (v) patient-administered mechanical plaque control (with manual or powered toothbrushes) has been shown to be an effective preventive measure; (vi) professional intervention comprising oral hygiene instructions and mechanical debridement revealed a reduction in clinical signs of inflammation; (vii) adjunctive measures (antiseptics, local and systemic antibiotics, air-abrasive devices) were not found to improve the efficacy of professionally administered plaque removal in reducing clinical signs of inflammation. Consensus was reached on recommendations for patients with dental implants and oral health care professionals with regard to the efficacy of measures to manage peri-implant mucositis. It was particularly emphasized that implant placement and prosthetic reconstructions need to allow proper personal cleaning, diagnosis by probing and professional plaque removal. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The effect of honey on mucositis induced by chemoradiation in head and neck cancer.

PubMed

Maiti, Pradip Kumar; Ray, Amitabh; Mitra, Tarak Nath; Jana, Utpal; Bhattacharya, Jibak; Ganguly, Subir

2012-07-01

The aim of this study was to evaluate the effect of pure natural honey on radiation-induced mucositis. Fifty-five patients diagnosed with head and neck cancer requiring radiation to the oropharyngeal mucosal area were divided into two groups (study arm-28 and control arm-27) to receive either chemoradiation or chemoradiation plus topical application of honey. Patients were treated using a telecobalt machine at 2 Gy per day, five times a week up to a total dose of 66 Gy. in the study arm, patients were advised to take 20 ml of honey 15 minutes before, 15 minutes after and similar amount at bed time. Patients were evaluated every week for the development of radiation mucositis using the WHO grading system. There was significant reduction in the symptomatic grades 3 and 4 mucositis in honey-treated patients compared to controls ie, 18% versus 41% for grade 3 and 4% versus 22% for grade 4 mucositis. Seventy-one per cent of patients treated with topical honey showed no change or a positive gain in body weight. In the control group also 22% had no weight loss, though none showed weight gain. Furthermore, it didn't affect blood sugar level when initial fasting blood sugar level was < 150 mg%. Honey is a cheap, simple, easily available and effective agent in reducing radiation-induced mucositis. Within the limits of this study the results showed the application of natural honey is effective in managing radiation induced mucositis, which warrants further multicentric randomised trials to validate the findings.

New frontiers in mucositis.

PubMed

Peterson, Douglas E; Keefe, Dorothy M; Sonis, Stephen T

2012-01-01

Mucositis is among the most debilitating side effects of radiotherapy, chemotherapy, and targeted anticancer therapy. Research continues to escalate regarding key issues such as etiopathology, incidence and severity across different mucosae, relationships between mucosal and nonmucosal toxicities, and risk factors. This approach is being translated into enhanced management strategies. Recent technology advances provide an important foundation for this continuum. For example, evolution of applied genomics is fostering development of new algorithms to rapidly screen genomewide single-nucleotide polymorphisms (SNPs) for patient-associated risk prediction. This modeling will permit individual tailoring of the most effective, least toxic treatment in the future. The evolution of novel cancer therapeutics is changing the mucositis toxicity profile. These agents can be associated with unique mechanisms of mucosal damage. Additional research is needed to optimally manage toxicity caused by agents such as mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors, without reducing antitumor effect. There has similarly been heightened attention across the health professions regarding clinical practice guidelines for mucositis management in the years following the first published guidelines in 2004. New opportunities exist to more effectively interface this collective guideline portfolio by capitalizing upon novel technologies such as an Internet-based Wiki platform. Substantive progress thus continues across many domains associated with mucosal injury in oncology patients. In addition to enhancing oncology patient care, these advances are being integrated into high-impact educational and scientific venues including the National Cancer Institute Physician Data Query (PDQ) portfolio as well as a new Gordon Research Conference on mucosal health and disease scheduled for June 2013.

The effect of a calcium phosphate mouth rinse on (chemo) radiation induced oral mucositis in head and neck cancer patients: a prospective study.

PubMed

Stokman, M A; Burlage, F R; Spijkervet, F K L

2012-08-01

Promising results of a calcium phosphate (CP) mouth rinse on reduced severity of oral mucositis have been reported. The aim of this study was to determine the effect of a CP mouth rinse on the frequency, duration and severity of (chemo) radiation induced oral mucositis in patients with head-neck cancer. patients with oral malignancies, treated with (chemo) radiotherapy, were included. Patients rinsed four times a day with a CP mouth rinse. Patients not willing to rinse with the CP mouth rinse served as control. Mucositis was scored according to the WHO score at baseline and twice a week during the full course of (chemo) radiotherapy. Patient's self-reported mouth-throat soreness (MTS) was evaluated at the same time interval using a diary in the CP mouth rinse group. The outcomes on MTS were compared with a historical control group. Fifty-two patients were analysed: 25 CP mouth rinse group, 11 control group and 16 historical group. There was no significant difference between the CP group and control group on development and severity of oral mucositis. No significant difference was found for subjective outcomes on MTS between the CP group and the historical group. The CP mouth rinse seems to have no influence on the frequency, duration and severity of oral mucositis during (chemo) radiation in patients with head and neck cancer. A trend to develop less MTS for drinking and eating was found when applying the CP mouth rinse. © 2012 John Wiley & Sons A/S.

Analysis of oral lesion biopsies identified and evaluated by visual examination, chemiluminescence and toluidine blue.

PubMed

Epstein, J B; Silverman, S; Epstein, J D; Lonky, S A; Bride, M A

2008-06-01

Conventional visual examination and palpation remains the gold-standard for the identification of oral mucosal lesions. The purpose of this study was to investigate the adjunctive value of a chemiluminescent light source (ViziLite, Zila Pharmaceuticals, Phoenix, Arizona) and application of pharmaceutical grade toluidine blue (TBlue(630), Zila Pharmaceuticals, Phoenix, Arizona) to further assess lesions identified during the conventional oral soft tissue examination. Lesions deemed clinically suspicious by visual examination under incandescent light were further assessed under chemiluminescence and then application of toluidine blue stain. Differences between the conventional visual examination and chemiluminescent examination were noted on four characteristics which may aid in lesion identification. Tissue retention of toluidine blue stain was documented. Each suspicious lesion was biopsied and diagnosed based upon routine histopathology. Both adjunctive exams were evaluated by comparing the histologic diagnosis. The additive value of toluidine blue stain retention was assessed in lesions diagnosed as "serious pathology" defined as severe dysplasia, carcinoma in situ and squamous cell carcinoma. Ninety-seven clinically suspicious lesions in 84 patients were identified. The chemiluminescent exam improved the brightness and/or sharpness of margin in 61.8% of identified lesions. Biopsied lesions with toluidine blue stain retention reduced the false positive rate by 55.26% while maintaining a 100% negative predictive value (NPV). Chemiluminescence was shown to increase the brightness and margins of mucosal lesions in a majority of cases and therefore may assist in identification of mucosal lesions not considered under traditional visual examination. Toluidine blue stain retention was associated with a large reduction in biopsies showing benign histology (false positive biopsy results), while maintaining a 100% NPV for the presence of severe dysplasia or cancer. Practitioners may consider use of these adjuncts in practice, however the results presented are based upon experienced providers in referral centers for mucosal disease or cancer centers and therefore positive findings may be an indication for referral to experienced providers.

Lactococci and lactobacilli as mucosal delivery vectors for therapeutic proteins and DNA vaccines

PubMed Central

2011-01-01

Food-grade Lactic Acid Bacteria (LAB) have been safely consumed for centuries by humans in fermented foods. Thus, they are good candidates to develop novel oral vectors, constituting attractive alternatives to attenuated pathogens, for mucosal delivery strategies. Herein, this review summarizes our research, up until now, on the use of LAB as mucosal delivery vectors for therapeutic proteins and DNA vaccines. Most of our work has been based on the model LAB Lactococcus lactis, for which we have developed efficient genetic tools, including expression signals and host strains, for the heterologous expression of therapeutic proteins such as antigens, cytokines and enzymes. Resulting recombinant lactococci strains have been tested successfully for their prophylactic and therapeutic effects in different animal models: i) against human papillomavirus type 16 (HPV-16)-induced tumors in mice, ii) to partially prevent a bovine β-lactoglobulin (BLG)-allergic reaction in mice and iii) to regulate body weight and food consumption in obese mice. Strikingly, all of these tools have been successfully transposed to the Lactobacillus genus, in recent years, within our laboratory. Notably, anti-oxidative Lactobacillus casei strains were constructed and tested in two chemically-induced colitis models. In parallel, we also developed a strategy based on the use of L. lactis to deliver DNA at the mucosal level, and were able to show that L. lactis is able to modulate the host response through DNA delivery. Today, we consider that all of our consistent data, together with those obtained by other groups, demonstrate and reinforce the interest of using LAB, particularly lactococci and lactobacilli strains, to develop novel therapeutic protein mucosal delivery vectors which should be tested now in human clinical trials. PMID:21995317

Mucosal transmission and pathogenesis of chronic wasting disease in ferrets.

PubMed

Perrott, Matthew R; Sigurdson, Christina J; Mason, Gary L; Hoover, Edward A

2013-02-01

Chronic wasting disease (CWD) of cervids is almost certainly transmitted by mucosal contact with the causative prion, whether by direct (animal-to-animal) or indirect (environmental) means. Yet the sites and mechanisms of prion entry remain to be further understood. This study sought to extend this understanding by demonstrating that ferrets exposed to CWD via several mucosal routes developed infection, CWD prion protein (PrP(CWD)) amplification in lymphoid tissues, neural invasion and florid transmissible spongiform encephalopathy lesions resembling those in native cervid hosts. The ferrets developed extensive PrP(CWD) accumulation in the nervous system, retina and olfactory epithelium, with lesser deposition in tongue, muscle, salivary gland and the vomeronasal organ. PrP(CWD) accumulation in mucosal sites, including upper respiratory tract epithelium, olfactory epithelium and intestinal Peyer's patches, make the shedding of prions by infected ferrets plausible. It was also observed that regionally targeted exposure of the nasopharyngeal mucosa resulted in an increased attack rate when compared with oral exposure. The latter finding suggests that nasal exposure enhances permissiveness to CWD infection. The ferret model has further potential for investigation of portals for initiation of CWD infection.

Mucosal transmission and pathogenesis of chronic wasting disease in ferrets

PubMed Central

Perrott, Matthew R.; Sigurdson, Christina J.; Mason, Gary L.

2013-01-01

Chronic wasting disease (CWD) of cervids is almost certainly transmitted by mucosal contact with the causative prion, whether by direct (animal-to-animal) or indirect (environmental) means. Yet the sites and mechanisms of prion entry remain to be further understood. This study sought to extend this understanding by demonstrating that ferrets exposed to CWD via several mucosal routes developed infection, CWD prion protein (PrPCWD) amplification in lymphoid tissues, neural invasion and florid transmissible spongiform encephalopathy lesions resembling those in native cervid hosts. The ferrets developed extensive PrPCWD accumulation in the nervous system, retina and olfactory epithelium, with lesser deposition in tongue, muscle, salivary gland and the vomeronasal organ. PrPCWD accumulation in mucosal sites, including upper respiratory tract epithelium, olfactory epithelium and intestinal Peyer’s patches, make the shedding of prions by infected ferrets plausible. It was also observed that regionally targeted exposure of the nasopharyngeal mucosa resulted in an increased attack rate when compared with oral exposure. The latter finding suggests that nasal exposure enhances permissiveness to CWD infection. The ferret model has further potential for investigation of portals for initiation of CWD infection. PMID:23100363

Mucosal wrinkling in animal antra induced by volumetric growth

NASA Astrophysics Data System (ADS)

Li, Bo; Cao, Yan-Ping; Feng, Xi-Qiao; Yu, Shou-Wen

2011-04-01

Surface wrinkling of animal mucosas is crucial for the biological functions of some tissues, and the change in their surface patterns is a phenotypic characteristic of certain diseases. Here we develop a biomechanical model to study the relationship between morphogenesis and volumetric growth, either physiological or pathological, of mucosas. Theoretical analysis and numerical simulations are performed to unravel the critical characteristics of mucosal wrinkling in a spherical antrum. It is shown that the thicknesses and elastic moduli of mucosal and submucosal layers dictate the surface buckling morphology. The results hold clinical relevance for such diseases as inflammation and gastritis.

The effect of a supersaturated calcium phosphate mouth rinse on the development of oral mucositis in head and neck cancer patients treated with (chemo)radiation: a single-center, randomized, prospective study of a calcium phosphate mouth rinse + standard of care versus standard of care.

PubMed

Lambrecht, Maarten; Mercier, Carole; Geussens, Yasmyne; Nuyts, Sandra

2013-10-01

Mucosal damage is an important and debilitating side effect when treating head and neck cancer patients with (chemo-)radiation. The aim of this randomized clinical trial was to investigate whether the addition of a neutral, supersaturated, calcium phosphate (CP) mouth rinse benefits the severity and duration of acute mucositis in head and neck cancer patients treated with (chemo)radiation. A total of 60 patients with malignant neoplasms of the head and neck receiving (chemo)radiation were included in this study. Fifty-eight patients were randomized into two treatment arms: a control group receiving standard of care (n = 31) and a study group receiving standard of care + daily CP mouth rinses (n = 27) starting on the first day of (chemo-)radiation. Oral mucositis and dysphagia were assessed twice a week using the National Cancer Institute common toxicity criteria scale version 3, oral pain was scored with a visual analogue scale. No significant difference in grade III mucositis (59 vs. 71 %; p = 0.25) and dysphagia (33 vs. 42 %, p = 0.39) was observed between the study group compared to the control group. Also no significant difference in time until development of peak mucositis (28.6 vs. 28.7 days; p = 0.48), duration of peak mucositis (22.7 vs. 24.6 days; p = 0.31), recuperation of peak dysphagia (20.5 vs 24.2 days; p = 0.13) and occurrence of severe pain (56 vs. 52 %, p = 0.5). In this randomized study, the addition of CP mouth rinse to standard of care did not improve the frequency, duration or severity of the most common acute toxicities during and early after (chemo)radiation. There is currently no evidence supporting its standard use in daily practice.

An overview of in vitro dissolution/release methods for novel mucosal drug delivery systems.

PubMed

Jug, Mario; Hafner, Anita; Lovrić, Jasmina; Kregar, Maja Lusina; Pepić, Ivan; Vanić, Željka; Cetina-Čižmek, Biserka; Filipović-Grčić, Jelena

2018-01-05

In vitro dissolution/release tests are an important tool in the drug product development phase as well as in its quality control and the regulatory approval process. Mucosal drug delivery systems are aimed to provide both local and systemic drug action via mucosal surfaces of the body and exhibit significant differences in formulation design, as well as in their physicochemical and release characteristics. Therefore it is not possible to devise a single test system which would be suitable for release testing of such complex dosage forms. This article is aimed to provide a comprehensive review of both compendial and noncompendial methods used for in vitro dissolution/release testing of novel mucosal drug delivery systems aimed for ocular, nasal, oromucosal, vaginal and rectal administration. Copyright © 2017 Elsevier B.V. All rights reserved.

Promotion of ulcerative duodenitis in young ferrets by oral immunization with Helicobacter mustelae and muramyl dipeptide.

PubMed

Whary, M T; Palley, L S; Batchelder, M; Murphy, J C; Yan, L; Taylor, N S; Fox, J G

1997-06-01

The purpose of this study was to determine whether oral immunization of ferret kits with a whole-cell sonicate of Helicobacter mustelae lysate (Hml) and the adjuvant muramyl dipeptide (MDP) would reduce the incidence of natural colonization with H. mustelae and the extent of Helicobacter-associated gastritis by enhancing the host mucosal immune response. Between the ages of 4 and 11 weeks, 44 ferret kits were gavaged with Hml and various doses of MDP. The extent of gastritis and duodenitis and the immune response to H. mustelae were evaluated. All kits became colonized naturally with H. mustelae and the majority developed mild to severe gastritis and duodenitis. Kits that received Hml with MDP developed significantly greater inflammation of the gastric antrum and duodenum, as compared to kits vaccinated with Hml alone. Vaccination with Hml and 50 micrograms of MDP was associated with severe lesions in the proximal duodenum characterized by accumulation of mononuclear inflammatory cells, mucosal erosion, and ulceration. Although serum antibody specific for H. mustelae in 4-week-old kits was approximately 50% of adult levels, a finding attributable to passively acquired maternal antibody, both systemic and mucosal antibody levels became depressed over time despite oral vaccination. The humoral immune response was sufficiently low to prevent detection of any significant dose effect of MDP on antibody levels among experimental groups. Oral vaccination of young ferrets with Hml and 50 micrograms MDP increased the risk of Helicobacter-associated mucosal ulceration in the proximal duodenum, which was associated with low humoral (but significant cell-mediated) immune responses to H. mustelae. In retrospect, the frequency of vaccination may have suppressed the systemic humoral immune response, thereby promoting mucosal damage by H. mustelae. The 50-microgram dose of MDP enhanced the cell-mediated immune response, which indirectly contributed to development of severe lesions. The increased frequency of mucosal damage associated with this vaccination regimen enhances the value of the ferret model for studying duodenal ulceration secondary to Helicobacter infection.

Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey.

PubMed

Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian; Drzewiecki, Krzysztof T; Prause, Jan U; Heegaard, Steffen

2016-06-01

Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma and conjunctival melanoma, which are very rare in Black people. The symptoms are not tumour-specific and are related to the organ system affected, and the disease is most often diagnosed at an advanced clinical stage. The diagnosis of a primary tumour is difficult, and metastatic cutaneous melanoma and choroidal melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins is the treatment of choice. The prognosis is poor, with the 5-year survival rate ranging from 0% (gastric melanoma) to 80% (conjunctival melanoma). © 2016 APMIS. Published by John Wiley & Sons Ltd.

Mucositis and salivary antioxidants in patients undergoing bone marrow transplantation (BMT)

PubMed Central

Mazzeo, Marcelo A.; López, María M.; Linares, Jorge A.; Jarchum, Gustavo; Wietz, Fernando M.; Finkelberg, Ana B.

2014-01-01

Objectives: High doses of chemotherapy generate DNA damage in patients undergoing bone marrow transplantation (BMT), due to the production of reactive oxygen species (ROS). In order to evaluate the local defensive effectiveness of the patient undergoing BMT, the concentrations of the antioxidants superoxide dismutase (SOD) and uric acid (UA) were measured in saliva. Study Design: Basal saliva samples were collected from 20 patients undergoing BMT at the Oncology Department, Sanatorio Allende (Córdoba), in the stages: initial, prior to conditioning therapy (I); middle: 7 to 10 days after BMT (M) and final stage, 30 days after discharge from isolation (F). SOD levels were determined using a RANDOX kit (RANSOD superoxide dismutase manual), and for uric acid enzymatic UOD / PAP spectrophotometric method, ( Trinder Color Kit , Wiener Lab) was used. Results: 85% of the patients developed oral mucositis. SOD concentration in the M stage was significantly higher (p<0.01) compared with stage I, and it reversed in stage F. UA concentration was significantly lower (p<0.001) in stage M compared with stage I, and in stage F it recovered the initial values. Conclusions: SOD increase in stage M coincided with the appearance of mucositis, which could be interpreted as a defensive mechanism of saliva against oxidative stress produced by chemotherapy. UA decrease in stage M would favour the development of higher degrees of mucositis. Key words:Bone marrow transplantation, mucositis, superoxide dismutase, uric acid. PMID:24608218

Development of a diagnostic diagram for rapid field assessment of acidosis severity in diarrheic calves.

PubMed

Bellino, Claudio; Arnaudo, Fabrizio; Biolatti, Cristina; Borrelli, Antonio; Gianella, Paola; Maurella, Cristiana; Zabaldano, Giuseppe; Cagnasso, Aurelio; D'Angelo, Antonio

2012-02-01

To develop a diagnostic diagram for rapid field assessment of acidosis severity in diarrheic calves. Prospective cross-sectional study. 148 Piedmontese calves (38 calves in preliminary experiments; 83 diarrheic calves and 27 healthy control calves in the primary experiment). Physical examination was performed and a standard data collection form was completed for each calf. Blood samples were obtained and submitted for evaluation of acid-base balance, performance of a CBC, and measurement of electrolyte and total protein concentrations. Severe metabolic acidosis (extracellular base excess more negative than -10 mmol/L) was associated with abnormal mental status, delayed or absent suckle reflex, abnormal posture or gait, enophthalmos, and cold oral mucosal membranes. Clinical signs associated with severe metabolic acidosis were arranged into a grid to create a diagnostic diagram. Sensitivity and specificity of the diagnostic diagram for the prediction of severe metabolic acidosis were 88% and 79%, respectively. Use of the diagnostic diagram may aid differentiation between severe and nonsevere acidosis patterns as determined on the basis of clinical signs.

Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.

PubMed

Grözinger, Gerd; Mann, Steven; Mehra, Tarun; Klumpp, Bernhard; Grosse, Ulrich; Nikolaou, Konstantin; Garbe, Claus; Clasen, Stephan

2016-06-01

Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

PubMed

Elyasi, Sepideh; Hosseini, Sare; Niazi Moghadam, Mohammad Reza; Aledavood, Seyed Amir; Karimi, Gholamreza

2016-11-01

Mucositis is a frequent severe complication of radiation therapy in patient with head and neck cancer. Silymarin is a polyphenolic flavonoid extracted from the milk thistle that exhibits strong antioxidant and antiinflammatory activities. In this study, we evaluate silymarin efficacy in prevention of radiotherapy induced mucositis in patients with head and neck cancer, as the first human study. During this pilot, randomized, double-blinded, placebo-controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting at the first day of radiotherapy for 6 weeks, on oral mucositis occurrence was assessed. Twenty-seven patients fulfilled the inclusion criteria assigned to the silymarin or placebo group. World Health Organization and National Cancer Institute-Common Terminology Criteria oral mucositis grading scale scores were recorded at baseline and weekly during these 6 weeks. The median World Health Organization and National Cancer Institute Common Terminology Criteria scores were significantly lower in silymarin group at the end of the first to sixth week (p < 0.05). The scores increased significantly in both placebo and silymarin groups during radiotherapy, but there was a delay for mucositis development and progression in silymarin group. Prophylactic administration of conventional form of silymarin tablets could significantly reduce the severity of radiotherapy induced mucositis and delay its occurrence in patients with head and neck cancer. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Sage tea-thyme-peppermint hydrosol oral rinse reduces chemotherapy-induced oral mucositis: A randomized controlled pilot study.

PubMed

Mutluay Yayla, Ezgi; Izgu, Nur; Ozdemir, Leyla; Aslan Erdem, Sinem; Kartal, Murat

2016-08-01

This pilot study aimed to investigate the preventive effect of sage tea-thyme-peppermint hydrosol oral rinse used in conjunction with basic oral care on chemotherapy-induced oral mucositis. An open-label randomized controlled study. Two oncology hospitals in Ankara, Turkey. Patients receiving 5-fluorouracil-based chemotherapy regimens were divided into the intervention group (N=30) and control group (N=30). Basic oral care was prescribed to the control group, while the intervention group was prescribed sage tea-thyme-peppermint hydrosol in addition to basic oral care. All patients were called to assess their compliance with the study instructions on day 5 and 14. Oral mucositis was evaluated using an inspection method or by assessing oral cavity photos based on the World Health Organization oral toxicity scale on day 5 and 14. Most of the patients in the intervention group did not develop oral mucositis on day 5. In addition, the incidence of grade 1 oral mucositis was statistically lower in the intervention group (10%) than the control group (53.3%) on day 5. By day 14, the majority of patients in both the groups had grade 0 oral mucositis. Sage tea-thyme-peppermint hydrosol oral rinse has promising results in alleviating oral mucositis. This hydrosol can be recommended for clinical use as it is well tolerated and cost-effective. However, further randomized controlled trials are needed to support the study. Copyright © 2016 Elsevier Ltd. All rights reserved.

Substitution urethroplasty of complex and long-segment urethral strictures: a rationale for procedure selection.

PubMed

Xu, Yue-Min; Qiao, Yong; Sa, Ying-Long; Wu, Den-Long; Zhang, Xin-Ru; Zhang, Jion; Gu, Bao-Jun; Jin, San-Bao

2007-04-01

We evaluated the applications and outcomes of substitution urethroplasty, using a variety of techniques, in 65 patients with complex, long-segment urethral strictures. From January 1995 to December 2005, 65 patients with complex urethral strictures >8cm in length underwent substitution urethroplasty. Of the 65 patients, 43 underwent one-stage urethral reconstruction using mucosal grafts (28 colonic mucosal graft, 12 buccal mucosal graft, and 3 bladder mucosal graft), 17 patients underwent one-stage urethroplasty using pedicle flaps, and 5 patients underwent staged Johanson's urethroplasty. The mean follow-up time was 4.8 yr (range; 0.8-10 yr), with an overall success rate of 76.92% (50 of 65 cases). Complications developed in 15 patients (23.08%) and included recurrent stricture in 7 (10.77%), urethrocutaneous fistula in 3 (4.62%), coloabdominal fistula in 1 (1.54%), penile chordee in 2 (3.08%), and urethral pseudodiverticulum in 2 (3.08%). Recurrent strictures and urethral pseudodiverticulum were treated successfully with a subsequent procedure, including repeat urethroplasty in six cases and urethrotomy or dilation in three. Coloabdominal fistula was corrected only by dressing change; five patients await further reconstruction. Penile skin, colonic mucosal, and buccal mucosal grafts are excellent materials for substitution urethroplasty. Colonic mucosal graft urethroplasty is a feasible procedure for complicated urethral strictures involving the entire or multiple portions of the urethra and the technique may also be considered for urethral reconstruction in patients in whom other conventional procedures failed.

Prophylaxis for mucositis induced by ambulatory chemotherapy: systematic review.

PubMed

Manzi, Natália de Melo; Silveira, Renata Cristina de Campos Pereira; dos Reis, Paula Elaine Diniz

2016-04-01

The aim of this study was to perform a systematic review of clinical trials covering interventions used as prophylaxis for oral mucositis induced by ambulatory antineoplastic chemotherapy. Oral mucositis in patients undergoing chemotherapy is a side effect that can impact the quality of treatment and can interfere with eating and therapeutic adherence. Quantitative systematic review. Relevant databases were searched, from January 2002-July 2013, by using the combination of the keywords mucositis, stomatitis, neoplasms, antineoplastic agents, drug therapy, prevention and control and chemotherapy. Two researchers independently read the titles and abstracts from every cross-reference. The quality of the included studies was analysed by the Jadad Scale and the Cochrane Collaboration Risk of Bias Tool. Data were extracted from the selected studies with a data collection form developed specifically for this purpose. Of the 23 controlled clinical trials that were identified in this study, five articles evaluated the use of oral cryotherapy to prevent oral mucositis and three studies analysed the prophylactic use of glutamine. Interventions of protocols for oral care, palifermin, allopurinol and chlorhexidine were evaluated by two articles each. Interventions of zinc sulphate, amifostine, chewing gum, sucralfate, recombination human intestinal trefoil factor, kefir and vitamin E were evaluated by one article each. There is strong evidence that cryotherapy can prevent oral mucositis arising from ambulatory treatment with 5-flurouracil chemotherapy. Other interventions, although showing positive results in preventing oral mucositis, require further study to confirm their conclusions. © 2015 John Wiley & Sons Ltd.

LED phototherapy to prevent mucositis: a case report.

PubMed

Lang-Bicudo, Leticia; Eduardo, Fernanda De Paula; Eduardo, Carlos De Paula; Zezell, Denise Maria

2008-12-01

The purpose of this case report was to evaluate the efficacy of phototherapy using light-emitting diodes (LEDs) to prevent oral mucositis in a Hodgkin's disease patient treated with the ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) chemotherapy regimen. Mucositis is a common dose-limiting complication of cancer treatment, and if severe it can lead to alterations in treatment planning or suspension of cancer therapy, with serious consequences for tumor response and survival. Therefore, low-power lasers and more recently LEDs, have been used for oral mucositis prevention and management, with good results. In this study, a 34-year-old man received intraoral irradiation with an infrared LED array (880 nm, 3.6 J/cm2, 74 mW) for five consecutive days, starting on chemotherapy day 1. In each chemotherapy cycle, he received the ABVD protocol on days 1 and 15, and received LED treatment for 5 d during each cycle. To analyze the results, the World Health Organization (WHO) scale was used to grade his mucositis, and a visual analogue scale (VAS) was used for pain evaluation, on days 1, 3, 7, 10, and 13 post-chemotherapy. The results showed that the patient did not develop oral mucositis during the five chemotherapy cycles, and he had no pain symptoms. LED therapy was a safe and effective method for preventing oral mucositis in this case report. However, further randomized studies with more patients are needed to prove the efficacy of this method.

Using Light to Treat Mucositis and Help Wounds Heal

NASA Technical Reports Server (NTRS)

Ignatius, Robert W.; Martin, Todd S.; Kirk, Charles

2008-01-01

A continuing program of research and development is focusing on the use of controlled illumination by light-emitting diodes (LEDs) to treat mucositis and to accelerate healing of wounds. The basic idea is to illuminate the affected area of a patient with light of an intensity, duration, and wavelength (or combination of wavelengths) chosen to produce a therapeutic effect while generating only a minimal amount of heat. This method of treatment was originally intended for treating the mucositis that is a common complication of chemotherapy and radiation therapy for cancer. It is now also under consideration as a means to accelerate the healing of wounds and possibly also to treat exposure to chemical and radioactive warfare agents. Radiation therapy and many chemotherapeutic drugs often damage the mucosal linings of the mouth and gastrointestinal tract, leading to mouth ulcers (oral mucositis), nausea, and diarrhea. Hyperbaric-oxygen therapy is currently the standard of care for ischemic, hypoxic, infected, and otherwise slowlyhealing problem wounds, including those of oral mucositis. Hyperbaric-oxygen therapy increases such cellular activities as collagen production and angiogenesis, leading to an increased rate of healing. Biostimulation by use of laser light has also been found to be effective in treating mucositis. For hyperbaricoxygen treatment, a patient must remain inside a hyperbaric chamber for an extended time. Laser treatment is limited by laser-wavelength capabilities and by narrowness of laser beams, and usually entails the generation of significant amounts of heat.

Utilization of Fc Receptors as a Mucosal Vaccine Strategy against an Intracellular Bacterium, Francisella tularensis1

PubMed Central

Rawool, Deepak B.; Bitsaktsis, Constantine; Li, Ying; Gosselin, Diane R.; Lin, Yili; Kurkure, Nitin V.; Metzger, Dennis W.; Gosselin, Edmund J.

2013-01-01

Numerous studies have demonstrated that targeting Ag to Fc receptors (FcR) on APCs can enhance humoral and cellular immunity. However, studies are lacking that examine both the use of FcR-targeting in generating immune protection against infectious agents and the use of FcRs in the induction of mucosal immunity. Francisella tularensis is a category A intracellular mucosal pathogen. Thus, intense efforts are underway to develop a vaccine against this organism. We hypothesized that protection against mucosal infection with F. tularensis would be significantly enhanced by targeting inactivated F. tularensis live vaccine strain (iFt) to FcRs at mucosal sites, via intranasal immunization with mAb-iFt complexes. These studies demonstrate for the first time that: 1) FcR-targeted immunogen enhances immunogen-specific IgA production and protection against subsequent infection in an IgA-dependent manner, 2) FcγR and neonatal FcR are crucial to this protection, and 3) inactivated F. tularensis, when targeted to FcRs, enhances protection against the highly virulent SchuS4 strain of F. tularensis, a category A biothreat agent. In summary, these studies show for the first time the use of FcRs as a highly effective vaccination strategy against a highly virulent mucosal intracellular pathogen. PMID:18390739

Lessons Learnt from Post-Infectious IBS

PubMed Central

Sarna, Sushil K.

2011-01-01

The development of IBS symptoms – altered bowel function and abdominal cramping in a subset of adult subjects exposed to severe enteric infections opened up an unprecedented opportunity to understand the etiology of this poorly understood disorder. Perhaps, for the reasons that these symptoms follow a severe enteric infection, and mucosal biopsy tissues are readily available, the focus of most studies thus far has been to show that mild/low-grade mucosal inflammation persisting after the initial infection has subsided causes the IBS symptoms. Parallel studies in non-infectious IBS patients, who did not have prior enteritis, showed similar mild mucosal inflammation. Together, these studies examined the mucosal infiltration of specific immune cells, increase of select inflammatory mediators, mast cell and enterochromaffin cell hyperplasia, and epithelial permeability. In spite of the fact that the data on these topics were not consistent among different studies and clinical trials with prednisone, fluoxetine, and ketotifen failed to provide relief of IBS symptoms, the predominant conclusions were that mild mucosal inflammation is the cause of IBS symptoms. However, the circular smooth muscle cells, and myenteric neurons are the primary regulators of gut motility function, while primary afferent neurons and CNS play essential roles in induction of visceral hypersensitivity – no explanation was provided as to how mild mucosal inflammation causes dysfunction in cells far removed. Accumulating evidence shows that mild mucosal inflammation in IBS patients is in physiological range. It has little deleterious effects on cells within its own environment and therefore it is unlikely to affect cells in the muscularis externa. This review discusses the disconnect between the focus on mild/low-grade mucosal inflammation and the potential mechanisms and molecular dysfunctions in smooth muscle cells, myenteric neurons, and primary afferent neurons that may underlie IBS symptoms. PMID:21897820

Phase II clinical trial of local use of GM-CSF for prevention and treatment of chemotherapy- and concomitant chemoradiotherapy-induced severe oral mucositis in advanced head and neck cancer patients: an evaluation of effectiveness, safety and costs.

PubMed

Mantovani, Giovanni; Massa, Elena; Astara, Giorgio; Murgia, Viviana; Gramignano, Giulia; Lusso, Maria Rita; Camboni, Paolo; Ferreli, Luca; Mocci, Miria; Perboni, Simona; Mura, Loredana; Madeddu, Clelia; Macciò, Antonio

2003-01-01

In the present open non-randomized phase II study we looked for effectiveness, safety, tolerability and costs of locally applied GM-CSF in preventing or treating mucositis in patients receiving chemotherapy or chemoradiotherapy for head and neck cancer. In addition to clinical mucositis scoring system, the effects of treatment with GM-CSF were evaluated by its impact on patient quality of life and by laboratory immunological assays such as serum proinflammatory cytokines, IL-2 and leptin. The trial was designed to assess the effectiveness of local GM-CSF treatment in two different settings: i) prophylaxis of mucositis; ii) treatment of mucositis. Prophylaxis was chosen for chemoradiotherapy treatments of high mucosatoxic potential, while curative treatment was reserved for chemotherapy or chemoradiotherapy treatments of lesser potential of inducing mucositis. From January 1998 to December 2001, 68 patients entered the study. The great majority of patients of both groups had head and neck cancer, were stage IV, PS ECOG 0-1, were habitual smokers and were treated with chemotherapy and concomitant (or sequential) chemoradiotherapy. Forty-six patients were included in the 'prophylactic' setting and 22 patients in the 'curative' setting. The main findings of our study are: only 50% of patients included in the 'prophylactic' setting developed mucositis; the duration of oral mucositis from appearance until complete remission was significantly shorter in the 'prophylactic' than in the 'curative' setting; the mean grade of oral mucositis at baseline, on day 3 of therapy and on day 6 of therapy was significantly lower in the 'prophylactic' than in the 'curative' setting; 24 (55.82%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis at baseline compared to 25 (80.60%) patients in the 'curative' setting (p=0.048). Thirteen (30.23%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis on day 3 of therapy compared to 19 (61.29%) patients in the 'curative' setting (p=0.015); 'prophylactic' setting was able to shorten grade 3/4 oral mucositis to grade 0/1 more effectively than the 'curative' one on day 6 of therapy (p=0.05). The present clinical trial is to date by far the largest study assessing the effectiveness of topical GM-CSF and it is the first study comparing the efficacy of topical GM-CSF in the 'prophylactic' setting, i.e., with the aim to prevent the chemoradiotherapy-induced oral mucositis, with that in the 'curative' treatment, i.e., the therapy for established oral mucositis. The topical application of GM-CSF was demonstrated to be effective for oral mucositis induced by chemotherapy and chemoradiotherapy regimens. Moreover, the 'prophylactic' setting was demonstrated to be more effective than the 'curative' one.

Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells.

PubMed

Hong, Bangxing; Song, Xiao-Tong; Rollins, Lisa; Berry, Lindsey; Huang, Xue F; Chen, Si-Yi

2011-02-01

Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20--an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs--restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses.

Comparison of International Guidelines on Mucosal Melanoma of the Head and Neck: A Comprehensive Review of the Role of Radiation Therapy.

PubMed

Pittaka, Maria; Kardamakis, Dimitrios; Spyropoulou, Despina

2016-01-01

Mucosal melanomas of the head and neck are rare pathological entities that correlate with poor prognosis due to their high propensity for local failure and distant metastases. The exact role of radiation therapy in the management of mucosal melanoma patients has not yet been fully proven, even though in everyday clinical practice these patients are referred for radiotherapy, in an effort to improve locoregional control. The guidelines of various societies on the role of radiation therapy for the treatment of mucosal melanoma of the head and neck region are very limited. We reviewed and analyzed the guidelines developed in the U.S.A. (National Comprehensive Cancer Network), Canada (Cancer Care Ontario and Canadian Medical Association), Europe (European Society for Medical Oncology and European Society for Radiotherapy and Oncology) and Australia and New Zealand (Cancer Council Australia) and isolated evidence for the management of mucosal melanomas of the head and neck region with radiation therapy worldwide. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

DNA from human polyomaviruses, TSPyV, MWPyV, HPyV6, 7 and 9 was not detected in primary mucosal melanomas.

PubMed

Ramqvist, Torbjörn; Nordfors, Cecilia; Dalianis, Tina; Ragnarsson-Olding, Boel

2014-02-01

Mucosal melanomas arise in non UV-light exposed areas and causative factors are yet unknown. Human polyomaviruses (HPyVs) are rapidly increasing in numbers and are potentially oncogenic, as has been established for MCPyV in Merkel cell carcinoma, an unusual skin cancer type. The aim of the present study was to investigate the association between TSPyV, MWPyV, HPyV6, 7 and 9 and mucosal melanoma. Fifty-five mucosal melanomas, were analyzed by a Luminex assay, for the presence of 10 HPyVs (BKPyV, JCPyV, KIPyV, WUPyV, TSPyV, MWPyV, HPyV6, 7 and 9) and two primate viruses (SV40 and LPyV). In 37 samples the DNA quality was satisfactory for analysis. However, none of the samples analyzed were positive for any of the examined viruses. None of the above-analyzed HPyVs were detected in mucosal melanoma samples, and they are for this reason unlikely to play a major role in the development of this tumor type.

A novel vitamin E derivative (TMG) protects against gastric mucosal damage induced by ischemia and reperfusion in rats.

PubMed

Ichikawa, Hiroshi; Yoshida, Norimasa; Takano, Hiroshisa; Ishikawa, Takeshi; Handa, Osamu; Takagi, Tomohisa; Naito, Yuji; Murase, Hironobu; Yoshikawa, Toshikazu

2003-01-01

The aim of the present study was to investigate the antioxidative effects of water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), on ischemia-reperfusion (I/R) -induced gastric mucosal injury in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery and reoxygenation was produced by removal of the clamp. The area of gastric mucosal erosion, the concentration of thiobarbituric acid-reactive substances, and the myeloperoxidase activity in gastric mucosa significantly increased in I/R groups compared with those of sham-operated groups. These increases were significantly inhibited by pretreatment with TMG. The contents of both mucosal TNF-alpha and CINC-2beta in I/R groups were also increased compared with the levels of those in sham-operated groups. These increases of the inflammatory cytokines were significantly inhibited by the treatment with TMG. It is concluded that TMG inhibited lipid peroxidation and reduced development of the gastric mucosal inflammation induced by I/R in rats.

Development of standard operating procedures to obtain longitudinal vaginal specimens from nulliparous rabbits as part of HIV vaccine mucosal immunogenicity studies.

PubMed

Gómez Román, Victor Raúl; Vinner, Lasse; Grevstad, Berit; Hansen, Jesper Juhl; Wegmann, Frank; Spetz, Anna-Lena; Fomsgaard, Anders

2010-12-15

The New Zealand white rabbit model (Oryctolagus cuniculus) is widely used to test whether HIV vaccine candidates elicit systemic antibody responses; however, its use in mucosal immunology has not been fully exploited due to the difficulty in collecting mucosal specimens longitudinally and reproducibly. Here we describe feasible and non-feasible methods to collect vaginal and nasal specimens from nulliparous rabbits. Non-feasible methods were those resulting in poor reproducibility and considerable animal twitching during sampling, whereas feasible methods resulted in no animal twitching and potential for sampling reproducibility. Standard operating procedures (SOPs) were implemented to collect vaginal swabs yielding total IgA titres ranging from 12,500 to 312,500. Intranasal immunisation with a naked DNA vaccine encoding HIV gp140 elicited HIV envelope-specific IgA detectable in nasal but not in vaginal secretions. Our methods provide an alternative to reliably assess pre- and post-vaccination mucosal antibody titres longitudinally in rabbits as part of mucosal HIV vaccine immunogenicity studies. Copyright © 2010 Elsevier B.V. All rights reserved.

Endoscopic mucosal resection for early gastric cancer. A case report.

PubMed

Gheorghe, Cristian; Sporea, Ioan; Becheanu, Gabriel; Gheorghe, Liana

2002-03-01

European experience in endoscopic mucosal resection (EMR) for early gastric cancer is still relatively low, since early stomach cancer is diagnosed at a much lower rate in Europe than in Japan and generally operable patients are referred to surgery for radical resection. Endoscopic mucosal resection or mucosectomy was developed as a promising technology to diagnose and treat mucosal lesions in the esophagus, stomach and colon. In contrast to surgical resection, EMR allows "early cancers" to be removed with a minimal cost, morbidity and mortality. We present the case of a patient with hepatic cirrhosis incidentally diagnosed with an elevated-type IIa early gastric cancer. Echoendoscopy was performed in order to assess the depth of invasion into the gastric wall confirming the only mucosal involvement. We performed an EMR using "cup and suction" method. After the procedure, the patient experienced an acute upper gastrointestinal bleeding from the ulcer bed requiring argon plasma coagulation. The histopathological examination confirmed an early cancer, without involvement of muscularis mucosae. The patient has had an uneventful evolution being well at six months after the procedure

Induction of strong anti-HIV cellular immunity by a combination of Clostridium perfringens expressing HIV gag and virus like particles.

PubMed

Pegu, Poonam; Helmus, Ruth; Gupta, Phalguni; Tarwater, Patrick; Caruso, Lori; Shen, Chengli; Ross, Ted; Chen, Yue

2011-12-01

The lower gastrointestinal tract is a major mucosal site of HIV entry and initial infection. Thus, the induction of strong cellular immune responses at this mucosal site will be an important feature of an effective HIV vaccine. We have used a novel prime-boost vaccination approach to induce immune responses at mucosal sites. Orally delivered recombinant Clostridium perfringens expressing HIV-1 gag (Cp-Gag) was evaluated for induction of HIV-1 Gag specific T cell responses in a prime-boost model with intranasal inoculation of HIV-1 virus like particles (VLP). HIV-1 specific cellular immune responses in both the effector (Lamina propria) and inductive sites (Peyer's patches) of the gastrointestinal (GI) tract were significantly higher in mice immunized using Cp-Gag and VLPs in a prime-boost approach compared to mice immunized with either Cp-Gag or VLPs alone. Such cellular immune response was found to be mediated by both CD8(+) and CD4(+) T cells. Such a strong mucosal immune response could be very useful in developing a mucosal vaccine against HIV-1.

Transcriptome analysis reveals regional and temporal differences in mucosal immune system development in the small intestine of neonatal calves.

PubMed

Liang, Guanxiang; Malmuthuge, Nilusha; Bao, Hua; Stothard, Paul; Griebel, Philip J; Guan, Le Luo

2016-08-11

Postnatal development of the mammalian mucosal immune system is crucial for responding to the rapid colonization by commensal bacteria and possible exposure to pathogens. This study analyzed expression patterns for mRNAs and their relationship with microRNAs (miRNAs) in the bovine small intestine during the critical neonatal period (0 to 42 days). This analysis revealed molecular mechanisms regulating the postnatal development of the intestinal mucosal immune system. Small intestine samples (jejunum and ileum) were collected from newborn male, Holstein calves immediately post-partum (n = 3) and at 7 (n = 5), 21 (n = 5), and 42 (n = 5) days of age and the transcriptomes were profiled using RNA-Seq. When analyzing all time points collectively, greater expression of genes encoding the complement functional pathway, as well as lower expression of genes encoding Toll-like receptors and NOD-like receptors were observed in the jejunum when compared to the ileum. In addition, significant changes in the expression of immune-related genes were detected within the first week post-partum in both jejunum and ileum. For example, increased expression of genes encoding tight junction proteins (claudin 1, claudin 4 and occludin), an antimicrobial peptide (Regenerating Islet-Derived 3-γ), NOD-like receptors (NACHT, LRR and PYD domain-containing protein 3), regulatory T cell marker (forkhead box P3), and both anti-inflammatory (interleukin 10) and pro-inflammatory (interleukin 8) cytokines was observed throughout the small intestine of 7-day-old calves when compared to newborn calves. Moreover, the expression of mucosal immune-related genes were either positively or negatively correlated with total bacterial population depending on both intestinal region and age. The integrated analysis of miRNAs and mRNAs supported the conclusion that miRNAs may regulate temporal changes in the expression of genes encoding tight junction proteins (miR-335), cytokines (miR-335) and bacterial recognition (miR-100) during the first week of small intestine development. The rapid development of transcriptional differences between jejunum and ileum reveal that these two intestinal regions make distinct contributions to the intestinal mucosal immune system during the early neonatal period. In addition, transcriptome analysis indicates that the first week after birth is a very dynamic developmental period for the intestinal mucosal immune system and these changes may be regulated by both miRNAs and microbial colonization. Findings from this study indicate that a detailed analysis of both the abundance and diversity of the colonizing microbiome may be necessary to understand factors regulating the rapid development of the mucosal immune system during the first week of life.

Intranasal and sublingual delivery of inactivated polio vaccine.

PubMed

Kraan, Heleen; Soema, Peter; Amorij, Jean-Pierre; Kersten, Gideon

2017-05-09

Polio is on the brink of eradication. Improved inactivated polio vaccines (IPV) are needed towards complete eradication and for the use in the period thereafter. Vaccination via mucosal surfaces has important potential advantages over intramuscular injection using conventional needle and syringe, the currently used delivery method for IPV. One of them is the ability to induce both serum and mucosal immune responses: the latter may provide protection at the port of virus entry. The current study evaluated the possibilities of polio vaccination via mucosal surfaces using IPV based on attenuated Sabin strains. Mice received three immunizations with trivalent sIPV via intramuscular injection, or via the intranasal or sublingual route. The need of an adjuvant for the mucosal routes was investigated as well, by testing sIPV in combination with the mucosal adjuvant cholera toxin. Both intranasal and sublingual sIPV immunization induced systemic polio-specific serum IgG in mice that were functional as measured by poliovirus neutralization. Intranasal administration of sIPV plus adjuvant induced significant higher systemic poliovirus type 3 neutralizing antibody titers than sIPV delivered via the intramuscular route. Moreover, mucosal sIPV delivery elicited polio-specific IgA titers at different mucosal sites (IgA in saliva, fecal extracts and intestinal tissue) and IgA-producing B-cells in the spleen, where conventional intramuscular vaccination was unable to do so. However, it is likely that a mucosal adjuvant is required for sublingual vaccination. Further research on polio vaccination via sublingual mucosal route should include the search for safe and effective adjuvants, and the development of novel oral dosage forms that improve antigen uptake by oral mucosa, thereby increasing vaccine immunogenicity. This study indicates that both the intranasal and sublingual routes might be valuable approaches for use in routine vaccination or outbreak control in the period after complete OPV cessation and post-polio eradication. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Serologic and mucosal immune response to rotavirus infection in the rabbit model.

PubMed Central

Conner, M E; Gilger, M A; Estes, M K; Graham, D Y

1991-01-01

We examined the humoral immune response to rotavirus infection in specific pathogen-free rabbits inoculated and challenged orally with rabbit Ala rotavirus (7.5 x 10(5) to 1 x 10(7) PFU). The humoral immune response in both serologic and mucosal samples was monitored by using total antibody enzyme-linked immunosorbent assays (ELISAs), isotype-specific ELISAs, and plaque reduction neutralization assays. Following a primary infection, all rabbits shed virus and serologic and mucosal antibody responses were initially detected by 1 week postinoculation. Intestinal immunoglobulin M was detected by 3 days postinoculation, and secretory immunoglobulin A was detected by 6 days postinoculation. Following challenge, rabbits were protected (no detectable virus shedding) from infection. An anamnestic immune response was observed only with mucosal neutralizing antibodies, and all serologic and mucosal immune responses persisted at high levels until at least 175 days postchallenge (204 days postinoculation). Detection of neutralization responses was influenced by the virus strain used in the neutralization assay; all inoculated rabbits developed detectable serum and intestinal neutralizing antibodies against the infecting (Ala) virus strain. Neutralization activity in both serum and mucosal samples was generally, but not exclusively, homotypic (VP7 serotype 3) after both primary and challenge inoculations with Ala virus. Heterotypic serum neutralization activity was observed with serotype 8 (9 of 12 rabbits) and 9 (12 of 12 rabbits) viruses and may be based on reactivity with the outer capsid protein VP4 or on a shared epitope in the C region of VP7. Comparisons of heterologous (serotype 3) and heterotypic neutralizing responses in mucosal and serologic samples revealed that 43% (21 of 49) of the responses were discordant. In 19 of 49 (39%) of these cases, a heterotypic serologic response was seen in the absence of a heterotypic mucosal response, but in 2 of 49 (4%) instances, a heterotypic mucosal response was seen in the absence of a concomitant serologic response. These results provide insight into factors which may affect detection of heterotypic responses. PMID:1850029

Fistula repair after hypospadias surgery using buccal mucosal graft.

PubMed

Hosseini, Jalil; Kaviani, Ali; Mohammadhosseini, Mojtaba; Rezaei, Alireza; Rezaei, Iraj; Javanmard, Babak

2009-01-01

The aim of this study was to evaluate the success rate of urethrocutaneous fistula repair using buccal mucosal graft in patients with a previous hypospadias repair. We reviewed records of our patients with urethrocutaneous fistula developed after hypospadias repair in whom buccal mucosal graft fistula repair had been performed. All of the patients had been followed up for 24 postoperative months. A successful surgical operation was defined as no fistula recurrence or urethral stricture. Retrograde urethrography and urethrocystoscopy would be performed in patients who had any history of decreased force and caliber of urine or any difficulty in urination. Fistula repair using buccal mucosa patch graft had been done in 14 children with urethrocutaneous fistula developing after hypospadias reconstruction. The mean age of the children was 8.70 +/- 1.99 years old (range, 4 to 11 years). Seven fistulas were in the midshaft, 4 were in the penoscrotal region, and 3 were in the coronal region. Repair of the fistulas was successful in 11 of 14 patients (78.6%). In the remaining children, the diameter of the fistula was smaller than that before the operation, offering a good opportunity for subsequent closure. Our findings showed that fistula repair using buccal mucosal graft can be one of the acceptable techniques for repairing fistulas developed after hypospadias repair.

Magnifying narrow-band imaging of gastric mucosal morphology predicts the H. pylori-related epigenetic field defect.

PubMed

Tahara, Tomomitsu; Yamazaki, Jumpei; Tahara, Sayumi; Okubo, Masaaki; Kawamura, Tomohiko; Horiguchi, Noriyuki; Ishizuka, Takamitsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Shibata, Tomoyuki; Kuroda, Makoto; Ohmiya, Naoki

2017-06-08

DNA methylation is associated with "field defect" in the gastric mucosa. To characterize "field defect" morphologically, we examined DNA methylation of non-neoplastic gastric mucosa in relation to their morphology seen by narrow-band imaging (NBI) with magnifying endoscopy. Magnifying NBI of non-neoplastic gastric body was classified as follows: normal-small and round pits with uniform subepithelial capillary networks; type 1-a little enlarged round pits with indistinct subepithelial capillary networks; type 2-remarkably enlarged pits with irregular vessels; and type 3-clearly demarcated oval or tubulovillous pits with bulky coiled or wavy vessels. Methylation of nine candidate genes (MYOD1, SLC16A12, GDNF, IGF2, MIR 124A1, CDH1, PRDM5, RORA and MLF1) were determined by bisulfite pyrosequencing. Infinium HumanMethylation450 array was used to characterize the methylation of >450,000 CpG sites. Mean Z score methylation of nine genes positively correlated with the changes of mucosal patterns from normal to types 1, 2, and 3 (P < 0.0001). Genome-wide analysis showed that development of mucosal patterns correlated with methylation accumulation especially at CpG islands. Genes with promoter CpG islands that were gradually methylated with the development of mucosal patterns significantly enriched the genes involved in zinc-related pathways. The results indicates that gastric mucosal morphology predicts a "field defect" in this tissue type. Accumulation of DNA methylation is associated with "field defect" in the non-neoplastic gastric mucosa. Endoscopic identification of "field defect" has important implications for preventing gastric cancer. Our results suggest that magnifying NBI of gastric mucosal morphology predicts a "field defect" in the gastric mucosa.

Comparison of the Luminal and Mucosa-Associated Microbiota in the Colon of Pigs with and without Swine Dysentery.

PubMed

Burrough, Eric R; Arruda, Bailey L; Plummer, Paul J

2017-01-01

Colonic contents and mucosal scrapings from pigs inoculated with Brachyspira hyodysenteriae or Brachyspira hampsonii were collected at necropsy and classified as either positive ( n  = 29) or negative ( n  = 7) for swine dysentery (SD) based upon lesions and positive culture from the source pig. The microbiota in each sample was analyzed by bacterial census taking (16S rRNA gene sequencing). Procrustes analysis revealed similar clustering by disease classification with a relatively high M2 value (0.44) suggesting differences in the microbiota between mucosal and luminal samples from the same pig. In both sample types, differences in richness and beta diversity were observed between disease statuses ( P  ≤ 0.014). The relative abundance of Brachyspirales, Campylobacterales, Desulfovibrionales , and Enterobacteriales was higher in pigs with dysentery for both mucosal scrapings and luminal samples while Clostridiales, Erysipelotrichales , and Fusobacteriales were significantly more abundant in the luminal contents only. For inoculated pigs that did not develop dysentery, Burkholderiales were more abundant in both sample types, Bacteroidales and Synergistales were more abundant in mucosal scrapings, and Lactobacillales and Bifidobacteriales were more abundant in luminal contents when compared with diseased pigs. Linear discriminant analysis of effect size revealed Brachyspira, Campylobacter, Mogibacterium , and multiple Desulfovibrio spp. as differential features in mucosal scrapings from pigs with dysentery while Lactobacillus and a Bifidobacterium spp. were differential in pigs without disease. These differential features were not observed in luminal samples. In summary, microbial profiles in both sample types differ significantly between disease states; however, evaluation of the mucosal microbiome specifically may be of higher value in elucidating bacterial mechanisms underlying development of SD.

B cell and T cell immunity in the female genital tract: potential of distinct mucosal routes of vaccination and role of tissue-associated dendritic cells and natural killer cells.

PubMed

Anjuère, F; Bekri, S; Bihl, F; Braud, V M; Cuburu, N; Czerkinsky, C; Hervouet, C; Luci, C

2012-10-01

The female genital mucosa constitutes the major port of entry of sexually transmitted infections. Most genital microbial pathogens represent an enormous challenge for developing vaccines that can induce genital immunity that will prevent their transmission. It is now established that long-lasting protective immunity at mucosal surfaces has to involve local B-cell and T-cell effectors as well as local memory cells. Mucosal immunization constitutes an attractive way to generate systemic and genital B-cell and T-cell immune responses that can control early infection by sexually transmitted pathogens. Nevertheless, no mucosal vaccines against sexually transmitted infections are approved for human use. The mucosa-associated immune system is highly compartmentalized and the selection of any particular route or combinations of routes of immunization is critical when defining vaccine strategies against genital infections. Furthermore, mucosal surfaces are complex immunocompetent tissues that comprise antigen-presenting cells and also innate immune effectors and non-immune cells that can act as 'natural adjuvants' or negative immune modulators. The functions of these cells have to be taken into account when designing tissue-specific antigen-delivery systems and adjuvants. Here, we will discuss data that compare different mucosal routes of immunization to generate B-cell and T-cell responses in the genital tract, with a special emphasis on the newly described sublingual route of immunization. We will also summarize data on the understanding of the effector and induction mechanisms of genital immunity that may influence the development of vaccine strategies against genital infections. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut.

PubMed

Chamcha, Venkateswarlu; Jones, Andrew; Quigley, Bernard R; Scott, June R; Amara, Rama Rao

2015-11-15

The induction of a potent humoral and cellular immune response in mucosal tissue is important for the development of an effective HIV vaccine. Most of the current HIV vaccines under development use the i.m. route for immunization, which is relatively poor in generating potent and long-lived mucosal immune responses. In this article, we explore the ability of an oral vaccination with a probiotic organism, Lactococcus lactis, to elicit HIV-specific immune responses in the mucosal and systemic compartments of BALB/c mice. We expressed the HIV-1 Gag-p24 on the tip of the T3 pilus of Streptococcus pyogenes as a fusion to the Cpa protein (LL-Gag). After four monthly LL-Gag oral immunizations, we observed strong Gag-specific IgG and IgA responses in serum, feces, and vaginal secretions. However, the Gag-specific CD8 T cell responses in the blood were at or below our detection limit. After an i.m. modified vaccinia Ankara/Gag boost, we observed robust Gag-specific CD8 T cell responses both in systemic and in mucosal tissues, including intraepithelial and lamina propria lymphocytes of the small intestine, Peyer's patches, and mesenteric lymph nodes. Consistent with strong immunogenicity, the LL-Gag induced activation of CD11c(+) CD11b(+) dendritic cells in the Peyer's patches after oral immunization. Our results demonstrate that oral immunization with L. lactis expressing an Ag on the tip of the group A Streptococcus pilus serves as an excellent vaccine platform to induce strong mucosal humoral and cellular immunity against HIV. Copyright © 2015 by The American Association of Immunologists, Inc.

HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation

PubMed Central

Heron, Samantha E.; Elahi, Shokrollah

2017-01-01

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to “inflammaging” that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome. Therefore, unraveling how HIV compromises the integrity of the oral mucosal tissues and innate immune components of the oral cavity and its association with induction of chronic inflammation are critical for the development of effective preventive interventions and therapeutic strategies. PMID:28326084

HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation.

PubMed

Heron, Samantha E; Elahi, Shokrollah

2017-01-01

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to "inflammaging" that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome. Therefore, unraveling how HIV compromises the integrity of the oral mucosal tissues and innate immune components of the oral cavity and its association with induction of chronic inflammation are critical for the development of effective preventive interventions and therapeutic strategies.

Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism

PubMed Central

Vujkovic-Cvijin, Ivan; Dunham, Richard M.; Iwai, Shoko; Maher, M. Cyrus; Albright, Rebecca G.; Broadhurst, Mara J.; Hernandez, Ryan D.; Lederman, Michael M.; Huang, Yong; Somsouk, Ma; Deeks, Steven G.; Hunt, Peter W.; Lynch, Susan V.; McCune, Joseph M.

2014-01-01

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease. PMID:23843452

Cellular Energetical Actions of “Chemical” and “Surgical” Vagotomy in Gastrointestinal Mucosal Damage and Protection: Similarities, Differences and Significance for Brain-Gut Function

PubMed Central

Szabo, Imre L.; Czimmer, Jozsef; Mozsik, Gyula

2016-01-01

Background The authors, as internists, registered significant difference in the long lasting actions of surgical and chemical (atropine treatment) vagotomy in patients with peptic ulcer during second half of the last century (efficency, gastric acid secretion, gastrointestinal side effects, briefly benefical and harmful actions were examined). Aims 1. Since the authors participated in the establishing of human clinical pharmacology in this field, they wanted to know more and more facts of the acute and chronic effects of surgical and chemical (atropine treatment) on the gastrointestinal mucosal biochemisms and their actions altered by bioactive compounds and scavengers regarding the development of gastric mucosal damage and protection. Methods The observations were carried out in animals under various experimental conditions (in intact, pylorus-ligated rats, in different experimental ulcer models, together with application of various mucosal protecting compounds) without and with surgical vagotomy and chemical vagotomy produced by atropine treatment. Results 1. No changes were obtained in the cellular energy systems (ATP, ADP, AMP, cAMP, “adenylate pool”, “energy charge“ [(ATP+ 0.5 ADP)/ (ATP+ADP+AMP)] of stomach (glandular part, forestomach) in pylorus ligated rats after surgical vagotomy in contrast to those produced by only chemical vagotomy; 2. The effects of the gastric mucosal protective compounds [atropine, cimetidine, prostaglandins, scavengers (like vitamin A, β-carotene), capsaicin] disappeared after surgical vagotomy; 3. The extents of different chemical agents induced mucosal damaging effects were enhanced by surgical vagotomy and was not altered by chemical vagotomy; 4. The existence of feedback mechanisms of pharmacological (cellular and intracellular) regulatory mechanisms between the membrane-bound ATP-dependent energy systems exists in the gastric mucosa of intact animals, and after chemical vagotomy, but not after surgical vagotomy. Conclusions 1. Increased vagal nerve activity takes place in the gastric mucosal damage; 2 both surgical and chemical vagotomy result mucosal protective affect on the gastric mucosal in different damaging experimental models; 3. The capsaicin-induced gastric mucosal damage depends on the applied doses, presence of anatomically intact vagal nerve (but independent from the chemical vagotomy), 4. The central and pheripheral neural regulations differ during gastric mucosal damage and protection induced by drugs, bioactive compounds, scavengers. PMID:27440445

Low-Dose Intestinal Trichuris muris Infection Alters the Lung Immune Microenvironment and Can Suppress Allergic Airway Inflammation.

PubMed

Chenery, Alistair L; Antignano, Frann; Burrows, Kyle; Scheer, Sebastian; Perona-Wright, Georgia; Zaph, Colby

2016-02-01

Immunological cross talk between mucosal tissues such as the intestine and the lung is poorly defined during homeostasis and disease. Here, we show that a low-dose infection with the intestinally restricted helminth parasite Trichuris muris results in the production of Th1 cell-dependent gamma interferon (IFN-γ) and myeloid cell-derived interleukin-10 (IL-10) in the lung without causing overt airway pathology. This cross-mucosal immune response in the lung inhibits the development of papain-induced allergic airway inflammation, an innate cell-mediated type 2 airway inflammatory disease. Thus, we identify convergent and nonredundant roles of adaptive and innate immunity in mediating cross-mucosal suppression of type 2 airway inflammation during low-dose helminth-induced intestinal inflammation. These results provide further insight in identifying novel intersecting immune pathways elicited by gut-to-lung mucosal cross talk. Copyright © 2016 Chenery et al.

Chronicles in drug discovery.

PubMed

Davies, Shelley L; Ferrer, Elisa; Moral, Maria Angels

2006-06-01

Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight new options to prevent oral mucositis, a treatment-limiting adverse effect of chemotherapy. Studies are currently focusing on mechanism-based therapies to prevent or repair DNA damage to epithelial and submucosal cells and the cascade or events that follow to cause tissue damage or analgesics to ease the associated oral cavity pain. Therapeutic limitations also exist for the use of the highly effective antibiotic gentamicin, as it evokes acute renal failure. Mechanistic investigations have shed some light on potential targets: the kallikreins, peroxynitrite-related pathways, superoxide production and the accumulation of aminoglycosides. New antibiotic strategies for trachoma, the leading cause of preventable blindness, are also explored along with studies to aid the development of vaccine candidates. Finally, we discuss the utility of allosteric-potentiating ligands to modulate nicotinic acetylcholine receptors, mimicking the reward/addictive effects of nicotine, as potential strategies for smoking cessation. (c) 2006 Prous Science. All rights reserved.

Adaptation of Haplobothrium globuliforme (Cestoda: Pseudophyllidea) to the intestinal architecture of the bowfin (Amia calva L).

PubMed

Joy, James E; Triest, William E; Walker, Ernest M

2009-02-01

Haplobothrium globuliforme maintains its position in the proximal mid-gut epithelium of Amia calva with the aid of tentacles, i.e., proboscides, everted from scolices of a primary strobila and craspedote proglottids of a secondary strobila. Weakly developed scolices of the secondary strobila appear to have little holdfast action, but the distinctly craspedote proglottids of these individuals project into the intestinal mucosa, altering the configuration of gut epithelial cells and pushing the tapeworm deeper into mucosal crypts. The basement membrane underlying the epithelium appears to act as a barrier that prevents tapeworms from penetrating into the deeper tissue layers of the lamina propria, muscularis mucosa, or submucosa. Scolex tegument modification occurs at the point of contact with host basement membrane. A mild background infiltrate of lymphocytes and granulocytes was evident adjacent to the scolex and proglottid tegument. There was no evidence of blood vessel proliferation, edema, mast cell degranulation, eosinophilia, or subsequent collagen formation associated with tapeworm activity.

Biomarkers in inflammatory bowel disease: current practices and recent advances.

PubMed

Iskandar, Heba N; Ciorba, Matthew A

2012-04-01

Crohn's disease and ulcerative colitis represent the two main forms of the idiopathic chronic inflammatory bowel diseases (IBD). Currently available blood and stool based biomarkers provide reproducible, quantitative tools that can complement clinical assessment to aid clinicians in IBD diagnosis and management. C-reactive protein and fecal based leukocyte markers can help the clinician distinguish IBD from noninflammatory diarrhea and assess disease activity. The ability to differentiate between forms of IBD and predict risk for disease complications is specific to serologic tests including antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins. Advances in genomic, proteomic, and metabolomic array based technologies are facilitating the development of new biomarkers for IBD. The discovery of novel biomarkers, which can correlate with mucosal healing or predict long-term disease course has the potential to significantly improve patient care. This article reviews the uses and limitations of currently available biomarkers and highlights recent advances in IBD biomarker discovery. Copyright © 2012 Mosby, Inc. All rights reserved.

The importance of the vaginal delivery route for antiretrovirals in HIV prevention

PubMed Central

Ferguson, Lindsay M; Rohan, Lisa Cencia

2012-01-01

The HIV/AIDS pandemic continues to be a global health priority, with high rates of new HIV-1 infections persisting in young women. One HIV prevention strategy is topical pre-exposure prophylactics or microbicides, which are applied vaginally or rectally to protect the user from HIV and possibly other sexually transmitted infections. Vaginal microbicide delivery will be the focus of this review. Multiple nonspecific and specific antiretroviral microbicide products have been clinically evaluated, and many are in preclinical development. The events of HIV mucosal transmission and dynamics of the cervicovaginal environment should be considered for successful vaginal microbicide delivery. Beyond conventional vaginal formulations, intravaginal rings, tablets and films are employed as platforms in the hope to increase the likelihood of microbicide use. Furthermore, combining multiple antiretrovirals within a given formulation, combining a microbicide product with a vaginal device and integrating novel drug-delivery strategies within a microbicide product are approaches to successful vaginal-microbicide delivery. PMID:22468220

Evaluation of mucosal adjuvants and immunization routes for the induction of systemic and mucosal humoral immune responses in macaques.

PubMed

Veazey, Ronald S; Siddiqui, Asna; Klein, Katja; Buffa, Viviana; Fischetti, Lucia; Doyle-Meyers, Lara; King, Deborah F; Tregoning, John S; Shattock, Robin J

2015-01-01

Delivering vaccine antigens to mucosal surfaces is potentially very attractive, especially as protection from mucosal infections may be mediated by local immune responses. However, to date mucosal immunization has had limited successes, with issues of both safety and poor immunogenicity. One approach to improve immunogenicity is to develop adjuvants that are effective and safe at mucosal surfaces. Differences in immune responses between mice and men have overstated the value of some experimental adjuvants which have subsequently performed poorly in the clinic. Due to their closer similarity, non-human primates can provide a more accurate picture of adjuvant performance. In this study we immunised rhesus macaques (Macaca mulatta) using a unique matrix experimental design that maximised the number of adjuvants screened while reducing the animal usage. Macaques were immunised by the intranasal, sublingual and intrarectal routes with the model protein antigens keyhole limpet haemocyanin (KLH), β-galactosidase (β-Gal) and ovalbumin (OVA) in combination with the experimental adjuvants Poly(I:C), Pam3CSK4, chitosan, Thymic Stromal Lymphopoietin (TSLP), MPLA and R848 (Resiquimod). Of the routes used, only intranasal immunization with KLH and R848 induced a detectable antibody response. When compared to intramuscular immunization, intranasal administration gave slightly lower levels of antigen specific antibody in the plasma, but enhanced local responses. Following intranasal delivery of R848, we observed a mildly inflammatory response, but no difference to the control. From this we conclude that R848 is able to boost antibody responses to mucosally delivered antigen, without causing excess local inflammation.

Using Monoclonal Antibodies to Prevent Mucosal Transmission of Epidemic Infectious Diseases

PubMed Central

Zeitlin, Larry; Cone, Richard A.

1999-01-01

Passive immunization with antibodies has been shown to prevent a wide variety of diseases. Recent advances in monoclonal antibody technology are enabling the development of new methods for passive immunization of mucosal surfaces. Human monoclonal antibodies, produced rapidly, inexpensively, and in large quantities, may help prevent respiratory, diarrheal, and sexually transmitted diseases on a public health scale. PMID:10081672

Transfer of a gene encoding the anticandidal protein histatin 3 to salivary glands.

PubMed

O'Connell, B C; Xu, T; Walsh, T J; Sein, T; Mastrangeli, A; Crystal, R G; Oppenheim, F G; Baum, B J

1996-12-01

Mucosal candidiasis, the most common opportunistic fungal infection in human immunodeficiency virus (HIV)-infected patients, is an early sign of clinically overt acquired immunodeficiency syndrome (AIDS) and an important cause of morbidity, particularly in HIV-infected children. The appearance of azole-resistant strains of Candida albicans had made clinical management of candidiasis increasingly difficult. We propose a novel approach to the management of candidal infections that involves the use of naturally occurring antifungal proteins, such as the histatins. Histatins are a family of small proteins that are secreted in human saliva. We have constructed recombinant adenovirus vectors that contain the histatin 3 cDNA. These vectors are capable of directing the expression of histatin 3 in the saliva of rats at up to 1,045 micrograms/ml, well above the levels found in normal human saliva. The adenovirus-directed histatin demonstrated a 90% candidacidal effect in the timed-kill assay against both fluconazole-susceptible and fluconazole-resistant strains of C. albicans and inhibited germination by 45% in the same strains. These studies suggest that a gene transfer approach to overexpress naturally occurring antifungal proteins may be useful in the management of mucosal candidiasis.

Histamine reduces boron neutron capture therapy-induced mucositis in an oral precancer model.

PubMed

Monti Hughes, A; Pozzi, Ecc; Thorp, S I; Curotto, P; Medina, V A; Martinel Lamas, D J; Rivera, E S; Garabalino, M A; Farías, R O; Gonzalez, S J; Heber, E M; Itoiz, M E; Aromando, R F; Nigg, D W; Trivillin, V A; Schwint, A E

2015-09-01

Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and inhibit long-term tumor development from field-cancerized tissue in the hamster cheek pouch model. However, BNCT-induced mucositis in field-cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients' treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT-induced severe mucositis in field-cancerized tissue. Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh : histamine 5 mg kg(-1) ; Hislow : histamine 1 mg kg(-1) ; and JNJ7777120: 10 mg kg(-1). Hislow reduced the incidence of severe mucositis in field-cancerized tissue to 17% vs 55%; Hishigh : 67%; JNJ7777120: 57%. Hislow was non-toxic and did not compromise the long-term therapeutic effect of BNCT or alter gross boron concentration. Histamine reduces BNCT-induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT-induced radiotoxicity in patients with head and neck cancer. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An ad hoc 3D-printed tool facilitates intraesophageal suturing in experimental surgery

PubMed Central

Steinemann, D.C.; Müller, P.C.; Apitz, M.; Nickel, F.; Kenngott, H.G.; Müller-Stich, B.P.; Linke, G.R.

2018-01-01

Background Three-dimensional printing (3DP) has become popular for development of anatomic models, preoperative planning, and production of tailored implants. A novel laparoscopic, transgastric procedure for distal esophageal mucosectomy was developed. During this procedure a space holder had to be introduced into the distal esophagus for exposure during suturing. The production process and evaluation of a 3DP space holder are described herein. Material and methods Computer-aided design software was used to develop models printed from polylactic acid. The prototype was adapted after testing in a cadaveric model. Subsequently the device was evaluated in a non-survival porcine model. A mucosal purse-string suture was placed as orally as possible in the esophagus, in the intervention group with and in the control group without use of the tool (n=8 each). The distance of the stitches from the Z-line was measured. The variability of stitches indicated the suture quality. Results The median maximum distance from Z-line to purse-string suture was larger in the intervention group (5.0 [3.3-6.4] versus 2.4 [2.0-4.1] cm;P=0.013). The time taken to place the sutures was shorter in the control group (P<0.001). Stitch variance tended to be greater in the intervention group (2.3 [0.9-2.5] versus 0.7 [0.2-0.4] cm;P=0.051). The time required for design and production of a tailored tool was below 24 h. Conclusions 3DP in experimental surgery enables rapid production, permits repeated adaptation until a tailored tool is obtained, and ensures independence from industrial partners. With the aid of the space holder more orally located esophageal lesions came within reach. PMID:29433890

High-frequency ultrasonic imaging of growth and development in manufactured engineered oral mucosal tissue surfaces.

PubMed

Winterroth, Frank; Kato, Hiroko; Kuo, Shiuhyang; Feinberg, Stephen E; Hollister, Scott J; Fowlkes, J Brian; Hollman, Kyle W

2014-09-01

This study uses high-resolution ultrasound to examine the growth and development of engineered oral mucosal tissues manufactured under aseptic conditions. The specimens are a commercially available natural tissue scaffold, AlloDerm, and oral keratinocytes seeded onto AlloDerm to form an ex vivo-produced oral mucosal equivalent (EVPOME) suitable for intra-oral grafting. The seeded cells produce a keratinized protective upper layer that smooths out any remaining surface irregularities on the underlying AlloDerm. Two-dimensional acoustic imaging of unseeded AlloDerm and developing EVPOMEs was performed on each day of their growth and development, each tissue specimen being imaged under aseptic conditions (total time from seeding to maturation: 11 d). Ultrasonic monitoring offers us the ability to determine the constituents of the EVPOME that are responsible for changes in its mechanical behavior during the manufacturing process. Ultrasonic monitoring affords us an opportunity to non-invasively assess, in real time, tissue-engineered constructs before release for use in patient care. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Novel transgenic rice-based vaccines.

PubMed

Azegami, Tatsuhiko; Itoh, Hiroshi; Kiyono, Hiroshi; Yuki, Yoshikazu

2015-04-01

Oral vaccination can induce both systemic and mucosal antigen-specific immune responses. To control rampant mucosal infectious diseases, the development of new effective oral vaccines is needed. Plant-based vaccines are new candidates for oral vaccines, and have some advantages over the traditional vaccines in cost, safety, and scalability. Rice seeds are attractive for vaccine production because of their stability and resistance to digestion in the stomach. The efficacy of some rice-based vaccines for infectious, autoimmune, and other diseases has been already demonstrated in animal models. We reported the efficacy in mice, safety, and stability of a rice-based cholera toxin B subunit vaccine called MucoRice-CTB. To advance MucoRice-CTB for use in humans, we also examined its efficacy and safety in primates. The potential of transgenic rice production as a new mucosal vaccine delivery system is reviewed from the perspective of future development of effective oral vaccines.

Mucosal melanoma of the head and neck.

PubMed

Ascierto, Paolo Antonio; Accorona, Remo; Botti, Gerardo; Farina, Davide; Fossati, Piero; Gatta, Gemma; Gogas, Helen; Lombardi, Davide; Maroldi, Roberto; Nicolai, Piero; Ravanelli, Marco; Vanella, Vito

2017-04-01

Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery. Many new treatment options in the last years, in particular targeted therapies (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) and immunotherapies (anti CTLA-4 and anti PD-1/PD-L1 antibodies), have changed the history of cutaneous melanoma. Despite the different biology, mucosal melanoma is currently treated in the same way as cutaneous melanoma; however, patients with mucosal melanoma were excluded from the majority of recent clinical trials. Recent molecular findings offer new hope for the development of more effective systemic therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Mucosal vaccination by adenoviruses displaying reovirus sigma 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weaver, Eric A.; Camacho, Zenaido T.; Hillestad, Matthew L.

We developed adenovirus serotype 5 (Ad5) vectors displaying the sigma 1 protein from reovirus as mucosal vaccines. Ad5-sigma retargets to JAM-1 and sialic acid, but has 40-fold reduced gene delivery when compared to Ad5. While weaker at transduction, Ad5-sigma generates stronger T cell responses than Ad5 when used for mucosal immunization. In this work, new Ad5-fiber-sigma vectors were generated by varying the number of fiber β-spiral shaft repeats (R) between the fiber tail and sigma. Increasing chimera length led to decreasing insertion of these proteinsAd5 virions. Ad-R3 and R14 vectors effectively targeted JAM-1 in vitro while R20 did not. Whenmore » wereused to immunize mice by the intranasal route, Ad5-R3-sigma produced higher serum and vaginal antibody responses than Ad5. These data suggest optimized Ad-sigma vectors may be useful vectors for mucosal vaccination. - Highlights: • Constructed adenoviruses (Ads) displaying different reovirus sigma 1 fusion proteins. • Progressively longer chimeras were more poorly encapsidated onto Ad virions. • Ad5-R3-sigma mediated better systemic and mucosal immune responses than Ad5.« less

Effectiveness of honey on radiation-induced oral mucositis, time to mucositis, weight loss, and treatment interruptions among patients with head and neck malignancies: A meta-analysis and systematic review of literature.

PubMed

Co, Jayson L; Mejia, Michael Benedict A; Que, Jocelyn C; Dizon, Janine Margarita R

2016-07-01

Mucositis is a disabling effect of radiotherapy in head and neck cancers. There is no current standard on management of radiation-induced mucositis. Honey has been shown to reduce radiation-induced mucositis. A systematic review and meta-analysis were undertaken to assess the ability of honey in reducing the severity of oral mucositis, time to mucositis, weight loss, and treatment interruptions. Eight studies were included and showed that honey was significantly better in lowering the risk for treatment interruptions, weight loss, and delaying time to mucositis, but not severity of mucositis. There is current evidence that honey is beneficial for patients with head and neck cancers by decreasing treatment interruptions, weight loss, and delaying the onset of oral mucositis, but not in decreasing peak mucositis score. In light of the results, honey is a reasonable treatment for radiation-induced mucositis, but more randomized clinical trials (RCTs) should be done. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1119-1128, 2016. © 2016 Wiley Periodicals, Inc.

Clinical guidelines for endoscopic mucosal resection of non-pedunculated colorectal lesions.

PubMed

Albéniz, Eduardo; Pellisé, María; Gimeno García, Antonio Z; Lucendo, Alfredo José; Alonso Aguirre, Pedro A; Herreros de Tejada, Alberto; Álvarez, Marco Antonio; Fraile, María; Herráiz Bayod, Maite; López Rosés, Leopoldo; Martínez Ares, David; Ono, Akiko; Parra Blanco, Adolfo; Redondo, Eduardo; Sánchez Yagüe, Andrés; Soto, Santiago; Díaz Tasende, José; Montes Díaz, Marta; Téllez, Manuel Rodríguez; García, Orlando; Zuñiga Ripa, Alba; Hernández Conde, Marta; Alberca de Las Parras, Fernando; Gargallo, Carla; Saperas, Esteban; Navas, Miguel Muñoz; Gordillo, Javier; Ramos Zabala, Felipe; Echevarría, José Manuel; Bustamante, Marco; González Haba, Mariano; González Huix, Ferrán; González Suárez, Begoña; Vila Costas, Juan José; Guarner Argente, Carlos; Múgica, Fernando; Cobián, Julyssa; Rodríguez Sánchez, Joaquín; López Viedma, Bartolomé; Pin, Noel; Marín Gabriel, José Carlos; Nogales, Óscar; de la Peña, Joaquín; Navajas León, Francisco Javier; León Brito, Helena; Remedios, David; Esteban, José Miguel; Barquero, David; Martínez Cara, Juan Gabriel; Martínez Alcalá, Felipe; Fernández Urién, Ignacio; Valdivielso, Eduardo

2018-03-01

This document summarizes the contents of the Clinical Guidelines for the Endoscopic Mucosal Resection of Non-Pedunculated Colorectal Lesions that was developed by the working group of the Spanish Society of Digestive Endoscopy (GSEED of Endoscopic Resection). This document presents recommendations for the endoscopic management of superficial colorectal neoplastic lesions. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Neonatal mucosal immunology.

PubMed

Torow, N; Marsland, B J; Hornef, M W; Gollwitzer, E S

2017-01-01

Although largely deprived from exogenous stimuli in utero, the mucosal barriers of the neonate after birth are bombarded by environmental, nutritional, and microbial exposures. The microbiome is established concurrently with the developing immune system. The nature and timing of discrete interactions between these two factors underpins the long-term immune characteristics of these organs, and can set an individual on a trajectory towards or away from disease. Microbial exposures in the gastrointestinal and respiratory tracts are some of the key determinants of the overall immune tone at these mucosal barriers and represent a leading target for future intervention strategies. In this review, we discuss immune maturation in the gut and lung and how microbes have a central role in this process.

M cell-targeting strategy facilitates mucosal immune response and enhances protection against CVB3-induced viral myocarditis elicited by chitosan-DNA vaccine.

PubMed

Ye, Ting; Yue, Yan; Fan, Xiangmei; Dong, Chunsheng; Xu, Wei; Xiong, Sidong

2014-07-31

Efficient delivery of antigen to mucosal associated lymphoid tissue is a first and critical step for successful induction of mucosal immunity by vaccines. Considering its potential transcytotic capability, M cell has become a more and more attractive target for mucosal vaccines. In this research, we designed an M cell-targeting strategy by which mucosal delivery system chitosan (CS) was endowed with M cell-targeting ability via conjugating with a CPE30 peptide, C terminal 30 amino acids of clostridium perfringens enterotoxin (CPE), and then evaluated its immune-enhancing ability in the context of coxsackievirus B3 (CVB3)-specific mucosal vaccine consisting of CS and a plasmid encoding CVB3 predominant antigen VP1. It had shown that similar to CS-pVP1, M cell-targeting CPE30-CS-pVP1 vaccine appeared a uniform spherical shape with about 300 nm diameter and +22 mV zeta potential, and could efficiently protect DNA from DNase I digestion. Mice were orally immunized with 4 doses of CPE30-CS-pVP1 containing 50 μg pVP1 at 2-week intervals and challenged with CVB3 4 weeks after the last immunization. Compared with CS-pVP1 vaccine, CPE30-CS-pVP1 vaccine had no obvious impact on CVB3-specific serum IgG level and splenic T cell immune responses, but significantly increased specific fecal SIgA level and augmented mucosal T cell immune responses. Consequently, much milder myocarditis and lower viral load were witnessed in CPE30-CS-pVP1 immunized group. The enhanced immunogenicity and immunoprotection were associated with the M cell-targeting ability of CPE30-CS-pVP1 which improved its mucosal uptake and transcytosis. Our findings indicated that CPE30-CS-pVP1 may represent a novel prophylactic vaccine against CVB3-induced myocarditis, and this M cell-targeting strategy indeed could be applied as a promising and universal platform for mucosal vaccine development. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Protective effect of compound bismuth and magnesium granules on aspirin-induced gastric mucosal injury in rats].

PubMed

Mu, F H; Hu, F L; Wei, H; Zhang, Y Y; Yang, G B; Lei, X Y; Yang, Y P; Sun, W N; Cui, M H

2016-02-01

To investigate the protective effect of compound bismuth and magnesium granules on aspirin-induced gastric mucosal injury in rats and its possible mechanism. Acute gastric mucosal injury model was developed with intraperitoneal injection of aspirin in Wistar rats. The rats were divided into normal control group, injury group, sucralfate protection group, compound bismuth and magnesium granules protection group and its herbal components protection group(each group 12 rats). In the protection groups, drugs as mentioned above were administered by gavage before treated with intraperitoneal injection of aspirin. To evaluate the extent of gastric mucosal injury and the protective effect of drugs, gastric mucosal lesion index, gastric mucosal blood flow, content of gastric mucosal hexosamine, prostaglandins (PG), nitric oxide(NO), tumor necrosis factor (TNF), and interleukin (IL) -1, 2, 8 were measured in each group, and histological changes were observed by gross as well as under microscope and electron microscope. Contents of hexosamine, NO, and PG in all the protection groups were significantly higher than those in the injury group (all P<0.01), and content of NO in the compound bismuth and magnesium granules group was significantly higher than that in the sucralfate group ((11.29±0.51) vs(10.80±0.36)nmol/ml, P<0.05). The gastric mucosal lesion index, contents of TNF, and IL-1, 2, 8 were significantly lower in all the protection groups than in the injury group (all P<0.01), and contents of IL-2 and IL-8 in the compound bismuth and magnesium granules group were significantly lower than those in the sucralfate group ((328.17±6.56) vs(340.23±8.05)pg/ml, P<0.01; (170.82±7.31) vs(179.31±7.80)pg/ml, P<0.05). Tissue injury and inflammatory reaction in all the protection groups were obviously mitigated compared with the injury group. Compound bismuth and magnesium granules and its herbal components may have significant protective effect on aspirin-induced gastric mucosal injury.

Effects of Helicobacter pylori Infection on the Expressions and Functional Activities of Human Duodenal Mucosal Bicarbonate Transport Proteins.

PubMed

Wen, Guorong; Jin, Hai; Deng, Shili; Xu, Jingyu; Liu, Xuemei; Xie, Rui; Tuo, Biguang

2016-12-01

The mechanisms for Helicobacter pylori (H. pylori)-induced duodenal ulcerogenesis are not fully understood. In this study, we investigated the effects of H. pylori infection on the expressions and functional activities of human duodenal mucosal bicarbonate transport proteins and hope to further clarify the pathogenesis of H. pylori-associated duodenal ulcer. The experiments were performed in the patients with H. pylori-associated duodenal ulcers, H. pylori-associated chronic gastritis, and H. pylori-negative healthy subjects. Duodenal mucosal bicarbonate secretion was measured by Ussing Chamber technology. The expressions of duodenal mucosal bicarbonate transport proteins, CFTR (cystic fibrosis transmembrane conductance regulator) and SLC26A6 (solute-linked carrier 26 gene A6), in the patients with H. pylori-associated duodenal ulcers were markedly lower than those in healthy controls. Basal and both forskolin- and prostaglandin E 2 -stimulated duodenal mucosal bicarbonate secretions in the patients with H. pylori-associated duodenal ulcers were also lower than those in healthy controls. After anti-H. pylori treatment for H. pylori-associated duodenal ulcers, duodenal mucosal bicarbonate secretion and CFTR and SLC26A6 expressions in H. pylori-eradicated patients recovered to levels comparable to healthy controls, but those were found to be not significantly altered in non-H. pylori-eradicated patients. The further results showed that decreases in the H. pylori-induced CFTR and SLC26A6 expression were related to the severity and virulent factors of H. pylori infection. H. pylori infection impairs the expressions and functional activities of duodenal mucosal bicarbonate transport proteins, CFTR and SLC26A6, which contributes to the development of duodenal ulcer. © 2016 John Wiley & Sons Ltd.

The Impact of Individual In Vivo Repair of DNA Double-Strand Breaks on Oral Mucositis in Adjuvant Radiotherapy of Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleckenstein, Jochen, E-mail: rajfle@uks.eu; Kuehne, Martin; Seegmueller, Katharina

2011-12-01

Purpose: To evaluate the impact of individual in vivo DNA double-strand break (DSB) repair capacity on the incidence of severe oral mucositis in patients with head-and-neck cancer undergoing adjuvant radiotherapy (RT) or radiochemotherapy (RCT). Patients and Methods: Thirty-one patients with resected head-and-neck cancer undergoing adjuvant RT or RCT were examined. Patients underwent RT of the primary tumor site and locoregional lymph nodes with a total dose of 60-66 Gy (single dose 2 Gy, five fractions per week). Chemotherapy consisted of two cycles of cisplatin and 5-fluorouracil. To assess DSB repair, {gamma}-H2AX foci in blood lymphocytes were quantified before and 0.5more » h, 2.5 h, 5 h, and 24 h after in vivo radiation exposure (the first fraction of RT). World Health Organization scores for oral mucositis were documented weekly and correlated with DSB repair. Results: Sixteen patients received RT alone; 15 patients received RCT. In patients who developed Grade {>=} 3 mucositis (n = 18) the amount of unrepaired DSBs 24 h after radiation exposure and DSB repair half-times did not differ significantly from patients with Grade {<=}2 mucositis (n = 13). Patients with a proportion of unrepaired DSBs after 24 h higher than the mean value + one standard deviation had an increased incidence of severe oral mucositis. Conclusions: Evaluation of in vivo DSB repair by determination of {gamma}-H2AX foci loss is feasible in clinical practice and allows identification of patients with impaired DSB repair. The incidence of oral mucositis is not closely correlated with DSB repair under the evaluated conditions.« less

Double-blinded, placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cerchietti, Leandro C.A.; Navigante, Alfredo H.; Internal Medicine Department, Instituto de Oncologia Angel H. Roffo, Universidad de Buenos Aires, Buenos Aires

2006-08-01

Purpose: We performed this double-blinded, placebo-controlled study to determine the safety and efficacy of L-alanyl-L-glutamine in the prevention of mucositis in patients with head-and-neck cancer. Methods and Materials: Thirty-two patients with head-and-neck cancer were treated with chemoradiotherapy (CRT) (radiotherapy daily up to 70 Gy plus cisplatin/5-fluoruracil once a week) and were asked to participate. Twenty-nine patients received the CRT schedule and were double-blindly assigned to receive either intravenous L-alanyl-L-glutamine 0.4 g/kg weight/day or an equal volume of saline (placebo) during chemotherapy days. Results: Fourteen patients received L-alanyl-L-glutamine and 15 received placebo. Mucositis was assessed by the Objective Mucositis Score (OMS)more » and the World Health Organization (WHO) grading system. There was a significant difference in incidence of mucositis developed in patients receiving placebo compared with those who received L-alanyl-L-glutamine (p = 0.035). The number of patients with severe objective mucositis (OMS >1.49) was higher in the placebo group compared with the L-alanyl-L-glutamine group (67% vs. 14%, p 0.007). L-alanyl-L-glutamine patients experienced less pain (three highest Numeric Rating Scale scores of 1.3/10 vs. 6.3/10 respectively, p = 0.008) and need for feeding tubes (14% vs. 60% respectively, p = 0.020) compared with placebo patients. No adverse effects related to the drug or the infusions were noted in either group. Conclusion: For patients with head-and-neck cancer receiving CRT, intravenous L-alanyl-L-glutamine may be an effective preventive measure to decrease the severity of mucositis.« less

Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma

PubMed Central

Ito, Misa; Hitomi, Suzuro; Nodai, Tomotaka; Sago, Teppei; Yamaguchi, Kiichiro; Harano, Nozomu; Gunjigake, Kaori; Hosokawa, Ryuji; Kawamoto, Tatsuo; Inenaga, Kiyotoshi

2017-01-01

During dental treatments, intraoral appliances frequently induce traumatic ulcers in the oral mucosa. Such mucosal injury-induced mucositis leads to severe pain, resulting in poor quality of life and decreased cooperation in the therapy. To elucidate mucosal pain mechanisms, we developed a new rat model of intraoral wire-induced mucositis and investigated pain mechanisms using our proprietary assay system for conscious rats. A thick metal wire was installed in the rats between the inferior incisors for one day. In the mucosa of the mandibular labial fornix region, which was touched with a free end of the wire, traumatic ulcer and submucosal abscess were induced on day 1. The ulcer was quickly cured until next day and abscess formation was gradually disappeared until five days. Spontaneous nociceptive behavior was induced on day 1 only, and mechanical allodynia persisted over day 3. Antibiotic pretreatment did not affect pain induction. Spontaneous nociceptive behavior was sensitive to indomethacin (cyclooxygenase inhibitor), ONO-8711 (prostanoid receptor EP1 antagonist), SB-366791, and HC-030031 (TRPV1 and TRPA1 antagonists, respectively). Prostaglandin E2 and 15-deoxyΔ12,14-prostaglandin J2 were upregulated only on day 1. In contrast, mechanical allodynia was sensitive to FSLLRY-NH2 (protease-activated receptor PAR2 antagonist) and RN-1734 (TRPV4 antagonist). Neutrophil elastase, which is known as a biased agonist for PAR2, was upregulated on days 1 to 2. These results suggest that prostanoids and PAR2 activation elicit TRPV1- and TRPA1-mediated spontaneous pain and TRPV4-mediated mechanical allodynia, respectively, independently of bacterial infection, following oral mucosal trauma. The pathophysiological pain mechanism suggests effective analgesic approaches for dental patients suffering from mucosal trauma-induced pain. PMID:28381109

Effect of Probiotic Bacteria on Microbial Host Defense, Growth, and Immune Function in Human Immunodeficiency Virus Type-1 Infection

PubMed Central

Cunningham-Rundles, Susanna; Ahrné, Siv; Johann-Liang, Rosemary; Abuav, Rachel; Dunn-Navarra, Ann-Margaret; Grassey, Claudia; Bengmark, Stig; Cervia, Joseph S.

2011-01-01

The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone. Pilot studies have shown that probiotic bacteria given as a supplement have improved growth and protected against loss of CD4+ T cells. The recognition that normal bacterial flora prime neonatal immune response and that abnormal flora have a profound impact on metabolism has generated insight into potential mechanisms of gut dysfunction in many settings including HIV-1 infection. As discussed here, current and emerging studies support the concept that probiotic bacteria can provide specific benefit in HIV-1 infection. Probiotic bacteria have proven active against bacterial vaginosis in HIV-1 positive women and have enhanced growth in infants with congenital HIV-1 infection. Probiotic bacteria may stabilize CD4+ T cell numbers in HIV-1 infected children and are likely to have protective effects against inflammation and chronic immune activation of the gastrointestinal immune system. PMID:22292110

Autofluorescence guided diagnostic evaluation of suspicious oral mucosal lesions: opportunities, limitations, and pitfalls

NASA Astrophysics Data System (ADS)

Vigneswaran, Nadarajah

2011-03-01

Wide-filed autofluorescence examination is currently considered as a standard of care for screening and diagnostic evaluation of early neoplastic changes of the skin, cervix, lung, bladder, gastrointestinal tract and oral cavity. Naturally occurring fluorophores within the tissue absorb UV and visible light and can re-emit some of this light at longer wavelengths in the form of fluorescence. This non-invasive tissue autofluorescence imaging is used in optical diagnostics, especially in the early detection of cancer. Usually, malignant transformation is associated with thickening of the epithelium, enhanced cellular density due to increased nuclear cytoplasmic ratio which may attenuate the excitation leading to a decrease in collagen autofluorescence. Hence, dysplastic and cancerous tissues often exhibit decreased blue-green autofluorescence and appear darker compared to uninvolved mucosa. Currently, there are three commercially available devices to examine tissue autofluorescence in the oral cavity. In this study we used the oral cancer screening device IdentafiTM 3000 to examine the tissue reflectance and autofluorescence of PML and confounding lesions of the oral cavity. Wide-field autofluorescence imaging enables rapid inspection of large mucosal surfaces, to aid in recognition of suspicious lesions and may also help in discriminate the PML (class 1) from some of the confounding lesions (class II). However, the presence of inflammation or pigments is also associated with loss of stromal autofluorescence, and may give rise to false-positive results with widefield fluorescence imaging. Clinicians who use these autofluorescence based oral cancer screening devices should be aware about the benign oral mucosal lesions that may give false positivity so that unnecessary patient's anxiety and the need for scalpel biopsy can be eliminated.

A systematic review and meta-analysis of the effort-reward imbalance model of workplace stress with indicators of immune function.

PubMed

Eddy, Pennie; Heckenberg, Rachael; Wertheim, Eleanor H; Kent, Stephen; Wright, Bradley J

2016-12-01

Despite considerable research into associations between the effort reward imbalance (ERI) model and various health outcomes over the past 20years, the underlying mechanisms responsible for the association remain unclear. Recently, ERI investigations have examined associations with immune sub-systems (e.g., leukocytes, cytokines and immunoglobulins). Synthesis of the amalgamated research evidence will aid clarity to this field of enquiry. We conducted a meta-analysis and reviewed the associations of ERI and over-commitment (OC) in the workplace with immunity. Electronic databases were searched with the phrase 'effort reward imbalance' which initially yielded 319 studies leading to 57 full text studies being screened. Seven studies that met inclusion criteria were combined using mixed and random effects models. Greater ERI was associated with lower immunity (r=-0.09, CI -0.14, -0.05, p<0.001). Sub-group analyses revealed the effect with mucosal immunity was stronger (r=-0.33, CI -0.47 to -0.18) than trends between both cytokine (r=-0.04, CI -0.07, -0.01) and leukocyte sub-groups (r=-0.02 CI -0.04, 0.01) respectively (k=7, N=9952). Over-commitment was also associated with lower immunity (r=-0.05, CI -0.09, 0.01, p=0.014); subgroup (leukocytes, cytokines, mucosal immunity) associations, however, were homogenous (Q=1.83, df=2, p=0.400, k=6, N=2358). Greater ERI and OC were both associated with lower immunity. The association between mucosal immunity and ERI was stronger than the cytokine and leukocyte sub-groups. OC moderated the relationship between ERI and immunity. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo confocal microscopy for the oral cavity: Current state of the field and future potential.

PubMed

Maher, N G; Collgros, H; Uribe, P; Ch'ng, S; Rajadhyaksha, M; Guitera, P

2016-03-01

Confocal microscopy (CM) has been shown to correlate with oral mucosal histopathology in vivo. The purposes of this review are to summarize what we know so far about in vivo CM applications for oral mucosal pathologies, to highlight some current developments with CM devices relevant for oral applications, and to formulate where in vivo CM could hold further application for oral mucosal diagnosis and management. Ovid Medline® and/or Google® searches were performed using the terms 'microscopy, confocal', 'mouth neoplasms', 'mouth mucosa', 'leukoplakia, oral', 'oral lichen planus', 'gingiva', 'cheilitis', 'taste', 'inflammatory oral confocal', 'mucosal confocal' and 'confocal squamous cell oral'. In summary, inclusion criteria were in vivo use of any type of CM for the human oral mucosa and studies on normal or pathological oral mucosa. Experimental studies attempting to identify proteins of interest and microorganisms were excluded. In total 25 relevant articles were found, covering 8 main topics, including normal oral mucosal features (n=15), oral dysplasia or neoplasia (n=7), inflamed oral mucosa (n=3), taste impairment (n=3), oral autoimmune conditions (n=2), pigmented oral pathology/melanoma (n=1), delayed type hypersensitivity (n=1), and cheilitis glandularis (n=1). The evidence for using in vivo CM in these conditions is poor, as it is limited to mainly small descriptive studies. Current device developments for oral CM include improved probe design. The authors propose that future applications for in vivo oral CM may include burning mouth syndrome, intra-operative mapping for cancer surgery, and monitoring and targeted biopsies within field cancerization. Copyright © 2016 Elsevier Ltd. All rights reserved.

Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of postoperative radiotherapy.

PubMed

Meleti, Marco; Leemans, C René; de Bree, Remco; Vescovi, Paolo; Sesenna, Enrico; van der Waal, Isaäc

2008-12-01

Treatment of head and neck mucosal melanoma remains a challenge. Surgery has traditionally been the main therapeutic approach. The role of postoperative radiotherapy has never been clearly established. The experience with a group of 42 patients (16 males, 26 females) with a primary head and neck mucosal melanoma is reported. Eleven of 19 patients (57.9%) receiving surgery alone developed a regional lymphatic metastasis. For patients receiving postoperative radiotherapy (19 patients), regional metastatic spread occurred in 4 patients (21%). Percentages of local failure were 57.9% (11/19) and 26.3% (5/19) for patients treated with surgery alone and for those treated with surgery and radiotherapy, respectively. Distant metastases occurred in 10 of 19 patients (52.6%) receiving surgery alone and in 9 of 19 patients (47.3%) receiving both therapies. The present evaluation confirms a poor prognosis for patients with head and neck mucosal melanoma, independent of the treatment modality. (c) 2008 Wiley Periodicals, Inc.

A melting method for RNA extraction from the mucosal membrane of the mouse middle ear.

PubMed

Seo, Young Joon; Kim, Sung Huhn; Moon, In Seok; Choi, Jae Young

2015-03-01

There is much confusion surrounding the methods of RNA extraction from the middle ear mucosa of mice. In this study, we worked to develop a "melting method," which is faster, purer, and more reliable than other methods in common use. Thirty-two ears were used for this study. Light microscopy with hematoxylin-eosin staining of the bullae, scanning electron microscopy (SEM), spectrophotometer analysis, and reverse transcription polymerase chain reaction were performed before and after melting the half lateral bullae, which were detached from the temporal bone by using a lateral retroauricular approach. Each resected half bulla contained a well distributed mucosal membrane. After a TRIzol melting duration of 10-30 minutes, only mucosal marker (MUC5AC) was expressed without bony marker (total osteocalcin). The same results were determined from SEM. This melting method, compared with stripping and irrigation methods, is effective and offers an easier, more robust approach to extracting RNA from the middle ear mucosal membranes of mice.

Maltase Has Most Versatile α-Hydrolytic Activity Among the Mucosal α-Glucosidases of the Small Intestine.

PubMed

Lee, Byung-Hoo; Hamaker, Bruce R

2018-06-01

Complete digestion of the glycemic carbohydrates to glucose takes place through the combined action of the 4 mucosal α-glucosidases (maltase-glucoamylase and sucrase-isomaltase) in the small intestine. Maltase digests α-1,2- and α-1,3-disaccharides better than the other α-glucosidases, and has, as well, the capability to effectively hydrolyze α-1,4 and α-1,6 linkages that form the major backbone of a starch molecule. This broad hydrolytic activity on α-linkages makes it an enzyme that has the most versatile α-hydrolytic activity among the 4mucosal α-glucosidases. The slowly digestible properties of the unusual linkages from this research suggest the development of new glycemic oligosaccharides which will be hydrolyzed slowly, compared to α-1,4 linkages, for modulating the postprandial glycemic response. In addition, using mammalian mucosal α-glucosidases is a better fit to characterize carbohydrate digestion properties, compared to fungal amyloglucosidase which is currently applied in in vitro assays.

SALSA-A dance on a slippery floor with changing partners.

PubMed

Reichhardt, M P; Holmskov, U; Meri, S

2017-09-01

It is becoming increasingly clear that the connections between our immune system and the microbiota colonizing us have a tremendous impact on human health. A number of innate molecular defence mechanisms cooperate to selectively target unwanted microorganisms at the mucosal surfaces. Amongst others these include the complement system, IgA and the SALSA molecule. The salivary scavenger and agglutinin (SALSA), also known as deleted in malignant brain tumors 1 (DMBT1), salivary agglutinin (SAG) or gp340 is a multifunctional molecule with important functions in innate immunity, inflammation and epithelial homeostasis. The SALSA protein is expressed at most mucosal surfaces, where it is one of the most abundant proteins. In the fetal meconium and infant intestine it may constitute even up to 10% of the total protein amount. SALSA is found either directly associated with the epithelial surface or secreted into the lining fluids. In the fluid-phase SALSA interacts with a number of bacterial and viral organisms, as well as with endogenous ligands, including IgA, lactoferrin, surfactant proteins and complement components. While complement has been shown to impact the mucosal environment, this remains an area of limited research. The multiple interactions of the SALSA molecule provide a scaffold, where this potent defence system may engage in cooperative microbial clearance together with corresponding mucosal host ligands. With its high abundance, and multiple effects on both host and microbes, the SALSA molecule is a key player in maintaining the immunological balance at the mucosal surfaces. This is further supported by observations linking the expression of different SALSA isoforms to the development of chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. This review describes the latest advances in understanding functions of SALSA and its different isoforms. Recently recognized functions are related to complement activation and regulation, endothelial development and epithelial homeostasis. In addition, we suggest mechanisms how SALSA regulates inflammation at the mucosal surfaces. Copyright © 2017 Elsevier Ltd. All rights reserved.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

PubMed

Dean, J A; Welsh, L C; Wong, K H; Aleksic, A; Dunne, E; Islam, M R; Patel, A; Patel, P; Petkar, I; Phillips, I; Sham, J; Schick, U; Newbold, K L; Bhide, S A; Harrington, K J; Nutting, C M; Gulliford, S L

2017-04-01

A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Role of gastric mucosal and gastric juice cytokine concentrations in development of bisphosphonate damage to gastric mucosa.

PubMed

Thomson, A B R; Appleman, S; Keelan, M; Wallace, J L

2003-02-01

Previous studies have shown that the bisphosphonates (BP) vary in their damaging effect on the gastric mucosa, and endoscopy scores (erosions or erosions plus ulcers) after 1 and 2 weeks use of BP were significantly lower in H. pylori-positive versus -negative subjects. The mechanism of this damaging effect of BP and the interaction with H. pylori is unknown. As part of a separately reported study of the incidence of gastric damage after 2 weeks of treatment of healthy female postmenopausal volunteers with risedronate (5 mg/day) or alendronate (10 mg/day), gastric aspirates were taken at the time of the baseline esophagogastroduodenoscopy (EGD), and again at 1 and 2 weeks after daily intake of a BP At the time of the third EGD, when the volunteers had been on risedronate or alendronate for 2 weeks, antral biopsies were taken from normal-appearing mucosa. Gastric juice and antral biopsies were assessed for their concentration of the cytokines interleukin-la (IL-1alpha), IL-8, IL-13, and epidermal growth factor (EGF). H. pylori, the use of BP, and development of gastric mucosal lesions had no effect on gastric mucosal concentrations of IL-1alpha, IL-13, or EGF. In contrast, the concentration of IL-8 in antral mucosal biopsies of volunteers given BP for 2 weeks was higher in the presence than in the absence of an H. pylori infection and was increased further in those who develop lesions associated with the use of BP. There was no correlation between gastric mucosal and gastric juice concentrations of IL-8. Gastric juice concentrations of IL-8 and EGF were not affected by H. pylori status, the use of BP, or the development of lesions. However, gastric juice concentrations of IL-1alpha were numerically lower in those who were negative for H. pylori with no mucosal lesions (Hp-L-), intermediate in those who were H. pylori-negative with lesions (Hp-L+), and highest in those who were positive for H. pylori and had lesions (Hp+L+). The gastric juice concentration of IL-13 was threefold higher in the absence than in the presence of H. pylori, and the relative abundance of IL-13 was: Hp-L- >Hp-L+ >Hp+L(-1) >Hp+L+. The prostaglandin E2 concentration in gastric antral biopsies was similar in the four groups and was unchanged with the in vitro biopsy incubation with celecoxib. We speculate that the higher gastric endoscopy scores observed with the use of BP in H. pylori negative as compared with H. pylori positive individuals is due to their lower mucosal concentration of IL-8 as well as the lower gastric juice concentration of IL-1alpha and higher concentration of IL-13.

Mucosal Immunology of Food Allergy

PubMed Central

Berin, M. Cecilia; Sampson, Hugh A.

2013-01-01

Food allergies are increasing in prevalence at a higher rate than can be explained by genetic factors, suggesting a role for as yet unidentified environmental factors. In this review, we summarize the state of knowledge about the healthy immune response to antigens in the diet and the basis of immune deviation that results in IgE sensitization and allergic reactivity to foods. The intestinal epithelium forms the interface between the external environment and the mucosal immune system, and emerging data suggest that the interaction between intestinal epithelial cells and mucosal dendritic cells is of particular importance in determining the outcome of immune responses to dietary antigens. Exposure to food allergens through non-oral routes, in particular through the skin, is increasingly recognized as a potentially important factor in the increasing rate of food allergy. There are many open questions on the role of environmental factors such as dietary factors and microbiota in the development of food allergy, but data suggest that both have an important modulatory effect on the mucosal immune system. Finally, we discuss recent developments in our understanding of immune mechanisms of clinical manifestations of food allergy. New experimental tools, particularly in the field of genomics and microbiome, are likely to shed light on factors responsible for the growing clinical problem of food allergy. PMID:23660362

Small- bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease

PubMed Central

2011-01-01

Background Due to the restrictive nature of a gluten-free diet, celiac patients are looking for alternative therapies. While drug-development programs include gluten challenges, knowledge regarding the duration of gluten challenge and gluten dosage is insufficient. We challenged adult celiac patients with gluten with a view to assessing the amount needed to cause some small-bowel mucosal deterioration. Methods Twenty-five celiac disease adults were challenged with low (1-3 g) or moderate (3-5g) doses of gluten daily for 12 weeks. Symptoms, small-bowel morphology, densities of CD3+ intraepithelial lymphocytes (IELs) and celiac serology were determined. Results Both moderate and low amounts of gluten induced small-bowel morphological damage in 67% of celiac patients. Moderate gluten doses also triggered mucosal inflammation and more gastrointestinal symptoms leading to premature withdrawals in seven cases. In 22% of those who developed significant small- intestinal damage, symptoms remained absent. Celiac antibodies seroconverted in 43% of the patients. Conclusions Low amounts of gluten can also cause significant mucosal deterioration in the majority of the patients. As there are always some celiac disease patients who will not respond within these conditions, sample sizes must be sufficiently large to attain to statistical power in analysis. PMID:22115041

Gastrointestinal sensitivity to soy and milk proteins in patients with IgA nephropathy.

PubMed

Kloster Smerud, H; Fellström, B; Hällgren, R; Osagie, S; Venge, P; Kristjánsson, G

2010-11-01

sensitivity to food antigens has been postulated as a contributing factor to the pathogenesis of IgA nephropathy (IgAN). in this study we used a recently developed mucosal patch technique to evaluate rectal mucosal sensitivity to soy and cow's milk (CM) proteins in IgAN patients (n = 28) compared to healthy subjects (n = 18). The rectal mucosal production of nitric oxide (NO) and release of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were measured. Serum samples were analyzed for IgA and IgG antibodies to alpha-lactalbumin, beta-lactoglobulin, casein and soy. 14 of 28 (14/28) patients experienced a rectal mucosal reaction, measured by increased NO and/or MPO levels, upon rectal challenge with soy and/or cow's milk proteins. The levels of IgG antibodies to alpha-lactalbumin, beta-lactoglobulin and casein were significantly higher in CM sensitive as compared with non-sensitive IgAN patients, whereas the mean serum levels of IgA antibodies were similar. No differences were seen in serum levels of IgA or IgG antibodies to soy. it is concluded that approximately half of our IgAN patients have a rectal mucosal sensitivity to soy or CM, and that an immune reactivity against antigens may be involved in the pathogenesis of IgAN in this subgroup of patients.

Photobiomodulation reduces oral mucositis by modulating NF-kB

NASA Astrophysics Data System (ADS)

Curra, Marina; Pellicioli, Ana Carolina Amorim; Filho, Nélson Alexandre Kretzmann; Ochs, Gustavo; Matte, Úrsula; Filho, Manoel Sant'Ana; Martins, Marco Antonio Trevizani; Martins, Manoela Domingues

2015-12-01

The aim of this study was to evaluate NF-kB during 5-fluorouracil (FU)-induced oral mucositis and ascertain whether photobiomodulation (PBM), as a preventive and/or therapeutic modality, influences this transcription factor. Ninety-six male golden Syrian hamsters were allocated into four groups: control (no treatment); PBM therapeutic, PBM preventive, and PBM combined. Animals received an injection of 5-FU on days 0 and 2. On days 3 and 4, the buccal mucosa was scratched. Irradiation was carried out using a 660-nm, 40-mW diode laser at 6 J/cm2 during 6 s/point, 0.24 J/point, for a total dose of 1.44 J/day of application. Animals were euthanized on days 0, 5, 10, and 15 (n=6). Buccal mucosa was removed for protein quantification by Western blot. Clinical analysis revealed that PBM groups exhibited less mucositis than controls on day 10. Control animals exhibited lower levels of NF-kB during mucositis development and healing. The preventive and combined protocols were associated with higher NF-kB levels at day 5; however, the therapeutic group had higher levels at days 10 and 15. These findings suggest that the preventive and/or therapeutic PBM protocols reduced the severity of oral mucositis by activating the NF-kB pathway.

Predominate HIV1-specific IgG activity in various mucosal compartments of HIV1-infected individuals.

PubMed

Lü, F X

2000-10-01

Evaluating mucosal humoral immunity is important for understanding local immunity induced by HIV infection or vaccination and designing prophylactic strategies. To characterize the mucosal humoral immunity following HIV infection, the levels of immunoglobulins (Igs), antibodies (Abs), and HIV1-specific Ab activity were evaluated in cervicovaginal secretions (CVS), saliva, breast milk, and sera of HIV-infected individuals. HIV1-specific IgG activity was significantly higher than that of IgA in CVS, saliva, and breast milk. The highest HIV1-specific IgG activity was found in breast milk. The data suggest that anti-HIV1 Abs in CVS were most likely serum derived. However, HIV1-specific Abs in saliva and breast milk were mainly locally produced. The prevalence of HIV1-specific Abs in seropositive subjects was 97% for IgG and 95% for IgA in CVS, 100% for IgG and 80% for IgA in saliva, and 59% for IgG and 94% for IgA in breast milk. These data provide evidence for both a better understanding of the nature of humoral mucosal responses after HIV1 infection and the development of strategies to induce desirable functional mucosal immunity for preventing HIV transmission. Copyright 2000 Academic Press.

Subgingival microbiome in patients with healthy and ailing dental implants

PubMed Central

Zheng, Hui; Xu, Lixin; Wang, Zicheng; Li, Lianshuo; Zhang, Jieni; Zhang, Qian; Chen, Ting; Lin, Jiuxiang; Chen, Feng

2015-01-01

Dental implants are commonly used to replace missing teeth. However, the dysbiotic polymicrobial communities of peri-implant sites are responsible for peri-implant diseases, such as peri-implant mucositis and peri-implantitis. In this study, we analyzed the microbial characteristics of oral plaque from peri-implant pockets or sulci of healthy implants (n = 10), peri-implant mucositis (n = 8) and peri-implantitis (n = 6) sites using pyrosequencing of the 16S rRNA gene. An increase in microbial diversity was observed in subgingival sites of ailing implants, compared with healthy implants. Microbial co-occurrence analysis revealed that periodontal pathogens, such as Porphyromonas gingivalis, Tannerella forsythia, and Prevotella intermedia, were clustered into modules in the peri-implant mucositis network. Putative pathogens associated with peri-implantitis were present at a moderate relative abundance in peri-implant mucositis, suggesting that peri-implant mucositis an important early transitional phase during the development of peri-implantitis. Furthermore, the relative abundance of Eubacterium was increased at peri-implantitis locations, and co-occurrence analysis revealed that Eubacterium minutum was correlated with Prevotella intermedia in peri-implantitis sites, which suggests the association of Eubacterium with peri-implantitis. This study indicates that periodontal pathogens may play important roles in the shifting of healthy implant status to peri-implant disease. PMID:26077225

Palifermin: new drug. Prevention of oral mucositis: inappropriate evaluation.

PubMed

2007-08-01

(1) Patients treated with high-dose chemotherapy combined with total body irradiation (myeloablative therapy) often develop oral mucositis. Prevention is based mainly on sucking ice during chemotherapy. (2) Palifermin is a growth factor marketed for the prevention of severe oral mucositis in adults with malignant haemopathies who are receiving myeloablative therapy followed by peripheral stem cell autografting. (3) Palifermin has not been compared with sucking ice, despite the efficacy of this simple treatment. (4) In a randomised placebo-controlled double-blind trial involving 212 adult patients treated with high-dose chemotherapy and total body irradiation, palifermin reduced the incidence of severe oral mucositis (63% versus 98%) and its duration (about 3 days versus 9 days). The myeloablative regimen used in this trial is not that commonly used in Europe. The efficacy of palifermin during less aggressive regimens, which cause less severe oral mucositis, is not known. (5) The main adverse events noted in clinical trials were erythema and cutaneous oedema. It is not known whether palifermin increases the long-term risk of cancer. (6) Treatment with palifermin is expensive, 4800.00 euros in France); the optimal dosing schedule is not known and the unit dose chosen by the manufacturer is wastefully large. (7) In practice, it remains to be demonstrated that palifermin is more effective than simply sucking ice.

Effect of selective elimination of the oral flora on mucositis in irradiated head and neck cancer patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spijkervet, F.K.; Van Saene, H.K.; Van Saene, J.J.

Recently it has been reported that chlorhexidine 0.1% rinsing was not successful in eradication of gram-negative bacilli in patients who have head and neck cancer. These bacilli could play a role in irradiation mucositis. This study reports the effect of lozenges containing 2 mg polymyxin E, 1.8 mg tobramycin, and 10 mg amphotericin B qid on the oropharyngeal flora in 15 irradiated head and neck cancer patients. The results were compared with those of a previous study in two groups of 15 patients comparing chlorhexidine rinsing with placebo. In all patients using lozenges, eradication of gram-negative bacilli and yeasts wasmore » achieved within 3 weeks. A significant increase of enterococci was found. Mucositis was significantly reduced compared with the previous two groups. All patients showed erythema only, whereas 80% of both the placebo and chlorhexidine rinsing patients suffered from severe mucositis, with signs of pseudomembranes developing from the third week of conventional irradiation protocol. The effect of selective elimination of gram-negative bacilli from the oropharynx and the prevention of severe mucositis may be explained by the eradication of these bacteria and/or neutralization of salivary endotoxin, released by gram-negative bacilli, mediating the inflammatory processes.« less

Activation of B Cells by a Dendritic Cell-Targeted Oral Vaccine

PubMed Central

Sahay, Bikash; Owen, Jennifer L.; Yang, Tao; Zadeh, Mojgan; Lightfoot, Yaíma L.; Ge, Jun-Wei; Mohamadzadeh, Mansour

2015-01-01

Production of long-lived, high affinity humoral immunity is an essential characteristic of successful vaccination and requires cognate interactions between T and B cells in germinal centers. Within germinal centers, specialized T follicular helper cells assist B cells and regulate the antibody response by mediating the differentiation of B cells into memory or plasma cells after exposure to T cell-dependent antigens. It is now appreciated that local immune responses are also essential for protection against infectious diseases that gain entry to the host by the mucosal route; therefore, targeting the mucosal compartments is the optimum strategy to induce protective immunity. However, because the gastrointestinal mucosae are exposed to large amounts of environmental and dietary antigens on a daily basis, immune regulatory mechanisms exist to favor tolerance and discourage autoimmunity at these sites. Thus, mucosal vaccination strategies must ensure that the immunogen is efficiently taken up by the antigen presenting cells, and that the vaccine is capable of activating humoral and cellular immunity, while avoiding the induction of tolerance. Despite significant progress in mucosal vaccination, this potent platform for immunotherapy and disease prevention must be further explored and refined. Here we discuss recent progress in the understanding of the role of different phenotypes of B cells in the development of an efficacious mucosal vaccine against infectious disease. PMID:24372255

Oral mucositis - self-care

MedlinePlus

Cancer treatment - mucositis; Cancer treatment - mouth pain; Cancer treatment - mouth sores; Chemotherapy - mucositis; Chemotherapy - mouth pain; Chemotherapy - mouth sores; Radiation therapy - mucositis; Radiation therapy - mouth pain; Radiation therapy - mouth ...

Dependences of mucosal dose on photon beams in head-and-neck intensity-modulated radiation therapy: a Monte Carlo study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chow, James C.L., E-mail: james.chow@rmp.uhn.on.ca; Department of Radiation Oncology, University of Toronto, Toronto, Ontario; Department of Physics, Ryerson University, Toronto, Ontario

2012-07-01

Dependences of mucosal dose in the oral or nasal cavity on the beam energy, beam angle, multibeam configuration, and mucosal thickness were studied for small photon fields using Monte Carlo simulations (EGSnrc-based code), which were validated by measurements. Cylindrical mucosa phantoms (mucosal thickness = 1, 2, and 3 mm) with and without the bone and air inhomogeneities were irradiated by the 6- and 18-MV photon beams (field size = 1 Multiplication-Sign 1 cm{sup 2}) with gantry angles equal to 0 Degree-Sign , 90 Degree-Sign , and 180 Degree-Sign , and multibeam configurations using 2, 4, and 8 photon beams inmore » different orientations around the phantom. Doses along the central beam axis in the mucosal tissue were calculated. The mucosal surface doses were found to decrease slightly (1% for the 6-MV photon beam and 3% for the 18-MV beam) with an increase of mucosal thickness from 1-3 mm, when the beam angle is 0 Degree-Sign . The variation of mucosal surface dose with its thickness became insignificant when the beam angle was changed to 180 Degree-Sign , but the dose at the bone-mucosa interface was found to increase (28% for the 6-MV photon beam and 20% for the 18-MV beam) with the mucosal thickness. For different multibeam configurations, the dependence of mucosal dose on its thickness became insignificant when the number of photon beams around the mucosal tissue was increased. The mucosal dose with bone was varied with the beam energy, beam angle, multibeam configuration and mucosal thickness for a small segmental photon field. These dosimetric variations are important to consider improving the treatment strategy, so the mucosal complications in head-and-neck intensity-modulated radiation therapy can be minimized.« less

Host-Microbiome Cross-talk in Oral Mucositis

PubMed Central

Vasconcelos, R.M.; Sanfilippo, N.; Paster, B.J.; Kerr, A.R.; Li, Y.; Ramalho, L.; Queiroz, E.L.; Smith, B.; Sonis, S.T.; Corby, P.M.

2016-01-01

Oral mucositis (OM) is among the most common, painful, and debilitating toxicities of cancer regimen–related treatment, resulting in the formation of ulcers, which are susceptible to increased colonization of microorganisms. Novel discoveries in OM have focused on understanding the host-microbial interactions, because current pathways have shown that major virulence factors from microorganisms have the potential to contribute to the development of OM and may even prolong the existence of already established ulcerations, affecting tissue healing. Additional comprehensive and disciplined clinical investigation is needed to carefully characterize the relationship between the clinical trajectory of OM, the local levels of inflammatory changes (both clinical and molecular), and the ebb and flow of the oral microbiota. Answering such questions will increase our knowledge of the mechanisms engaged by the oral immune system in response to mucositis, facilitating their translation into novel therapeutic approaches. In doing so, directed clinical strategies can be developed that specifically target those times and tissues that are most susceptible to intervention. PMID:27053118

Mucosal adjuvants and long-term memory development with special focus on CTA1-DD and other ADP-ribosylating toxins.

PubMed

Lycke, N; Bemark, M

2010-11-01

The ultimate goal for vaccination is to stimulate protective immunological memory. Protection against infectious diseases not only relies on the magnitude of the humoral immune response, but more importantly on the quality and longevity of it. Adjuvants are critical components of most non-living vaccines. Although little attention has been given to qualitative aspects of the choice of vaccine adjuvant, emerging data demonstrate that this function may be central to vaccine efficacy. In this review we describe efforts to understand more about how adjuvants influence qualitative aspects of memory development. We describe recent advances in understanding how vaccines induce long-lived plasma and memory B cells, and focus our presentation on the germinal center reaction. As mucosal vaccination requires powerful adjuvants, we have devoted much attention to the adenosine diphosphate (ADP)-ribosylating cholera toxin and the CTA1-DD adjuvants as examples of how mucosal adjuvants can influence induction of long-term memory.

Eosinophils in mucosal immune responses

PubMed Central

Travers, J; Rothenberg, M E

2015-01-01

Eosinophils, multifunctional cells that contribute to both innate and adaptive immunity, are involved in the initiation, propagation and resolution of immune responses, including tissue repair. They achieve this multifunctionality by expression of a diverse set of activation receptors, including those that directly recognize pathogens and opsonized targets, and by their ability to store and release preformed cytotoxic mediators that participate in host defense, to produce a variety of de novo pleotropic mediators and cytokines and to interact directly and indirectly with diverse cell types, including adaptive and innate immunocytes and structural cells. Herein, we review the basic biology of eosinophils and then focus on new emerging concepts about their role in mucosal immune homeostasis, particularly maintenance of intestinal IgA. We review emerging data about their development and regulation and describe new concepts concerning mucosal eosinophilic diseases. We describe recently developed therapeutic strategies to modify eosinophil levels and function and provide collective insight about the beneficial and detrimental functions of these enigmatic cells. PMID:25807184

Development of amino acid substituted gemini surfactant-based mucoadhesive gene delivery systems for potential use as noninvasive vaginal genetic vaccination.

PubMed

Singh, Jagbir; Michel, Deborah; Getson, Heather M; Chitanda, Jackson M; Verrall, Ronald E; Badea, Ildiko

2015-02-01

Recently, we synthesized amino acid- and peptide-substituted gemini surfactants, 'biolipids' that exhibited high transfection efficiency in vitro. In this study, we developed these plasmid DNA and gemini surfactant lipid particles for noninvasive administration in vaginal cavity. Novel formulations of these gene delivery systems were prepared with poloxamer 407 to induce in situ gelling of the formulation and diethylene glycol monoethyl ether to improve their penetration across mucosal tissue. Poloxamer at 16% w/v concentration in diethylene glycol monoethyl ether aqueous solution produced dispersions that gelled near body temperature and had a high yield value, preventing leakage of the formulation from the vaginal cavity. Intravaginal administration in rabbits showed that the glycyl-lysine-substituted gemini surfactant led to a higher gene expression compared with the parent unsubstituted gemini surfactant. This provides a proof-of-concept that amino acid substituted gemini surfactants can be used as noninvasive mucosal (vaginal) gene delivery systems to treat diseases associated with mucosal epithelia.

Intra-abdominal infection combined with intra-abdominal hypertension aggravates the intestinal mucosal barrier dysfunction.

PubMed

Li, Yuan; Ren, Jianan; Wu, Xiuwen; Li, Jieshou

2018-02-28

Some patients with intra-abdominal infection (IAI) may develop intra-abdominal hypertension (IAH) during treatment. The present study investigated the impact of IAI combined with IAH on the intestinal mucosal barrier in a rabbit model. Forty-eight New Zealand white rabbits were randomly divided into four groups: (i) IAI and IAH; (ii) IAI alone; (iii) IAH alone; and (iv) Control group. IAI model: cecal ligation and puncture for 48 h; IAH model: raised intra-abdominal pressure (IAP) of 20 mmHg for 4 h. Pathological changes in intestinal mucosa were confirmed by light and scanning electron microscopy. FITC-conjugated dextran (FITC-dextran) by gavage was used to measure intestinal mucosal permeability in plasma. Endotoxin, d-Lactate, and diamine oxidase (DAO) in plasma were measured to determine intestinal mucosal damage. Malonaldehyde (MDA), superoxide dismutase (SOD), and GSH in ileum tissues were measured to evaluate intestinal mucosal oxidation and reducing state. Histopathologic scores were significantly higher in the IAI and IAH group, followed by IAI alone, IAH alone, and the control group. FITC-dextran, d-Lactate, DAO, and endotoxin in plasma and MDA in ileum tissues had similar trends. GSH and SOD were significantly lowest the in IAI and IAH group. Occludin levels were lowest in the ileums of the IAI and IAH group. All differences were statistically significant ( P -values <0.001). IAI combined with IAH aggravates damage of the intestinal mucosal barrier in a rabbit model. The combined effects were significantly more severe compared with a single factor. IAI combined with IAH should be prevented and treated effectively. © 2018 The Author(s).

Supplemental calcium attenuates the colitis-related increase in diarrhea, intestinal permeability, and extracellular matrix breakdown in HLA-B27 transgenic rats.

PubMed

Schepens, Marloes A A; Schonewille, Arjan J; Vink, Carolien; van Schothorst, Evert M; Kramer, Evelien; Hendriks, Thijs; Brummer, Robert-Jan; Keijer, Jaap; van der Meer, Roelof; Bovee-Oudenhoven, Ingeborg M J

2009-08-01

We have shown in several controlled rat and human infection studies that dietary calcium improves intestinal resistance and strengthens the mucosal barrier. Reinforcement of gut barrier function may alleviate inflammatory bowel disease (IBD). Therefore, we investigated the effect of supplemental calcium on spontaneous colitis development in an experimental rat model of IBD. HLA-B27 transgenic rats were fed a purified high-fat diet containing either a low or high calcium concentration (30 and 120 mmol CaHPO4/kg diet, respectively) for almost 7 wk. Inert chromium EDTA (CrEDTA) was added to the diets to quantify intestinal permeability by measuring urinary CrEDTA excretion. Relative fecal wet weight was determined to quantify diarrhea. Colonic inflammation was determined histologically and by measuring mucosal interleukin (IL)-1beta. In addition, colonic mucosal gene expression of individual rats was analyzed using whole-genome microarrays. The calcium diet significantly inhibited the increase in intestinal permeability and diarrhea with time in HLA-B27 rats developing colitis compared with the control transgenic rats. Mucosal IL-1beta levels were lower in calcium-fed rats and histological colitis scores tended to be lower (P = 0.08). Supplemental calcium prevented the colitis-induced increase in the expression of extracellular matrix remodeling genes (e.g. matrix metalloproteinases, procollagens, and fibronectin), which was confirmed by quantitative real-time PCR and gelatin zymography. In conclusion, dietary calcium ameliorates several important aspects of colitis severity in HLA-B27 transgenic rats. Reduction of mucosal irritation by luminal components might be part of the mechanism. These results show promise for supplemental calcium as effective adjunct therapy for IBD.

A novel Toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis

PubMed Central

Ungaro, Ryan; Fukata, Masayuki; Hsu, David; Hernandez, Yasmin; Breglio, Keith; Chen, Anli; Xu, Ruliang; Sotolongo, John; Espana, Cecillia; Zaias, Julia; Elson, Greg; Mayer, Lloyd; Kosco-Vilbois, Marie; Abreu, Maria T.

2009-01-01

Dysregulated innate immune responses to commensal bacteria contribute to the development of inflammatory bowel disease (IBD). TLR4 is overexpressed in the intestinal mucosa of IBD patients and may contribute to uncontrolled inflammation. However, TLR4 is also an important mediator of intestinal repair. The aim of this study is to examine the effect of a TLR4 antagonist on inflammation and intestinal repair in two murine models of IBD. Colitis was induced in C57BL/6J mice with dextran sodium sulfate (DSS) or by transferring CD45Rbhi T cells into RAG1−/− mice. An antibody (Ab) against the TLR4/MD-2 complex or isotype control Ab was administered intraperitoneally during DSS treatment, recovery from DSS colitis, or induction of colitis in RAG1−/− mice. Colitis severity was assessed by disease activity index (DAI) and histology. The effect of the Ab on the inflammatory infiltrate was determined by cell isolation and immunohistochemistry. Mucosal expression of inflammatory mediators was analyzed by real-time PCR and ELISA. Blocking TLR4 at the beginning of DSS administration delayed the development of colitis with significantly lower DAI scores. Anti-TLR4 Ab treatment decreased macrophage and dendritic cell infiltrate and reduced mucosal expression of CCL2, CCL20, TNF-α, and IL-6. Anti-TLR4 Ab treatment during recovery from DSS colitis resulted in defective mucosal healing with lower expression of COX-2, PGE2, and amphiregulin. In contrast, TLR4 blockade had minimal efficacy in ameliorating inflammation in the adoptive transfer model of chronic colitis. Our findings suggest that anti-TLR4 therapy may decrease inflammation in IBD but may also interfere with colonic mucosal healing. PMID:19359427

Chamomile infusion cryotherapy to prevent oral mucositis induced by chemotherapy: a pilot study.

PubMed

Dos Reis, Paula Elaine Diniz; Ciol, Marcia A; de Melo, Nilce Santos; Figueiredo, Paulo Tadeu de Souza; Leite, André Ferreira; Manzi, Natália de Melo

2016-10-01

The aim of this study is to compare cryotherapy made only with water and cryotherapy made with chamomile infusion for prevention and reduction of intensity of oral mucositis in patients with cancer receiving 5-fluorouracil and leucovorin. This is a randomized pilot study with two groups: cryotherapy made only with water (control group, n = 18) and cryotherapy made with chamomile infusion (chamomile group, n = 20). Both groups were instructed to swish the ice around in their oral cavity for at least 30 min during chemotherapy. Assessment of oral mucosa occurred on days 8, 15, and 22 after the first day of chemotherapy. Fifty percent of the patients in the control and 30 % in the chamomile group developed oral mucositis. Mouth pain score was higher in patients in the control group on all evaluations (p = 0.02 for day 8, p = 0.09 for day 15, and p = 0.14 for day 22). Patients in the chamomile group never developed mucositis with grade 2 or higher. Presence of ulceration was statistically significant on day 8 (16 % in the control vs. 0 % in the chamomile group, p = 0.10), but not in days 15 and 22, although 11 % still had ulcerations in the control group and none in the chamomile group. The occurrence of oral mucositis was lower in patients in the chamomile group than in the control group. When compared to the controls, the chamomile group presented less mouth pain and had no ulcerations. Cryotherapy was well tolerated by both groups, and no toxicity related to chamomile was identified.

Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes.

PubMed

Wang, Xiaoting; Ota, Naruhisa; Manzanillo, Paolo; Kates, Lance; Zavala-Solorio, Jose; Eidenschenk, Celine; Zhang, Juan; Lesch, Justin; Lee, Wyne P; Ross, Jed; Diehl, Lauri; van Bruggen, Nicholas; Kolumam, Ganesh; Ouyang, Wenjun

2014-10-09

The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4(+) T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.

Macroscopic findings in collagenous colitis: a multi-center, retrospective, observational cohort study

PubMed Central

Koulaouzidis, Anastasios; Yung, Diana E.; Nemeth, Artur; Sjöberg, Klas; Giannakou, Andry; Qureshi, Raheel; Bartzis, Leonidas; McNeill, Morna; Johansson, Gabriele Wurm; Lucendo, Alfredo J.; Fineron, Paul; Trimble, Ken C.; Saeed, Athar; Plevris, John N.; Toth, Ervin

2017-01-01

Background Collagenous colitis (CC) is by definition a histological diagnosis. However, colonoscopy often reveals characteristic endoscopic findings. The aim of this study was to evaluate the frequency and type of endoscopic findings in patients diagnosed with CC in 4 participating centers. Methods This was a retrospective study; the databases of 2 university hospitals in Edinburgh (Scotland) and Malmö (Sweden), and 2 district general hospitals in Tomelloso (Spain) and Gateshead (England) were interrogated for patients diagnosed with CC between May 2008 and August 2013. Endoscopy reports and images were retrieved and reviewed; data on lesions, sedation, bowel preparation and endoscopist experience were abstracted. Categorical data are reported as mean±SD. Fischer’s exact, chi-square and t (unpaired) tests were used to compare datasets. A two-tailed P-value of <0.05 was considered statistically significant. Results 607 patients (149 male, mean age 66.9±12.25 years) were diagnosed with CC. A total of 108/607 (17.8%) patients had one or more suggestive endoscopy findings: i.e., mucosal erythema/edema, 91/607 (15%); linear colonic mucosal defects, 12/607 (2%); or mucosal scarring, 5/607 (0.82%). For colonic mucosa erythema, there was no difference in the odds of finding erythema with the use of different bowel preparation methods (P=0.997). For colonic mucosal defects there was some evidence (P=0.005) that patients colonoscoped by experienced endoscopists had 87% less odds of developing such defects. Moreover, there was evidence that analgesia reduced the odds of developing mucosal defects by 84%. Conclusion A significant minority of patients with CC have endoscopic findings in colonoscopy. The description of such findings appears to be related to the endoscopist’s experience. PMID:28469361

Mechanisms of gastroprotection.

PubMed

Konturek, S J

1990-01-01

Gastric mucosa is constantly exposed to various irritants, but it usually maintains its integrity owing to several lines of defense, including mucus-alkaline secretion, mucosal hydrophobicity, rich mucosal blood flow, stabilization of tissue lysosomes, maintenance of mucosal sulfhydryls, and rapid proliferation and renewal of mucosal cells. Prostaglandins (PG) inhibit experimental gastric mucosal damage and ulcerations induced by a wide variety of agents, hence PG have been proposed to contribute to the overall protective process by activation of various mucosal defence lines--particularly by prevention of vasocongestion, ischemia, and deep hemorrhagic necrosis. The relation between tissue PG generation and mucosal protection does not appear to be closely related, and probably only minute amounts of PG are required to maintain mucosal integrity. In contrast to PG, other products of arachidonate metabolism, such as TxA2, LTC4 or LTD4, and the related lipid, platelet-activating factor, appear to mediate mucosal damage mainly by the disturbance in mucosal microcirculation and tissue ischemia. Gastroprotection can be achieved by stimulation of mucosal biosynthesis of protective PG or by the inhibition of the release or action of the proulcerogenic arachidonate metabolites. Certain natural substances, such as sulfhydryls, epidermal growth factor, or polyamines, protect the mucosa via a PG-independent mechanism, probably by enhancing the tissue repair processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Transmigrated neutrophils in the intestinal lumen engage ICAM 1 to regulate the epithelial barrier and neutrophil recruitment

PubMed Central

Sumagin, Ronen; Robin, Alex Z.; Nusrat, Asma; Parkos, Charles A.

2014-01-01

Neutrophil (PMN) transepithelial migration (TEM) and accumulation in luminal spaces is a hallmark of mucosal inflammation. TEM has been extensively modeled, however the functional consequences and molecular basis of PMN interactions with luminal epithelial ligands are not clear. Here we report that cytokine-induced expression of a PMN ligand, intercellular adhesion molecule-1 (ICAM-1), exclusively on the luminal (apical) membrane of the intestinal epithelium results in accumulation and enhanced motility of transmigrated PMN on the apical epithelial surface. Using complementary in-vitro and in-vivo approaches we demonstrate that ligation of epithelial ICAM-1 by PMN or with specific antibodies results in myosin light chain kinase (MLCK)-dependent increases in epithelial permeability that are associated with enhanced PMN TEM. Effects of ICAM-1 ligation on epithelial permeability and PMN migration in-vivo were blocked after intraluminal addition of peptides derived from the cytoplasmic domain of ICAM-1. These findings provide new evidence for functional interactions between PMN and epithelial cells after migration into the intestinal lumen. While such interactions may aid in clearance of invading microorganisms by promoting PMN recruitment, engagement of ICAM-1 under pathologic conditions would increase accumulation of epithelial-associated PMN, thus contributing to mucosal injury as observed in conditions including ulcerative colitis. PMID:24345805

Unraveling Molecular Signatures of Immunostimulatory Adjuvants in the Female Genital Tract through Systems Biology

PubMed Central

Brinkenberg, Ingrid; Samuelson, Emma; Thörn, Karolina; Nielsen, Jens; Harandi, Ali M.

2011-01-01

Sexually transmitted infections (STIs) unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha-galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome data determined which signature pathways, processes and networks are shared by or otherwise exclusive to these 2 classes of experimental vaginal adjuvants in the mouse vagina. To our knowledge, this is the first integrated genome-wide transcriptome analysis of the effects of immunomodulatory adjuvants on the female genital tract of a mammal. These results could inform rational development of effective mucosal adjuvants for vaccination against STIs. PMID:21666746

Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

PubMed

Yokota, T; Ogawa, T; Takahashi, S; Okami, K; Fujii, T; Tanaka, K; Iwae, S; Ota, I; Ueda, T; Monden, N; Matsuura, K; Kojima, H; Ueda, S; Sasaki, K; Fujimoto, Y; Hasegawa, Y; Beppu, T; Nishimori, H; Hirano, S; Naka, Y; Matsushima, Y; Fujii, M; Tahara, M

2017-05-05

Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).

Development of an oral care guide for patients undergoing autologous stem cell transplantation.

PubMed

Salvador, Prisco T

2006-01-01

Nurses identified oral mucositis as a recurring issue in clinical practice. To meet this challenge, a group of nurses took a leadership role in developing an oral care guide. The University Health Network Nursing Research Utilization Model and the Neuman Systems Model served as conceptual frameworks. A flowchart was developed to ensure a coordinated and continuous provision of oral care. Educational presentations were conducted to familiarize nurses and members of the multidisciplinary team of the practice changes. The introduction of the oral care regimen as primary prevention, plus systematic oral assessment and monitoring had the potential to reduce the occurrence and severity of oral mucositis in patients undergoing autologous stem cell transplantation.

Advances in HIV Microbicide Development

PubMed Central

Olsen, Joanna S.; Easterhoff, David; Dewhurst, Stephen

2014-01-01

There is an urgent need for a way to control the spread of the global HIV pandemic. A microbicide, or topical drug applied to the mucosal environment to block transmission, is a promising HIV prevention strategy. The development of a safe and efficacious microbicide requires a thorough understanding of the mucosal environment and it's role in HIV transmission. Knowledge of the key events in viral infection identifies points at which the virus might be most effectively targeted by a microbicide. The cervicovaginal and rectal mucosa play an important role in the innate defense against HIV, and microbicides must not interfere with these functions. In this review we discuss the current research on HIV microbicide development. PMID:22098355

Lactococcus lactis As a Versatile Vehicle for Tolerogenic Immunotherapy

PubMed Central

Cook, Dana P.; Gysemans, Conny; Mathieu, Chantal

2018-01-01

Genetically modified Lactococcus lactis bacteria have been engineered as a tool to deliver bioactive proteins to mucosal tissues as a means to exert both local and systemic effects. They have an excellent safety profile, the result of years of human consumption in the food industry, as well as a lack of toxicity and immunogenicity. Also, containment strategies have been developed to promote further application as clinical protein-based therapeutics. Here, we review technological advancements made to enhanced the potential of L. lactis as live biofactories and discuss some examples of tolerogenic immunotherapies mediated by mucosal drug delivery via L. lactis. Additionally, we highlight their use to induce mucosal tolerance by targeted autoantigen delivery to the intestine as an approach to reverse autoimmune type 1 diabetes. PMID:29387056

Advances in mucoadhesion and mucoadhesive polymers.

PubMed

Khutoryanskiy, Vitaliy V

2011-06-14

Mucoadhesion is the ability of materials to adhere to mucosal membranes in the human body and provide a temporary retention. This property has been widely used to develop polymeric dosage forms for buccal, oral, nasal, ocular and vaginal drug delivery. Excellent mucoadhesive properties are typical for hydrophilic polymers possessing charged groups and/or non-ionic functional groups capable of forming hydrogen bonds with mucosal surfaces. This feature article considers recent advances in the study of mucoadhesion and mucoadhesive polymers. It provides an overview on the structure of mucosal membranes, properties of mucus gels and the nature of mucoadhesion. It describes the most common methods to evaluate mucoadhesive properties of various dosage forms and discusses the main classes of mucoadhesives. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer.

PubMed

Baker, Kristi; Rath, Timo; Flak, Magdalena B; Arthur, Janelle C; Chen, Zhangguo; Glickman, Jonathan N; Zlobec, Inti; Karamitopoulou, Eva; Stachler, Matthew D; Odze, Robert D; Lencer, Wayne I; Jobin, Christian; Blumberg, Richard S

2013-12-12

Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance. Copyright © 2013 Elsevier Inc. All rights reserved.

Protection against Foot-and-Mouth Disease Virus in Guinea Pigs via Oral Administration of Recombinant Lactobacillus plantarum Expressing VP1

PubMed Central

Wang, Miao; Pan, Li; Zhou, Peng; Lv, Jianliang; Zhang, Zhongwang; Wang, Yonglu; Zhang, Yongguang

2015-01-01

Mucosal vaccination is an effective strategy for generating antigen-specific immune responses against mucosal infections of foot-and-mouth disease virus (FMDV). In this study, Lactobacillus plantarum strains NC8 and WCFS1 were used as oral delivery vehicles containing a pSIP411-VP1 recombinant plasmid to initiate mucosal and systemic immune responses in guinea pigs. Guinea pigs were orally vaccinated (three doses) with NC8-pSIP411, NC8-pSIP411-VP1, WCFS1-pSIP411, WCFS1-pSIP411-VP1 or milk. Animals immunized with NC8-pSIP411-VP1 and WCFS1-pSIP411-VP1 developed high levels of antigen-specific serum IgG, IgA, IgM, mucosal secretory IgA (sIgA) and neutralizing antibodies, and revealed stronger cell-mediated immune responses and enhanced protection against FMDV challenge compared with control groups. The recombinant pSIP411-VP1 effectively improved immunoprotection against FMDV in guinea pigs. PMID:26629822

Mucosal Herpes Immunity and Immunopathology to Ocular and Genital Herpes Simplex Virus Infections

PubMed Central

Chentoufi, Aziz Alami; BenMohamed, Lbachir

2012-01-01

Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 & HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed. PMID:23320014

Selective mucosal ablation using CO2 laser for the development of novel endoscopic submucosal dissection: comparison of continuous wave and nanosecond pulsed wave

NASA Astrophysics Data System (ADS)

Ishii, K.; Watanabe, S.; Obata, D.; Hazama, H.; Morita, Y.; Matsuoka, Y.; Kutsumi, H.; Azuma, T.; Awazu, K.

2010-02-01

Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment technique for small early gastric cancers. Procedures are carried out using some specialized electrosurgical knifes with a submucosal injection solution. However it is not widely used because its procedure is difficult. The objective of this study is to develop a novel ESD method which is safe in principle and widely used by using laser techniques. In this study, we used CO2 lasers with a wavelength of 10.6 μm for mucosal ablation. Two types of pulse, continuous wave and pulsed wave with a pulse width of 110 ns, were studied to compare their values. Porcine stomach tissues were used as a sample. Aqueous solution of sodium hyaluronate (MucoUpR) with 50 mg/ml sodium dihydrogenphosphate is injected to a submucosal layer. As a result, ablation effect by CO2 laser irradiation was stopped because submucosal injection solution completely absorbed CO2 laser energy in the invasive energy condition which perforates a muscle layer without submucosal injection solution. Mucosal ablation by the combination of CO2 Laser and a submucosal injection solution is a feasible technique for treating early gastric cancers safely because it provides a selective mucosal resection and less-invasive interaction to muscle layer.

Pediatric Helicobacter pylori gastropathy demonstrates a unique pattern of gastric foveolar hyperplasia.

PubMed

Saghier, Sadaf; Schwarz, Steven M; Anderson, Virginia; Gupta, Raavi; Heidarian, Amin; Rabinowitz, Simon S

2018-04-25

Helicobacter pylori (Hp) are the most common agents causing gastric mucosal injury worldwide. Foveolar hyperplasia is a key component of the stomach's reaction to injury. This study examines histopathologic characteristics associated with Helicobacter pylori and with non- Helicobacter pylori-associated gastropathy in children and adolescents, and compares the prevalence of foveolar hyperplasia among these disease subgroups and normal control subjects. Eighty-one gastric antral and corpus biopsies from subjects 2-19 years of age were studied. Twenty-two subjects with Helicobacter pylori gastritis were compared to 23 with non-Helicobacter pylori gastropathy and to 36 controls (normal biopsies). Foveolar length, full mucosal thickness, and the foveolar length: full mucosal thickness ratio were derived by a morphometric technique previously developed to analyze adult gastric tissue. Compared to controls, Helicobacter pylori gastritis demonstrated significant increases in antral foveolar length (P < .0001), full mucosal thickness (P < .0001), as well as corpus foveolar length (P < .05) and corpus full mucosal thickness (P < .05). Non-Helicobacter pylori-associated gastropathy also was characterized by increased antral foveolar length (P < .0001) and full mucosal thickness (P < .001) but corresponding corpus measurements did not differ from controls. Antral foveolar length in non-Helicobacter pylori gastropathy was increased, when compared to Helicobacter pylori gastritis (P < .05), while corpus values were not. The non-Helicobacter pylori gastropathy group demonstrated increased antral foveolar length: full mucosal thickness ratios, compared with Helicobacter pylori gastritis (P < .001) and with normal controls (P < .0001). An objective, quantitative approach to measuring foveolar hyperplasia in adults was successfully applied to pediatric biopsies and yielded a richer characterization of gastric pathology in children. Foveolar hyperplasia appears to be a generalized phenomenon in the presence of pediatric Helicobacter pylori gastritis but is limited to the antrum in non-Helicobacter pylori gastropathy. © 2018 John Wiley & Sons Ltd.

Differential Apoptosis in Mucosal and Dermal Wound Healing

PubMed Central

Johnson, Ariel; Francis, Marybeth; DiPietro, Luisa Ann

2014-01-01

Objectives: Dermal and mucosal healing are mechanistically similar. However, scarring and closure rates are dramatically improved in mucosal healing, possibly due to differences in apoptosis. Apoptosis, nature's preprogrammed form of cell death, occurs via two major pathways, extrinsic and intrinsic, which intersect at caspase3 (Casp3) cleavage and activation. The purpose of this experiment was to identify the predominant pathways of apoptosis in mucosal and dermal wound healing. Approach: Wounds (1 mm biopsy punch) were made in the dorsal skin (n=3) or tongue (n=3) of female Balb/C mice aged 6 weeks. Wounds were harvested at 6 h, 24 h, day 3 (D3), D5, D7, and D10. RNA was isolated and analyzed using real time reverse transcriptase–polymerase chain reaction. Expression levels for genes in the intrinsic and extrinsic apoptotic pathways were compared in dermal and mucosal wounds. Results: Compared to mucosal healing, dermal wounds exhibited significantly higher expression of Casp3 (at D5; p<0.05), Casp7 (at D5; p<0.05), Trp53 (at 24 h and D5; p<0.05), Tnfrsf1b (at 24 h; p<0.05), FasR (at 24 h, D5, and D7; p<0.05), and Casp8 (at 24 h; p<0.05) and significantly lower gene expression of Tradd (at 24 h; p<0.05). Innovation: Our observations indicate differential execution of apoptosis in oral wound healing compared to skin. Conclusion: Expression patterns of key regulators of apoptosis in wound healing indicate that apoptosis occurs predominantly through the intrinsic pathway in the healing mucosa, but predominantly through the extrinsic pathway in the healing skin. The identification of differences in the apoptotic pathways in skin and mucosal wounds may allow the development of therapeutics to improve skin healing. PMID:25493209

Design Aspects of a Case-Control Clinical Investigation of the Effect of HIV on Oral and Gastrointestinal Soluble Innate Factors and Microbes

PubMed Central

Phelan, Joan A.; Abrams, William R.; Norman, Robert G.; Li, Yihong; Laverty, Maura; Corby, Patricia M.; Nembhard, Jason; Neri, Dinah; Barber, Cheryl A.; Aberg, Judith A.; Fisch, Gene S.; Poles, Michael A.; Malamud, Daniel

2014-01-01

Introduction The impaired host defense system in HIV infection impacts the oral and gastrointestinal microbiota and associated opportunistic infections. Antiretroviral treatment is predicted to partially restore host defenses and decrease the oral manifestation of HIV/AIDS. Well-designed longitudinal studies are needed to better understand the interactions of soluble host defense proteins with bacteria and virus in HIV/AIDS. “Crosstalk” was designed as a longitudinal study of host responses along the gastrointestinal (GI) tract and interactions between defense molecules and bacteria in HIV infection and subsequent therapy. Purpose The clinical core formed the infrastructure for the study of the interactions between the proteome, microbiome and innate immune system. The core recruited and retained study subjects, scheduled visits, obtained demographic and medical data, assessed oral health status, collected samples, and guided analysis of the hypotheses. This manuscript presents a well-designed clinical core that may serve as a model for studies that combine clinical and laboratory data. Methods Crosstalk was a case-control longitudinal clinical study an initial planned enrollment of 170 subjects. HIV+ antiretroviral naïve subjects were followed for 9 visits over 96 weeks and HIV uninfected subjects for 3 visits over 24 weeks. Clinical prevalence of oral mucosal lesions, dental caries and periodontal disease were assessed. Results During the study, 116 subjects (47 HIV+, 69 HIV-) were enrolled. Cohorts of HIV+ and HIV- were demographically similar except for a larger proportion of women in the HIV- group. The most prevalent oral mucosal lesions were oral candidiasis and hairy leukoplakia in the HIV+ group. Discussion The clinical core was essential to enable the links between clinical and laboratory data. The study aims to determine specific differences between oral and GI tissues that account for unique patterns of opportunistic infections and to delineate the differences in their susceptibility to infection by HIV and their responses post-HAART. PMID:25409430

Design aspects of a case-control clinical investigation of the effect of HIV on oral and gastrointestinal soluble innate factors and microbes.

PubMed

Phelan, Joan A; Abrams, William R; Norman, Robert G; Li, Yihong; Laverty, Maura; Corby, Patricia M; Nembhard, Jason; Neri, Dinah; Barber, Cheryl A; Aberg, Judith A; Fisch, Gene S; Poles, Michael A; Malamud, Daniel

2014-01-01

The impaired host defense system in HIV infection impacts the oral and gastrointestinal microbiota and associated opportunistic infections. Antiretroviral treatment is predicted to partially restore host defenses and decrease the oral manifestation of HIV/AIDS. Well-designed longitudinal studies are needed to better understand the interactions of soluble host defense proteins with bacteria and virus in HIV/AIDS. "Crosstalk" was designed as a longitudinal study of host responses along the gastrointestinal (GI) tract and interactions between defense molecules and bacteria in HIV infection and subsequent therapy. The clinical core formed the infrastructure for the study of the interactions between the proteome, microbiome and innate immune system. The core recruited and retained study subjects, scheduled visits, obtained demographic and medical data, assessed oral health status, collected samples, and guided analysis of the hypotheses. This manuscript presents a well-designed clinical core that may serve as a model for studies that combine clinical and laboratory data. Crosstalk was a case-control longitudinal clinical study an initial planned enrollment of 170 subjects. HIV+ antiretroviral naïve subjects were followed for 9 visits over 96 weeks and HIV uninfected subjects for 3 visits over 24 weeks. Clinical prevalence of oral mucosal lesions, dental caries and periodontal disease were assessed. During the study, 116 subjects (47 HIV+, 69 HIV-) were enrolled. Cohorts of HIV+ and HIV- were demographically similar except for a larger proportion of women in the HIV- group. The most prevalent oral mucosal lesions were oral candidiasis and hairy leukoplakia in the HIV+ group. The clinical core was essential to enable the links between clinical and laboratory data. The study aims to determine specific differences between oral and GI tissues that account for unique patterns of opportunistic infections and to delineate the differences in their susceptibility to infection by HIV and their responses post-HAART.

Monodisperse, Uniformly-Shaped Particles for Controlled Respiratory Vaccine Delivery

NASA Astrophysics Data System (ADS)

Fromen, Catherine Ann

The majority of the world's most infectious diseases occur at the air-tissue interface called the mucosa, including HIV/AIDS, tuberculosis, measles, and bacterial or viral gut and respiratory infections. Despite this, vaccines have generally been developed for the systemic immune system and fail to provide protection at the mucosal site. Vaccine delivery directly to the lung mucosa could provide superior lung protection for many infectious diseases, such as TB or influenza, as well as systemic and therapeutic vaccines for diseases such as Dengue fever, asthma, or cancer. Specifically, precision engineered biomaterials are believed to offer tremendous opportunities for a new generation of vaccines. The goal of this approach is to leverage naturally occurring processes of the immune system to produce memory responses capable of rapidly destroy virulent pathogens without harmful exposure. Considerable knowledge of biomaterial properties and their interaction with the immune system of the lung is required for successful translation. The overall goal of this work was to fabricate and characterize nano- and microparticles using the Particle Replication In Non-wetting Templates (PRINT) fabrication technique and optimize them as pulmonary vaccine carriers. (Abstract shortened by ProQuest.).

Functional, histological structure and mastocytes alterations in rat urinary bladders following acute and [corrected] chronic cyclophosphamide treatment.

PubMed

Juszczak, K; Gil, K; Wyczolkowski, M; Thor, P J

2010-08-01

Neurogenic inflammation is linked to urinary bladder overactivity development. Cyclophosphamide (CYP) damages all mucosal defence lines of urinary bladder and induces cystitis with overactivity. The aim of this study was to estimate the effect of CYP on rat urinary bladder function, histological structure and mastocytes numbers following acute and chronic CYP treatment. Fourty two female rats were divided into four groups: I (control), II (acute cystitis), III (chronic cystitis), IV (sham group). Acute and chronic cystitis were induced by CYP in single dose and four doses (1(st), 3(rd), 5(th), 7(th) day), respectively. In group I-III the cystometric evaluation was performed. Sections of the bladder were stained with HE and toluidine blue for the detection of mastocytes. The severity of inflammation was examined according to mucosal abrasion, haemorrhage, leukocyte infiltration and oedema. Acute and chronic CYP treatment caused inflammatory macroscopic and microscopic changes (mucosal abrasion, haemorrhage, oedema) and increased infiltration of inflammatory cells in urinary bladder. Acute treatment induced the infiltration of mastocytes within bladder wall contrary to chronic one decrement. Acute treatment caused more severe mucosal abrasion, whereas chronic one revealed more developed haemorrhage changes. Additionally, cystometric evaluation revealed urinary bladder overactivity development in both types of cystitis. Basal pressure and detrusor overactivity index after acute treatment increased considerably in comparison with the increase obtained after chronic one. Our results proved that acute model of CYP-induced cystitis in rats is more credible for further evaluation of neurogenic inflammation response in pathogenesis of overactive bladder as compared to chronic one.

Reduced Epithelial Na+/H+ Exchange Drives Gut Microbial Dysbiosis and Promotes Inflammatory Response in T Cell-Mediated Murine Colitis

PubMed Central

Midura-Kiela, Monica T.; Ramalingam, Rajalakshmy; Larmonier, Claire B.; Chase, John H.; Caporaso, J. Gregory; Besselsen, David G.; Ghishan, Fayez K.; Kiela, Pawel R.

2016-01-01

Inflammatory bowel diseases (IBD) are associated with functional inhibition of epithelial Na+/H+ exchange. In mice, a selective disruption of NHE3 (Slc9a3), a major apical Na+/H+ exchanger, also promotes IBD-like symptoms and gut microbial dysbiosis. We hypothesized that disruption of Na+/H+ exchange is necessary for the development of dysbiosis, which promotes an exacerbated mucosal inflammatory response. Therefore, we performed a temporal analysis of gut microbiota composition, and mucosal immune response to adoptive T cell transfer was evaluated in Rag2-/- and NHE3-/-/Rag2-/- (DKO) mice with and without broad-spectrum antibiotics. Microbiome (16S profiling), colonic histology, T cell and neutrophil infiltration, mucosal inflammatory tone, and epithelial permeability were analyzed. In adoptive T cell transfer colitis model, Slc9a3 status was the most significant determinant of gut microbial community. In DKO mice, NHE3-deficiency and dysbiosis were associated with dramatically accelerated and exacerbated disease, with rapid body weight loss, increased mucosal T cell and neutrophil influx, increased mucosal cytokine expression, increased permeability, and expansion of CD25-FoxP3+ Tregs; this enhanced susceptibility was alleviated by oral broad-spectrum antibiotics. Based on these results and our previous work, we postulate that epithelial electrolyte homeostasis is an important modulator in the progression of colitis, acting through remodeling of the gut microbial community. PMID:27050757

A Novel Combination of Wheat Peptides and Fucoidan Attenuates Ethanol-Induced Gastric Mucosal Damage through Anti-Oxidant, Anti-Inflammatory, and Pro-Survival Mechanisms

PubMed Central

Kan, Juntao; Hood, Molly; Burns, Charlie; Scholten, Jeff; Chuang, Jennifer; Tian, Feng; Pan, Xingchang; Du, Jun; Gui, Min

2017-01-01

Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal–regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms. PMID:28878183

A Novel Combination of Wheat Peptides and Fucoidan Attenuates Ethanol-Induced Gastric Mucosal Damage through Anti-Oxidant, Anti-Inflammatory, and Pro-Survival Mechanisms.

PubMed

Kan, Juntao; Hood, Molly; Burns, Charlie; Scholten, Jeff; Chuang, Jennifer; Tian, Feng; Pan, Xingchang; Du, Jun; Gui, Min

2017-09-06

Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal-regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.

Mucosal and systemic immune responses elicited by recombinant Lactococcus lactis expressing a fusion protein composed of pertussis toxin and filamentous hemagglutinin from Bordetella pertussis.

PubMed

Torkashvand, Ali; Bahrami, Fariborz; Adib, Minoo; Ajdary, Soheila

2018-05-05

We constructed a food-grade expression system harboring a F1S1 fusion protein of Bordetella pertussis to be produced in Lactococcus lactis NZ3900 as a new oral vaccine model against whooping cough, caused by B. pertussis. F1S1 was composed of N-terminally truncated S1 subunit of pertussis toxin and type I immunodominant domain of filamentous hemagglutinin which are both known as protective immunogens against pertussis. The recombinant L. lactis was administered via oral or intranasal routes to BALB/c mice and the related specific systemic and mucosal immune responses were then evaluated. The results indicated significantly higher levels of specific IgA in the lung extracts and IgG in sera of mucosally-immunized mice, compared to their controls. It was revealed that higher levels of IgG2a, compared to IgG1, were produced in all mucosally-immunized mice. Moreover, immunized mice developed Th1 responses with high levels of IFN-γ production by the spleen cells. These findings provide evidence for L. lactis to be used as a suitable vehicle for expression and delivery of F1S1 fusion protein to mucosa and induction of appropriate systemic and mucosal immune responses against pertussis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Gastrointestinal cell lines form polarized epithelia with an adherent mucus layer when cultured in semi-wet interfaces with mechanical stimulation.

PubMed

Navabi, Nazanin; McGuckin, Michael A; Lindén, Sara K

2013-01-01

Mucin glycoproteins are secreted in large quantities by mucosal epithelia and cell surface mucins are a prominent feature of the glycocalyx of all mucosal epithelia. Currently, studies investigating the gastrointestinal mucosal barrier use either animal experiments or non-in vivo like cell cultures. Many pathogens cause different pathology in mice compared to humans and the in vitro cell cultures used are suboptimal because they are very different from an in vivo mucosal surface, are often not polarized, lack important components of the glycocalyx, and often lack the mucus layer. Although gastrointestinal cell lines exist that produce mucins or polarize, human cell line models that reproducibly create the combination of a polarized epithelial cell layer, functional tight junctions and an adherent mucus layer have been missing until now. We trialed a range of treatments to induce polarization, 3D-organization, tight junctions, mucin production, mucus secretion, and formation of an adherent mucus layer that can be carried out using standard equipment. These treatments were tested on cell lines of intestinal (Caco-2, LS513, HT29, T84, LS174T, HT29 MTX-P8 and HT29 MTX-E12) and gastric (MKN7, MKN45, AGS, NCI-N87 and its hTERT Clone5 and Clone6) origins using Ussing chamber methodology and (immuno)histology. Semi-wet interface culture in combination with mechanical stimulation and DAPT caused HT29 MTX-P8, HT29 MTX-E12 and LS513 cells to polarize, form functional tight junctions, a three-dimensional architecture resembling colonic crypts, and produce an adherent mucus layer. Caco-2 and T84 cells also polarized, formed functional tight junctions and produced a thin adherent mucus layer after this treatment, but with less consistency. In conclusion, culture methods affect cell lines differently, and testing a matrix of methods vs. cell lines may be important to develop better in vitro models. The methods developed herein create in vitro mucosal surfaces suitable for studies of host-pathogen interactions at the mucosal surface.

Gastrointestinal Cell Lines Form Polarized Epithelia with an Adherent Mucus Layer when Cultured in Semi-Wet Interfaces with Mechanical Stimulation

PubMed Central

Navabi, Nazanin; McGuckin, Michael A.; Lindén, Sara K.

2013-01-01

Mucin glycoproteins are secreted in large quantities by mucosal epithelia and cell surface mucins are a prominent feature of the glycocalyx of all mucosal epithelia. Currently, studies investigating the gastrointestinal mucosal barrier use either animal experiments or non-in vivo like cell cultures. Many pathogens cause different pathology in mice compared to humans and the in vitro cell cultures used are suboptimal because they are very different from an in vivo mucosal surface, are often not polarized, lack important components of the glycocalyx, and often lack the mucus layer. Although gastrointestinal cell lines exist that produce mucins or polarize, human cell line models that reproducibly create the combination of a polarized epithelial cell layer, functional tight junctions and an adherent mucus layer have been missing until now. We trialed a range of treatments to induce polarization, 3D-organization, tight junctions, mucin production, mucus secretion, and formation of an adherent mucus layer that can be carried out using standard equipment. These treatments were tested on cell lines of intestinal (Caco-2, LS513, HT29, T84, LS174T, HT29 MTX-P8 and HT29 MTX-E12) and gastric (MKN7, MKN45, AGS, NCI-N87 and its hTERT Clone5 and Clone6) origins using Ussing chamber methodology and (immuno)histology. Semi-wet interface culture in combination with mechanical stimulation and DAPT caused HT29 MTX-P8, HT29 MTX-E12 and LS513 cells to polarize, form functional tight junctions, a three-dimensional architecture resembling colonic crypts, and produce an adherent mucus layer. Caco-2 and T84 cells also polarized, formed functional tight junctions and produced a thin adherent mucus layer after this treatment, but with less consistency. In conclusion, culture methods affect cell lines differently, and testing a matrix of methods vs. cell lines may be important to develop better in vitro models. The methods developed herein create in vitro mucosal surfaces suitable for studies of host-pathogen interactions at the mucosal surface. PMID:23869232

Multiple lentigines, myxoid tumours and endocrine overactivity; four cases of Carney's complex.

PubMed

Handley, J; Carson, D; Sloan, J; Walsh, M; Thornton, C; Hadden, D; Bingham, E A

1992-04-01

Four patients with Carney's complex, one sporadic and three familial, are described. The sporadic case was a young male with centrofacial lentigines, who developed cyclical Cushing's syndrome secondary to bilateral pigmented nodular adrenocortical disease, two separate left atrial myxomas, and buccal mucosal myxomas. The three familial cases, who all had varying degrees of centrofacial/mucosal lentigines and cutaneous myxoid tumours, were a woman with myxoid mammary fibroadenomatosis and a left atrial myxoma, her daughter who developed a prolactin-secreting pituitary adenoma, and her son who had bilateral large-cell calcified Sertoli cell testicular tumours, and an axillary psammomatous melanotic schwannoma.

Mucosal and systemic adjuvant activity of alphavirus replicon particles

NASA Astrophysics Data System (ADS)

Thompson, Joseph M.; Whitmore, Alan C.; Konopka, Jennifer L.; Collier, Martha L.; Richmond, Erin M. B.; Davis, Nancy L.; Staats, Herman F.; Johnston, Robert E.

2006-03-01

Vaccination represents the most effective control measure in the fight against infectious diseases. Local mucosal immune responses are critical for protection from, and resolution of, infection by numerous mucosal pathogens. Antigen processing across mucosal surfaces is the natural route by which mucosal immunity is generated, as peripheral antigen delivery typically fails to induce mucosal immune responses. However, we demonstrate in this article that mucosal immune responses are evident at multiple mucosal surfaces after parenteral delivery of Venezuelan equine encephalitis virus replicon particles (VRP). Moreover, coinoculation of null VRP (not expressing any transgene) with inactivated influenza virions, or ovalbumin, resulted in a significant increase in antigen-specific systemic IgG and fecal IgA antibodies, compared with antigen alone. Pretreatment of VRP with UV light largely abrogated this adjuvant effect. These results demonstrate that alphavirus replicon particles possess intrinsic systemic and mucosal adjuvant activity and suggest that VRP RNA replication is the trigger for this activity. We feel that these observations and the continued experimentation they stimulate will ultimately define the specific components of an alternative pathway for the induction of mucosal immunity, and if the activity is evident in humans, will enable new possibilities for safe and inexpensive subunit and inactivated vaccines. vaccine vector | Venezuelan equine encephalitis virus | viral immunology | RNA virus

A Novel Peptide to Treat Oral Mucositis Blocks Endothelial and Epithelial Cell Apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu Xiaoyan; Chen Peili; Sonis, Stephen T.

2012-07-01

Purpose: No effective agents currently exist to treat oral mucositis (OM) in patients receiving chemoradiation for the treatment of head-and-neck cancer. We identified a novel 21-amino acid peptide derived from antrum mucosal protein-18 that is cytoprotective, mitogenic, and motogenic in tissue culture and animal models of gastrointestinal epithelial cell injury. We examined whether administration of antrum mucosal protein peptide (AMP-p) could protect against and/or speed recovery from OM. Methods and Materials: OM was induced in established hamster models by a single dose of radiation, fractionated radiation, or fractionated radiation together with cisplatin to simulate conventional treatments of head-and-neck cancer. Results:more » Daily subcutaneous administration of AMP-p reduced the occurrence of ulceration and accelerated mucosal recovery in all three models. A delay in the onset of erythema after irradiation was observed, suggesting that a protective effect exists even before injury to mucosal epithelial cells occurs. To test this hypothesis, the effects of AMP-p on tumor necrosis factor-{alpha}-induced apoptosis were studied in an endothelial cell line (human dermal microvascular endothelial cells) as well as an epithelial cell line (human adult low-calcium, high-temperature keratinocytes; HaCaT) used to model the oral mucosa. AMP-p treatment, either before or after cell monolayers were exposed to tumor necrosis factor-{alpha}, protected against development of apoptosis in both cell types when assessed by annexin V and propidium iodide staining followed by flow cytometry or ligase-mediated polymerase chain reaction. Conclusions: These observations suggest that the ability of AMP-p to attenuate radiation-induced OM could be attributable, at least in part, to its antiapoptotic activity.« less

The Role of Microbiota on the Gut Immunology.

PubMed

Min, Yang Won; Rhee, Poong-Lyul

2015-05-01

The human gut contains >100 trillion microbes. This microbiota plays a crucial role in the gut homeostasis. Importantly, the microbiota contributes to the development and regulation of the gut immune system. Dysbiosis of the gut microbiota could also cause several intestinal and extraintestinal diseases. Many experimental studies help us to understand the complex interplay between the host and microbiota. This review presents our current understanding of the mucosal immune system and the role of gut microbiota for the development and functionality of the mucosal immunity, with a particular focus on gut-associated lymphoid tissues, mucosal barrier, TH17 cells, regulatory T cells, innate lymphoid cells, dendritic cells, and IgA-producing B cells and plasma cells. Comparative studies using germ-free and conventionally-raised animals reveal that the presence of microbiota is important for the development and regulation of innate and adaptive immune systems. The host-microbial symbiosis seems necessary for gut homeostasis. However, the precise mechanisms by which microbiota contributes to development and functionality of the immune system remain to be elucidated. Understanding the complex interplay between the host and microbiota and further investigation of the host-microbiota relationship could provide us the insight into the therapeutic and/or preventive strategy for the disorders related to dysbiosis of the gut microbiota. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Malignancy, weight loss, and the small intestinal mucosa

PubMed Central

Barry, R. E.

1974-01-01

The mucosal architecture and mucosal dynamics of the small bowel have been studied in patients with malignant disease not of the gastrointestinal tract but associated with severe weight loss. Mucosal changes in malignant disease are demonstrated by stereomicroscopy, mucosal architectural measurement, and decreased lactose utilization. Measurement of the epithelial DNA loss rate indicates, in association with mucosal measurement, that the architectural changes are caused by a hypoplasia of the epithelium. Similar findings are demonstrated in patients with profound weight loss due to other non-malignant wasting diseases. Although mucosal changes undoubtedly occur in malignant disease, the changes are not specific for malignancy and the concept of `cancer enteropathy' is not tenable. It is suggested that mucosal changes are the effect of and not the cause of cachexia. ImagesFig 1 PMID:4430474

Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma.

PubMed

Hintzsche, Jennifer D; Gorden, Nicholas T; Amato, Carol M; Kim, Jihye; Wuensch, Kelsey E; Robinson, Steven E; Applegate, Allison J; Couts, Kasey L; Medina, Theresa M; Wells, Keith R; Wisell, Joshua A; McCarter, Martin D; Box, Neil F; Shellman, Yiqun G; Gonzalez, Rene C; Lewis, Karl D; Tentler, John J; Tan, Aik Choon; Robinson, William A

2017-06-01

Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (P<0.05). KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%). Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients. Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas. Alternative splicing in four genes were observed in SF3B1-mutant samples compared with the wild-type samples. This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1. This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date. The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes. These findings expand our knowledge of this rare disease.

Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma

PubMed Central

Hintzsche, Jennifer D.; Gorden, Nicholas T.; Amato, Carol M.; Kim, Jihye; Wuensch, Kelsey E.; Robinson, Steven E.; Applegate, Allison J.; Couts, Kasey L.; Medina, Theresa M.; Wells, Keith R.; Wisell, Joshua A.; McCarter, Martin D.; Box, Neil F.; Shellman, Yiqun G.; Gonzalez, Rene C.; Lewis, Karl D.; Tentler, John J.

2017-01-01

Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (P<0.05). KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%). Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients. Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas. Alternative splicing in four genes were observed in SF3B1-mutant samples compared with the wild-type samples. This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1. This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date. The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes. These findings expand our knowledge of this rare disease. PMID:28296713

Mucosal immunity and probiotics in fish.

PubMed

Lazado, Carlo C; Caipang, Christopher Marlowe A

2014-07-01

Teleost mucosal immunity has become the subject of unprecedented research studies in recent years because of its diversity and defining characteristics. Its immune repertoire is governed by the mucosa-associated lymphoid tissues (MALT) which are divided into gut-associated lymphoid tissues (GALT), skin-associated lymphoid tissues (SALT), and gill-associated lymphoid tissues (GIALT). The direct contact with its immediate environment makes the mucosal surfaces of fish susceptible to a wide variety of pathogens. The inherent immunocompetent cells and factors in the mucosal surfaces together with the commensal microbiota have pivotal role against pathogens. Immunomodulation is a popular prophylactic strategy in teleost and probiotics possess this beneficial feature. Most of the studies on the immunomodulatory properties of probiotics in fish mainly discussed their impacts on systemic immunity. In contrast, few of these studies discussed the immunomodulatory features of probiotics in mucosal surfaces and are concentrated on the influences in the gut. Significant attention should be devoted in understanding the relationship of mucosal immunity and probiotics as the present knowledge is limited and are mostly based on extrapolations of studies in humans and terrestrial vertebrates. In the course of the advancement of mucosal immunity and probiotics, new perspectives in probiotics research, e.g., probiogenomics have emerged. This review affirms the relevance of probiotics in the mucosal immunity of fish by revisiting and bridging the current knowledge on teleost mucosal immunity, mucosal microbiota and immunomodulation of mucosal surfaces by probiotics. Expanding the knowledge of immunomodulatory properties of probiotics especially on mucosal immunity is essential in advancing the use of probiotics as a sustainable and viable strategy for successful fish husbandry. Copyright © 2014 Elsevier Ltd. All rights reserved.

How the microbiota shapes rheumatic diseases.

PubMed

Van de Wiele, Tom; Van Praet, Jens T; Marzorati, Massimo; Drennan, Michael B; Elewaut, Dirk

2016-07-01

The human gut harbours a tremendously diverse and abundant microbial community that correlates with, and even modulates, many health-related processes. The mucosal interfaces are particularly active sites of microorganism-host interplay. Growing insight into the characteristic composition and functionality of the mucosal microbiota has revealed that the microbiota is involved in mucosal barrier integrity and immune function. This involvement affects proinflammatory and anti-inflammatory processes not only at the epithelial level, but also at remote sites such as the joints. Here, we review the role of the gut microbiota in shaping local and systemic immune responses and how disturbances in the host-microorganism interplay can potentially affect the development and progression of rheumatic diseases. Increasing our understanding of how to promote host-microorganism homeostasis could therefore reveal novel strategies for the prevention or alleviation of rheumatic disease.

Experimental Models of C. albicans-Streptococcal Co-infection.

PubMed

Sobue, Takanori; Diaz, Patricia; Xu, Hongbin; Bertolini, Martinna; Dongari-Bagtzoglou, Anna

2016-01-01

Interactions of C. albicans with co-colonizing bacteria at mucosal sites can be synergistic or antagonistic in disease development, depending on the bacterial species and mucosal site. Mitis group streptococci and C. albicans colonize the oral mucosa of the majority of healthy individuals. These streptococci have been termed "accessory pathogens," defined by their ability to initiate multispecies biofilm assembly and promote the virulence of the mixed bacterial biofilm community in which they participate. To demonstrate whether interactions with Mitis group streptococci limit or promote the potential of C. albicans to become an opportunistic pathogen, in vitro and in vivo co-infection models are needed. Here, we describe two C. albicans-streptococcal co-infection models: an organotypic oral mucosal tissue model that incorporates salivary flow and a mouse model of oral co-infection that requires reduced levels of immunosuppression compared to single fungal infection.

Mucosal melanoma: pathogenesis, clinical behavior, and management.

PubMed

Postow, Michael A; Hamid, Omid; Carvajal, Richard D

2012-10-01

Mucosal melanoma represents a rare subtype of melanoma with distinct biological, clinical, and management considerations. Knowledge regarding optimal treatment strategies for mucosal melanoma is limited and based primarily upon small case series and single-institution, retrospective analyses. Surgery remains the standard of care for loco-regional management, but the common presence of multifocal disease and the high rate of distant recurrence should be considered before pursuing aggressive surgical interventions associated with inherent significant morbidity. The role of sentinel lymph node biopsy and lymph node dissection remains unclear. Radiotherapy has not been shown to improve overall survival but may reduce the rate of local recurrence. Significant advances in the treatment of metastatic disease have been made with novel immunotherapeutic agents, the discovery of KIT and BRAF mutations and the development of targeted agents that inhibit these oncogenic pathways.

The oesophageal zero-stress state and mucosal folding from a GIOME perspective

PubMed Central

Liao, Donghua; Zhao, Jingbo; Yang, Jian; Gregersen, Hans

2007-01-01

The oesophagus is a cylindrical organ with a collapsed lumen and mucosal folds. The mucosal folding may serve to advance the function of the oesophagus, i.e. the folds have a major influence on the flow of air and bolus through the oesophagus. Experimental studies have demonstrated oesophageal mucosal folds in the no-load state. This indicates that mucosal buckling must be considered in the analysis of the mechanical reference state since the material stiffness drops dramatically after tissue collapse. Most previous work on the oesophageal zero-stress state and mucosal folding has been experimental. However, numerical analysis offers a promising alternative approach, with the additional ability to predict the mucosal buckling behaviour and to calculate the regional stress and strain in complex structures. A numerical model used for describing the mechanical behaviour of the mucosal-folded, three-layered, two-dimensional oesophageal model is reviewed. GIOME models can be used in the future to predict the tissue function physiologically and pathologically. PMID:17457964

Ascorbic acid deficiency aggravates stress-induced gastric mucosal lesions in genetically scorbutic ODS rats.

PubMed

Ohta, Y; Chiba, S; Imai, Y; Kamiya, Y; Arisawa, T; Kitagawa, A

2006-12-01

We examined whether ascorbic acid (AA) deficiency aggravates water immersion restraint stress (WIRS)-induced gastric mucosal lesions in genetically scorbutic ODS rats. ODS rats received scorbutic diet with either distilled water containing AA (1 g/l) or distilled water for 2 weeks. AA-deficient rats had 12% of gastric mucosal AA content in AA-sufficient rats. AA-deficient rats showed more severe gastric mucosal lesions than AA-sufficient rats at 1, 3 or 6 h after the onset of WIRS, although AA-deficient rats had a slight decrease in gastric mucosal AA content, while AA-sufficient rats had a large decrease in that content. AA-deficient rats had more decreased gastric mucosal nonprotein SH and vitamin E contents and increased gastric mucosal lipid peroxide content than AA-sufficient rats at 1, 3 or 6 h of WIRS. These results indicate that AA deficiency aggravates WIRS-induced gastric mucosal lesions in ODS rats by enhancing oxidative damage in the gastric mucosa.

Determining the activity of mucosal adjuvants.

PubMed

Baudner, Barbara C; Giudice, Giuseppe Del

2010-01-01

Mucosal vaccination offers the advantage of blocking pathogens at the portal of entry, improving patient's compliance, facilitating vaccine delivery, and decreasing the risk of unwanted spread of infectious agents via contaminated syringes.Recent advances in vaccinology have created an array of vaccine constructs that can be delivered to mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts using intranasal, oral, and vaginal routes. Due to the different characteristics of mucosal immune response, as compared with systemic response, mucosal immunization requires particular methods of antigen presentation. Well-tolerated adjuvants that enhance the efficacy of such vaccines will play an important role in mucosal immunization. Among promising mucosal adjuvants, mutants of cholera toxin and the closely related heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli present powerful tools, augmenting the local and systemic serum antibody response to co-administered antigens.In this chapter, we describe the formulation and application of vaccines using the genetically modified LTK63 mutant as a prototype of the family of these mucosal adjuvants and the tools to determine its activity in the mouse model.

Randomized, Double-Blind, Placebo-Controlled Trial of Shuanghua Baihe Tablets to Prevent Oral Mucositis in Patients With Nasopharyngeal Cancer Undergoing Chemoradiation Therapy.

PubMed

Zheng, Baomin; Zhu, Xiaodong; Liu, Mengzhong; Yang, Zhenzhou; Yang, Ling; Lang, Jinyi; Shi, Mei; Wu, Gang; He, Xia; Chen, Xiaozhong; Xi, Xuping; Zhao, Dan; Zhu, Guangying

2018-02-01

Oral mucositis is a common unpreventable complication associated with chemoradiation therapy. Shuanghua Baihe tablets have been approved by the Chinese Food and Drug Administration for treating recurrent oral mucosa ulceration. This study assessed whether Shuanghua Baihe tablets could prevent oral mucositis during chemoradiation therapy for locally advanced nasopharyngeal carcinoma. This multicenter, randomized, double-blind, placebo-controlled trial was conducted at 11 hospitals in China between January 22, 2014, and September 21, 2015. Eligible patients (N=240, 18-70 years old) with pathologically diagnosed locally advanced nasopharyngeal carcinoma were randomly assigned (computer-block randomization; 1:1) to receive Shuanghua Baihe tablets or a placebo (4 tablets, 3 times a day, for 7 weeks) at the initiation of chemoradiation therapy. Administration of Shuanghua Baihe tablets could be ended if grade 3 or higher oral mucositis developed and patients were unwilling to continue taking the drug. The primary endpoints were oral mucositis incidence and latency. The incidence of oral mucositis during this study was significantly lower in the Shuanghua Baihe group (85.0%; 95% confidence interval [CI], 78.6%-91.4%) than in the placebo group (96.6%; 95% CI, 93.4%-99.9%; P=.0028). The median latency period was 28 days in the Shuanghua Baihe group and 14 days in the placebo group (hazard ratio, 0.17; 95% CI, 0.12-0.23; P<.0001). Compared with placebo, Shuanghua Baihe tablets significantly reduced the oral mucositis severity scores recorded by the investigators (Oral Mucositis Score, 24.0 [range, 0.0-67.8] vs 57.5 [range, 0.0-98.0]; P<.0001), full-time nurses (Oral Assessment Guide score, 462.0 [range, 392.0-664.7] vs 520.4 [range, 392.0-714.0]; P<.0001), and patients (score for soreness of mouth and throat, 4.0 [range, 0-10] vs 6.0 [range, 0-10]; P<.0001). No serious adverse events were observed, and the incidence of mild or moderate gastrointestinal adverse events associated with Shuanghua Baihe tablets was 3.3%. The short-term response rate was similar in patients receiving Shuanghua Baihe tablets and those receiving placebo during chemoradiation therapy during this study. Shuanghua Baihe tablets reduced the occurrence, latency, and severity of oral mucositis in patients with nasopharyngeal cancer during chemoradiation therapy treatment. Copyright © 2017. Published by Elsevier Inc.

Gastric adaptation to injury by repeated doses of aspirin strengthens mucosal defence against subsequent exposure to various strong irritants in rats.

PubMed Central

Brzozowski, T; Konturek, P C; Konturek, S J; Ernst, H; Stachura, J; Hahn, E G

1995-01-01

Gastric adaptation to injury during repeated doses of acetyl salicylic acid (ASA) is a well documented finding but it is not known whether this adaptation affects the tolerance of the mucosa to other strong irritants. Gastric adaptation was induced by repeated daily doses of acidified ASA (100 mg/kg in 1.5 ml of 0.2 N HCl) given intragastrically (series A rats). Control rats with an intact stomach were given daily intragastric vehicle only (1.5 ml of 0.2 N HCl) (series B). After full adaptation to ASA (5 days), rats were challenged again with acidified ASA or, for comparison, with strong irritants such as 100% ethanol, 200 mM acidified taurocholate, or 25% NaCl for 1 hour or with water immersion and restraint for 3.5 hours. The first dose of ASA produced numerous gastric lesions and deep histological necrosis accompanied by a fall in the gastric blood flow, negligible expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) or their receptors, and no evidence of mucosal proliferation. As adaptation to ASA developed, however, the areas of gastric lesions were reduced by more than 80% and there was a noticeable decrease in deep necrosis, a partial restoration of gastric blood flow, an approximately four-fold increase in EGF expression (but not in TGF alpha) and its receptors, and an appreciable increase in mucosal cell proliferation compared with vehicle treated rats. Increases in the mucosal expression of EGF receptors and the luminal content of EGF were also found in ASA adapted animals. In ASA adapted rats subsequently challenged with 100% ethanol, 200 mM TC, 25% NaCl, or stress, the area of the gastric lesions and deep histological necrosis were appreciably reduced compared with values in vehicle treated rats. This increased mucosal tolerance to strong irritants was also accompanied by the return of the gastric blood flow towards control levels and further significant increases in the mucosal expression of EGF receptors and mucosal cell proliferation. Gastric adaptation to ASA enhances the mucosal resistance to injury by strong irritants probably as a result of the restoration of the gastric blood flow and increased cell proliferation that may result from increased mucosal expression of EGF and its receptors. Images Figure 1 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:8537043

Expression of AID, P53, and Mlh1 proteins in endoscopically resected differentiated-type early gastric cancer

PubMed Central

Takeda, Yohei; Yashima, Kazuo; Hayashi, Akihiro; Sasaki, Shuji; Kawaguchi, Koichiro; Harada, Kenichi; Murawaki, Yoshikazu; Ito, Hisao

2012-01-01

AIM: To analyze the expression of the tumor-related proteins in differentiated-type early gastric carcinoma (DEGC) samples. METHODS: Tumor specimens were obtained from 102 patients (75 males and 27 females) who had received an endoscopic tumor resection at Tottori University Hospital between 2007 and 2009. Ninety-one cancer samples corresponded to noninvasive or intramucosal carcinoma according to the Vienna classification system, and 11 samples were submucosal invasive carcinomas. All of the EGCs were histologically differentiated carcinomas. All patients were classified as having Helicobacter pylori (H. pylori) infections by endoscopic atrophic changes or by testing seropositive for H. pylori IgG. All of the samples were histopathologically classified as either tubular or papillary adenocarcinoma according to their structure. The immunohistochemical staining was performed in a blinded manner with respect to the clinical information. Two independent observers evaluated protein expression. All data were statistically analyzed then. RESULTS: The rates of aberrant activation-induced cytidine deaminase (AID) expression and P53 overexpression were both 34.3% in DEGCs. The expression of Mlh1 was lost in 18.6% of DEGCs. Aberrant AID expression was not significantly associated with P53 overexpression in DEGCs. However, AID expression was associated with the severity of mononuclear cell activity in the non-cancerous mucosa adjacent to the tumor (P = 0.064). The rate of P53 expression was significantly greater in flat or depressed tumors than in elevated tumors. The frequency of Mlh1 loss was significantly increased in distal tumors, elevated gross-type tumors, papillary histological-type tumors, and tumors with a severe degree of endoscopic atrophic gastritis (P < 0.05). CONCLUSION: Aberrant AID expression, P53 overexpression, and the loss of Mlh1 were all associated with clinicopathological features and gastric mucosal alterations in DEGCs. The aberrant expression of AID protein may partly contribute to the induction of nuclear P53 expression. PMID:22737274

Natural Products for Management of Oral Mucositis Induced by Radiotherapy and Chemotherapy

PubMed Central

Aghamohamamdi, Azar; Hosseinimehr, Seyed Jalal

2015-01-01

Oral mucositis is a common side effect of systemic chemotherapy and radiotherapy of head and neck in patients with cancer. Severe oral mucositis is painful and affects oral functions, including intake of food and medications and speech. Prevention of oral mucositis affects the life quality of patients. Recent studies have been focused on natural products to improve or reduce this complication. Many clinical trials have been performed to assess natural products for treatment of mucositis and their results are promising. The authors reviewed the evidence for natural products in the prevention and treatment of oral mucositis induced by radiation therapy and chemotherapy. PMID:26306626

Effect of nabumetone and aspirin on colonic mucosal bleeding time.

PubMed

Basson, M D; Panzini, L; Palmer, R H

2001-04-01

The management of patients taking aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) who require colonoscopy remains controversial because of concerns over bleeding after biopsy or polypectomy. To determine whether patients using the NSAID nabumetone, a non-acidic prodrug with mixed activity against cyclooxygenase-1 (COX-1) and COX-2, exhibited prolonged mucosal bleeding times and how this might compare with mucosal bleeding times in patients using aspirin. We assessed triplicate mucosal bleeding times in patients undergoing screening flexible sigmoidoscopy. We compared 90 patients who had taken no aspirin or NSAIDs within the previous 2 weeks, to 60 patients who had received nabumetone 1 g b.d. by mouth for the previous 2 weeks, and 30 patients who had taken 325 mg aspirin daily for the previous 2 weeks. In each case, the investigator performing the study was blinded to the patient's medication. Mucosal bleeding times did not differ significantly among control or nabumetone-using patients. However, the patients receiving aspirin exhibited significant prolongation. Mucosal bleeding time correlated statistically significantly, but weakly, with skin bleeding time. Nabumetone does not appear to prolong mucosal bleeding time after mucosal pinch biopsy, and skin bleeding time does not reliably screen for prolonged mucosal bleeding time.

GNAQ mutation in a patient with metastatic mucosal melanoma.

PubMed

Kim, Chung-Young; Kim, Dae Won; Kim, Kevin; Curry, Jonathan; Torres-Cabala, Carlos; Patel, Sapna

2014-07-16

Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma.

GNAQ mutation in a patient with metastatic mucosal melanoma

PubMed Central

2014-01-01

Background Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. Case presentation A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. Conclusion Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma. PMID:25030020

Effects of mucosal loading on vocal fold vibration.

PubMed

Tao, Chao; Jiang, Jack J

2009-06-01

A chain model was proposed in this study to examine the effects of mucosal loading on vocal fold vibration. Mucosal loading was defined as the loading caused by the interaction between the vocal folds and the surrounding tissue. In the proposed model, the vocal folds and the surrounding tissue were represented by a series of oscillators connected by a coupling spring. The lumped masses, springs, and dampers of the oscillators modeled the tissue properties of mass, stiffness, and viscosity, respectively. The coupling spring exemplified the tissue interactions. By numerically solving this chain model, the effects of mucosal loading on the phonation threshold pressure, phonation instability pressure, and energy distribution in a voice production system were studied. It was found that when mucosal loading is small, phonation threshold pressure increases with the damping constant R(r), the mass constant R(m), and the coupling constant R(mu) of mucosal loading but decreases with the stiffness constant R(k). Phonation instability pressure is also related to mucosal loading. It was found that phonation instability pressure increases with the coupling constant R(mu) but decreases with the stiffness constant R(k) of mucosal loading. Therefore, it was concluded that mucosal loading directly affects voice production.

Effects of mucosal loading on vocal fold vibration

NASA Astrophysics Data System (ADS)

Tao, Chao; Jiang, Jack J.

2009-06-01

A chain model was proposed in this study to examine the effects of mucosal loading on vocal fold vibration. Mucosal loading was defined as the loading caused by the interaction between the vocal folds and the surrounding tissue. In the proposed model, the vocal folds and the surrounding tissue were represented by a series of oscillators connected by a coupling spring. The lumped masses, springs, and dampers of the oscillators modeled the tissue properties of mass, stiffness, and viscosity, respectively. The coupling spring exemplified the tissue interactions. By numerically solving this chain model, the effects of mucosal loading on the phonation threshold pressure, phonation instability pressure, and energy distribution in a voice production system were studied. It was found that when mucosal loading is small, phonation threshold pressure increases with the damping constant Rr, the mass constant Rm, and the coupling constant Rμ of mucosal loading but decreases with the stiffness constant Rk. Phonation instability pressure is also related to mucosal loading. It was found that phonation instability pressure increases with the coupling constant Rμ but decreases with the stiffness constant Rk of mucosal loading. Therefore, it was concluded that mucosal loading directly affects voice production.

The mucosal immune system of fish: the evolution of tolerating commensals while fighting pathogens

PubMed Central

Gomez, Daniela; Sunyer, J Oriol; Salinas, Irene

2013-01-01

The field of mucosal immunology research has grown fast over the past few years, and our understanding on how mucosal surfaces respond to complex antigenic cocktails is expanding tremendously. With the advent of new molecular sequencing techniques, it is easier to understand how the immune system of vertebrates is, to a great extent, orchestrated by the complex microbial communities that live in symbiosis with their hosts. The commensal microbiota is now seen as the “extended self” by many scientists. Similarly, fish immunologist are devoting important research efforts to the field of mucosal immunity and commensals. Recent breakthroughs on our understanding of mucosal immune responses in teleost fish open up the potential of teleosts as animal research models for the study of human mucosal diseases. Additionally, this new knowledge places immunologists in a better position to specifically target the fish mucosal immune system while rationally designing mucosal vaccines and other immunotherapies. In this review, an updated view on how teleost skin, gills and gut immune cells and molecules, function in response to pathogens and commensals is provided. Finally, some of the future avenues that the field of fish mucosal immunity may follow in the next years are highlighted. PMID:24099804

Chemical burns of the oral mucosa: report of a case.

PubMed

Isenberg, S R; Hier, L A; Chauvin, P J

1996-03-01

Clinical diagnosis of a chemical burn of the oral mucous membranes may be a diagnostic challenge. This article's intent is to illustrate the typical appearance of a chemical mucosal burn and to increase awareness of the various compounds which, when in contact with the mucous membranes, can result in a burn. The authors present a case involving a self-inflicted chemical injury of the oral mucous membranes and illustrate how the submission of an easily-obtained tissue specimen for pathologic examination may aid in the diagnosis. Because these superficial tissues can be obtained and submitted without the need for local anesthetic, pathologic examination is a quick, easy, and valuable diagnostic test when a patient's history is difficult to obtain or intentionally misleading.

[Gastritis and gastropathy].

PubMed

Mihály, Emese; Micsik, Tamás; Juhász, Márk; Herszényi, László; Tulassay, Zsolt

2014-01-12

Alterations of the stomach mucosa in response to different adverse effects result in various morphological and clinical symptoms. Gastric mucosa alterations can be classified on the bases of diverse viewpoints. It makes this overview difficult, that identical toxic effects may cause different mucosal changes and different toxic agents may produce similar mucosal appearance. The more accurate understanding of the pathological processes which develop in the stomach mucosa needs reconsideration. The authors make an attempt to define gastritis and gastropathy in order to classify and present their features. Gastritis is a histological definition indicating mucosal inflammation. Acute gastritis is caused by infections. The two most important forms of chronic gastritis are metaplastic atrophic gastritis with an autoimmune origin and Helicobacter pylori inflammation. Gastropathy is the name of different structural alterations of the mucosa. Its most important feature is the paucity of inflammatory signs. Gastropathies can be divided into 4 categories based on the nature of the underlying pathological effect, on its morphological appearance and the way of the development. Differential diagnosis is an important pathological and clinical task because different treatment methods and prognosis.

The Oral Mucosa Immune Environment and Oral Transmission of HIV/SIV

PubMed Central

Wood, Lianna F.; Chahroudi, Ann; Chen, Hui-Ling; Jaspan, Heather B.; Sodora, Donald L.

2013-01-01

Summary The global spread of human immunodeficiency virus (HIV) is dependent on the ability of this virus to efficiently cross from one host to the next by traversing a mucosal membrane. Unraveling how mucosal exposure of HIV results in systemic infection is critical for the development of effective therapeutic strategies. This review focuses on understanding the immune events associated with the oral route of transmission (via breastfeeding or sexual oral intercourse), which occurs across the oral and/or gastrointestinal mucosa. Studies in both humans and simian immunodeficiency virus (SIV) monkey models have identified viral changes and immune events associated with oral HIV/SIV exposure. This review covers our current knowledge of HIV oral transmission in both infants and adults, the use of SIV models in understanding early immune events, oral immune factors that modulate HIV/SIV susceptibility (including mucosal inflammation), and interventions that may impact oral HIV transmission rates. Understanding the factors that influence oral HIV transmission will provide the foundation for developing immune therapeutic and vaccine strategies that can protect both infants and adults from oral HIV transmission. PMID:23772613

[Treatment and prevention of cancer treatment related oral mucositis].

PubMed

Ruiz-Esquide, Gonzalo; Nervi, Bruno; Vargas, Alex; Maíz, Alberto

2011-03-01

One of the most common and troublesome complications of modern intensive anticancer treatments is oral mucositis. The purpose of this review is to summarize current evidence and clinical guidelines regarding its prevention and therapy. The use of keratinocyte growth factor-1, supplementary glutamine and other recently developed treatment modalities are discussed. The injury of the oral mucosa caused by antineoplastic agents promotes the local expression of multiple pro-inflammatory and pro-apoptotic molecules and eventually leads to the development of ulcers. Such lesions predispose patients to several infectious and nutritional complications. Also, they lead to modification of treatment schedules, potentially affecting overall prognosis. Local cryotherapy with ice chips and phototherapy with low energy laser may be useful as preventive measures. Mouthwashes with allopurinol and phototherapy with low energy laser can be used as treatment. In radiotherapy, special radiation administration techniques should be used to minimize mucosal injury. Pain control should always be optimized, with the use of patient controlled analgesia and topical use of morphine. Supplemental glutamine should not be used outside of research protocols. Lastly, thorough attention should be paid to general care and hygiene measures.

[Clinical profile of cytomegalovirus (CMV) enterocolitis in acquired immunodeficiency syndrome].

PubMed

De Lima, D B; Fernandes, O; Gomes, V R; Da Silva, E J; De Pinho, P R; De Paiva, D D

2000-01-01

To determine the clinical profile of CMV colitis in AIDS patients, comparing clinical, endoscopic parameters and survival time between 2 groups of AIDS patients having chronic diarrhea. Group A being CMV colitis and group B without CMV colitis. 48 patients with diarrhea that lasted more than 30 days, being 27 in Group A and 21 in Group B, were studied. Age, risk factors, interval time between the diagnosis of HIV infection and the beginning of diarrhea, hematochesia, the endoscopic findings and life table in both groups, were analysed. All of them were diagnosed by stool culture and stools for ovum and parasites, along colonoscopy with biopsies. The unpaired t test was used to assess statistical significance of differences observed in the means of continuous and the chi-square with Yates correction for non-parametric variables. The survival curves were assessed by the Kaplan-Meier and the Mantel-Haenszel's tests. A P value of less than 0,05 was considered to indicate statistical significance. The mucosal lesions associated with the CMV infection are typically ulcerative on a background of hemorrhagic erythema 14 (51,8%) p < 0,01. The life table analysis disclosed shorter survival time in the CMV colitis group 0,005> P>0,001. The others studied data did not achieve statistical significance. AIDS patients with CMV colitis have a poorer long-term survival. Among the colonoscopic findings, ulcerations with hemorrhagic background were the most common lesions.

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis.

PubMed

Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A; Lozza, Laura; Saikali, Philippe; Sander, Leif E; Vogelzang, Alexis; Kaufmann, Stefan H E; Kupz, Andreas

2016-11-22

Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (T RM ) cells have been implicated in protective immune responses against viral infections, but the role of T RM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and T RM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4 + T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8 + T cells displayed prototypical T RM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. BCG remains the only licensed vaccine against TB. Parenterally administered BCG has variable efficacy against pulmonary TB, and thus, improved prevention strategies and a more refined understanding of correlates of vaccine protection are required. Induction of memory T cells has been shown to be essential for protective TB vaccines. Mimicking the natural infection route by mucosal vaccination has been known to generate superior protection against TB in animal models; however, the mechanisms of protection have remained elusive. Here we performed an in-depth analysis to dissect the immunological mechanisms associated with superior mucosal protection in the mouse model of TB. We found that mucosal, and not subcutaneous, BCG vaccination generates lung-resident memory T cell populations that confer protection against pulmonary TB. We establish a comprehensive phenotypic characterization of these populations, providing a framework for future vaccine development. Copyright © 2016 Perdomo et al.

Transforming growth factor-alpha stimulates enterocyte proliferation and accelerates intestinal recovery following methotrexate-induced intestinal mucositis in a rat and a cell culture model.

PubMed

Sukhotnik, Igor; Shteinberg, Dan; Ben Lulu, Shani; Bashenko, Yulia; Mogilner, Jorge G; Ure, Benno M; Shaoul, Ron; Shamian, Benhoor; Coran, Arnold G

2008-12-01

Recent evidence suggests that transforming growth factor-alpha (TGF-alpha) enhances enterocyte proliferation and exerts a gut trophic effect. The purpose of the present study was to evaluate the effect of TGF-alpha on enterocyte proliferation and intestinal recovery following methotrexate (MTX)-induced intestinal mucositis in rats and in Caco-2 cells. Nonpretreated Caco-2 cells and those pretreated with MTX were incubated with increasing concentrations of TGF-alpha. Cell proliferation was determined by FACS cytometry. Adult rats were divided into three groups: control rats treated with vehicle, MTX rats treated with one dose (20 microg/kg) of MTX given intraperitoneally, and MTX-TGF-alpha rats treated with one dose of MTX followed by two doses of TGF-alpha (75 microg/kg a day). Three days after MTX injection, rats were sacrificed. Intestinal mucosal damage (Park's score), mucosal structural changes, and enterocyte proliferation were measured at sacrifice. Western blotting was used to determine the level of extracellular signal-related kinase (ERK) protein, a marker of cell proliferation. A nonparametric Kruskal-Wallis ANOVA test was used for statistical analysis with P value less than 0.05 considered statistically significant. The in vitro experiment demonstrated that treatment with TGF-alpha of Caco-2 cells resulted in a significant stimulation of cell proliferation in a dose-dependent manner. The in vivo experiment showed that treatment with TGF-alpha resulted in a significant increase in bowel and mucosal weight, DNA and protein content in jejunum and ileum, villus height in jejunum and ileum, crypt depth in ileum, and increased cell proliferation in jejunum and ileum compared to the MTX group. MTX-TGF-alpha rats also had a significantly lower intestinal injury score in ileum when compared to MTX animals. The increase in levels of cell proliferation in MTX-TGF-alpha rats corresponded with the increase in ERK protein levels in intestinal mucosa. Treatment with TGF-alpha prevents mucosal injury, enhances ERK-induced enterocyte proliferation, and improves intestinal recovery following MTX-induced intestinal mucositis in rats. These findings correlated with the observation that TGF-alpha also caused a significant stimulation of cell proliferation in a Caco-2 cell culture model treated with MTX. These observations may have significant implications for the treatment of patients on chemotherapy who develop severe mucositis.

Adrenal maturation, nutritional status, and mucosal immunity in Bolivian youth.

PubMed

Hodges-Simeon, Carolyn R; Prall, Sean P; Blackwell, Aaron D; Gurven, Michael; Gaulin, Steven J C

2017-09-10

Humans-and several other apes-exhibit a unique pattern of post-natal adrenal maturation; however, the causes and consequences of variation in adrenal development are not well understood. In this study, we examine developmental and age-related maturation of the adrenal gland (measured via dehydroepiandrosterone-sulfate [DHEA-S]) for potential life-history associations with growth and mucosal immunity in a rural population of immune-challenged Bolivian juveniles and adolescents. Salivary DHEA-S, anthropometrics, and salivary mucosal immunity (secretory IgA [sIgA]) were measured in 171 males and females, aged 8-23. Males with greater energy (i.e. fat) stores showed higher DHEA-S levels. Controlling for age and energetic condition (to control for phenotypic correlation), higher DHEA-S was associated with higher mucosal immunity (sIgA) among both males and females. Higher DHEA-S levels were positively associated with growth (i.e. height and strength) in males. In accordance with predictions derived from life-history theory, males with higher energy stores secrete more adrenal androgens. This suggests that adrenal maturation is costly and subject to constraints; that is, only males with sufficient reserves will invest in accelerated adrenal maturation. Further, DHEA-S appears to have a measureable influence on immunocompetence in adolescent males and females; therefore, deficits in DHEA-S may have important consequences for health and maturation during this period. Adrenal maturation is an important, but understudied component of human growth and development. © 2017 Wiley Periodicals, Inc.

Mucosal IgA increase in rats by continuous CLA feeding during suckling and early infancy.

PubMed

Pérez-Cano, Francisco J; Ramírez-Santana, Carolina; Molero-Luís, Marta; Castell, Margarida; Rivero, Montserrat; Castellote, Cristina; Franch, Angels

2009-03-01

The aim of this work was to establish the effect of the cis9,trans11 conjugated linoleic acid (CLA) isomer on mucosal immunity during early life in rats, a period when mucosal immunoglobulin production is poorly developed, as is also the case in humans. CLA supplementation was performed during three life periods: gestation, suckling, and early infancy. The immune status of supplemented animals was evaluated at two time points: at the end of the suckling period (21-day-old rats) and 1 week after weaning (28-day-old rats). Secretory IgA was quantified in intestinal washes from 28-day-old rats by ELISA technique. IgA, TGFbeta, and PPARgamma mRNA expression was measured in small intestine and colon by real time PCR, using Taqman specific probes and primers. IgA mucosal production was enhanced in animals supplemented with CLA during suckling and early infancy: in 28-day-old rats, IgA mRNA expression was increased in small intestine and colon by approximately 6- and 4-fold, respectively, and intestinal IgA protein by approximately 2-fold. TGFbeta gene expression was independent of age and type of tissue considered, and was not modified by dietary CLA. Gene expression of PPARgamma, a possible mediator of CLA's effects was also upregulated in animals receiving CLA during early life. In conclusion, dietary supplementation with CLA during suckling and extended to early infancy enhances development of the intestinal immune response in rats.

Acute effects of carprofen and meloxicam on canine gastrointestinal permeability and mucosal absorptive capacity.

PubMed

Craven, Melanie; Chandler, Marge L; Steiner, Jörg M; Farhadi, Ashkan; Welsh, Elizabeth; Pratschke, Kathryn; Shaw, Darren J; Williams, David A

2007-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed to dogs for their analgesic, antipyretic, and anti-inflammatory properties. Their beneficial actions can be offset by gastrointestinal (GI) toxicosis. Endoscopy has traditionally been employed to detect GI lesions, but alterations in GI permeability precede the development of mucosal damage. Carprofen and meloxicam alter GI permeability and mucosal absorptive capacity of dogs. Twenty adult dogs treated with an NSAID for >7 days were evaluated by permeability tests while receiving either carprofen (10 dogs) or meloxicam (10 dogs). Prospective, longitudinal observational study. A 6-sugar permeability test (sucrose, lactulose, rhamnose, 3-O-methyl-D-glucose, D-xylose, and sucralose) was performed on the day before NSAID treatment, and after 3 and 8 days of treatment. There were no significant differences in the urinary recovery ratios of lactulose: rhamnose, D-xylose: 3-O-methyl-D-glucose, or sucralose recovery within either group at any time during the study. Sucrose permeability in the meloxicam group did not alter significantly over time. However, sucrose permeability in the carprofen group decreased significantly by day 3 (P = .049) and increased again by day 8 (P = .049), to a level that was not significantly different to permeability before treatment (P = .695). The absence of increased GI permeability and diminished mucosal absorptive capacity in this group of dogs does not support the development of acute GI toxicosis during treatment with either meloxicam or carprofen.

NHE8 plays important roles in gastric mucosal protection

PubMed Central

Xu, Hua; Li, Jing; Chen, Huacong; Wang, Chunhui

2013-01-01

Sodium/hydrogen exchanger (NHE) 8 is an apically expressed membrane protein in the intestinal epithelial cells. It plays important roles in sodium absorption and bicarbonate secretion in the intestine. Although NHE8 mRNA has been detected in the stomach, the precise location and physiological role of NHE8 in the gastric glands remain unclear. In the current study, we successfully detected the expression of NHE8 in the glandular region of the stomach by Western blotting and located NHE8 protein at the apical membrane in the surface mucous cells by a confocal microscopic method. We also identified the expression of downregulated-in-adenoma (DRA) in the surface mucous cells in the stomach. Using NHE8−/− mice, we found that NHE8 plays little or no role in basal gastric acid production, yet NHE8−/− mice have reduced gastric mucosal surface pH and higher incidence of developing gastric ulcer. DRA expression was reduced significantly in the stomach in NHE8−/− mice. The propensity for gastric ulcer, reduced mucosal surface pH, and low DRA expression suggest that NHE8 is indirectly involved in gastric bicarbonate secretion and gastric mucosal protection. PMID:23220221

Dorsal buccal mucosal graft urethroplasty by a ventral sagittal urethrotomy and minimal-access perineal approach for anterior urethral stricture.

PubMed

Gupta, N P; Ansari, M S; Dogra, P N; Tandon, S

2004-06-01

To present the technique of dorsal buccal mucosal graft urethroplasty through a ventral sagittal urethrotomy and minimal access perineal approach for anterior urethral stricture. From July 2001 to December 2002, 12 patients with a long anterior urethral stricture had the anterior urethra reconstructed, using a one-stage urethroplasty with a dorsal onlay buccal mucosal graft through a ventral sagittal urethrotomy. The urethra was approached via a small perineal incision irrespective of the site and length of the stricture. The penis was everted through the perineal wound. No urethral dissection was used on laterally or dorsally, so as not to jeopardize the blood supply. The mean (range) length of the stricture was 5 (3-16) cm and the follow-up 12 (10-16) months. The results were good in 11 of the 12 patients. One patient developed a stricture at the proximal anastomotic site and required optical internal urethrotomy. Dorsal buccal mucosal graft urethroplasty via a minimal access perineal approach is a simple technique with a good surgical outcome; it does not require urethral dissection and mobilization and hence preserves the blood supply.

A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

PubMed

Lilleby, K; Garcia, P; Gooley, T; McDonnnell, P; Taber, R; Holmberg, L; Maloney, D G; Press, O W; Bensinger, W

2006-06-01

Forty patients with multiple myeloma scheduled to receive melphalan 200 mg/m(2) followed by autologous stem cell transplantation were randomly assigned to receive oral cryotherapy or room temperature normal saline rinses 30 min before and for 6 h after high-dose therapy. Patients were evaluated for the development of mucositis using the National Cancer Institute grading system as well as evaluation of secondary measures such as days of total parenteral nutrition (TPN), narcotic use, hospitalization, weight loss and resumption of oral caloric intake for 28 days after transplant. Patients self-scored their pain, swallowing, drinking, eating, sleeping and taste alterations for 28 days. The primary end point of this trial was the incidence of grades 3-4 mucositis. Compared to the normal saline group, patients using cryotherapy experienced less grade 3-4 mucositis, 14 vs 74%, P=0.0005. Patients receiving cryotherapy also had statistically lower uses of narcotics and TPN, although there were no differences in length of hospitalization or weight loss. Patient-reported pain was significantly lower and activities were significantly better in the cryotherapy group.

Bladder Mucosal Graft Vaginoplasty: A Case Report.

PubMed

Chiaramonte, Cinzia; Vestri, Elettra; Tripi, Flavia; Giannone, Antonino Giulio; Cimador, Marcello; Cataliotti, Ferdinando

2018-06-18

Female vaginoplasty reconstruction, by choice, is usually performed with adjacent tissue. However in some clinical conditions such as high urogenital confluence sinus, cloacal malformation with extreme vaginal hypoplasia, local tissue may not be available. When vaginal replacement is performed in pediatric patients intestinal segments is preferred to non-operative procedures that require continuative dilations. However mucus production, malignant transformation risk and diversion colitis are important side effects. We present a nouvel technique for vaginoplasty in a female child presenting with an isolated urogenital sinus malformation without virilization. The patient at 20 months underwent vaginoplasty using tubularized bladder mucosal graft. Surgical procedure was devoid of complications. Pubertal development occurred at age of 15. She underwent regular follow up until 18 years of age. At this age we performed clinical evaluation: absence of vaginal introitus stenosis and good cosmetic results were observed. Then she underwent vaginoscopy with multiple biopsies. Pathology examination of the bladder mucosal graft evidenced a normal structure of the mucosa, with a stratified squamous epithelium. Different techniques are taken into account for vaginal reconstruction according to the severity and to the type of malformation. We describe the use of bladder mucosal graft with favorable results after long term follow-up. Copyright © 2018. Published by Elsevier Inc.

Induction of innate immunity in control of mucosal transmission of HIV.

PubMed

Wang, Yufei; Lehner, Thomas

2011-09-01

To present evidence of the role of innate mucosal immunity and to harness this arm of immunity in protection against HIV infection. Dendritic cells, monocytes, natural killer (NK) cells and γδ T cells are critical in innate immunity, which is mediated by Toll-like receptor (TLR) and recently identified stress pathways. Complement factors, cytokines and chemokines have diverse functions usually affecting HIV infection indirectly. A novel group of innate intracellular HIV restriction factors has been identified - APOBEC3G, TRIM5α and tetherin - all of which are upregulated by type I interferons and some by vaccination and TLR agonists. Whereas innate immunity conventionally lacks memory, recent evidence suggests that some of the cells and intracellular factors may express immunological memory-like features. Innate mucosal immunity may provide early effective control of HIV transmission and replication. Some vaccines can enhance innate immune factors, such as APOBEC3G and control HIV during the eclipse period, allowing full weight of neutralizing and/or cytotoxic T cells to develop and prevent mucosal HIV infection. The next generation of vaccines should be designed to target both innate and adaptive immune memory responses.

Ghrelin may reduce radiation-induced mucositis and anorexia in head-neck cancer.

PubMed

Guney, Yildiz; Ozel Turkcu, Ummuhani; Hicsonmez, Ayse; Nalca Andrieu, Meltem; Kurtman, Cengiz

2007-01-01

Body weight loss is common in cancer patients, and is often associated with poor prognosis, it greatly impairs quality of life (QOL). Radiation therapy (RT) is used in head and neck cancers (HNC) either as a primary treatment or as an adjuvant therapy to surgery. Patients with HNC are most susceptible to malnutrition especially due to anorexia, which is aggravated by RT. Multiple pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta), interferon (IFN)-gamma and tumor necrosis factor-alpha(TNF-alpha), have been all associated with the development of both anorexia and oral mucositis. Radiation-induced mucositis occurs in almost all patients, who are treated for HNC, it could also cause weight loss. Ghrelin is a novel 28-amino acid peptide, which up-regulates body weight through appetite control, increase food intake, down-regulate energy expenditure and induces adiposity. Furthermore, ghrelin inhibits pro-inflammatory cytokines such as IL-1alpha, IL-1beta, TNF-alpha which may cause oral mucositis and aneroxia, which are the results of weight loss. Thus weight loss during RT is an early indicator of nutritional decline, we propose that recombinant ghrelin used prophylactically could be useful as an appetite stimulant; and preventive of mucositis because of its anti-inflammatory effect, it might help patients maintain weight over the course of curative RT of the HNC and can improve specific aspects of QOL. This issue warrants further studies.

Human Enterovirus 71 Protein Displayed on the Surface of Saccharomyces cerevisiae as an Oral Vaccine.

PubMed

Zhang, Congdang; Wang, Yi; Ma, Shuzhi; Li, Leike; Chen, Liyun; Yan, Huimin; Peng, Tao

2016-06-01

Human enterovirus 71 (EV-A71), a major agent of hand, foot, and mouth disease, has become an important public health issue in recent years. No effective antiviral or vaccines against EV-A71 infection are currently available. EV-A71 infection intrudes bodies through the gastric mucosal surface and it is necessary to enhance mucosal immune response to protect children from these pathogens. Recently, the majority of EV-A71 vaccine candidates have been developed for parenteral immunization. However, parenteral vaccine candidates often induce poor mucosal responses. On the other hand, oral vaccines could induce effective mucosal and systemic immunity, and could be easily and safely administered. Thus, proper oral vaccines have attached more interest compared with parenteral vaccine. In this study, the major immunogenic capsid protein of EV-A71 was displayed on the surface of Saccharomyces cerevisiae. Oral immunization of mice with surface-displayed VP1 S. cerevisiae induced systemic humoral and mucosal immune responses, including virus-neutralizing titers, VP1-specific antibody, and the induction of Th1 immune responses in the spleen. Furthermore, oral immunization of mother mice with surface-displayed VP1 S. cerevisiae conferred protection to neonatal mice against the lethal EV-A71 infection. Furthermore, we observed that multiple boost immunization as well as higher immunization dosage could induce higher EV-A71-specific immune response. Our results demonstrated that surface-displayed VP1 S. cerevisiae could be used as potential oral vaccine against EV-A71 infection.

Multiscale modeling of mucosal immune responses

PubMed Central

2015-01-01

Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM. Background Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Implementation Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. Conclusion We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation. PMID:26329787

Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa: a novel role of mitochondrial aconitase oxidation.

PubMed

Maity, Pallab; Bindu, Samik; Dey, Sumanta; Goyal, Manish; Alam, Athar; Pal, Chinmay; Mitra, Kalyan; Bandyopadhyay, Uday

2009-01-30

We have investigated the role of mitochondria on the development of indomethacin (a non-steroidal anti-inflammatory drug)-induced gastric mucosal apoptosis and associated gastropathy in rat. Transmission electron microscopic studies indicate that indomethacin damages mitochondrial ultrastructure and causes mitochondrial dysfunction as evident from decreased stage-3 respiration, dehydrogenase activity, and transmembrane potential (DeltaPsi(m)). Mitochondrial pathology is associated with increased generation of intra-mitochondrial-reactive oxygen species, such as O(2)(*), H(2)O(2) and *OH, leading to oxidative stress. O(2)(*) is the most effective to damage mitochondrial aconitase, leading to the release of iron from its iron-sulfur cluster. The released iron, by interacting with intra-mitochondrial H(2)O(2), forms *OH. Immunoprecipitation of mitochondrial aconitase and subsequent Western immunoblotting indicate carbonylation of aconitase along with the loss of activity in vivo after indomethacin treatment. The release of iron has been documented by fluorescence imaging of mucosal cells by using Phen Green SK, a specific probe for chelatable iron. Interestingly, intra-mitochondrial *OH generation is crucial for the development of mitochondrial pathology and activation of mitochondrial death pathway by indomethacin. Scavenging of *OH by dimethyl sulfoxide or alpha-phenyl-n-tert-butylnitrone, a spin-trap, prevents indomethacin-induced mitochondrial ultrastructural changes, oxidative stress, collapse of DeltaPsi(m), and mitochondrial dysfunction. The scavengers also restore indomethacin-induced activation of caspase-9 and caspase-3 to block mitochondrial pathway of apoptosis and gastric mucosal damage. This study, thus, reveals the critical role of O(2)(*)-mediated mitochondrial aconitase inactivation to release intra-mitochondrial iron, which by generating *OH promotes gastric mucosal cell apoptosis and gastropathy during indomethacin treatment.

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

PubMed

Astronomo, Rena D; Santra, Sampa; Ballweber-Fleming, Lamar; Westerberg, Katharine G; Mach, Linh; Hensley-McBain, Tiffany; Sutherland, Laura; Mildenberg, Benjamin; Morton, Georgeanna; Yates, Nicole L; Mize, Gregory J; Pollara, Justin; Hladik, Florian; Ochsenbauer, Christina; Denny, Thomas N; Warrier, Ranjit; Rerks-Ngarm, Supachai; Pitisuttithum, Punnee; Nitayapan, Sorachai; Kaewkungwal, Jaranit; Ferrari, Guido; Shaw, George M; Xia, Shi-Mao; Liao, Hua-Xin; Montefiori, David C; Tomaras, Georgia D; Haynes, Barton F; McElrath, Juliana M

2016-12-01

HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1 JR-CSF and HIV-1 Bal26 infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Multiscale modeling of mucosal immune responses.

PubMed

Mei, Yongguo; Abedi, Vida; Carbo, Adria; Zhang, Xiaoying; Lu, Pinyi; Philipson, Casandra; Hontecillas, Raquel; Hoops, Stefan; Liles, Nathan; Bassaganya-Riera, Josep

2015-01-01

Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation.Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM.

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

PubMed Central

Statovci, Donjete; Aguilera, Mònica; MacSharry, John; Melgar, Silvia

2017-01-01

Recent findings point toward diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host’s physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota, and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fiber, represent a growing health risk contributing to the increased occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory bowel diseases (IBD) and asthma are chronic mucosal inflammatory conditions of unknown etiology with increasing prevalence worldwide. These conditions have a multifactorial etiology including genetic factors, environmental factors, and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibers, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma. PMID:28804483

Inflammation drives dysbiosis and bacterial invasion in murine models of ileal Crohn's disease.

PubMed

Craven, Melanie; Egan, Charlotte E; Dowd, Scot E; McDonough, Sean P; Dogan, Belgin; Denkers, Eric Y; Bowman, Dwight; Scherl, Ellen J; Simpson, Kenneth W

2012-01-01

Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn's Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis. We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI; 0.1 mg/mouse), or high dose indomethacin (HDI; 1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype. Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% gram + Firmicutes to >95% gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2(-/-), and reduced dysbiosis in ileitis-resistant CCR2(-/-) mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion. Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.

Oral Mucositis: Melatonin Gel an Effective New Treatment

PubMed Central

Abdel Moneim, Ahmed Esmat; Guerra-Librero, Ana; Florido, Javier; Shen, Ying-Qiang; Fernández-Gil, Beatriz; Acuña-Castroviejo, Darío; Escames, Germaine

2017-01-01

The current treatment for cervico-facial cancer involves radio and/or chemotherapy. Unfortunately, cancer therapies can lead to local and systemic complications such as mucositis, which is the most common dose-dependent complication in the oral cavity and gastrointestinal tract. Mucositis can cause a considerably reduced quality of life in cancer patients already suffering from physical and psychological exhaustion. However, the role of melatonin in the treatment of mucositis has recently been investigated, and offers an effective alternative therapy in the prevention and/or management of radio and/or chemotherapy-induced mucositis. This review focuses on the pathobiology and management of mucositis in order to improve the quality of cancer patients’ lives. PMID:28481279

Endoscopic mucosal autograft for treating esophageal caustic strictures: preliminary human experience.

PubMed

He, Kexin; Zhao, Lili; Bu, Shoushan; Liu, Li; Wang, Xiang; Wang, Min; Fan, Zhining

2018-06-11

 Esophageal caustic stricture is a stubborn disease and postoperative restenosis limits the clinical efficacy of endoscopic dilation. Autologous mucosal grafts have been successfully applied in the treatment of urethral stricture and in the prevention of stricture after extensive mucosal resection. We aimed to use mucosal autografting performed endoscopically to treat refractory esophageal stricture. METHODS : Three patients with intractable corrosive esophageal stricture were treated endoscopically by combining dilation with autologous mucosal transplantation. RESULTS : All procedures were successful with no severe complications. Mucosal regeneration was shown at the transplanted segments. One patient was able to maintain a normal diet with complete remission after 1 year of follow-up. Intraluminal stenosis and dysphagia were significantly improved in another two patients. CONCLUSIONS : Mucosal autografting can achieve esophageal re-epithelialization, inhibit undesired fibrosis, prevent restenosis, and promote functional regeneration. © Georg Thieme Verlag KG Stuttgart · New York.

Cryotherapy effect on oral mucositis severity among recipients of bone marrow transplantation: a literature review.

PubMed

Tayyem, Abdel-Qader Mahmoud

2014-08-01

Oral mucositis is a distressing toxic effect of cancer therapy and one of the major side effects of the myeloablative conditioning used to prepare patients for bone marrow transplantation (BMT). Oral cryotherapy is one of the recent modalities used to prevent and manage oral mucositis. The purpose of this review is to clarify the cryotherapy effect on oral mucositis severity among patients receiving myeloablative conditioning followed by BMT. A literature search was performed using six different electronic databases: CINAHL®, MEDLINE®, Nursing Ovid, PubMed, Springer, and Science Direct. Six articles were deemed relevant and included in this review. Oral mucositis increases mortality rate, length of hospital stay, opioid use, and the need for parenteral nutrition usage. It also decreases patient's quality of life and his or her desire to complete treatment. However, oral cryotherapy significantly minimizes the incidence and severity of oral mucositis and decreases secondary oral mucositis complications. Using oral cryotherapy concurrently with a regular oral care protocol can improve its efficacy for preventing and managing oral mucositis. Additional studies should be conducted to create standard oral cryotherapy protocols.

Multilayer engineered nanoliposomes as a novel tool for oral delivery of lipopeptide-based vaccines against group A Streptococcus.

PubMed

Marasini, Nirmal; Giddam, Ashwini K; Ghaffar, Khairunnisa A; Batzloff, Michael R; Good, Michael F; Skwarczynski, Mariusz; Toth, Istvan

2016-05-01

To develop an oral nanovaccine delivery system for lipopeptide-based vaccine candidate against group A Streptococcus. Lipid-core peptide-1-loaded nanoliposomes were prepared as a template and coated with opposite-charged polyelectrolytes to produce particles with size <200 nm. Efficacy of this oral nanovaccine delivery system was evaluated in mice model. Polymer-coated liposomes produced significantly higher antigen-specific mucosal IgA and systemic IgG titers in comparison to vaccine formulated with a strong mucosal adjuvant upon oral immunization in mice. Moreover, high levels of systemic antibody titers were retained even at day 185 postprimary immunization. Efficient oral delivery platform for lipopeptide-based vaccines has been developed.

Mucosal vaccines to prevent porcine reproductive and respiratory syndrome: a new perspective.

PubMed

Renukaradhya, Gourapura J; Dwivedi, Varun; Manickam, Cordelia; Binjawadagi, Basavaraj; Benfield, David

2012-06-01

Porcine reproductive and respiratory syndrome (PRRS) is an economically important infectious disease of swine. Constant emergence of variant strains of PRRS virus (PPRSV) and virus-mediated immune evasion followed by viral persistence result in increased incidence and recurrence of PRRS in swine herds. Current live and killed PRRSV vaccines administered by a parenteral route are ineffective in inducing complete protection. Thus, new approaches in design and delivery of PRRSV vaccines are needed to reduce the disease burden of the swine industry. Induction of an effective mucosal immunity to several respiratory pathogens by direct delivery of a vaccine to mucosal sites has proven to be effective in a mouse model. However, there are challenges in eliciting mucosal immunity to PRRS due to our limited understanding of safe and potent mucosal adjuvants, which could potentiate the mucosal immune response to PRRSV. The purpose of this review is to discuss methods for induction of protective mucosal immune responses in the respiratory tract of pigs. The manuscript also discusses how PRRSV modulates innate, adaptive and immunoregulatory responses at both mucosal and systemic sites of infected and/or vaccinated pigs. This information may help in the design of innovative mucosal vaccines to elicit superior cross-protective immunity against divergent field strains of PRRSV.

Ionic basis of membrane potentials of epithelial cells in rat small intestine

PubMed Central

Barry, R. J. C.; Eggenton, Jacqueline

1972-01-01

1. Potentials across the mucosal and serosal membranes of the epithelial cells of rat jejunum together with transmural potentials were recorded using everted sac preparations. 2. Ionic changes in either mucosal or serosal fluids affect mucosal or serosal membrane potentials respectively with comparable changes in the transmural potential. The contralateral membrane potential is relatively unaffected. 3. Replacement of mucosal sodium chloride by potassium chloride or lithium chloride had little effect on potentials, but its replacement by mannitol or Tris chloride increased the negativity of the mucosal potential, giving linear relationships against log10[Na]m with slopes of 41·4 and 30·7 mV respectively for tenfold change in [Na]m. 4. At constant [Na]m, potassium or lithium increased the mucosal potential by 25·7 and 19·8 mV respectively for tenfold concentration changes. 5. Qualitatively similar changes occurred in the serosal potential when the ionic composition of the serosal fluid was varied. 6. Mucosal potential changes in response to modifications of the ionic composition of the mucosal fluid were the same in the presence and absence of galactose. 7. Sodium and potassium diffusion potentials largely determine both the mucosal and serosal membrane potentials. For the mucosal membrane, PK:PNa is 1·26:1, and is probably higher for the serosal membrane. Chloride makes no significant contribution to membrane potentials. 8. Potentials generated by the electrogenic sodium pump are superimposed on diffusion potentials across the serosal membrane. PMID:4646579

High-resolution electrical mapping of porcine gastric slow-wave propagation from the mucosal surface.

PubMed

Angeli, T R; Du, P; Paskaranandavadivel, N; Sathar, S; Hall, A; Asirvatham, S J; Farrugia, G; Windsor, J A; Cheng, L K; O'Grady, G

2017-05-01

Gastric motility is coordinated by bioelectrical slow waves, and gastric dysrhythmias are reported in motility disorders. High-resolution (HR) mapping has advanced the accurate assessment of gastric dysrhythmias, offering promise as a diagnostic technique. However, HR mapping has been restricted to invasive surgical serosal access. This study investigates the feasibility of HR mapping from the gastric mucosal surface. Experiments were conducted in vivo in 14 weaner pigs. Reference serosal recordings were performed with flexible-printed-circuit (FPC) arrays (128-192 electrodes). Mucosal recordings were performed by two methods: (i) FPC array aligned directly opposite the serosal array, and (ii) cardiac mapping catheter modified for gastric mucosal recordings. Slow-wave propagation and morphology characteristics were quantified and compared between simultaneous serosal and mucosal recordings. Slow-wave activity was consistently recorded from the mucosal surface from both electrode arrays. Mucosally recorded slow-wave propagation was consistent with reference serosal activation pattern, frequency (P≥.3), and velocity (P≥.4). However, mucosally recorded slow-wave morphology exhibited reduced amplitude (65-72% reduced, P<.001) and wider downstroke width (18-31% wider, P≤.02), compared to serosal data. Dysrhythmias were successfully mapped and classified from the mucosal surface, accorded with serosal data, and were consistent with known dysrhythmic mechanisms in the porcine model. High-resolution gastric electrical mapping was achieved from the mucosal surface, and demonstrated consistent propagation characteristics with serosal data. However, mucosal signal morphology was attenuated, demonstrating necessity for optimized electrode designs and analytical algorithms. This study demonstrates feasibility of endoscopic HR mapping, providing a foundation for advancement of minimally invasive spatiotemporal gastric mapping as a clinical and scientific tool. © 2016 John Wiley & Sons Ltd.

Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis.

PubMed

Weijenborg, Pim W; Smout, André J P M; Verseijden, Caroline; van Veen, Henk A; Verheij, Joanne; de Jonge, Wouter J; Bredenoord, Albert J

2014-08-01

Increased esophageal sensitivity and impaired mucosal integrity have both been described in patients with gastroesophageal reflux disease, but the relationship between hypersensitivity and mucosal integrity is unclear. The aim of the present study was to investigate acid sensitivity in patients with erosive and nonerosive reflux disease and control subjects to determine the relation with functional esophageal mucosal integrity changes as well as to investigate cellular mechanisms of impaired mucosal integrity in these patients. In this prospective experimental study, 12 patients with nonerosive reflux disease, 12 patients with esophagitis grade A or B, and 11 healthy control subjects underwent an acid perfusion test and upper endoscopy. Mucosal integrity was measured during endoscopy by electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance, transepithelial permeability and gene expression of tight junction proteins and filaggrin. Patients with nonerosive reflux disease and esophagitis were more sensitive to acid perfusion compared with control subjects, having a shorter time to perception of heartburn and higher perceived intensity of heartburn. In reflux patients, enhanced acid sensitivity was associated with impairment of in vivo and vitro esophageal mucosal integrity. Mucosal integrity was significantly impaired in patients with esophagitis, displaying higher transepithelial permeability and lower extracellular impedance. Although no significant differences in the expression of tight junction proteins were found in biopsies among patient groups, mucosal integrity parameters in reflux patients correlated negatively with the expression of filaggrin. In conclusion, sensitivity to acid is enhanced in patients with gastroesophageal reflux disease, irrespective of the presence of erosions, and is associated with impaired esophageal mucosal integrity. Mucosal integrity of the esophagus is associated with the expression of filaggrin. Copyright © 2014 the American Physiological Society.

Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis

PubMed Central

Asquith, Mark; Stauffer, Patrick; Davin, Sean; Mitchell, Claire; Lin, Phoebe; Rosenbaum, James T.

2017-01-01

Objective The HLA-B27/β2 microglobulin (β2m) transgenic rat is a leading model of B27-associated spondyloarthopathy and disease is dependent on the presence of intestinal bacteria. We have shown previously that adult HLA-B27/β2m rats have an altered intestinal microbiota. In this study we sought to better define age-dependent changes to both mucosal immune function and dysbiosis in this model. Methods Intestinal contents were collected from wild type and HLA-B27/β2m+ rats post-weaning (3 and 6 weeks), at disease onset (10 wks) and after the establishment of disease (16 wks). Microbial community structure was determined by 16s sequencing and qRT-PCR. Mucosal and systemic Th1, Th17 and Treg responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. Results An inflammatory cytokine signature and elevated AMP expression during the post-weaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA-B27/β2m+ rats. An early and sustained expansion of the Th17 pool was specifically observed in cecal and colonic mucosa of HLA-B27/β2m rats. Strongly elevated Akkermansia mucinphilia colonization and IgA coating of intestinal bacteria was significantly associated with HLA-B27 expression and arthritis development. Conclusions and Perspectives HLA-B27/β2m expression in this rat model renders the host hyper-responsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA-B27/β2m+ve animals. Perturbed mucosal immunity and dysbiosis strongly merit further study in both pre-diseased and diseased SpA patient populations. PMID:26992013

Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen

PubMed Central

Arias, Mauricio A.; Loxley, Andrew; Eatmon, Christy; Van Roey, Griet; Fairhurst, David; Mitchnick, Mark; Dash, Philip; Cole, Tom; Wegmann, Frank; Sattentau, Quentin; Shattock, Robin

2011-01-01

Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates. PMID:21145913

Carnauba wax nanoparticles enhance strong systemic and mucosal cellular and humoral immune responses to HIV-gp140 antigen.

PubMed

Arias, Mauricio A; Loxley, Andrew; Eatmon, Christy; Van Roey, Griet; Fairhurst, David; Mitchnick, Mark; Dash, Philip; Cole, Tom; Wegmann, Frank; Sattentau, Quentin; Shattock, Robin

2011-02-01

Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates. Copyright © 2010 Elsevier Ltd. All rights reserved.

[Secondary tumors of the gastrointestinal tract].

PubMed

Langner, C

2012-02-01

Metastatic involvement of the gastrointestinal tract is rare and may cause considerable difficulties with respect to differential diagnosis. The gastrointestinal tract may either be affected by direct invasion, intraperitoneal dissemination or hematogenous cancer spread, the latter most often originating from malignant melanoma, breast and lung carcinomas. Metastatic deposits primarily develop within the submucosa. Secondary involvement of the mucosa typically leads to centrally depressed and/or ulcerated (volcano-like) nodular lesions. In histology, lack of a mucosal in situ component favors diagnosis of metastasis, whereas presence of an adenomatous precursor lesion is regarded to be characteristic of primary tumors. This concept, however, has recently been challenged by demonstrating metastatic cancer growth along intact basement membranes within the mucosal layer, i.e. mucosal colonization. The histopathological, immunohistochemical and clinical features of secondary gastrointestinal tumors are discussed in detail, focusing on criteria for differential diagnosis. The prognosis of affected patients is generally poor.

Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development

PubMed Central

Bondaryk, Małgorzata; Kurzątkowski, Wiesław

2013-01-01

Recent progress in medical sciences and therapy resulted in an increased number of immunocompromised individuals. Candida albicans is the leading opportunistic fungal pathogen causing infections in humans, ranging from superficial mucosal lesions to disseminated or bloodstream candidiasis. Superficial candidiasis not always presents a risk to the life of the infected host, however it significantly lowers the quality of life. Superficial Candida infections are difficult to treat and their frequency of occurrence is currently rising. To implement successful treatment doctors should be up to date with better understanding of C. albicans resistance mechanisms. Despite high frequency of Candida infections there is a limited number of antimycotics available for therapy. This review focuses on current understanding of the mode of action and resistance mechanisms to conventional and emerging antifungal agents for treatment of superficial and mucosal candidiasis. PMID:24353489

Mimicking herpes simplex virus 1 and herpes simplex virus 2 mucosal behavior in a well-characterized human genital organ culture.

PubMed

Steukers, Lennert; Weyers, Steven; Yang, Xiaoyun; Vandekerckhove, Annelies P; Glorieux, Sarah; Cornelissen, Maria; Van den Broeck, Wim; Temmerman, Marleen; Nauwynck, Hans J

2014-07-15

We developed and morphologically characterized a human genital mucosa explant model (endocervix and ectocervix/vagina) to mimic genital herpes infections caused by herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Subsequent analysis of HSV entry receptor expression throughout the menstrual cycle in genital tissues was performed, and the evolution of HSV-1/-2 mucosal spread over time was assessed. Nectin-1 and -2 were expressed in all tissues during the entire menstrual cycle. Herpesvirus entry mediator expression was limited mainly to some connective tissue cells. Both HSV-1 and HSV-2 exhibited a plaque-wise mucosal spread across the basement membrane and induced prominent epithelial syncytia. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Newcastle disease virus expressing human immunodeficiency virus type 1 envelope glycoprotein induces strong mucosal and serum antibody responses in Guinea pigs.

PubMed

Khattar, Sunil K; Samal, Sweety; Devico, Anthony L; Collins, Peter L; Samal, Siba K

2011-10-01

Human immunodeficiency virus type 1 (HIV-1) is transmitted mainly through mucosal sites. Optimum strategies to elicit both systemic and mucosal immunity are critical for the development of vaccines against HIV-1. We therefore sought to evaluate the induction of systemic and mucosal immune responses by the use of Newcastle disease virus (NDV) as a vaccine vector. We generated a recombinant NDV, designated rLaSota/gp160, expressing the gp160 envelope (Env) protein of HIV-1 from an added gene. The gp160 protein expressed by rLaSota/gp160 virus was detected on an infected cell surface and was incorporated into the NDV virion. Biochemical studies showed that gp160 present in infected cells and in the virion formed a higher-order oligomer that retained recognition by conformationally sensitive monoclonal antibodies. Expression of gp160 did not increase the virulence of recombinant NDV (rNDV) strain LaSota. Guinea pigs were administered rLaSota/gp160 via the intranasal (i.n.) or intramuscular (i.m.) route in different prime-boost combinations. Systemic and mucosal antibody responses specific to the HIV-1 envelope protein were assessed in serum and vaginal washes, respectively. Two or three immunizations via the i.n. or i.m. route induced a more potent systemic and mucosal immune response than a single immunization by either route. Priming by the i.n. route was more immunogenic than by the i.m. route, and the same was true for the boosts. Furthermore, immunization with rLaSota/gp160 by any route or combination of routes induced a Th1-type response, as reflected by the induction of stronger antigen-specific IgG2a than IgG1 antibody responses. Additionally, i.n. immunization elicited a stronger neutralizing serum antibody response to laboratory-adapted HIV-1 strain MN.3. These data illustrate that it is feasible to use NDV as a vaccine vector to elicit potent humoral and mucosal responses to the HIV-1 envelope protein.

An oral vaccine based on U-Omp19 induces protection against B. abortus mucosal challenge by inducing an adaptive IL-17 immune response in mice.

PubMed

Pasquevich, Karina A; Ibañez, Andrés E; Coria, Lorena M; García Samartino, Clara; Estein, Silvia M; Zwerdling, Astrid; Barrionuevo, Paula; Oliveira, Fernanda S; Seither, Christine; Warzecha, Heribert; Oliveira, Sergio C; Giambartolomei, Guillermo H; Cassataro, Juliana

2011-01-14

As Brucella infections occur mainly through mucosal surfaces, the development of mucosal administered vaccines could be radical for the control of brucellosis. In this work we evaluated the potential of Brucella abortus 19 kDa outer membrane protein (U-Omp19) as an edible subunit vaccine against brucellosis. We investigated the protective immune response elicited against oral B. abortus infection after vaccination of mice with leaves from transgenic plants expressing U-Omp19; or with plant-made or E. coli-made purified U-Omp19. All tested U-Omp19 formulations induced protection against Brucella when orally administered without the need of adjuvants. U-Omp19 also induced protection against a systemic challenge when parenterally administered. This built-in adjuvant ability of U-Omp19 was independent of TLR4 and could be explained at least in part by its capability to activate dendritic cells in vivo. While unadjuvanted U-Omp19 intraperitoneally administered induced a specific Th1 response, following U-Omp19 oral delivery a mixed specific Th1-Th17 response was induced. Depletion of CD4(+) T cells in mice orally vaccinated with U-Omp19 resulted in a loss of the elicited protection, indicating that this cell type mediates immune protection. The role of IL-17 against Brucella infection has never been explored. In this study, we determined that if IL-17A was neutralized in vivo during the challenge period, the mucosal U-Omp19 vaccine did not confer mucosal protection. On the contrary, IL-17A neutralization during the infection did not influence at all the subsistence and growth of this bacterium in PBS-immunized mice. All together, our results indicate that an oral unadjuvanted vaccine based on U-Omp19 induces protection against a mucosal challenge with Brucella abortus by inducing an adaptive IL-17 immune response. They also indicate different and important new aspects i) IL-17 does not contribute to reduce the bacterial burden in non vaccinated mice and ii) IL-17 plays a central role in vaccine mediated anti-Brucella mucosal immunity.

Visual perception enhancement for detection of cancerous oral tissue by multi-spectral imaging

NASA Astrophysics Data System (ADS)

Wang, Hsiang-Chen; Tsai, Meng-Tsan; Chiang, Chun-Ping

2013-05-01

Color reproduction systems based on the multi-spectral imaging technique (MSI) for both directly estimating reflection spectra and direct visualization of oral tissues using various light sources are proposed. Images from three oral cancer patients were taken as the experimental samples, and spectral differences between pre-cancerous and normal oral mucosal tissues were calculated at three time points during 5-aminolevulinic acid photodynamic therapy (ALA-PDT) to analyze whether they were consistent with disease processes. To check the successful treatment of oral cancer with ALA-PDT, oral cavity images by swept source optical coherence tomography (SS-OCT) are demonstrated. This system can also reproduce images under different light sources. For pre-cancerous detection, the oral images after the second ALA-PDT are assigned as the target samples. By using RGB LEDs with various correlated color temperatures (CCTs) for color difference comparison, the light source with a CCT of about 4500 K was found to have the best ability to enhance the color difference between pre-cancerous and normal oral mucosal tissues in the oral cavity. Compared with the fluorescent lighting commonly used today, the color difference can be improved by 39.2% from 16.5270 to 23.0023. Hence, this light source and spectral analysis increase the efficiency of the medical diagnosis of oral cancer and aid patients in receiving early treatment.

Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

PubMed

Riley, Philip; McCabe, Martin G; Glenny, Anne-Marie

2016-10-01

In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

Aldesleukin and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

ClinicalTrials.gov

2018-05-23

Metastatic Melanoma; Stage III Mucosal Melanoma of the Head and Neck; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma; Stage IVA Mucosal Melanoma of the Head and Neck; Stage IVB Mucosal Melanoma of the Head and Neck; Stage IVC Mucosal Melanoma of the Head and Neck

Assays to Study the Interaction of Campylobacter jejuni with the Mucosal Surface.

PubMed

Clyne, Marguerite; Duggan, Gina; Dunne, Ciara; Dolan, Brendan; Alvarez, Luis; Bourke, Billy

2017-01-01

Mucosal colonization and overcoming the mucosal barrier are essential steps in the establishment of infection by Campylobacter jejuni. The interaction between C. jejuni and host cells, including binding and invasion, is thought to be the key virulence factor important for pathogenesis of C. jejuni infections in animals or humans. The intestinal mucosal barrier is composed of a polarized epithelium covered by a thick adherent mucus gel layer. There is a requirement for cell culture assays of infection to accurately represent the in vivo mucosal surface. In this chapter, we describe the use of a number of cell culture models and the use of polarized in vitro organ culture to examine the interaction of C. jejuni with mucosal surfaces.

Enhanced mucosal immune responses induced by a combined candidate mucosal vaccine based on Hepatitis A virus and Hepatitis E virus structural proteins linked to tuftsin.

PubMed

Gao, Yan; Su, Qiudong; Yi, Yao; Jia, Zhiyuan; Wang, Hao; Lu, Xuexin; Qiu, Feng; Bi, Shengli

2015-01-01

Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are the most common causes of infectious hepatitis. These viruses are spread largely by the fecal-oral route and lead to clinically important disease in developing countries. To evaluate the potential of targeting hepatitis A and E infection simultaneously, a combined mucosal candidate vaccine was developed with the partial open reading frame 2 (ORF2) sequence (aa 368-607) of HEV (HE-ORF2) and partial virus protein 1 (VP1) sequence (aa 1-198) of HAV (HA-VP1), which included the viral neutralization epitopes. Tuftsin is an immunostimulatory peptide which can enhance the immunogenicity of a protein by targeting it to macrophages and dendritic cells. Here, we developed a novel combined protein vaccine by conjugating tuftsin to HE-ORF2 and HA-VP1 and used synthetic CpG oligodeoxynucleotides (ODNs) as the adjuvant. Subsequent experiments in BALB/c mice demonstrated that tuftsin enhanced the serum-specific IgG and IgA antibodies against HEV and HAV at the intestinal, vaginal and pulmonary interface when delivered intranasally. Moreover, mice from the intranasally immunized tuftsin group (HE-ORF2-tuftsin + HA-VP1-tuftsin + CpG) showed higher levels of IFN-γ-secreting splenocytes (Th1 response) and ratio of CD4+/CD8+ T cells than those of the no-tuftsin group (HE-ORF2 + HA-VP1 + CpG). Thus, the tuftsin group generated stronger humoral and cellular immune responses compared with the no-tuftsin group. Moreover, enhanced responses to the combined protein vaccine were obtained by intranasal immunization compared with intramuscular injection. By integrating HE-ORF2, HA-VP1 and tuftsin in a vaccine, this study validated an important concept for further development of a combined mucosal vaccine against hepatitis A and E infection.

Use of Bidens pilosa L. (Asteraceae) and Curcuma longa L. (Zingiberaceae) to treat intestinal mucositis in mice: Toxico-pharmacological evaluations.

PubMed

Bastos, Carla Caroline Cunha; Ávila, Paulo Henrique Marcelino de; Filho, Edvande Xavier Dos Santos; Ávila, Renato Ivan de; Batista, Aline Carvalho; Fonseca, Simone Gonçalves; Lima, Eliana Martins; Marreto, Ricardo Neves; Mendonça, Elismauro Francisco de; Valadares, Marize Campos

2016-01-01

Several studies towards the development of an effective treatment for intestinal mucositis have been reported, since this condition represents a major problem in clinical oncology practice due to cytotoxic effects of chemotherapy. However standardized protocols and universally accepted treatment options are yet to be established. Given above, this study evaluated the protective effects of a mucoadhesive formulation containing both Bidens pilosa L. (Asteraceae) (BP) and curcuminoids from Curcuma longa L. (Zingiberaceae) (CL) on intestinal mucositis induced by 5-fluoruoacil (5-FU) in mice. As expected, animals only treated with 5-FU (200 mg/kg) showed a significant reduction of 60.3 and 42.4% in villi and crypts size, respectively, when compared to control. On the other hand, the proposed therapeutic/prophylactic treatment with mucoadhesive formulations managed to reduce histopathologic changes in mice bearing mucositis, especially at 125 mg/kg BP + 15 mg/kg CL dose. The formulation promoted an increase of 275.5% and 148.7% for villi and crypts size, respectively. Moreover, chemotherapy-related weight loss was reduced by 7.4% following the treatment. In addition, an increase of 10 and 30.5% in red and white blood cells was observed when compared to 5-FU group. Furthermore, treatments with the mucoadhesive formulation containing BP/CL up modulated Ki-67 and Bcl-2 expression while reduced pro-apoptotic regulator Bax. The formulation also modulated inflammatory response triggered by 5-FU through reduction of 68% of myeloperoxidase activity and a 4-fold increase in anti-inflammatory IL-10 levels. In parallel, the oxidative stress via lipid peroxidation was reduced as indicated by decrease of 63% of malondialdehyde concentrations. Additionally, the new formulation presented low acute oral systemic toxicity, being classified in the category 5 (2000 mg/kg < LD 50  < 5000 mg/kg) of the Globally Harmonized Classification System. This study showed an interesting potential of the mucoadhesive formulation of BP/CL for the treatment of 5-FU-induced intestinal mucositis. Given the perspectives for the development of a new medicine, clinical studies are in progress to better understand the protective effects of this innovative formulation in treating mucositis.

Long-term mucosal recovery and healing in celiac disease is the rule - not the exception.

PubMed

Hære, Petter; Høie, Ole; Schulz, Tom; Schönhardt, Irina; Raki, Melinda; Lundin, Knut E A

2016-12-01

The prevalence of persistent villous atrophy (VA) in patients with celiac disease (CD) on a gluten-free diet (GFD) varies greatly between studies. Most studies show a relatively high prevalence of mucosal atrophy and inflammation in treated patients, a finding which have led to a concept of non-responsive CD. Few studies have examined the prevalence of long-term mucosal healing. Our study aimed to determine the extent of mucosal healing in a cohort of Norwegian patients with CD treated with GFD for several years. Adult patients diagnosed with VA between 1989 and 2009 were included. We performed a follow-up gastroscopy with duodenal biopsies. Two pathologists evaluated the biopsies according to the Marsh-Oberhuber classification. Mucosal healing was defined as Marsh 0 while mucosal recovery was defined as Marsh 0-2. Duodenal biopsies were obtained from 127 adult patients with established CD. After a follow-up time of 8.1 years (median, range 2.3-22.3), 103 (81%) of the patients showed mucosal healing, 120 patients (94%) showed mucosal recovery, and 7 patients (6%) showed persistent VA. In addition, 103 of the 127 patients (81%) had undergone a routine follow-up biopsy 12.6 months (median, range 5.2-28.8) after diagnosis. At the time of the routine follow-up, only 52 of these patients (50.5%) had achieved mucosal recovery. Although half of the patients had persistent VA at the time of routine follow-up, both long-term mucosal recovery and healing is possible for the vast majority of adult patients with CD.

Influence of source and micronization of soya bean meal on growth performance, nutrient digestibility and ileal mucosal morphology of Iberian piglets.

PubMed

Berrocoso, J D; Cámara, L; Rebollar, P G; Guzmán, P; Mateos, G G

2014-04-01

The effects of inclusion in the diet of different sources of soya bean meal (SBM) on growth performance, total tract apparent digestibility (TTAD) and apparent ileal digestibility (AID) of major dietary components and mucosal ileum morphology were studied in Iberian pigs weaned at 30 days of age. From 30 to 51 days of age (phase I), there was a control diet based on regular soya bean meal (R-SBM; 44% CP) of Argentina (ARG) origin and five extra diets in which a high-protein soya bean meal (HP-SBM; 49% CP) of the USA or ARG origin, either ground (990 μm) or micronized (60 μm), or a soya protein concentrate (SPC; 65% CP) substituted the R-SBM. From 51 to 61 days of age (phase II), all pigs were fed a common commercial diet in mash form. The following pre-planned orthogonal contrasts were conducted: (1) R-SBM v. all the other diets, (2) SPC v. all the HP-SBM diets, (3) micronized HP-SBM v. ground HP-SBM, (4) HP-SBM of ARG origin v. HP-SBM of US origin and (5) interaction between source and the degree of grinding of the HP-SBM. Dietary treatment did not affect growth performance of the pigs at any age but from 30 to 51 days of age, post weaning diarrhoea (PWD) was higher (P<0.001) and the TTAD and AID of all nutrients were lower for pigs fed the R-SBM diet than for pigs fed the HP-SBM or the SPC diets. However, no differences between the HP-SBM and the SPC containing diets were detected for any trait. The TTAD of organic matter (P=0.07) and gross energy (GE) (P=0.05) tended to be higher for the micronized HP-SBM than for the ground HP-SBM and that of GE was higher (P<0.05) for US meal than for the ARG meal. Pigs fed R-SBM had lower villus height (P<0.01) than pigs fed HP-SBM or SPC but no differences in ileal mucosal morphology were detected between SPC and HP-SBM containing diets. It is concluded that feeding the HP-SBM or SPC-reduced PWD and improved nutrient digestibility and ileal morphology as compared with feeding the R-SBM, but had no effect on pig performance. The inclusion in the diet of added value soya products (micronized SBM or SPC) in substitution of the R-SBM increased the TTAD of all nutrients and reduced PWD but had no advantage in terms of growth performance over the use of ground HP-SBM.

[Effectiveness of palifermin in the prevention of oral mucositis in patients with haematological cancers].

PubMed

Ayago Flores, D; Ferriols Lisart, R

2010-01-01

To assess the effectiveness of palifermin for the prevention of oral mucositis in patients with haematological cancers. Retrospective observational study of cohorts of patients with haematological cancer undergoing cytotoxic therapy causing hematopoietic ablation. The main variable assessed was the duration of the oral mucositis. Secondary variables assessed were incidence of mucositis, febrile or septic neutropenia and the administration of opioids and parenteral nutrition. We included 36 patients in this study, 11 in the group that received palifermin and 25 in the control group. The duration of oral mucositis was 4.6+/-3.1 days (median: 5 days) in the patients treated with palifermin in comparison with 7.4+/-4.0 days (median: 6 days) in patients treated with conventional prophylactic therapy (p<0.05). However, no significant differences were seen in the incidence of mucositis, febrile or septic neutropenia, opioid administration of the use of parenteral nutrition. Prophylactic treatment with palifermin reduces the duration of oral mucosities in patients with haematological cancer. Further studies are necessary with larger samples to be able to assess palifermin and its influence on other variables, such as incidence of mucositis, sepsis, febrile neutropenia, etc. Copyright © 2009 SEFH. Published by Elsevier Espana. All rights reserved.

Screening and referral of oral mucosal pathology: a check-up of Australian dentists.

PubMed

Allen, K; Farah, C S

2015-03-01

Oral squamous cell carcinomas and potentially malignant oral disorders can be detected early by visually inspecting the oral soft tissues. This study aimed to determine Australian dentists' opinions and practices regarding oral mucosal screening, referral and oral cancer prevention. Nine hundred and ninety-nine randomly selected general dentists were mailed a questionnaire. The questionnaire queried practitioners' opinions and perceptions of oral mucosal screening, their referral practices and their beliefs regarding detection and prevention of oral cancer. A total of n=640 individuals responded, yielding a response rate of 70.2%. Most Australian dentists reported to routinely perform oral mucosal screening. Lack of training, confidence, time and financial incentives were seen as barriers to performing mucosal screening to at least some degree by participants in this study. Most dentists manage referrals for oral mucosal pathology appropriately; however, only about half believe in following up with referred patients. Only half of dentists surveyed believed that they could influence a patient to quit smoking. Australian dentists place importance on oral mucosal screening. Some changes to dental education and training could be made to further improve confidence and ability of dentists in detecting and referring oral mucosal pathology. © 2015 Australian Dental Association.

A double-blind, placebo-controlled, randomised trial of active manuka honey and standard oral care for radiation-induced oral mucositis.

PubMed

Bardy, Joy; Molassiotis, Alex; Ryder, W David; Mais, Kathleen; Sykes, Andrew; Yap, Beng; Lee, Lip; Kaczmarski, Ed; Slevin, Nicholas

2012-04-01

Our aim was to investigate the effect of active manuka honey on radiation-induced mucositis. A total of 131 patients diagnosed with head and neck cancer who were having radiotherapy to the oral cavity or oropharyngeal area were recruited into the study, and were randomly allocated to take either manuka honey or placebo (golden syrup) 20 ml 4 times daily for 6 weeks. Mucositis was assessed according to the Radiation Therapy Oncology Group (RTOG) scale at baseline, weekly during radiotherapy, and twice weekly thereafter until the mucositis resolved. The patient's weight was recorded at the same time as the mucositis was assessed. Throat swabs to identify bacterial or fungal infections were taken at baseline, and during and after radiotherapy. There was no significant difference between honey and golden syrup in their effects on mucositis. Active manuka honey did not improve mucositis, but both the honey and the syrup seemed to be associated with a reduction in bacterial infections. Compliance was a problem after the onset of mucositis, which may have affected the findings. Copyright © 2011 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Candida innate immunity at the mucosa.

PubMed

Richardson, Jonathan P; Moyes, David L; Ho, Jemima; Naglik, Julian R

2018-03-09

The tremendous diversity in microbial species that colonise the mucosal surfaces of the human body is only now beginning to be fully appreciated. Distinguishing between the behaviour of commensal microbes and harmful pathogens that reside at mucosal sites in the body is a complex, and exquisitely fine-tuned process central to mucosal health. The fungal pathobiont Candida albicans is frequently isolated from mucosal surfaces with an asymptomatic carriage rate of approximately 60% in the human population. While normally a benign member of the microbiota, overgrowth of C. albicans often results in localised mucosal infection causing morbidity in otherwise healthy individuals, and invasive infection that often causes death in the absence of effective immune defence. C. albicans triggers numerous innate immune responses at mucosal surfaces, and detection of C. albicans hyphae in particular, stimulates the production of antimicrobial peptides, danger-associated molecular patterns and cytokines that function to reduce fungal burdens during infection. This review will summarise our current understanding of innate immune responses to C. albicans at mucosal surfaces. Copyright © 2018. Published by Elsevier Ltd.

Mucosal vaccination--an old but still vital strategy.

PubMed

Długońska, Henryka; Grzybowski, Marcin

2012-01-01

The basic premise of vaccinology is to achieve strong protective immunity against defined infectious agents by a vaccine mimicking the effects of natural primary exposure to a pathogen. Because an exposure of humans and animals to microbes occurs mostly through mucosal surfaces, targeting the mucosa seems a rational and efficient vaccination strategy. Many experimental and clinical data confirmed that mucosal immunization offers many advantages over widely used in human and veterinary medicine subcutaneous or intramuscular immunization. In the present article selected aspects regarding mucosal vaccination are discussed. The structure and function of mucosa-associated lymphoid tissue (MALT), comprised of four main mucosal compartments forming a structural and functional unity as well as pivotal cellular MALT components (dendritic and M cells) were briefly characterized. Particular attention was focused on the mode of simple but efficacious delivery of vaccine antigens to mucosal surfaces. A few trials to generate potential mucosal vaccines against toxoplasmosis introduced by nasal or oral routes to experimental animals are also presented.

Fibrin sealant for closure of mucosal penetration at the cardia during peroral endoscopic myotomy: A retrospective study at a single center

PubMed Central

Zhang, Wen-Gang; Linghu, En-Qiang; Li, Hui-Kai

2017-01-01

AIM To assess the efficacy and safety of fibrin sealant for closure of mucosal penetration at the cardia during peroral endoscopic myotomy (POEM). METHODS Twenty-four patients who underwent POEM and experienced mucosal injury of the cardia during the procedure were retrospectively identified. Of the 24 patients, 21 had mucosal penetration and 3 had only slight mucosal damage without penetration. The 21 patients with mucosal penetration received fibrin sealant for closure at the site of penetration. Penetration-related characteristics, treatment, and recovery were reviewed for all 21 patients to assess the efficacy and safety of fibrin sealant for closure of mucosal penetration at the cardia. Clinical data, including general characteristics, procedure-related parameters, Eckardt scores, lower esophageal sphincter pressures (LESP), and esophagogastroduodenoscopy (EGD) results, were analyzed to determine their influence on treatment success after mucosal penetration during POEM. RESULTS All 21 patients had a solitary mucosal penetration in the cardia (12 in esophageal region of the cardia, 9 in the stomach region of the cardia, and 1 in both the esophageal and stomach regions). Twelve had a hole-like penetration and 9 had a linear penetration. For those with a hole-like penetration, the mean size was 0.14 cm2 (0.02-0.32 cm2). For those with a linear penetration, the median size was 0.37 cm (0.10-1.00 cm). Closure of the mucosal penetration using fibrin sealant was performed successfully in all 21 patients (two patients required 5 mL fibrin sealant, and the remaining 19 patients required 2.5 mL). Two patients had a nasogastric tube placed for five days after POEM; the remaining 19 patients were kept fasting for 3 d. All 21 patients were discharged after a median of 5 d (range: 5-7 d) postoperatively. During a median 42 mo (range: 9-62 mo) follow-up, all 21 patients with a mucosal penetration successfully healed without the occurrence of infection, ulcer, or esophagitis. Furthermore, the median LESP decreased from 31.9 mmHg (range: 21.9-67.1 mmHg) preoperatively to 20.3 mmHg (range: 6.0-41.0 mmHg) postoperatively (P < 0.05). The median preoperative and postoperative Eckardt scores were 5.0 (range; 4-10) and 1.0 (range: 0-4), respectively (P < 0.05). Of the 21 patients with mucosal penetration, symptom remission, which is defined as a postoperative Eckardt score ≤ 3, was achieved in 20 patients (95.2%) indicating that mucosal penetration did not influence the success of POEM treatment if closed successfully using fibrin sealant. CONCLUSION Fibrin sealant is safe and effective for closure of mucosal penetration during POEM. Mucosal penetrations do not appear to influence the treatment success of POEM if closed successfully using fibrin sealant. Additional studies regarding the feasibility, efficacy, and safety of fibrin sealant for closure of larger mucosal penetrations is warranted. PMID:28321165

Overview of the causes of chronic diarrhea in children

USDA-ARS?s Scientific Manuscript database

The major causes and the prevalence of chronic diarrhea differ between developed and developing countries. In the developing world, chronic diarrhea is typically associated with serial enteric infections and malnutrition; it is manifested by a chronic enteropathy, with impaired mucosal healing, and ...

Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells

PubMed Central

Ohno, Masashi; Sugitani, Yoshihiko; Nishino, Kyohei; Inatomi, Osamu; Sugimoto, Mitsushige; Kawahara, Masahiro; Andoh, Akira

2017-01-01

Background and Aims Curcumin is a hydrophobic polyphenol derived from turmeric, a traditional Indian spice. Curcumin exhibits various biological functions, but its clinical application is limited due to its poor absorbability after oral administration. A newly developed nanoparticle curcumin shows improved absorbability in vivo. In this study, we examined the effects of nanoparticle curcumin (named Theracurmin) on experimental colitis in mice. Methods BALB/c mice were fed with 3% dextran sulfate sodium (DSS) in water. Mucosal cytokine expression and lymphocyte subpopulation were analyzed by real-time PCR and flow cytometry, respectively. The profile of the gut microbiota was analyzed by real-time PCR. Results Treatment with nanoparticle curcumin significantly attenuated body weight loss, disease activity index, histological colitis score and significantly improved mucosal permeability. Immunoblot analysis showed that NF-κB activation in colonic epithelial cells was significantly suppressed by treatment with nanoparticle curcumin. Mucosal mRNA expression of inflammatory mediators was significantly suppressed by treatment with nanoparticle curcumin. Treatment with nanoparticle curcumin increased the abundance of butyrate-producing bacteria and fecal butyrate level. This was accompanied by increased expansion of CD4+ Foxp3+ regulatory T cells and CD103+ CD8α− regulatory dendritic cells in the colonic mucosa. Conclusions Treatment with nanoparticle curcumin suppressed the development of DSS-induced colitis potentially via modulation of gut microbial structure. These responses were associated with induction of mucosal immune cells with regulatory properties. Nanoparticle curcumin is one of the promising candidates as a therapeutic option for the treatment of IBD. PMID:28985227

A multi-component herbal preparation, STW 5, shows anti-apoptotic effects in radiation induced intestinal mucositis in rats.

PubMed

Khayyal, Mohamed T; Abdel-Naby, Doaa H; Abdel-Aziz, Heba; El-Ghazaly, Mona A

2014-09-25

Intestinal mucositis is a common adverse effect in patients undergoing radiotherapy and constitutes a treatment-limiting condition. Since no agents are yet known that can adequately guard against its development, the search continues to find safe and effective measures. The present study was intended to investigate whether the herbal preparation, STW 5, could offer a potentially effective agent in this respect. Intestinal mucositis was induced in rats by exposing them to whole body gamma-irradiation (6 Gy). Rats were treated orally with STW 5 (5 or 10 ml/kg) for five days before and two days after irradiation. One day later, rats were sacrificed and segments of small intestine were examined histologically. Intestinal homogenates and serum samples were used to assess relevant parameters for apoptosis and different markers for inflammation and oxidative stress. Exposure to radiation produced dose-dependent extents of intestinal injury associated with apoptotic changes with high radiation levels. Apoptosis was associated with an increase in cytosolic calcium, depletion of mitochondrial cytochrome c, B-cell lymphoma-2 and complex I. Oxidative stress parameters (reduced glutathione, thiobarbituric acid reactive substance and total nitrate/nitrite) were deranged. Inflammation markers (tumor necrosis factor and myeloperoxidase) and indices of intestinal damage (serum diamine oxidase) were increased. STW 5 protected to a large extent against histological changes and counteracted the deranged parameters. The findings provide experimental evidence for the potential beneficial use of STW5 in protecting against the development of radiation-induced intestinal mucositis and associated changes in tissue biomarkers. Copyright © 2014 The Authors. Published by Elsevier GmbH.. All rights reserved.

The role of alternative and natural agents, cryotherapy, and/or laser for management of alimentary mucositis.

PubMed

Migliorati, Cesar A; Oberle-Edwards, Loree; Schubert, Mark

2006-06-01

To review the literature and update the current guidelines of alternative/natural agents, cryotherapy, and/or laser therapy in the management of alimentary mucositis (AM). The original guidelines developed by the Multinational Association for Supportive Care in Cancer (MASCC)/International Society for Oral Oncology (ISOO) mucositis study group were the basis for this study. A medical librarian conducted an initial Medline search to identify research articles published between 2002 and 2005 in English language. A search term combination that included stomatitis, mucositis, mucous membrane, neoplasm, lasers, complimentary therapies, amino acids, antioxidants, vitamins, minerals, plant extracts, and cryotherapy was conducted. This initial search identified articles with a strong scientific methodology that included both preclinical and clinical research. Using standardized scoring forms, authors reviewed and scored individual articles. A consensus result of the review was achieved in a meeting of reviewers in June of 2005. The initial search identified a total of 167 new articles. Of these, 14 were selected and reviewed: alternative/natural therapy (one preclinical study); cryotherapy (four clinical studies); lasers (two clinical studies); and alternative/natural agents (seven clinical studies). A new guideline could be established for the use of cryotherapy in the management of AM in hematopoietic stem cell transplant (HSCT) patients receiving melphalan in the conditioning phase. The rapid progress in the understanding of AM created a need for new prevention and management protocols. Frequent literature review is now necessary to identify agents and protocols being developed in this important area of supportive care in cancer.

CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization.

PubMed

Sundling, Christopher; Schön, Karin; Mörner, Andreas; Forsell, Mattias N E; Wyatt, Richard T; Thorstensson, Rigmor; Karlsson Hedestam, Gunilla B; Lycke, Nils Y

2008-12-01

Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.

Mucosal immunization with PspA (Pneumococcal surface protein A)-adsorbed nanoparticles targeting the lungs for protection against pneumococcal infection

PubMed Central

Rodrigues, Tasson C.; Oliveira, Maria Leonor S.; Soares-Schanoski, Alessandra; Chavez-Rico, Stefanni L.; Figueiredo, Douglas B.; Gonçalves, Viviane M.; Ferreira, Daniela M.; Kunda, Nitesh K.; Saleem, Imran Y.

2018-01-01

Burden of pneumonia caused by Streptococcus pneumoniae remains high despite the availability of conjugate vaccines. Mucosal immunization targeting the lungs is an attractive alternative for the induction of local immune responses to improve protection against pneumonia. Our group had previously described the development of poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) polymeric nanoparticles (NPs) adsorbed with Pneumococcal surface protein A from clade 4 (PspA4Pro) within L-leucine microcarriers (nanocomposite microparticles—NCMPs) for mucosal delivery targeting the lungs (NP/NCMP PspA4Pro). NP/NCMP PspA4Pro was now used for immunization of mice. Inoculation of this formulation induced anti-PspA4Pro IgG antibodies in serum and lungs. Analysis of binding of serum IgG to intact bacteria showed efficient binding to bacteria expressing PspA from clades 3, 4 and 5 (family 2), but no binding to bacteria expressing PspA from clades 1 and 2 (family 1) was observed. Both mucosal immunization with NP/NCMP PspA4Pro and subcutaneous injection of the protein elicited partial protection against intranasal lethal pneumococcal challenge with a serotype 3 strain expressing PspA from clade 5 (PspA5). Although similar survival levels were observed for mucosal immunization with NP/NCMP PspA4Pro and subcutaneous immunization with purified protein, NP/NCMP PspA4Pro induced earlier control of the infection. Conversely, neither immunization with NP/NCMP PspA4Pro nor subcutaneous immunization with purified protein reduced bacterial burden in the lungs after challenge with a serotype 19F strain expressing PspA from clade 1 (PspA1). Mucosal immunization with NP/NCMP PspA4Pro targeting the lungs is thus able to induce local and systemic antibodies, conferring protection only against a strain expressing PspA from the homologous family 2. PMID:29360883

Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral trans-Infection of CD4+ T Cells.

PubMed

Jiang, Ai-Ping; Jiang, Jin-Feng; Wei, Ji-Fu; Guo, Ming-Gao; Qin, Yan; Guo, Qian-Qian; Ma, Li; Liu, Bao-Chi; Wang, Xiaolei; Veazey, Ronald S; Ding, Yong-Bing; Wang, Jian-Hua

2015-12-30

The gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4(+) T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viral trans-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection. In this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1 trans-infection of CD4(+) T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters.

PubMed

Barr, Jeremy J; Auro, Rita; Sam-Soon, Nicholas; Kassegne, Sam; Peters, Gregory; Bonilla, Natasha; Hatay, Mark; Mourtada, Sarah; Bailey, Barbara; Youle, Merry; Felts, Ben; Baljon, Arlette; Nulton, Jim; Salamon, Peter; Rohwer, Forest

2015-11-03

Bacteriophages (phages) defend mucosal surfaces against bacterial infections. However, their complex interactions with their bacterial hosts and with the mucus-covered epithelium remain mostly unexplored. Our previous work demonstrated that T4 phage with Hoc proteins exposed on their capsid adhered to mucin glycoproteins and protected mucus-producing tissue culture cells in vitro. On this basis, we proposed our bacteriophage adherence to mucus (BAM) model of immunity. Here, to test this model, we developed a microfluidic device (chip) that emulates a mucosal surface experiencing constant fluid flow and mucin secretion dynamics. Using mucus-producing human cells and Escherichia coli in the chip, we observed similar accumulation and persistence of mucus-adherent T4 phage and nonadherent T4∆hoc phage in the mucus. Nevertheless, T4 phage reduced bacterial colonization of the epithelium >4,000-fold compared with T4∆hoc phage. This suggests that phage adherence to mucus increases encounters with bacterial hosts by some other mechanism. Phages are traditionally thought to be completely dependent on normal diffusion, driven by random Brownian motion, for host contact. We demonstrated that T4 phage particles displayed subdiffusive motion in mucus, whereas T4∆hoc particles displayed normal diffusion. Experiments and modeling indicate that subdiffusive motion increases phage-host encounters when bacterial concentration is low. By concentrating phages in an optimal mucus zone, subdiffusion increases their host encounters and antimicrobial action. Our revised BAM model proposes that the fundamental mechanism of mucosal immunity is subdiffusion resulting from adherence to mucus. These findings suggest intriguing possibilities for engineering phages to manipulate and personalize the mucosal microbiome.

Indomethacin induced gastropathy in CD18, intercellular adhesion molecule 1, or P-selectin deficient mice

PubMed Central

Morise, Z; Granger, D; Fuseler, J; Anderson, D; Grisham, M

1999-01-01

BACKGROUND—Neutrophil-endothelial cell interactions are thought to play a critical role in the pathophysiology of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy.
AIMS—To optimise a mouse model of NSAID induced gastropathy and to evaluate the importance of adhesion molecules using adhesion molecule deficient mice.
METHODS—Gastropathy was induced in C57BL/6 mice or their adhesion molecule deficient counterparts via oral administration of indomethacin (20 mg/kg). Lesion scores, mucosal permeability, and histopathology were used to assess gastric mucosal injury.
RESULTS—Intragastric administration of indomethacin induced linear haemorrhagic mucosal lesions, primarily in the corpus of the stomach that were first observed at six hours. These lesions continued to develop over the next six hours with maximal lesion scores and mucosal permeabilities at 12 hours. When indomethacin was administered to mice deficient in CD18, intercellular adhesion molecule 1 (ICAM-1), or P-selectin, there were significant decreases in lesion scores compared with their C57BL/6 controls. In addition, mucosal permeabilities were found to be significantly lower in CD18 or ICAM-1 deficient mice observed at 12 hours.
CONCLUSION—Certain leucocyte and endothelial cell adhesion molecules are important determinants for full expression of indomethacin induced gastropathy. It is proposed that this modification of the mouse model may be useful for the investigation of other pathophysiological mechanisms of NSAID induced gastropathy.


Keywords: indomethacin; gastropathy; cyclooxygenase; intercellular adhesion molecule; VCAM; vascular cell adhesion molecule; P-selectin PMID:10486359

Mitochondrial gene polymorphisms that protect mice from colitis.

PubMed

Bär, Florian; Bochmann, Wiebke; Widok, Andrea; von Medem, Kilian; Pagel, Rene; Hirose, Misa; Yu, Xinhua; Kalies, Kathrin; König, Peter; Böhm, Ruwen; Herdegen, Thomas; Reinicke, Anna T; Büning, Jürgen; Lehnert, Hendrik; Fellermann, Klaus; Ibrahim, Saleh; Sina, Christian

2013-11-01

Dysregulated energy homeostasis in the intestinal mucosa frequently is observed in patients with ulcerative colitis (UC). Intestinal tissues from these patients have reduced activity of the mitochondrial oxidative phosphorylation (OXPHOS) complex, so mitochondrial dysfunction could contribute to the pathogenesis of UC. However, little is known about the mechanisms by which OXPHOS activity could be altered. We used conplastic mice, which have identical nuclear but different mitochondrial genomes, to investigate activities of the OXPHOS complex. Colitis was induced in C57BL/6J wild-type (B6.B6) and 3 strains of conplastic mice (B6.NZB, B6.NOD, and B6.AKR) by administration of dextran sodium sulfate or rectal application of trinitrobenzene sulfonate. Colon tissues were collected and analyzed by histopathology, immunohistochemical analysis, and immunoblot analysis; we also measured mucosal levels of adenosine triphosphate (ATP) and reactive oxygen species, OXPHOS complex activity, and epithelial cell proliferation and apoptosis. We identified mice with increased mucosal OXPHOS complex activities and levels of ATP. These mice developed less-severe colitis after administration of dextran sodium sulfate or trinitrobenzene sulfonate than mice with lower mucosal levels of ATP. Colon tissues from these mice also had increased enterocyte proliferation and transcription factor nuclear factor-κB activity, which have been shown to protect the mucosal barrier-defects in these processes have been associated with inflammatory bowel disease. Variants in mitochondrial DNA that increase mucosal levels of ATP protect mice from colitis. Increasing mitochondrial ATP synthesis in intestinal epithelial cells could be a therapeutic approach for UC. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Shear properties of vocal fold mucosal tissues and their effect on vocal fold oscillation

NASA Astrophysics Data System (ADS)

Chan, Roger Wai Kai

Viscoelastic shear properties of vocal fold mucosal tissues and phonosurgical biomaterials were measured with a parallel-plate rotational rheometer. Elastic, viscous and damping properties were quantified as a function of frequency (0.01 Hz to 15 Hz) for human vocal fold mucosal tissues (N = 15), implantable biomaterials commonly used in the treatment of vocal fold paralysis (Teflon, gelatin, and collagen) (the non-mucosal group), and biomaterials currently or potentially useful in the treatment of vocal fold mucosal defects (adipose tissue or fat, hyaluronic acid, and fibronectin) (the mucosal group). It was found that intersubject differences as large as an order of magnitude were often observed for the shear properties of vocal fold mucosal tissues, part of which may be age- and gender-related. Shear properties of the non-mucosal group biomaterials were often much higher than those of the mucosal group biomaterials, which were relatively close to the shear properties of mucosal tissues. Viscoelastic and rheological modeling showed that shear properties of human vocal fold mucosa may be described by a quasi-linear viscoelastic theory and a statistical network theory, based upon which extrapolations to audio frequencies were possible. A theory of small-amplitude vocal fold oscillation was revisited to describe the effects of tissue shear properties on vocal fold oscillation and phonation threshold pressure, a measure of the 'ease' of phonation and an objective indication of vocal function. It was found that phonation threshold pressure is directly related to the viscous shear modulus or the 'effective damping modulus', a concept proposed to quantify the effective amount of damping in vocal fold oscillation. The mucosal group biomaterials were incorporated into the artificial vocal fold mucosa of a physical model in order to empirically assess their effects on phonation threshold pressure. Results showed that higher threshold pressures were consistently observed for higher concentrations of hyaluronic acid and for hyaluronic acid mixed with fibronectin, in correlation with their differences in viscous shear modulus and effective damping modulus. Implications for phonosurgery were discussed in terms of the choice of optimal biomaterials for the surgical management of vocal fold mucosal defects and lamina propria deficiencies.

Enhancement of Antituberculosis Immunity in a Humanized Model System by a Novel Virus-Vectored Respiratory Mucosal Vaccine.

PubMed

Yao, Yushi; Lai, Rocky; Afkhami, Sam; Haddadi, Siamak; Zganiacz, Anna; Vahedi, Fatemeh; Ashkar, Ali A; Kaushic, Charu; Jeyanathan, Mangalakumari; Xing, Zhou

2017-07-01

The translation of preclinically promising novel tuberculosis vaccines to ultimate human applications has been challenged by the lack of animal models with an immune system equivalent to the human immune system in its genetic diversity and level of susceptibility to tuberculosis. We have developed a humanized mice (Hu-mice) tuberculosis model system to investigate the clinical relevance of a novel virus-vectored (VV) tuberculosis vaccine administered via respiratory mucosal or parenteral route. We find that VV vaccine activates T cells in Hu-mice as it does in human vaccinees. The respiratory mucosal route for delivery of VV vaccine in Hu-mice, but not the parenteral route, significantly reduces the humanlike lung tuberculosis outcomes in a human T-cell-dependent manner. Our results suggest that the Hu-mouse can be used to predict the protective efficacy of novel tuberculosis vaccines/strategies before they proceed to large, expensive human trials. This new vaccine testing system will facilitate the global pace of clinical tuberculosis vaccine development. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Immunogenicity of Recombinant Classic Swine Fever Virus CD8+ T Lymphocyte Epitope and Porcine Parvovirus VP2 Antigen Coexpressed by Lactobacillus casei in Swine via Oral Vaccination ▿

PubMed Central

Xu, Yigang; Cui, Lichun; Tian, Changyong; Zhang, Guocai; Huo, Guicheng; Tang, Lijie; Li, Yijing

2011-01-01

Classical swine fever virus (CSFV) and porcine parvovirus (PPV) are highly contagious pathogens, resulting in enormous economic losses in pig industries worldwide. Because vaccines play an important role in disease control, researchers are seeking improved vaccines that could induce antiviral immune responses against CSFV and PPV at the mucosal and systemic levels simultaneously. In this study, a genetically engineered Lactobacillus strain coexpressing the CSFV-specific cytotoxic T lymphocyte (CTL) epitope 290 and the VP2 antigen of PPV was developed, and its immunopotentiating capacity as an oral vaccine in pigs was analyzed. The data demonstrated that in the absence of any adjuvant, the recombinant Lactobacillus strain can efficiently stimulate mucosal and systemic CSFV-specific CD8+ CTL responses to protect pigs against CSFV challenge. Moreover, anti-PPV-VP2 serum IgG and mucosal IgA were induced in pigs immunized orally with the recombinant Lactobacillus strain, showing a neutralizing effect on PPV infection. The results suggest that the recombinant Lactobacillus microecological agent may be a valuable component of a strategy for development of a vaccine against CSFV and PPV. PMID:21940406

Old and New Lymphocyte Players in Inflammatory Bowel Disease.

PubMed

Giuffrida, Paolo; Corazza, Gino Roberto; Di Sabatino, Antonio

2018-02-01

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.

HIV infection and specific mucosal immunity: workshop 4B.

PubMed

Challacombe, S J; Fidel, P L; Tugizov, S; Tao, L; Wahl, S M

2011-04-01

Most HIV infections are transmitted across mucosal epithelium. An area of fundamental importance is understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, which leads to increased susceptibility to bacterial, fungal, and viral infections of oral and other mucosae. This workshop attempted to address 5 basic issues-namely, HIV acquisition across mucosal surfaces, innate and adaptive immunity in HIV resistance, antiviral activity of breast milk as a model mucosal fluid, neutralizing immunoglobulin A antibodies against HIV, and progress toward a mucosal vaccine against HIV. The workshop attendants agreed that progress had been made in each area covered, with much recent information. However, these advances revealed how little work had been performed on stratified squamous epithelium compared with columnar epithelium, and the attendants identified several important biological questions that had not been addressed. It is increasingly clear that innate immunity has an important biological role, although basic understanding of the mechanisms of normal homeostasis is still being investigated. Application of the emerging knowledge was lacking with regard to homeostatic mucosal immunity to HIV and its role in changing this homeostasis. With regard to breast milk, a series of studies have demonstrated the differences between transmitters and nontransmitters, although whether these findings could be generalized to other secretions such as saliva was less clear. Important progress toward an oral mucosal HIV vaccine has been made, demonstrating proof of principle for administering vaccine candidates into oral lymphoid tissues to trigger anti-HIV local and systemic immune responses. Similarly, experimental data emphasized the central role of neutralizing antibodies to prevent HIV infection via mucosal routes.

Gallic acid prevents nonsteroidal anti-inflammatory drug-induced gastropathy in rat by blocking oxidative stress and apoptosis.

PubMed

Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd Shameel; Maity, Pallab; Adhikari, Susanta S; Bandyopadhyay, Uday

2010-07-15

Nonsteroidal anti-inflammatory drug (NSAID)-induced oxidative stress plays a critical role in gastric mucosal cell apoptosis and gastropathy. NSAIDs induce the generation of hydroxyl radical ((*)OH) through the release of free iron, which plays an important role in developing gastropathy. Thus, molecules having both iron-chelating and antiapoptotic properties will be beneficial in preventing NSAID-induced gastropathy. Gallic acid (GA), a polyphenolic natural product, has the capacity to chelate free iron. Here, we report that GA significantly prevents, as well as heals, NSAID-induced gastropathy. In vivo, GA blocks NSAID-mediated mitochondrial oxidative stress by preventing mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. In vitro, GA scavenges free radicals and blocks (*)OH-mediated oxidative damage. GA also attenuates gastric mucosal cell apoptosis in vivo as well as in vitro in cultured gastric mucosal cells as evident from the TUNEL assay. GA prevents NSAID-induced activation of caspase-9, a marker for the mitochondrial pathway of apoptosis, and restores NSAID-mediated collapse of the mitochondrial transmembrane potential and dehydrogenase activity. Thus, the inhibition of mitochondrial oxidative stress by GA is associated with the inhibition of NSAID-induced mitochondrial dysfunction and activation of apoptosis in gastric mucosal cells, which are responsible for gastric injury or gastropathy. Copyright 2010 Elsevier Inc. All rights reserved.

Foot-and-mouth disease virus replicates only transiently in well-differentiated porcine nasal epithelial cells.

PubMed

Dash, Pradyot; Barnett, Paul V; Denyer, Michael S; Jackson, Terry; Stirling, Catrina M A; Hawes, Philippa C; Simpson, Jennifer L; Monaghan, Paul; Takamatsu, Haru-H

2010-09-01

Three-dimensional (3D) porcine nasal mucosal and tracheal mucosal epithelial cell cultures were developed to analyze foot-and-mouth disease virus (FMDV) interactions with mucosal epithelial cells. The cells in these cultures differentiated and polarized until they closely resemble the epithelial layers seen in vivo. FMDV infected these cultures predominantly from the apical side, primarily by binding to integrin alphav beta6, in an Arg-Gly-Asp (RGD)-dependent manner. However, FMDV replicated only transiently without any visible cytopathic effect (CPE), and infectious progeny virus could be recovered only from the apical side. The infection induced the production of beta interferon (IFN-beta) and the IFN-inducible gene Mx1 mRNA, which coincided with the disappearance of viral RNA and progeny virus. The induction of IFN-beta mRNA correlated with the antiviral activity of the supernatants from both the apical and basolateral compartments. IFN-alpha mRNA was constitutively expressed in nasal mucosal epithelial cells in vitro and in vivo. In addition, FMDV infection induced interleukin 8 (IL-8) protein, granulocyte-macrophage colony-stimulating factor (GM-CSF), and RANTES mRNA in the infected epithelial cells, suggesting that it plays an important role in modulating the immune response.

IgA response and protection following nasal vaccination of chickens with Newcastle disease virus DNA vaccine nanoencapsulated with Ag@SiO2 hollow nanoparticles

PubMed Central

Zhao, Kai; Rong, Guangyu; Hao, Yan; Yu, Lu; Kang, Hong; Wang, Xin; Wang, Xiaohua; Jin, Zheng; Ren, Zhiyu; Li, Zejun

2016-01-01

Newcastle disease caused by ND virus (NDV) is a highly contagious disease of birds. Vaccine for effective protection of poultry animals from NDV infection is urgently needed. Mucosal immunity plays a very important role in the antiviral immune response. In this study, a NDV F gene-containing DNA vaccine encapsulated in Ag@SiO2 hollow nanoparticles (pFDNA-Ag@SiO2-NPs) with an average diameter of 500 nm were prepared to assess the mucosal immune response. These nanoparticles exhibited low cytotoxicity and did not destroy the bioactivity of plasmid DNA, which could be expressed in vitro. The plasmid DNA was sustainably released after an initial burst release. In vivo immunization showed that the intranasal immunization of chickens with pFDNA-Ag@SiO2-NPs induced high titers of serum antibody, significantly promoted lymphocyte proliferation and induced higher expression levels of IL-2 and IFN-γ in a dose-dependent manner. These results indicated that the Ag@SiO2 hollow nanoparticles could serve as an efficient and safe delivery carrier for NDV DNA vaccine to induce mucosal immunity. This study has provided promising results for the further development of mucosal vaccines encapsulated in inorganic nanoparticles. PMID:27170532

Oral mucosal lesions and immune status in HIV-infected Indian children.

PubMed

Subramaniam, Priya; Kumar, Krishna

2015-04-01

Pediatric HIV is growing at an alarming rate in developing countries. Due to their compromised immune status, children infected with HIV are prone to a number of opportunistic infections. Oral manifestations are the first signs of the disease in many of them. To assess the oral mucosal status of Indian children with HIV, based on their CD4 cell counts. Two hundred and twenty one HIV infected children aged 6-18 years from various HIV centers, were divided into three groups, based on their CD4 cell counts; Group 1: ≥500, Group 2: 201-499 and Group 3: ≤200 cells. The children in each group were further considered as 'prior to antiretroviral treatment (ART)' and 'on ART'. Oral mucosal examination was done based on presumptive criteria given by Ramos-Gomez for diagnosis of oro-facial lesions commonly associated with HIV infection in children. Data obtained was subjected to statistical analysis. Angular cheilitis and pseudomembranous candidiasis were the frequently seen oral lesions. Children with CD4 cell count ≥500 had significantly fewer oral lesions each. A high percentage of HIV-infected children were affected with oral mucosal lesions. There was a significant association between immune status and frequency of oral lesions. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Selection of new lactic acid bacteria strains bearing probiotic features from mucosal microbiota of healthy calves: Looking for immunobiotics through in vitro and in vivo approaches for immunoprophylaxis applications.

PubMed

Sandes, Sávio; Alvim, Luige; Silva, Bruno; Acurcio, Leonardo; Santos, Cinara; Campos, Márcia; Santos, Camila; Nicoli, Jacques; Neumann, Elisabeth; Nunes, Álvaro

2017-07-01

From the birth, since their mucosal microbiota and immune system are not fully developed, newborn calves are susceptible to several mucosal pathogenic microorganisms. Operating through humoral and non-humoral mechanisms in the host, several lactic acid bacteria strains bearing probiotic features are often employed in livestock as food supplement, improving animal production performance, promoting health and reducing the severity of mucosal infections. Accordingly, we isolated, species-level identified and screened for their probiotic potentials seventy lactic acid bacteria strains from upper airway, vaginal and intestinal mucosa of healthy calves. Based on in vitro approaches, we selected three strains: Lactobacillus fermentum V3B-08 isolated from upper airway mucosa, Weissella hellenica V1V-30 isolated from vaginal mucosa and Lactobacillus farciminis B4F-06 isolated from intestinal mucosa were used to mono-colonize germ-free mice in the same site in which these strains were isolated, aiming to characterize their immunomodulatory features. These strains were able to colonize germ-free mice mucosa and trigger sIgA synthesis at a local level, in addition to stimulating, in different ways, adaptive immune responses at a systemic level. Copyright © 2017 Elsevier GmbH. All rights reserved.

[Research progress of relationship between diabetes and intestinal epithelial tight junction barrier and intervetion of berberine].

PubMed

Qin, Xin; Dong, Hui; Lu, Fu-Er

2016-06-01

Intestinal tight junction is an important part of the small intestinal mucosa barrier. It plays a very significant role in maintaining the intestinal mucosal permeability and integrity, preventing the bacterial endotoxin and toxic macromolecular substances into the body so as to keep a stable internal environment. Numerous studies have shown that intestinal mucosal barrier dysfunction is closely related to the development of diabetes. Therefore, protecting intestinal tight junction and maintaining the mucosal barrier have great significance in the prevention and treatment of diabetes. The effect of berberine in diabetes treatment is obvious. However, the pharmacological study found that the bioavailability of berberine is extremely low. Some scholars put forward that the major site of pharmaceutical action of berberine might be in the gut. Studies have shown that berberine could regulate the intestinal flora and intestinal hormone secretion, protect the intestinal barrier, inhibit the absorption of glucose, eliminate the intestinal inflammation and so on. Recently studies have found that the hypoglycemic effect of berberine is likely to relate with the influence on intestinal tight junction and the protection of mucosal barrier. Here is the review about the association between intestinal tight junction barrier dysfunction and diabetes, and the related hypoglycemic mechanism of berberine. Copyright© by the Chinese Pharmaceutical Association.

IgA response and protection following nasal vaccination of chickens with Newcastle disease virus DNA vaccine nanoencapsulated with Ag@SiO2 hollow nanoparticles

NASA Astrophysics Data System (ADS)

Zhao, Kai; Rong, Guangyu; Hao, Yan; Yu, Lu; Kang, Hong; Wang, Xin; Wang, Xiaohua; Jin, Zheng; Ren, Zhiyu; Li, Zejun

2016-05-01

Newcastle disease caused by ND virus (NDV) is a highly contagious disease of birds. Vaccine for effective protection of poultry animals from NDV infection is urgently needed. Mucosal immunity plays a very important role in the antiviral immune response. In this study, a NDV F gene-containing DNA vaccine encapsulated in Ag@SiO2 hollow nanoparticles (pFDNA-Ag@SiO2-NPs) with an average diameter of 500 nm were prepared to assess the mucosal immune response. These nanoparticles exhibited low cytotoxicity and did not destroy the bioactivity of plasmid DNA, which could be expressed in vitro. The plasmid DNA was sustainably released after an initial burst release. In vivo immunization showed that the intranasal immunization of chickens with pFDNA-Ag@SiO2-NPs induced high titers of serum antibody, significantly promoted lymphocyte proliferation and induced higher expression levels of IL-2 and IFN-γ in a dose-dependent manner. These results indicated that the Ag@SiO2 hollow nanoparticles could serve as an efficient and safe delivery carrier for NDV DNA vaccine to induce mucosal immunity. This study has provided promising results for the further development of mucosal vaccines encapsulated in inorganic nanoparticles.

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

PubMed Central

van Putten, Jos P.M.; Strijbis, Karin

2017-01-01

Mucosal surfaces line our body cavities and provide the interaction surface between commensal and pathogenic microbiota and the host. The barrier function of the mucosal layer is largely maintained by gel-forming mucin proteins that are secreted by goblet cells. In addition, mucosal epithelial cells express cell-bound mucins that have both barrier and signaling functions. The family of transmembrane mucins consists of diverse members that share a few characteristics. The highly glycosylated extracellular mucin domains inhibit invasion by pathogenic bacteria and can form a tight mesh structure that protects cells in harmful conditions. The intracellular tails of transmembrane mucins can be phosphorylated and connect to signaling pathways that regulate inflammation, cell-cell interactions, differentiation, and apoptosis. Transmembrane mucins play important roles in preventing infection at mucosal surfaces, but are also renowned for their contributions to the development, progression, and metastasis of adenocarcinomas. In general, transmembrane mucins seem to have evolved to monitor and repair damaged epithelia, but these functions can be highjacked by cancer cells to yield a survival advantage. This review presents an overview of the current knowledge of the functions of transmembrane mucins in inflammatory processes and carcinogenesis in order to better understand the diverse functions of these multifunctional proteins. PMID:28052300

Preparation of mucosal nanoparticles and polymer-based inactivated vaccine for Newcastle disease and H9N2 AI viruses

PubMed Central

Naggar, Heba M. El; Madkour, Mohamed Sayed; Hussein, Hussein Ali

2017-01-01

Aim: To develop a mucosal inactivated vaccines for Newcastle disease (ND) and H9N2 viruses to protect against these viruses at sites of infections through mucosal immunity. Materials and Methods: In this study, we prepared two new formulations for mucosal bivalent inactivated vaccine formulations for Newcastle and Avian Influenza (H9N2) based on the use of nanoparticles and polymer adjuvants. The prepared vaccines were delivered via intranasal and spray routes of administration in specific pathogen-free chickens. Cell-mediated and humoral immune response was measured as well as challenge trial was carried out. In addition, ISA71 water in oil was also evaluated. Results: Our results showed that the use of spray route as vaccination delivery method of polymer and nanoparticles Montanide™ adjuvants revealed that it enhanced the cell mediated immune response as indicated by phagocytic activity, gamma interferon and interleukin 6 responses and induced protection against challenge with Newcastle and Avian Influenza (H9N2) viruses. Conclusion: The results of this study demonstrate the potentiality of polymer compared to nanoparticles adjuvantes when used via spray route. Mass application of such vaccines will add value to improve the vaccination strategies against ND virus and Avian influenza viruses. PMID:28344402

Quantitative evaluation of mucosal vascular contrast in narrow band imaging using Monte Carlo modeling

NASA Astrophysics Data System (ADS)

Le, Du; Wang, Quanzeng; Ramella-Roman, Jessica; Pfefer, Joshua

2012-06-01

Narrow-band imaging (NBI) is a spectrally-selective reflectance imaging technique for enhanced visualization of superficial vasculature. Prior clinical studies have indicated NBI's potential for detection of vasculature abnormalities associated with gastrointestinal mucosal neoplasia. While the basic mechanisms behind the increased vessel contrast - hemoglobin absorption and tissue scattering - are known, a quantitative understanding of the effect of tissue and device parameters has not been achieved. In this investigation, we developed and implemented a numerical model of light propagation that simulates NBI reflectance distributions. This was accomplished by incorporating mucosal tissue layers and vessel-like structures in a voxel-based Monte Carlo algorithm. Epithelial and mucosal layers as well as blood vessels were defined using wavelength-specific optical properties. The model was implemented to calculate reflectance distributions and vessel contrast values as a function of vessel depth (0.05 to 0.50 mm) and diameter (0.01 to 0.10 mm). These relationships were determined for NBI wavelengths of 410 nm and 540 nm, as well as broadband illumination common to standard endoscopic imaging. The effects of illumination bandwidth on vessel contrast were also simulated. Our results provide a quantitative analysis of the effect of absorption and scattering on vessel contrast. Additional insights and potential approaches for improving NBI system contrast are discussed.

Herbs in Oral Mucositis

PubMed Central

Baharvand, Maryam; Jafari, Soudeh

2017-01-01

Oral mucositis is an inflammatory mucosal destruction as a result of chemotherapy and/or radiation therapy, which in severe cases can impair patients’ quality of life. Moreover, mucosal infection and/or systemic involvement due to compromised immunity leads to delay or discontinuation of the treatment. Many strategies and agents have been suggested for the management of this condition. Because of their lower side effects compared to chemical drugs, general interest in evaluating therapeutic effects of herbs has been increased intensively. Herbal plants apply their effect through different mechanisms of action: antioxidant, analgesic, anti-inflammatory, antifungal, antiseptic, and anticarcinogenic activity. Recently, various natural agents in plants have been noticed in mucositis, which may improve the symptoms through different interventions. The purpose of this review is to focus on the preventive or therapeutic use of herbal medicine to alleviate oral mucositis. PMID:28511530

Simian immunodeficiency virus SIVmac239 infection and simian human immunodeficiency virus SHIV89.6P infection result in progression to AIDS in cynomolgus macaques of Asian origin.

PubMed

Okamura, Tomotaka; Tsujimura, Yusuke; Soma, Shogo; Takahashi, Ichiro; Matsuo, Kazuhiro; Yasutomi, Yasuhiro

2016-12-01

Simian immunodeficiency virus (SIV) infection models in cynomolgus macaques are important for analysis of the pathogenesis of immunodeficiency virus and for studies on the efficacy of new vaccine candidates. However, very little is known about the pathogenesis of SIV or simian human immunodeficiency virus (SHIV) in cynomolgus macaques from different Asian countries. In the present study, we analysed the infectivity and pathogenicity of CCR5-tropic SIVmac and those of dual-tropic SHIV89.6P inoculated into cynomolgus macaques in Indonesian, Malaysian or Philippine origin. The plasma viral loads in macaques infected with either SIVmac239 or SHIV89.6P were maintained at high levels. CD4+ T cell levels in macaques infected with SIVmac239 gradually decreased. All of the macaques infected with SHIV89.6P showed greatly reduced CD4+ T-cell numbers within 6 weeks of infection. Eight of the 11 macaques infected with SIVmac239 were killed due to AIDS symptoms after 2-4.5 years, while four of the five macaques infected with SHIV89.6P were killed due to AIDS symptoms after 1-3.5 years. We also analysed cynomolgus macaques infected intrarectally with repeated low, medium or high doses of SIVmac239, SIVmac251 or SHIV89.6P. Infection was confirmed by quantitative RT-PCR at more than 5000, 300 and 500 TCID50 for SIVmac239, SIVmac251 and SHIV89.6P, respectively. The present study indicates that cynomolgus macaques of Asian origin are highly susceptible to SIVmac and SHIV infection by both intravenous and mucosal routes. These models will be useful for studies on virus pathogenesis, vaccination and therapeutics against human immunodeficiency virus/AIDS.

Palifermin in the management of mucositis in hematological malignancies: current evidences and future perspectives.

PubMed

Niscola, Pasquale; Scaramucci, Laura; Giovannini, Marco; Ales, Micaela; Bondanini, Francesco; Cupelli, Luca; Dentamaro, Teresa; Lamanda, Michela; Natale, Giuseppina; Palumbo, Roberto; Romani, Claudio; Tendas, Andrea; Tolu, Barbara; Violo, Leano; de Fabritiis, Paolo

2009-10-01

In the management of hematological malignancies, chemotherapy-induced mucositis is an increasingly recognized problem, leading to potentially severe clinical complications, treatment delays, increased costs and impairment of patient's quality of life. Many forms of cytotoxic treatments given in this setting may induce several degrees of mucositis. In particular, conditioning therapy with hematopoietic stem cell transplantation (HSCT) induces a disruption of the mucosal barrier function throughout the entire gastrointestinal tract facilitating the spreading of bacteria and endotoxin with subsequent increased risk of septicemia and, in the allogeneic setting, a worsening of Graft Versus Host Disease (GVHD). To review the role of palifermin and of other existing and potential treatments for chemotherapy-induced mucositis in the context of current knowledge of pathobiology in the setting of hematological malignancies. We searched for palifermin and mucositis of any region of the gastrointestinal tract using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. The pathobiology of mucositis is complex, and agents that target mechanisms to prevent mucositis or accelerate healing are highly required. In this regard, palifermin (recombinant human keratinocyte growth factor) has been demonstrated to reduce the severity and the duration of oral mucositis and to significantly improve several treatment outcomes in patients submitted to autologous HSCT; data are insufficient to recommend its use in the non-autologous HSCT settings, although interesting properties of this agent deserves other investigations in order to explore other possible indications.

Retinaldehyde dehydrogenase 2 as a molecular adjuvant for enhancement of mucosal immunity during DNA vaccination.

PubMed

Holechek, Susan A; McAfee, Megan S; Nieves, Lizbeth M; Guzman, Vanessa P; Manhas, Kavita; Fouts, Timothy; Bagley, Kenneth; Blattman, Joseph N

2016-11-04

In order for vaccines to induce efficacious immune responses against mucosally transmitted pathogens, such as HIV-1, activated lymphocytes must efficiently migrate to and enter targeted mucosal sites. We have previously shown that all-trans retinoic acid (ATRA) can be used as a vaccine adjuvant to enhance mucosal CD8 + T cell responses during vaccination and improve protection against mucosal viral challenge. However, the ATRA formulation is incompatible with most recombinant vaccines, and the teratogenic potential of ATRA at high doses limits its usage in many clinical settings. We hypothesized that increasing in vivo production of retinoic acid (RA) during vaccination with a DNA vector expressing retinaldehyde dehydrogenase 2 (RALDH2), the rate-limiting enzyme in RA biosynthesis, could similarly provide enhanced programming of mucosal homing to T cell responses while avoiding teratogenic effects. Administration of a RALDH2- expressing plasmid during immunization with a HIVgag DNA vaccine resulted in increased systemic and mucosal CD8 + T cell numbers with an increase in both effector and central memory T cells. Moreover, mice that received RALDH2 plasmid during DNA vaccination were more resistant to intravaginal challenge with a recombinant vaccinia virus expressing the same HIVgag antigen (VACVgag). Thus, RALDH2 can be used as an alternative adjuvant to ATRA during DNA vaccination leading to an increase in both systemic and mucosal T cell immunity and better protection from viral infection at mucosal sites. Copyright © 2016 Elsevier Ltd. All rights reserved.

Comparative Efficacy of Aloe vera and Benzydamine Mouthwashes on Radiation-induced Oral Mucositis: A Triple-blind, Randomised, Controlled Clinical Trial.

PubMed

Sahebjamee, Mahnaz; Mansourian, Arash; Hajimirzamohammad, Mohammad; Mohammad, Haji Mirza Mohammad; Zadeh, Mohsen Taghi; Bekhradi, Reza; Kazemian, Ali; Manifar, Soheila; Ashnagar, Sajjad; Doroudgar, Kiavash

2015-01-01

To compare the efficacy of an Aloe vera mouthwash with a benzydamine mouthwash in the alleviation of radiation- induced mucositis in head and neck cancer patients using a triple-blind, randomised controlled trial. Twenty-six eligible head and neck cancer patients who were to receive conventional radiation therapy at the radiation oncology department were randomised to receive an Aloe vera mouthwash or a benzydamine mouthwash. Mucositis severity was assessed during the course of radiation therapy using the WHO grading system. At baseline, there was no difference in the distribution of mucositis severity between the two groups. The mean interval between radiation therapy and onset of mucositis was similar for both groups (Aloe vera 15.69±7.77 days, benzydamine 15.85±12.96 days). The mean interval between the start of radiation therapy and the maximum severity of mucositis were was also similar in both the Aloe vera and benzydamine groups (Aloe vera 23.38±10.75 days, benzydamine 23.54±15.45 days). Mean changes of mucositis severity over time in both groups were statistically similar and the effect of both treatments did not change signficantly with time (p=0.09). Aloe vera mouthwash was as beneficial as benzydamine mouthwash in alleviating the severity of radiation-induced mucositis and showed no side effects. The Aloe vera mouthwash could be an alternative agent in the treatment of radiation-induced mucositis in patients with head and neck cancers.

The effect of topical application of pure honey on radiation-induced mucositis: a randomized clinical trial.

PubMed

Motallebnejad, M; Akram, S; Moghadamnia, A; Moulana, Z; Omidi, S

2008-03-01

Radiation-induced mucositis is an early effect of head and neck radiotherapy. Mucositis can cause ulcers, and patients may experience pain and dysphasia which need treatment. The aim of this study is to evaluate the effect of pure natural honey on radiation induced mucositis. In this randomized single blind (examiner blind) clinical trial 40 patients with head and neck cancer requiring radiation to the oropharyngeal mucosa were randomly assigned to two groups. Twenty patients assigned to the study group received honey, while both the study and control groups received standard head and neck radiation therapy based on a standard protocol. In the study group patients were instructed to take 20 ml of honey 15 minutes before radiation therapy, then again at intervals of 15 minutes and six hours after radiation. In the control group patients were instructed to rinse with 20 ml of saline before and after radiation. Patients were evaluated weekly for progression of mucositis using the Oral Mucositis Assessing Scale (OMAS). Data were analyzed using the independent t-test, Mann-Whitney, and Friedman tests. A significant reduction in mucositis among honey-received patients compared with controls (p=0.000) occurred. Within the limits of this study the results showed the application of natural honey is effective in managing radiation induced mucositis. Natural honey is a product with rich nutritional qualities that could be a pleasant, simple, and economic modality for the management of radiation mucositis.

Effect of Kangfuxin Solution on Chemo/Radiotherapy-Induced Mucositis in Nasopharyngeal Carcinoma Patients: A Multicenter, Prospective Randomized Phase III Clinical Study

PubMed Central

Luo, Yangkun; Feng, Mei; Fan, Zixuan; Zhu, Xiaodong; Jin, Feng; Li, Rongqing; Wu, Jingbo; Yang, Xia; Jiang, Qinghua; Bai, Hongfang; Huang, Yecai; Lang, Jinyi

2016-01-01

Objective. To evaluate the efficacy and safety of Kangfuxin Solution, a pure Chinese herbal medicine, on mucositis induced by chemoradiotherapy in nasopharyngeal carcinoma patients. Methods. A randomized, parallel-group, multicenter clinical study was performed. A total of 240 patients were randomized to receive either Kangfuxin Solution (test group) or compound borax gargle (control group) during chemoradiotherapy. Oral mucositis, upper gastrointestinal mucositis, and oral pain were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and the Verbal Rating Scale (VRS). Results. Of 240 patients enrolled, 215 were eligible for efficacy analysis. Compared with the control group, the incidence and severity of oral mucositis in the test group were significantly reduced (P = 0.01). The time to different grade of oral mucositis occurrence (grade 1, 2, or 3) was longer in test group (P < 0.01), and the accumulated radiation dose was also higher in test group comparing to the control group (P < 0.05). The test group showed lower incidence of oral pain and gastrointestinal mucositis than the control group (P < 0.01). No significant adverse events were observed. Conclusion. Kangfuxin Solution demonstrated its superiority to compound borax gargle on mucositis induced by chemoradiotherapy. Its safety is acceptable for clinical application. PMID:27375766

Human intestinal mucosal mast cells: expanded population in untreated coeliac disease.

PubMed Central

Strobel, S; Busuttil, A; Ferguson, A

1983-01-01

Previous retrospective studies of intestinal mucosal mast cells in coeliac disease have given divergent results, and we have recently reported that inappropriate methodology could account for these discrepancies. In this prospective study, mucosal mast cell counts were performed in Carnoy fixed, peroral jejunal biopsy specimens from patients with coeliac disease, both untreated and treated with a gluten-free diet; and from controls (mainly irritable bowel syndrome). Mean mucosal mast cell count in 27 control subjects was 146/mm2, SD 29. Significantly higher values were obtained in untreated coeliac disease (mean 243, SD 41, p less than 0.001) returning to the normal range in coeliacs treated with a gluten-free diet with normal jejunal biopsy morphology. In seven patients mucosal mast cell counts were performed in multiple jejunal biopsies, and these showed that mucosal mast cell distribution was not patchy. There was no evidence of degranulation of intestinal mucosal mast cells under the conditions of routine biopsy (overnight fast). An increase in mucosal mast cells in untreated coeliac disease may be one explanation for the high number of IgE positive stained cells in the intestinal mucosa that has been reported by some authors. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:6826106

Severity of Oral Mucositis in Children following Chemotherapy and Radiotherapy and Its Implications at a Single Oncology Centre in Durango State, Mexico.

PubMed

Carreón-Burciaga, Ramón G; Castañeda-Castaneira, Enrique; González-González, Rogelio; Molina-Frechero, Nelly; Gaona, Enrique; Bologna-Molina, Ronell

2018-01-01

Mucositis is an adverse effect of chemotherapy (QT) and/or radiotherapy (RT). The purpose of this study was to investigate the occurrence of oral mucositis in children undergoing cancer treatment. Fifty-one children with cancer who had received QT, RT, or both (QT-RT) underwent clinical evaluations; World Health Organization criteria were used to establish the degree and severity of mucositis. The correlations between the clinical data, type of cancer, and therapy were statistically analysed. Mucositis was present in 88.23% of the patients; 57.78%, 7.78%, and 24.44% received QT, RT, and QT-RT, respectively. Severity scores of 1 and 2 were the most common; scores of 3-4 were observed in patients who received QT-RT or more than 7 treatment cycles. There was a significant association between mucositis, the type of treatment, and the number of cycles received ( p < 0.05). It is important to implement therapeutic protocols that help maintain excellent oral health and reduce the risk of oral mucositis. Stomatologists should be consulted to assess patients' oral cavities and provide preventive treatment prior to QT and/or RT administration. It is important to integrate a stomatologist into the oncological working group to focus on preventing and managing oral mucositis.

Genetic modification to induce CXCR2 overexpression in mesenchymal stem cells enhances treatment benefits in radiation-induced oral mucositis.

PubMed

Shen, Zongshan; Wang, Jiancheng; Huang, Qiting; Shi, Yue; Wei, Zhewei; Zhang, Xiaoran; Qiu, Yuan; Zhang, Min; Wang, Yi; Qin, Wei; Huang, Shuheng; Huang, Yinong; Liu, Xin; Xia, Kai; Zhang, Xinchun; Lin, Zhengmei

2018-02-14

Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR 2 -overexpressing MSCs (MSCs CXCR2 ) for mucositis treatment. Indeed, MSCs CXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSC CXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.

Oral Mucosal Lesions in Indians From Northeast Brazil

PubMed Central

Cury, Patricia Ramos; Porto, Lia Pontes Arruda; dos Santos, Jean Nunes; e Ribeiro, Livia Silva Figueiredo; de Aquino Xavier, Flavia Caló; Figueiredo, Andreia Leal; Ramalho, Luciana Maria Pedreira

2014-01-01

Abstract The aim of this cross-sectional study was to evaluate the prevalence of oral mucosal lesions, and their risk indicators in adult Kiriri Indians from Northeast Brazil. Clinical oral examination was performed on a representative sample of 223 Indians (age ≥19 years). A systematic evaluation of lips, labial mucosa and sulcus, commissures, buccal mucosa and sulcus, gingiva and alveolar ridge, tongue, floor of the mouth, and soft and hard palate was performed. Bivariate analysis was conducted to assess associations between mucosal conditions and age, gender, income, educational level, diabetic status, and smoking status. Mucosal lesions were found in 50 participants (22.4%). The most prevalent lesions were fistulae (6.2%) and traumatic ulcers (4.48%). Oral mucosal was associated with higher age (≥35 years; odds ratio [OR] = 1.99, 95% confidence interval [CI]: 1.05–3.76, P = 0.03) and lower education level (<9 years; OR = 2.13, 95% CI: 0.96–4.71, P = 0.06). Mucosal conditions are prevalent in Kiriri Indians and the presence of mucosal lesions is associated with advanced age and lower education. A public health program aimed at preventing and treating mucosal lesions and targeted toward the high-risk group is vital to improve the oral health status of this population. PMID:25501053

Current and Future Targets for Mucosal Healing in Inflammatory Bowel Disease

PubMed Central

Atreya, Raja; Neurath, Markus F.

2017-01-01

The induction and subsequent maintenance of mucosal healing has emerged as one of the central therapeutic goals in the management of patients with inflammatory bowel disease (IBD) (Crohn's disease and ulcerative colitis). Current and novel treatment options are assessed regarding their therapeutic efficacy on the basis of their ability to induce mucosal healing. However, there is still substantial debate about the precise definition of mucosal healing. Here, we will give an overview regarding the definitions of mucosal healing as well as its probable effects on long-term disease behavior and finally focus on current and potential therapeutic targets to achieve this therapeutic goal in IBD patients. PMID:28612022

Mouse Conjunctival Forniceal Gene Expression during Postnatal Development and Its Regulation by Krüppel-like Factor 4

PubMed Central

Gupta, Divya; Harvey, Stephen A. K.; Kaminski, Naftali

2011-01-01

Purpose. To identify the changes in postnatal mouse conjunctival forniceal gene expression and their regulation by Klf4 during the eye-opening stage when the goblet cells first appear. Methods. Laser microdissection (LMD) was used to collect conjunctival forniceal cells from postnatal (PN) day 9, PN14 and PN20 wild-type (WT), and PN14 Klf4-conditional null (Klf4CN) mice, in which goblet cells are absent, developing, present, and missing, respectively. Microarrays were used to compare gene expression among these groups. Expression of selected genes was validated by quantitative RT-PCR, and spatiotemporal expression was assessed by in situ hybridization. Results. This study identified 668, 251, 1160, and 139 transcripts that were increased and 492, 377, 1419, and 57 transcripts that were decreased between PN9 and PN14, PN14 and PN20, PN9 and PN20, and PN14 WT and Klf4CN conjunctiva, respectively. Transcripts encoding transcription factors Spdef, FoxA1, and FoxA3 that regulate goblet cell development in other mucosal epithelia, and epithelium-specific Ets (ESE) transcription factor family members were increased during conjunctival development. Components of pathways related to the mesenchymal–epithelial transition, glycoprotein biosynthesis, mucosal immunity, signaling, and endocytic and neural regulation were increased during conjunctival development. Conjunctival Klf4 target genes differed significantly from the previously identified corneal Klf4 target genes, implying tissue-dependent regulatory targets for Klf4. Conclusions. The changes in gene expression accompanying mouse conjunctival development were identified, and the role of Klf4 in this process was determined. This study provides new probes for examining conjunctival development and function and reveals that the gene regulatory network necessary for goblet cell development is conserved across different mucosal epithelia. PMID:21398290

Forsythoside A Inhibits BVDV Replication via TRAF2-Dependent CD28-4-1BB Signaling in Bovine PBMCs.

PubMed

Song, Quan-Jiang; Weng, Xiao-Gang; Cai, Dong-Jie; Zhang, Wang; Wang, Jiu-Feng

2016-01-01

Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea/mucosal disease (BVD/MD), is an important pathogen of cattle and other wild animals throughout the world. BVDV infection typically leads to an impaired immune response in cattle. In the present study, we investigated the effect of Forsythoside A (FTA) on BVDV infection of bovine peripheral blood mononuclear cells (PBMCs). We found that Forsythoside A could not only promote proliferation of PBMCs and T cells activation but also inhibit the replication of BVDV as well as apoptosis induced by BVDV. FTA treatment could counteract the BVDV-induced overproduction of IFN-γ to maintain the immune homeostasis in bovine PBMCs. At same time, FTA can enhance the secretion of IL-2. What's more, BVDV promotes the expression of CD28, 4-1BB and TRAF-2, which can be modulated by FTA. Our data suggest that FTA protects PBMCs from BVDV infection possibly via TRAF2-dependent CD28-4-1BB signaling, which may activate PBMCs in response to BVDV infection. Therefore, this aids in the development of an effective adjuvant for vaccines against BVDV and other specific FTA-based therapies for preventing BVDV infection.

[Endoscopy-assisted sialolithectomy for the calculus of the Stensen's duct].

PubMed

Ye, Xin; Xie, Xiaoyan; Liu, Denggao; Zhang, Lei; Zhang, Zuyan; Yu, Guangyan

2014-11-01

To investigate the clinical effects of endoscopy-assisted sialolithectomy for the calculus in the Stensen's duct. From August 2005 to July 2013, 67 consecutive patients with calculus (or foreign bodies) in the Stensen's duct underwent explorative and interventional endoscopy in our hospital. The stones (or foreign bodies) were removed by endoscopy-assisted technique. After operation, the patients were followed-up periodically, and treatment effects were analyzed. Among the 67 patients, the stones (or foreign bodies) were completely removed in 58 cases, and almost completely removed in 3 cases, with a success rate of 87% (58/67). Among the 61 stone-removed cases, treatment options included direct removal with aid of basket or forceps (24 cases), basket entrapment and opening-up of the ostium (21 cases), basket entrapment and mucosal incision near the ostium (8 cases), open removal via buccal incision (2 cases) and open removal via pre-auricular flap (6 cases). During the 6-90 months' follow-up of the 61 cases, 48 cases were asymptomatic, 7 had mild symptoms, 3 developed ductal obturation, 1 had numbness in the parotid region, and the remaining 2 were missed. Endoscopy-assisted sialolithectomy is a safe and effective gland-preservation technique for the patients with parotid gland calculus.

Past, present and future of Barrett's oesophagus.

PubMed

Tan, W K; di Pietro, M; Fitzgerald, R C

2017-07-01

Barrett's oesophagus is a condition which predisposes towards development of oesophageal adenocarcinoma, a highly lethal tumour which has been increasing in incidence in the Western world over the past three decades. There have been tremendous advances in the field of Barrett's oesophagus, not only in diagnostic modalities, but also in therapeutic strategies available to treat this premalignant disease. In this review, we discuss the past, present and future of Barrett's oesophagus. We describe the historical and new evolving diagnostic criteria of Barrett's oesophagus, while also comparing and contrasting the British Society of Gastroenterology guidelines, American College of Gastroenterology guidelines and International Benign Barrett's and CAncer Taskforce (BOBCAT) for Barrett's oesophagus. Advances in endoscopic modalities such as confocal and volumetric laser endomicroscopy, and a non-endoscopic sampling device, the Cytosponge, are described which could aid in identification of Barrett's oesophagus. With regards to therapy we review the evidence for the utility of endoscopic mucosal resection and radiofrequency ablation when coupled with better characterization of dysplasia. These endoscopic advances have transformed the management of Barrett's oesophagus from a primarily surgical disease into an endoscopically managed condition. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma.

PubMed

Furney, Simon J; Turajlic, Samra; Stamp, Gordon; Nohadani, Mahrokh; Carlisle, Anna; Thomas, J Meirion; Hayes, Andrew; Strauss, Dirk; Gore, Martin; van den Oord, Joost; Larkin, James; Marais, Richard

2013-07-01

Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular, the mutation signatures are not indicative of ultraviolet light- or tobacco smoke-induced DNA damage. Genes previously reported as mutated in other cancers were also mutated in mucosal melanoma. Notably, there were substantially more copy number and structural variations in mucosal melanoma than have been reported in cutaneous melanoma. Thus, mucosal and cutaneous melanomas are distinct diseases with discrete genetic features. Our data suggest that different mechanisms underlie the genesis of these diseases and that structural variations play a more important role in mucosal than in cutaneous melanomagenesis. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Sequential Combination Chemotherapy of Dacarbazine (DTIC) with Carboplatin and Paclitaxel for Patients with Metastatic Mucosal Melanoma of Nasal Cavity and Paranasal Sinuses.

PubMed

Omata, W; Tsutsumida, A; Namikawa, K; Takahashi, A; Oashi, K; Yamazaki, N

2017-01-01

By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma. In this communication, we present a retrospective analysis of the sequential combination chemotherapy of DTIC with carboplatin and paclitaxel (CP) for metastatic mucosal melanoma of nasal cavity and paranasal sinuses. The objective response rate of seven patients is 14.3% by RECIST 1.1 and the overall survival (OS) is 12.5 months. These data indicate that the sequential combination chemotherapy of DTIC with CP could be an option for patients with metastatic mucosal melanoma of nasal cavity and paranasal sinuses who are currently ending into dismal prognosis.

The effect of oral mucositis on morbidity and mortality in bone marrow transplant.

PubMed

Gabriel, Don A; Shea, Thomas; Olajida, Oludamilola; Serody, Jonathan S; Comeau, Terrance

2003-12-01

Oral mucosal ulceration is a frequent complication in bone marrow transplantation, resulting from epithelial injury caused by cytotoxic chemotherapy and radiation conditioning, as well as from pre-existing infection. Oral mucositis causes pain, interferes with patient nutrition, and can lead to systemic infection and other complications that increase patient morbidity and mortality; this complication also markedly increases the expense of bone marrow transplantation. A variety of interventions have been assessed for preventing oral mucositis or reducing the severity of mucositis and its sequelae. These include meticulous pretransplantation and ongoing mouth care, calcium phosphate solution, near-infrared light and lower-energy laser treatment, interleukin-11, sucralfate, oral glutamine, granulocyte-macrophage colony-stimulating factor rinse, tretinoin, and keratinocyte growth factor; particularly promising results have been observed with use of the cytoprotectant/radioprotectant agent amifostine. Reduction in the severity and duration of oral mucositis and its sequelae in patients undergoing bone marrow transplantation can have a substantial impact on morbidity and mortality and cost of care. Further systematic evaluation of approaches to prevention and management of oral mucositis is necessary to define optimal strategies in the transplantation setting.

Effect of oral glutamine on enterocyte turnover during methotrexate-induced mucositis in rats.

PubMed

Sukhotnik, Igor; Mogilner, Jorge G; Karry, Rahel; Shamian, Benhoor; Lurie, Michael; Kokhanovsky, Natalie; Ure, Benno M; Coran, Arnold G

2009-01-01

The objective of this study was to evaluate the effects of oral glutamine in preventing intestinal mucosal damage caused by methotrexate (MTX) in rats. Male Sprague-Dawley rats were divided into 3 experimental groups: control rats, rats treated intraperitoneally with MTX (MTX rats) and rats treated with oral glutamine in the drinking water (2%) 72 h following intraperitoneal injection of a single dose of MTX (MTX-glutamine rats). Intestinal mucosal damage (Park's injury score), mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 h following MTX injection. RT-PCR was used to determine Bax and Bcl-2 mRNA expression. MTX-glutamine rats demonstrated greater jejunal and ileal mucosal weight and mucosal DNA, greater ileal villus height and crypt depth, and a greater index of proliferation in the jejunum and ileum compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-glutamine rats (vs. MTX) was accompanied by decreased Bax and increased Bcl-2 mRNA expression. Treatment with oral glutamine prevents mucosal injury and improves intestinal recovery following MTX injury in the rat.

Why mucosal health?

USDA-ARS?s Scientific Manuscript database

Aquaculture species depend more heavily on mucosal barriers than their terrestrial agricultural counterparts as they are continuously interacting with the aquatic microbiota. Unlike classical immune centers, such as the spleen and kidney, the accessibility of mucosal surfaces through immersion/dip t...

Update on primary mucosal melanoma.

PubMed

Tacastacas, Joselin D; Bray, Julie; Cohen, Yoon K; Arbesman, Joshua; Kim, Julian; Koon, Henry B; Honda, Kord; Cooper, Kevin D; Gerstenblith, Meg R

2014-08-01

Mucosal melanomas are aggressive cancers of mucosal surfaces with clinical and pathologic characteristics distinct from cutaneous melanomas, warranting different staging systems and treatment approaches. Surgical resection is performed frequently for the primary tumor, although the utility of lymph node surgery and radiation therapy is not established. Therapies targeted against C-KIT activating mutations, identified in many mucosal melanomas, are emerging as promising treatments. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Induction of mucosal IgA by a novel jet delivery technique for HIV-1 DNA.

PubMed

Lundholm, P; Asakura, Y; Hinkula, J; Lucht, E; Wahren, B

1999-04-09

Novel ways of delivering plasmid DNA to elicit humoral IgA, IgG and cell-mediated immune responses in mice were investigated. Intraoral administration of DNA in the cheek, using a jet immunization technique, elicited the highest IgA mucosal responses. Intranasal immunization gave strong mucosal IgA responses and persistent systemic IgG. Immunoglobulin isotype analysis revealed an IgG1 profile for intramuscular tongue and gene gun immunizations and an IgG2a profile following oral jet injection and intranasal application. The route of delivery was of importance for the characteristics and quality of the mucosal immune response following DNA immunization. For DNA vaccine delivery, the intraoral jet injection technique has the advantages of being a simple and rapid way of administering the DNA in solution and of provoking specific mucosal IgA when administered in the mucosal associated lymphoid tissue.

Mucosal delivery of liposome-chitosan nanoparticle complexes.

PubMed

Carvalho, Edison L S; Grenha, Ana; Remuñán-López, Carmen; Alonso, Maria José; Seijo, Begoña

2009-01-01

Designing adequate drug carriers has long been a major challenge for those working in drug delivery. Since drug delivery strategies have evolved for mucosal delivery as the outstanding alternative to parenteral administration, many new drug delivery systems have been developed which evidence promising properties to address specific issues. Colloidal carriers, such as nanoparticles and liposomes, have been referred to as the most valuable approaches, but still have some limitations that can become more inconvenient as a function of the specific characteristics of administration routes. To overcome these limitations, we developed a new drug delivery system that results from the combination of chitosan nanoparticles and liposomes, in an approach of combining their advantages, while avoiding their individual limitations. These lipid/chitosan nanoparticle complexes are, thus, expected to protect the encapsulated drug from harsh environmental conditions, while concomitantly providing its controlled release. To prepare these assemblies, two different strategies have been applied: one focusing on the simple hydration of a previously formed dry lipid film with a suspension of chitosan nanoparticles, and the other relying on the lyophilization of both basic structures (nanoparticles and liposomes) with a subsequent step of hydration with water. The developed systems are able to provide a controlled release of the encapsulated model peptide, insulin, evidencing release profiles that are dependent on their lipid composition. Moreover, satisfactory in vivo results have been obtained, confirming the potential of these newly developed drug delivery systems as drug carriers through distinct mucosal routes.

Rifaximin Reduces the Number and Severity of Intestinal Lesions Associated With Use of Nonsteroidal Anti-Inflammatory Drugs in Humans.

PubMed

Scarpignato, Carmelo; Dolak, Werner; Lanas, Angel; Matzneller, Peter; Renzulli, Cecilia; Grimaldi, Maria; Zeitlinger, Markus; Bjarnason, Ingvar

2017-04-01

The intestinal microbiota might contribute to enteropathy associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs), but there have been few human studies of this association. We performed a placebo-controlled study to determine whether a delayed-release antibiotic formulation (rifaximin-extended intestinal release [EIR]) prevents the development of intestinal lesions in subjects taking daily NSAIDs. Sixty healthy volunteers (median age, 26 y; 42% female) were given the NSAID diclofenac (75 mg twice daily) plus omeprazole (20 mg once daily), and either rifaximin-EIR (400 mg) or placebo, twice daily for 14 days. Subjects were assessed by videocapsule endoscopy at baseline and after 2 weeks of treatment. The primary end point was the proportion of subjects developing at least 1 small-bowel mucosal break at week 2. Secondary end points were the change in the mean number of mucosal lesions and the number of subjects with large erosions and/or ulcers after 14 days of exposure. We detected mucosal breaks in 20% of subjects given rifaximin and in 43% of subjects given placebo (P = .05 in the post hoc sensitivity analysis). None of the subjects in the rifaximin group developed large lesions, compared with 9 subjects in the placebo group (P < .001). Our findings indicate that intestinal bacteria contribute to the development of NSAID-associated enteropathy in human beings. Clinical trial no: EudraCT 2013-000730-36. Copyright © 2017. Published by Elsevier Inc.

Intranasal delivery of recombinant parvovirus-like particles elicits cytotoxic T-cell and neutralizing antibody responses.

PubMed

Sedlik, C; Dridi, A; Deriaud, E; Saron, M F; Rueda, P; Sarraseca, J; Casal, J I; Leclerc, C

1999-04-01

We previously demonstrated that chimeric porcine parvovirus-like particles (PPV:VLP) carrying heterologous epitopes, when injected intraperitoneally into mice without adjuvant, activate strong CD4(+) and CD8(+) T-cell responses specific for the foreign epitopes. In the present study, we investigated the immunogenicity of PPV:VLP carrying a CD8(+) T-cell epitope from the lymphocytic choriomeningitis virus (LCMV) administered by mucosal routes. Mice immunized intranasally with recombinant PPV:VLP, in the absence of adjuvant, developed high levels of PPV-specific immunoglobulin G (IgG) and/or IgA in their serum, as well as in mucosal sites such as the bronchoalveolar and intestinal fluids. Antibodies in sera from mice immunized parenterally or intranasally with PPV:VLP were strongly neutralizing in vitro. Intranasal immunization with PPV:VLP carrying the LCMV CD8(+) T-cell epitope also elicited a strong peptide-specific cytotoxic-T-cell (CTL) response. In contrast, mice orally immunized with recombinant PPV:VLP did not develop any antibody or CTL responses. We also showed that mice primed with PPV:VLP are still able to develop strong CTL responses after subsequent immunization with chimeric PPV:VLP carrying a foreign CD8(+) T-cell epitope. These results highlight the attractive potential of PPV:VLP as a safe, nonreplicating antigen carrier to stimulate systemic and mucosal immunity after nasal administration.

Intranasal Delivery of Recombinant Parvovirus-Like Particles Elicits Cytotoxic T-Cell and Neutralizing Antibody Responses

PubMed Central

Sedlik, C.; Dridi, A.; Deriaud, E.; Saron, M. F.; Rueda, P.; Sarraseca, J.; Casal, J. I.; Leclerc, C.

1999-01-01

We previously demonstrated that chimeric porcine parvovirus-like particles (PPV:VLP) carrying heterologous epitopes, when injected intraperitoneally into mice without adjuvant, activate strong CD4+ and CD8+ T-cell responses specific for the foreign epitopes. In the present study, we investigated the immunogenicity of PPV:VLP carrying a CD8+ T-cell epitope from the lymphocytic choriomeningitis virus (LCMV) administered by mucosal routes. Mice immunized intranasally with recombinant PPV:VLP, in the absence of adjuvant, developed high levels of PPV-specific immunoglobulin G (IgG) and/or IgA in their serum, as well as in mucosal sites such as the bronchoalveolar and intestinal fluids. Antibodies in sera from mice immunized parenterally or intranasally with PPV:VLP were strongly neutralizing in vitro. Intranasal immunization with PPV:VLP carrying the LCMV CD8+ T-cell epitope also elicited a strong peptide-specific cytotoxic-T-cell (CTL) response. In contrast, mice orally immunized with recombinant PPV:VLP did not develop any antibody or CTL responses. We also showed that mice primed with PPV:VLP are still able to develop strong CTL responses after subsequent immunization with chimeric PPV:VLP carrying a foreign CD8+ T-cell epitope. These results highlight the attractive potential of PPV:VLP as a safe, nonreplicating antigen carrier to stimulate systemic and mucosal immunity after nasal administration. PMID:10074120

Identification of risk factors for mucosal injury during laparoscopic Heller myotomy for achalasia.

PubMed

Tsuboi, Kazuto; Omura, Nobuo; Yano, Fumiaki; Hoshino, Masato; Yamamoto, Se-Ryung; Akimoto, Shusuke; Masuda, Takahiro; Kashiwagi, Hideyuki; Yanaga, Katsuhiko

2016-02-01

Mucosal injury during myotomy is the most frequent complication seen with the Heller-Dor procedure for achalasia. The present study aimed to examine risk factors for such mucosal injury during this procedure. This was a retrospective analysis of patients who underwent the laparoscopic Heller-Dor procedure for achalasia at a single facility. Variables for evaluation included patient characteristics, preoperative pathophysiological findings, and surgeon's operative experience. Logistic regression was used to identify risk factors. We also examined surgical outcomes and the degree of patient satisfaction in relation to intraoperative mucosal injury. Four hundred thirty-five patients satisfied study criteria. Intraoperative mucosal injury occurred in 67 patients (15.4%). In univariate analysis, mucosal injury was significantly associated with the patient age ≥60 years, disease history ≥10 years, prior history of cardiac diseases, preoperative esophageal transverse diameter ≥80 mm, and surgeon's operative experience with fewer than five cases. In multivariate analysis involving these factors, the following variables were identified as risk factors: age ≥60 years, esophageal transverse diameter ≥80 mm, and surgeon's operative experience with fewer than five cases. The mucosal injury group had significant extension of the operative time and increased blood loss. However, there were no significant differences between the two groups in the incidence of reflux esophagitis or the degree of symptom alleviation postoperatively. The fragile esophagus caused by advanced patient age and/or dilatation were risk factor for mucosal injury during laparoscopic Heller-Dor procedure. And novice surgeon was also identified as an isolated risk factor for mucosal injury.

Increased melatonin in oral mucosal tissue of oral lichen planus (OLP) patients: A possible link between melatonin and its role in oral mucosal inflammation.

PubMed

Luengtrakoon, Kirawut; Wannakasemsuk, Worraned; Vichitrananda, Vilasinee; Klanrit, Poramaporn; Hormdee, Doosadee; Noisombut, Rajda; Chaiyarit, Ponlatham

2017-06-01

The existence of extra-pineal melatonin has been observed in various tissues. No prior studies of melatonin in human oral mucosal tissue under the condition of chronic inflammation have been reported. The aim of this study was to investigate the presence of melatonin in oral mucosal tissue of patients with oral lichen planus (OLP) which was considered as a chronic inflammatory immune-mediated disease causing oral mucosal damage and ulcerations. Sections from formalin-fixed and paraffin-embedded oral mucosal tissue of OLP patients (n=30), and control subjects (n=30) were used in this study. Immunohistochemical staining was performed and the semiquantitative scoring system was used to assess the levels of arylalkylamine-N-acetyltransferase (AANAT: a rate-limiting enzyme in the biosynthesis pathway of melatonin), melatonin, and melatonin receptor 1 (MT1) in oral mucosa of OLP patients and normal oral mucosa of control subjects. AANAT, melatonin, and MT1were detected in oral mucosal tissue of OLP patients and control subjects. Immunostaining scores of AANAT, melatonin, and MT1 in oral mucosal tissue of OLP patients were significantly higher than those in control subjects (p=0.002, p<0.001, and p=0.031, respectively). Increased levels of AANAT, melatonin, and MT1 in the inflamed oral mucosal tissue of OLP patients imply that chronic inflammation may induce the local biosynthesis of melatonin via AANAT, and may enhance the action of melatonin via MT1. Copyright © 2017 Elsevier Ltd. All rights reserved.

Esophageal mucosal breaks in gastroesophageal reflux disease partially responsive to proton pump inhibitor therapy.

PubMed

Shaheen, Nicholas J; Denison, Hans; Björck, Karin; Silberg, Debra G

2013-04-01

Approximately 20-30% of patients with gastroesophageal reflux disease (GERD) do not experience complete symptom resolution during proton pump inhibitor (PPI) therapy. The aim of this study was to determine the prevalence of esophageal mucosal breaks among patients who have a partial response to PPI therapy. This was an analysis of data from a phase 2b clinical trial carried out to assess the efficacy and safety of a reflux inhibitor, lesogaberan (AZD3355), as an add-on to PPI therapy in this patient population (clinicaltrials.gov reference: NCT01005251). A total of 661 patients with persistent GERD symptoms who had received a minimum of 4 weeks of PPI therapy were included in the study. The prevalence of esophageal mucosal breaks was assessed according to (i) the most recent endoscopy results from within the previous 24 months, if available ("historical" endoscopies), and (ii) the results of endoscopies performed at study baseline ("baseline" endoscopies). Baseline endoscopies were not carried out in patients who had a historical endoscopy showing an absence of esophageal mucosal breaks. Historical endoscopy results were available for 244 patients, of whom 48 (19.7%) had esophageal mucosal breaks. Baseline endoscopies were carried out in 465 patients, of whom 146 (31.4%) had esophageal mucosal breaks. Sensitivity analyses showed a prevalence of esophageal mucosal breaks of 20-30%. In both the historical and baseline endoscopies, most esophageal mucosal breaks were Los Angeles grades A or B. In patients with GERD symptoms partially responsive to PPI therapy, mild-to-moderate severity esophageal mucosal breaks are common (prevalence 20-30%), and may contribute to symptom etiology.

Macroscopic and microscopic effects of GaAIAs diode laser and dexamethasone therapies on oral mucositis induced by fluorouracil in rats.

PubMed

Lara, Renata Nemetala; da Guerra, Eliete Neves Silva; de Melo, Nilce Santos

2007-01-01

To present an animal model for mucositis induced by fluorouracil in rats, and test two therapeutic options, the GaAIAs laser and topical dexamethasone, analysing them with regard to the quality and quantity of tissue alterations and comparing them with the phases of mucositis. Forty-five Wistar rats (250 g) were treated with fluorouracil (60 mg/kg) and, in order to mimic the clinical effect of chronic irritation, the palatal mucosa was irritated by superficial scratching with an 18-gauge needle. When all of the rats presented oral ulcers of mucositis, they were randomly allocated to one of three groups: group I was treated with laser (GaAIAs), group II was treated with topical dexamethasone, and group III was not treated. Excisional biopsies of the palatal mucosa were then performed, and the rats were killed. Tissue sections were stained with haematoxylin and eosin for morphological analyses, and with toluidine blue for mast-cell counts. Group I specimens showed higher prevalence of ulcers, bacterial biofilm, necrosis and vascularisation, while group II specimens showed higher prevalance of granulation tissue formation. There were no significant statistical differences in the numbers of mast cells and epithelial thickness between groups. For the present model of mucositis, rats with palatal mucositis treated with laser (GaAIAs) showed characteristics compatible with the ulcerative phase of oral mucositis, and rats treated with topical dexamethasone showed characteristics compatible with the healing phase of mucositis. Topical dexamethasone was more efficient in the treatment of rats' oral mucositis than the laser.

Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole.

PubMed

Kovanda, Laura L; Marty, Francisco M; Maertens, Johan; Desai, Amit V; Lademacher, Christopher; Engelhardt, Marc; Lu, Qiaoyang; Hope, William W

2017-06-01

Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUC ave ]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate. Copyright © 2017 Kovanda et al.

Impact of Mucositis on Absorption and Systemic Drug Exposure of Isavuconazole

PubMed Central

Marty, Francisco M.; Maertens, Johan; Desai, Amit V.; Lademacher, Christopher; Engelhardt, Marc; Lu, Qiaoyang

2017-01-01

ABSTRACT Isavuconazonium sulfate is the water-soluble prodrug of isavuconazole. Population analyses have demonstrated relatively predictable pharmacokinetic (PK) behavior in diverse patient populations. We evaluated the impact of mucositis on the oral isavuconazole exposure using population PK modeling. This study included patients treated in two phase 3 trials of isavuconazole, SECURE for treatment of invasive aspergillosis (IA) and other filamentous fungi and VITAL for patients with mucormycosis, invasive fungal disease (IFD) caused by other rare fungi, or IA and renal impairment. Mucositis was reported by site investigators and its impact on oral bioavailability was assessed. Use of the oral formulation was at the discretion of the investigator. Patients with plasma samples collected during the use of isavuconazonium sulfate were included in the construction of population PK model. Of 250 patients included, 56 patients had mucositis at therapy onset or as an adverse event during oral isavuconazole therapy. Levels of oral bioavailability were comparable, at 98.3% and 99.8%, respectively. The average drug exposures (average area under the curve [AUCave]) calculated from either the mean or median parameter estimates were not different between patients with and without mucositis. Mortality and overall clinical responses were similar between patients receiving oral therapy with and without mucositis. We found that isavuconazole exposures and clinical outcomes in this subset of patients with mucositis who were able to take oral isavuconazonium sulfate were comparable to those in patients without mucositis, despite the difference in oral bioavailability. Therefore, mucositis may not preclude use of the oral formulation of isavuconazonium sulfate. PMID:28289034

Impact of mucosal inflammation on risk of colorectal neoplasia in patients with ulcerative colitis: a systematic review and meta-analysis.

PubMed

Flores, Brisas M; O'Connor, Anthony; Moss, Alan C

2017-12-01

Long-standing ulcerative colitis is an established risk factor for colorectal neoplasia. A number of observational studies have suggested that evidence of mucosal inflammation (endoscopic or histologic) is associated with a greater risk for colorectal neoplasia than is mucosal healing. Our goal was to systematically analyze the risk of colorectal neoplasia in patients with ulcerative colitis who have ongoing mucosal inflammation to better inform surveillance strategies. We performed a systematic review and meta-analysis of the effect of endoscopic and/or histologic inflammation on the risk of colorectal neoplasia in cohort and case-control studies. Sensitivity analyses for study setting and case definition were performed. Six studies met the inclusion criteria, incorporating outcomes in 1443 patients. No study used a single validated measure for mucosal inflammation. The pooled odds ratio for colorectal neoplasia was 3.5 (95% confidence interval [CI], 2.6-4.8; P < .001) in those with any mucosal inflammation and 2.6 (95% CI, 1.5-4.5; P = .01) in those with histologic inflammation, when compared with those with mucosal healing. The overall quality of the studies was good. The presence of objective evidence of mucosal inflammation during follow-up in patients with ulcerative colitis is associated with a greater risk of subsequent colorectal neoplasia than in those with mucosal healing. This risk factor should be considered in guidelines on surveillance intervals for these patients. Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Endoscopic diode-laser applications in airway surgery

NASA Astrophysics Data System (ADS)

Pankratov, Michail M.; Wang, Zhi; Rebeiz, Elie E.; Perrault, Donald F., Jr.; Shapshay, Stanley M.; Gleich, Lyon L.

1994-09-01

A technique was developed to secure small mucosal grafts onto the airway wound with fibrin/albumin tissue adhesive mixed with ICG dye and irradiated with a 810 nm diode laser. An in vitro study of the tensile strength produced strong mucosal soldering which was adequate to fix grafts in place. In vivo studies showed that wounds with mucosal grafts were completely covered by regenerated squamous cells in 1 week and by ciliated epithelium in 2 weeks. Excellent healing was observed at 6 and 14 days postoperatively and the histology at 28 days found normal epithelium over the vocal cord lesion. This soldering technique is a less traumatic treatment for patients with extensive lesions of the larynx of various origin. Diode laser soldering with ICG-doped fibrin tissue adhesive was evaluated in tracheal anastomosis as a substitute for absorbable sutures. In vitro studies demonstrated strong anastomoses with minimal tissue damage. In vivo animal study showed that these anastomoses had less fibrosis and tissue damage than control animals repaired with sutures only.

Probiotics as Antifungals in Mucosal Candidiasis.

PubMed

Matsubara, Victor H; Bandara, H M H N; Mayer, Marcia P A; Samaranayake, Lakshman P

2016-05-01

Candidais an opportunistic pathogen that causes mucosal and deep systemic candidiasis. The emergence of drug resistance and the side effects of currently available antifungals have restricted their use as long-term prophylactic agents for candidal infections. Given this scenario, probiotics have been suggested as a useful alternative for the management of candidiasis. We analyzed the available data on the efficacy of probiotics in candidal colonization of host surfaces. A number of well-controlled studies indicate that probiotics, particularly lactobacilli, suppressCandidagrowth and biofilm development in vitro.A few clinical trials have also shown the beneficial effects of probiotics in reducing oral, vaginal, and enteric colonization byCandida; alleviation of clinical signs and symptoms; and, in some cases, reducing the incidence of invasive fungal infection in critically ill patients. Probiotics may serve in the future as a worthy ally in the battle against chronic mucosal candidal infections. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Gastroprotective effects of the isopropanol extract of Artemisia princeps and its gastroretentive floating tablets on gastric mucosal injury.

PubMed

Kim, Joo-Il; Park, Sang-Wook; Lim, Jhong-Jae; Sohn, Se-Il; Shin, Ji-Su; Park, Sang Cheol; Jang, Young Pyo; Chung, Eun Kyoung; Lee, Hong-Woo; Lee, Kyung-Tae

2017-12-20

In this study, we investigated the gastroprotective effect of an isopropanol extract from the aerial parts of Artemisia princeps (IPAP) and developed a gastroretentive floating tablet of IPAP (IPAP-FR) for maximized local gastroprotective effects. Pre-treatment with IPAP ameliorated the gastric mucosal hemorrhagic lesions in ethanol/HCl- or indomethacin- treated rats. IPAP decreased mucosal hemorrhage of gastric ulcers induced by ethanol or indomethacin plus pyloric ligation in rats. The optimized floating tablet, IPAP-FR, floated on medium surface with more sustained eupatilin release compared to the non-floating control tablet. X-ray photographs in beagle dogs showed that IPAPFR was retained for > 2 h in the stomach. In the ethanol-induced gastric ulcer rat model, the gastric hemorrhagic lesion was improved more substantially with IPAP-FR compared to the non-floating control tablet. Based on these data, our data suggest that IPAP-FR has an improved therapeutic potential for the treatment of gastric ulcer.

Multifunctional particle-constituted microneedle arrays as cutaneous or mucosal vaccine adjuvant-delivery systems

PubMed Central

Wang, Xueting; Wang, Ning; Li, Ning; Zhen, Yuanyuan; Wang, Ting

2016-01-01

ABSTRACT To overcome drawbacks of current injection vaccines, such as causing needle phobia, needing health professionals for inoculation, and generating dangerous sharps wastes, researchers have designed novel vaccines that are combined with various microneedle arrays (MAs), in particular, with the multifunctional particle-constructed MAs (MPMAs). MPMAs prove able to enhance vaccine stability through incorporating vaccine ingredients in the carrier, and can be painlessly inoculated by minimally trained workers or by self-administration, leaving behind no metal needle pollution while eliciting robust systemic and mucosal immunity to antigens, thanks to delivering vaccines to cutaneous or mucosal compartments enriched in professional antigen-presenting cells (APCs). Especially, MPMAs can be easily integrated with functional molecules fulfilling targeting vaccine delivery or controlling immune response toward a Th1 or Th2 pathway to generate desired immunity against pathogens. Herein, we introduce the latest research and development of various MPMAs which are a novel but promising vaccine adjuvant delivery system (VADS). PMID:27159879

Younger age at diagnosis predisposes to mucosal recovery in celiac disease on a gluten-free diet: A meta-analysis

PubMed Central

Mátrai, Péter; Hegyi, Péter; Szabó, Imre; Vincze, Áron; Balaskó, Márta; Mosdósi, Bernadett; Sarlós, Patrícia; Simon, Mária; Márta, Katalin; Mikó, Alexandra; Pécsi, Dániel; Demcsák, Alexandra; Bajor, Judit

2017-01-01

Background and aims Persistent intestinal damage is associated with higher complication rates in celiac disease. We aimed to assess the potential modifiers of mucosal recovery. Materials and methods We screened databases (PubMed, Embase, Cochrane Trials, and Web of Science) for papers on celiac disease. Papers discussing (1) celiac patients (2) follow-up biopsy and (3) mucosal recovery after commencement of a gluten-free diet were included. The primary outcome was to produce a comprehensive analysis of complete mucosal recovery (i.e., Marsh 0 on follow-up). We compared children’s recovery ratios to those of adults. Patients following a strict gluten-free dietary regimen were included in a subgroup. Summary point estimates, 95% confidence intervals (CIs), and 95% predictive intervals (PIs) were calculated. Heterogeneity was tested with I2-statistic. The PROSPERO registration number is CRD42016053482. Results The overall complete mucosal recovery ratio, calculated from 37 observational studies, was 0.36 (CI: 0.28–0.44, PI: -0.12–0.84; I2: 98.4%, p<0.01). Children showed higher complete mucosal recovery ratio than adults (p<0.01): 0.65 (CI: 0.44–0.85, PI: -0.10–1.39; I2: 96.5%, p<0.01) as opposed to 0.24 (CI: 0.15–0.33, PI: -0.19–1.08; I2: 96.3%, p<0.01). In the strict dietary adherence subgroup, complete mucosal recovery ratio was 0.47 (CI: 0.24–0.70, PI: -0.47–1.41; I2: 98.8%, p<0.001). On meta-regression, diagnostic villous atrophy (Marsh 3) ratio (-8.97, p<0.01) and male ratio (+6.04, p<0.01) proved to be a significant determinant of complete mucosal recovery, unlike duration of gluten-free diet (+0.01, p = 0.62). The correlation between complete mucosal recovery ratio and age on diagnosis is of borderline significance (-0.03, p = 0.05). Conclusions There is considerable heterogeneity across studies concerning complete mucosal recovery ratios achieved by a gluten-free diet in celiac disease. Several celiac patients fail to achieve complete mucosal recovery even if a strict dietary regimen is followed. Younger age on diagnosis, less severe initial histologic damage and male gender predispose for achieving mucosal recovery. PMID:29095937

Younger age at diagnosis predisposes to mucosal recovery in celiac disease on a gluten-free diet: A meta-analysis.

PubMed

Szakács, Zsolt; Mátrai, Péter; Hegyi, Péter; Szabó, Imre; Vincze, Áron; Balaskó, Márta; Mosdósi, Bernadett; Sarlós, Patrícia; Simon, Mária; Márta, Katalin; Mikó, Alexandra; Pécsi, Dániel; Demcsák, Alexandra; Bajor, Judit

2017-01-01

Persistent intestinal damage is associated with higher complication rates in celiac disease. We aimed to assess the potential modifiers of mucosal recovery. We screened databases (PubMed, Embase, Cochrane Trials, and Web of Science) for papers on celiac disease. Papers discussing (1) celiac patients (2) follow-up biopsy and (3) mucosal recovery after commencement of a gluten-free diet were included. The primary outcome was to produce a comprehensive analysis of complete mucosal recovery (i.e., Marsh 0 on follow-up). We compared children's recovery ratios to those of adults. Patients following a strict gluten-free dietary regimen were included in a subgroup. Summary point estimates, 95% confidence intervals (CIs), and 95% predictive intervals (PIs) were calculated. Heterogeneity was tested with I2-statistic. The PROSPERO registration number is CRD42016053482. The overall complete mucosal recovery ratio, calculated from 37 observational studies, was 0.36 (CI: 0.28-0.44, PI: -0.12-0.84; I2: 98.4%, p<0.01). Children showed higher complete mucosal recovery ratio than adults (p<0.01): 0.65 (CI: 0.44-0.85, PI: -0.10-1.39; I2: 96.5%, p<0.01) as opposed to 0.24 (CI: 0.15-0.33, PI: -0.19-1.08; I2: 96.3%, p<0.01). In the strict dietary adherence subgroup, complete mucosal recovery ratio was 0.47 (CI: 0.24-0.70, PI: -0.47-1.41; I2: 98.8%, p<0.001). On meta-regression, diagnostic villous atrophy (Marsh 3) ratio (-8.97, p<0.01) and male ratio (+6.04, p<0.01) proved to be a significant determinant of complete mucosal recovery, unlike duration of gluten-free diet (+0.01, p = 0.62). The correlation between complete mucosal recovery ratio and age on diagnosis is of borderline significance (-0.03, p = 0.05). There is considerable heterogeneity across studies concerning complete mucosal recovery ratios achieved by a gluten-free diet in celiac disease. Several celiac patients fail to achieve complete mucosal recovery even if a strict dietary regimen is followed. Younger age on diagnosis, less severe initial histologic damage and male gender predispose for achieving mucosal recovery.

Immediate effect of benzalkonium chloride in decongestant nasal spray on the human nasal mucosal temperature.

PubMed

Lindemann, J; Leiacker, R; Wiesmiller, K; Rettinger, G; Keck, T

2004-08-01

Benzalkonium chloride is a preservative commonly used in nasal decongestant sprays. It has been suggested that benzalkonium chloride may be harmful to the nasal mucosa. Decongestion with the vasoconstrictor xylometazoline containing benzalkonium chloride has been shown to cause a significant reduction of the nasal mucosal temperature. The purpose of the present study was to determine the short-term influence of xylometazoline nasal spray with and without benzalkonium chloride on the nasal mucosal temperature. Healthy volunteers (30) were included in the study. Fifteen volunteers received xylometazoline nasal spray (1.0 mg/mL) containing benzalkonium chloride (0.1 mg/mL) and 15 age-matched subjects, received xylometazoline nasal spray without benzalkonium chloride. Using a miniaturized thermocouple the septal mucosal temperature was continuously measured at defined intranasal detection sites before and after application of the nasal spray. The mucosal temperature values did not significantly differ between the group receiving xylometazoline containing benzalkonium chloride and the group receiving xylometazoline spray without benzalkonium chloride before and after decongestion (P > 0.05). In both study groups septal mucosal temperatures significantly decreased after decongestion (P < 0.05) because of a reduction of the nasal mucosal blood flow following vasoconstriction. This study indicates that benzalkonium chloride itself does not seem to influence nasal blood flow and nasal mucosal temperature in topical nasal decongestants.

Intradermal immunisation using the TLR3-ligand Poly (I:C) as adjuvant induces mucosal antibody responses and protects against genital HSV-2 infection

PubMed Central

Bardel, Emilie; Doucet-Ladeveze, Remi; Mathieu, Cyrille; Harandi, Ali M; Dubois, Bertrand; Kaiserlian, Dominique

2016-01-01

Development of vaccines able to induce mucosal immunity in the genital and gastrointestinal tracts is a major challenge to counter sexually transmitted pathogens such as HIV-1 and HSV-2. Herein, we showed that intradermal (ID) immunisation with sub-unit vaccine antigens (i.e., HIV-1 gp140 and HSV-2 gD) delivered with Poly(I:C) or CpG1668 as adjuvant induces long-lasting virus-specific immunoglobulin (Ig)-G and IgA antibodies in the vagina and feces. Poly(I:C)-supplemented sub-unit viral vaccines caused minimal skin reactogenicity at variance to those containing CpG1668, promoted a delayed-type hypersensitivity (DTH) to the vaccine and protected mice from genital and neurological symptoms after a lethal vaginal HSV-2 challenge. Interestingly, Poly(I:C12U) (Ampligen), a Poly(I:C) structural analogue that binds to TLR3 but not MDA-5, promoted robust mucosal and systemic IgG antibodies, a weak skin DTH to the vaccine but not IgA responses and failed to confer protection against HSV-2 infection. Moreover, Poly(I:C) was far superior to Poly(I:C12U) at inducing prompt and robust upregulation of IFNß transcripts in lymph nodes draining the injection site. These data illustrate that ID vaccination with glycoproteins and Poly(I:C) as adjuvant promotes long-lasting mucosal immunity and protection from genital HSV-2 infection, with an acceptable skin reactogenicity profile. The ID route thus appears to be an unexpected inductive site for mucosal immunity and anti-viral protection suitable for sub-unit vaccines. This works further highlights that TLR3/MDA5 agonists such as Poly(I:C) may be valuable adjuvants for ID vaccination against sexually transmitted diseases. PMID:29263853

Colonoscopic allergen provocation test with rBet v 1 in patients with pollen-associated food allergy.

PubMed

Pickert, C N; Lorentz, A; Manns, M P; Bischoff, S C

2012-10-01

After consumption of fruits, nuts, and vegetables, several patients with pollen allergy experience gastrointestinal (GI) tract symptoms that are possibly caused by pollen-associated food allergy. The aim of this study was to evaluate the colonoscopic allergen provocation (COLAP) test using the recombinant birch pollen allergen Bet v 1 (rBet v 1) for in vivo diagnosis of pollen-associated food allergy manifesting in the GI tract. Thirty-four patients with a history of adverse reactions to food, GI tract symptoms, and birch pollen pollinosis and five healthy controls underwent COLAP test. Twenty minutes after endoscopic challenge of the cecal mucosa with rBet v 1, the mucosal wheal and flare reaction was registered semiquantitatively, and tissue biopsy specimens were examined for eosinophil mucosal activation. The mucosal reaction to rBet v 1 was correlated with the presence of pollinosis (P = 0.004), history of adverse reaction to Bet v 1-associated food allergens (P = 0.001), and tissue eosinophils' activation (P < 0.001). A wheal and flare reaction in the COLAP test was observed in 13 of 16 patients (81%) with a history of GI tract symptoms associated with the ingestion of Bet v 1-related foods and in four of 18 (22%) patients with a negative history (P < 0.001). The control group did not develop visible mucosal reactions to rBet v 1. Systemic anaphylactic reactions did not occur. The mucosal administration of rBet v 1 by COLAP test provides a new diagnostic tool that might support the diagnosis of Bet v 1-associated food allergy manifesting in the GI tract. © 2012 John Wiley & Sons A/S.

Immunological evaluation of colonic delivered Hepatitis B surface antigen loaded TLR-4 agonist modified solid fat nanoparticles.

PubMed

Sahu, Kantrol Kumar; Pandey, Ravi Shankar

2016-10-01

Hepatitis B is one of the leading liver diseases and remains a major global health problem. Currently available vaccines provide protection but often results in weaker/minimal mucosal immunity. Thus the present study is devoted to the development and in-vivo exploration of the colonically delivered biomimetic nanoparticles which capably enhance humoral as well as cellular immune response. In present work, Hepatitis B surface antigen (HBsAg) entrapped nanoparticles containing Monophosphoryl lipid A (MPLA) (HB+L-NP) were prepared by solvent evaporation method and characterized for particle size (~210nm), shape, zeta potential (-24mV±0.68), entrapment efficiency (58.45±1.68%), in-vitro release and antigen integrity. Dose escalation study was done to confirm prophylactic immune response following defined doses of prepared nanoparticulate formulations with or without MPLA. Intramuscular administered alum based marketed HBsAg (Genevac B) was used as standard (10μg) and were able to induce significant systemic (IgG) but remarkably low mucosal immune (IgA) response. Notably, HB+L-NP (0.5ml-10μg) induced strong systemic and robust mucosal immunity (510 and 470 mIU/ml respectively, p<0.001) from which mucosal was more significant due to the involvement of Common Mucosal Immune System (CMIS). Likewise, significant cellular immune response was elicited by HB+L-NP through T-cell activation (mixed Th1 and Th2) as confirmed by significantly increased cytokines level (IL-2 and Interferon-γ) in spleen homogenates. This study supports that delivery of HBsAg to the colon may open new vista in designing oral vaccines later being one of most accepted route for potential vaccines in future. Copyright © 2016 Elsevier B.V. All rights reserved.

TLR7 and 9 agonists are highly effective mucosal adjuvants for norovirus virus-like particle vaccines

PubMed Central

Hjelm, Brooke E; Kilbourne, Jacquelyn; Herbst-Kralovetz, Melissa M

2014-01-01

Virus-like particles (VLPs) are an active area of vaccine research, development and commercialization. Mucosal administration of VLPs provides an attractive avenue for delivery of vaccines with the potential to produce robust immune responses. Nasal and oral delivery routes are particularly intriguing due to differential activation of mucosa-associated lymphoid tissues. We compared both intranasal and oral administration of VLPs with a panel of toll-like receptor (TLR) agonists (TLR3, 5, 7, 7/8, and 9) to determine the mucosal adjuvant activity of these immunomodulators. We selected Norwalk virus (NV) VLPs because it is an effective model antigen and an active area of research and commercialization. To prioritize these adjuvants, VLP-specific antibody production in serum (IgG, IgG1, IgG2a), vaginal lavages (IgG, IgA), and fecal pellets (IgA) were measured across a longitudinal timeseries in vaccinated mice. Additional distal mucosal sites (nasal, brochoalveolar, salivary, and gastrointestinal) were evaluated for VLP-specific responses (IgA). Intranasal co-delivery of VLPs with TLR7 or TLR9 agonists produced the most robust and broad-spectrum immune responses, systemically and at distal mucosal sites inducing VLP-specific antibodies at all sites evaluated. In addition, these VLP-specific antibodies blocked binding of NV VLPs to histo-blood group antigen (H type 1), supporting their functionality. Oral administration and/or other TLR agonists tested in the panel did not consistently enhance VLP-specific immune responses. This study demonstrates that intranasal co-delivery of VLPs with TLR7 or TLR9 agonists provides dose-sparing advantages for induction of specific and functional antibody responses against VLPs (i.e., non-replicating antigens) in the respiratory, gastrointestinal, and reproductive tract. PMID:24280723

Mucosal Transcriptomics Implicates Under Expression of BRINP3 in the Pathogenesis of Ulcerative Colitis

PubMed Central

Smith, Philip J.; Levine, Adam P.; Dunne, Jenny; Guilhamon, Paul; Turmaine, Mark; Sewell, Gavin W.; O'Shea, Nuala R.; Vega, Roser; Paterson, Jennifer C.; Oukrif, Dahmane; Beck, Stephan; Bloom, Stuart L.; Novelli, Marco; Rodriguez-Justo, Manuel; Smith, Andrew M.

2014-01-01

Background: Mucosal abnormalities are potentially important in the primary pathogenesis of ulcerative colitis (UC). We investigated the mucosal transcriptomic expression profiles of biopsies from patients with UC and healthy controls, taken from macroscopically noninflamed tissue from the terminal ileum and 3 colonic locations with the objective of identifying abnormal molecules that might be involved in disease development. Methods: Whole-genome transcriptional analysis was performed on intestinal biopsies taken from 24 patients with UC, 26 healthy controls, and 14 patients with Crohn's disease. Differential gene expression analysis was performed at each tissue location separately, and results were then meta-analyzed. Significantly, differentially expressed genes were validated using quantitative polymerase chain reaction. The location of gene expression within the colon was determined using immunohistochemistry, subcellular fractionation, electron and confocal microscopy. DNA methylation was quantified by pyrosequencing. Results: Only 4 probes were abnormally expressed throughout the colon in patients with UC with Bone morphogenetic protein/Retinoic acid Inducible Neural-specific 3 (BRINP3) being the most significantly underexpressed. Attenuated expression of BRINP3 in UC was independent of current inflammation, unrelated to phenotype or treatment, and remained low at rebiopsy an average of 22 months later. BRINP3 is localized to the brush border of the colonic epithelium and expression is influenced by DNA methylation within its promoter. Conclusions: Genome-wide expression analysis of noninflamed mucosal biopsies from patients with UC identified BRINP3 as significantly underexpressed throughout the colon in a large subset of patients with UC. Low levels of this gene could predispose or contribute to the maintenance of the characteristic mucosal inflammation seen in this condition. PMID:25171508

Effect of topical chamomile on immunohistochemical levels of IL-1β and TNF-α in 5-fluorouracil-induced oral mucositis in hamsters.

PubMed

Curra, Marina; Martins, Marco Antonio T; Lauxen, Isabel S; Pellicioli, Ana Carolina A; Sant'Ana Filho, Manoel; Pavesi, Vanessa Christina S; Carrard, Vinicius C; Martins, Manoela D

2013-02-01

The aim of the present study was to evaluate the effect of topical chamomile and corticosteroid treatment on the profile of tissue cytokines (IL-1β and TNF-α) in 5-fluorouracil-induced oral mucositis in hamsters. Thirty-six hamsters were randomly separated into three groups (12 animals each): Group I--without treatment (control); Group II-treatment with chamomile (Ad-Muc(®)); and Group III--treatment with corticosteroid (betamethasone elixir- Celestone(®)). The animals received an intraperitoneal injection of 5--fluorouracil on Days 0 and 2. On Days 3 and 4, the buccal mucosa was scratched and therapy was initiated on Day 5. Three animals from each group were killed on Days 0, 5, 10, and 14 and the buccal mucosa was removed. The streptavidin-biotin complex method was used to delineate the in situ distribution, localization, and semiquantitative analysis of IL-1β and TNF-α. Data from the semiquantitative analysis of immunohistochemical staining were comparatively analyzed using the Kruskal-Wallis test, followed by Dunn's multiple comparisons test. The distribution and localization of IL-1β and TNF-α immunolabeling were similar. These proteins exhibited a diffuse pattern distributed throughout the connective tissue. The epithelium and adipose tissue were negative for both proteins. The semiquantitative analysis revealed that immunolabeling of IL-1β and TNF-α increased in all groups with the development of mucositis. On Day 10 (period of peak mucositis), the group treated with chamomile had lower scores for both pro-inflammatory cytokines. Treatment with topical chamomile reduced the tissue levels of IL-1β and TNF-α, thereby demonstrating anti-inflammatory action in oral mucositis in hamsters.

Longitudinal study of esophageal mucosal damage after esophagectomy and gastric interposition: relationship between reflux-related mucosal injury and Notch signaling

PubMed Central

Yuan, Yong; Tong, Tie-Jun; Zeng, Xiao-Xi; Yang, Yu-Shang; Wang, Zhi-Qiang; Wang, Yun-Cang; Gou, Jun-He

2017-01-01

Background Esophagectomy with gastric interposition could serve as a good human reflux model to study the molecular pathogenesis of esophageal mucosal damage induced by gastroesophageal reflux. This study was to investigate the role of Notch signaling in reflux injury of esophageal mucosa. Methods Patients undergoing Ivor-Lewis esophagectomy for early stage esophageal squamous cell carcinoma were included. Follow-ups were scheduled at 6, 18, 36 and 48 months postoperatively, including reflux symptom assessment, endoscopic and histological evaluation of esophageal mucosal damage. The expressions of Notch1 and its downstream target gene Hes1 were evaluated by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). Results Forty-four out of 48 patients completed four follow-ups. Injuries of esophageal remnant confirmed by endoscopical and histological examinations were both more often with a longer postoperative period (P<0.05). The mRNA expression levels of Notch1 and Hes1 were decreased in a time-dependent manner after operation (P<0.001). Notch1 and Hes1 mRNA levels were significantly higher in normal squamous mucosa than in esophagitis, and higher in esophagitis than in metaplasia (P<0.05). Immunohistochemical study also demonstrated a similar protein expression pattern. Samples with endoscopic evidence of mucosal damage exhibited lower expression of Notch1 mRNA levels as compared to biopsies without visualized damage (P=0.035). Conclusions This is the first longitudinal study on Notch signaling in human esophagectomy model, our preliminary findings suggest decreased Notch signaling might be involved in the development of mucosa damage caused by gastroesophageal reflux. PMID:29312733

Relationship between lesion formation and permeability of rat gastric mucosa to H+ and other cations.

PubMed Central

Bunce, K. T.; McCarthy, J. J.; Spraggs, C. F.; Stables, R.

1982-01-01

The relationship between lesion formation and ionic permeability has been investigated in rat gastric mucosa in vivo. Changes in these parameters were measured in the mucosa treated topically with prostaglandins E2 and A2 and/or aspirin. Particular attention was paid to the net flux of H+ ions across the gastric mucosa. The effect of aspirin concentrations of 5 mM, 20 mM and '40 mM' (the latter, a suspension in a saturated solution) was investigated. Aspirin concentrations of 20 mM and '40 mM' produced a marked increase in lesion formation and increased the net mucosal to serosal flux of H+ ions. Aspirin 5 mM produced a significant increase in lesion formation but did not cause a significant change in net H+ ion flux. This result suggests that aspirin can have a direct irritant effect on the gastric mucosa and that the back diffusion of H+ ions is not a pre-requisite for the development of overt mucosal ulceration. The effect of topically applied prostaglandin E2 (PGE2) on aspirin-induced gastric mucosal damage was investigated. Concentrations of PGE2 of 10(-5) M and 10(-4) M ameliorated aspirin-induced damage, but these changes were not necessarily accompanied by a significant reduction in net H+ ion flux. Again, this result is not consistent with a direct relationship between lesion formation and mucosal permeability to H+ ions. Since PGA2 did not ameliorate aspirin-induced mucosal damage, the protective effect of PGE2 could not be attributed to its conversion to PGA2 in the acidic environment of the gastric lumen.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6964662

May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat.

PubMed

Abalo, R; Uranga, J A; Pérez-García, I; de Andrés, R; Girón, R; Vera, G; López-Pérez, A E; Martín-Fontelles, M I

2017-03-01

The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg -1 injection -1 , 1 injection day -1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg -1 injection -1 , cumulative dose of 300 mg kg -1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea. © 2016 John Wiley & Sons Ltd.

Siblings of patients with Crohn's disease exhibit a biologically relevant dysbiosis in mucosal microbial metacommunities.

PubMed

Hedin, Charlotte; van der Gast, Christopher J; Rogers, Geraint B; Cuthbertson, Leah; McCartney, Sara; Stagg, Andrew J; Lindsay, James O; Whelan, Kevin

2016-06-01

To determine the existence of mucosal dysbiosis in siblings of patients with Crohn's disease (CD) using 454 pyrosequencing and to comprehensively characterise and determine the influence of genotypical and phenotypical factors, on that dysbiosis. Siblings of patients with CD have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. Whether the mucosal microbiota is disrupted in these at-risk individuals is unknown. Rectal biopsy DNA was extracted from 21 patients with quiescent CD, 17 of their healthy siblings and 19 unrelated healthy controls. Mucosal microbiota was analysed by 16S rRNA gene pyrosequencing and were classified into core and rare species. Genotypical risk was determined using Illumina Immuno BeadChip, faecal calprotectin by ELISA and blood T-cell phenotype by flow cytometry. Core microbiota of both patients with CD and healthy siblings was significantly less diverse than controls. Metacommunity profiling (Bray-Curtis (SBC) index) showed the sibling core microbial composition to be more similar to CD (SBC=0.70) than to healthy controls, whereas the sibling rare microbiota was more similar to healthy controls (SBC=0.42). Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity both between siblings and controls, and between patients and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect. Individuals with elevated CD-risk display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. This dysbiosis in healthy people at risk of CD implicates microbiological processes in CD pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Rationally designed nanocarriers for intranasaltherapy of allergic rhinitis: influence of carrier type on in vivo nasal deposition

PubMed Central

Sallam, Marwa Ahmed; Helal, Hala Mahmoud; Mortada, Sana Mohamed

2016-01-01

The aim of this study is to develop a locally acting nasal delivery system of triamcinolone acetonide (TA) for the maintenance therapy of allergic rhinitis. The effect of encapsulating TA in different nanocarriers on its mucosal permeation and retention as well as in vivo nasal deposition has been studied. A comparative study was established between polymeric oil core nanocapsules (NCs), lipid nanocarriers such as nanoemulsion (NE), and nanostructured lipid carriers (NLCs). The elaborated nanocarriers were compared with TA suspension and the commercially available suspension “Nasacort®”. The study revealed that NC provided the highest mucosal retention, as 46.14%±0.048% of the TA initial dose was retained after 24 hours, while showing the least permeation through the nasal mucosa. On the other hand, for TA suspension and Nasacort®, the mucosal retention did not exceed 23.5%±0.047% of the initial dose after 24 hours. For NE and NLC, values of mucosal retention were 19.4%±0.041% and 10.97%±0.13%, respectively. NC also showed lower mucosal irritation and superior stability compared with NE. The in vivo nasal deposition study demonstrated that NC maintained drug in its site of action (nasal cavity mucosa) for the longest period of time. The elaborated polymeric oil core NCs are efficient carriers for the administration of nasally acting TA as it produced the least permeation results, thus decreasing systemic absorption of TA. Although NCs have been administered via various routes, this is the first study to implement the polymeric oil core NC as an efficient carrier for localized nasal drug delivery. PMID:27307734

Mucosal and salivary microbiota associated with recurrent aphthous stomatitis.

PubMed

Kim, Yun-Ji; Choi, Yun Sik; Baek, Keum Jin; Yoon, Seok-Hwan; Park, Hee Kyung; Choi, Youngnim

2016-04-01

Recurrent aphthous stomatitis (RAS) is a common oral mucosal disorder of unclear etiopathogenesis. Although recent studies of the oral microbiota by high-throughput sequencing of 16S rRNA genes have suggested that imbalances in the oral microbiota may contribute to the etiopathogenesis of RAS, no specific bacterial species associated with RAS have been identified. The present study aimed to characterize the microbiota in the oral mucosa and saliva of RAS patients in comparison with control subjects at the species level. The bacterial communities of the oral mucosa and saliva from RAS patients with active lesions (RAS, n = 18 for mucosa and n = 8 for saliva) and control subjects (n = 18 for mucosa and n = 7 for saliva) were analyzed by pyrosequencing of the 16S rRNA genes. There were no significant differences in the alpha diversity between the controls and the RAS, but the mucosal microbiota of the RAS patients showed increased inter-subject variability. A comparison of the relative abundance of each taxon revealed decreases in the members of healthy core microbiota but increases of rare species in the mucosal and salivary microbiota of RAS patients. Particularly, decreased Streptococcus salivarius and increased Acinetobacter johnsonii in the mucosa were associated with RAS risk. A dysbiosis index, which was developed using the relative abundance of A. johnsonii and S. salivarius and the regression coefficients, correctly predicted 83 % of the total cases for the absence or presence of RAS. Interestingly, A. johnsonii substantially inhibited the proliferation of gingival epithelial cells and showed greater cytotoxicity against the gingival epithelial cells than S. salivarius. RAS is associated with dysbiosis of the mucosal and salivary microbiota, and two species associated with RAS have been identified. This knowledge may provide a diagnostic tool and new targets for therapeutics for RAS.

Anti-inflammatory effects of the selective phosphodiesterase 3 inhibitor, cilostazol, and antioxidants, enzymatically-modified isoquercitrin and α-lipoic acid, reduce dextran sulphate sodium-induced colorectal mucosal injury in mice.

PubMed

Kangawa, Yumi; Yoshida, Toshinori; Abe, Hajime; Seto, Yoshiki; Miyashita, Taishi; Nakamura, Michi; Kihara, Tohru; Hayashi, Shim-Mo; Shibutani, Makoto

2017-04-04

Developing effective treatments and preventing inflammatory bowel disease (IBD) are urgent challenges in improving patients' health. It has been suggested that platelet activation and reactive oxidative species generation are involved in the pathogenesis of IBD. We examined the inhibitory effects of a selective phosphodiesterase-3 inhibitor, cilostazol (CZ), and two antioxidants, enzymatically modified isoquercitrin (EMIQ) and α-lipoic acid (ALA), against dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were treated with 0.3% CZ, 1.5% EMIQ, and 0.2% ALA in their feed. Colitis was induced by administering 5% DSS in drinking water for 8days. The inhibitory effects of these substances were evaluated by measuring relevant clinical symptoms (faecal blood, diarrhoea, and body weight loss), colon length, plasma cytokine and chemokine levels, whole genome gene expression, and histopathology. Diarrhoea was suppressed by each treatment, while CZ prevented shortening of the colon length. All treatment groups exhibited decreased plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α compared with the DSS group. Microarray analysis showed that cell adhesion, cytoskeleton regulation, cell proliferation, and apoptosis, which might be related to inflammatory cell infiltration and mucosal healing, were affected in all the groups. DSS-induced mucosal injuries such as mucosal loss, submucosal oedema, and inflammatory cell infiltration in the distal colon were prevented by CZ or antioxidant treatment. These results suggest that anti-inflammatory effects of these agents reduced DSS-induced mucosal injuries in mice and, therefore, may provide therapeutic benefits in IBD. Copyright © 2016 Elsevier GmbH. All rights reserved.

Total Mucosal Irradiation with Intensity-modulated Radiotherapy in Patients with Head and Neck Carcinoma of Unknown Primary: A Pooled Analysis of Two Prospective Studies.

PubMed

Richards, T M; Bhide, S A; Miah, A B; Del Rosario, L; Bodla, S; Thway, K; Gujral, D M; Rooney, K P; Schick, U; McGovern, T; Grove, L; Newbold, K L; Harrington, K J; Nutting, C M

2016-09-01

To determine the clinical outcomes of an intensity-modulated radiotherapy technique for total mucosal irradiation (TM-IMRT) in patients with head and neck carcinoma of unknown primary (HNCUP). A single-centre prospective phase II trial design was used in two sequential studies to evaluate TM-IMRT for HNCUP. Patients were investigated for primary tumour site using examination under anaesthetic and biopsies, computed tomography ± magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Patients received IMRT to the potential primary tumour sites and elective cervical nodes. Concomitant chemotherapy was used in patients who received primary radiotherapy or those with nodal extracapsular extension. Thirty-six patients with HNCUP were recruited; 72% male. Twenty-five patients (69.4%) had p16-positive disease. Two year mucosal and local nodal control rates were 97.1% (95% confidence interval 91.4-100) and 89.8% (78.4-100), respectively. One mucosal primary was detected 7.3 months after TM-IMRT and three patients died from recurrent/metastatic squamous cell carcinoma of the head and neck. Twelve patients (33%) developed grade 3 (Late Effects in Normal Tissue-Subjective, Objective, Management and Analytical; LENT-SOMA) dysphagia with a 1 year enteric tube feeding rate of 2.7%. The high-grade subjective xerostomia rate (LENT-SOMA) at 24 months after IMRT was 15%. At a median follow-up of 36.1 months, the use of TM-IMRT was associated with good local control. Toxicity was comparable with previously reported TM-IMRT regimens encompassing similar mucosal volumes. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease

PubMed Central

Craven, Melanie; Egan, Charlotte E.; Dowd, Scot E.; McDonough, Sean P.; Dogan, Belgin; Denkers, Eric Y.; Bowman, Dwight; Scherl, Ellen J.; Simpson, Kenneth W.

2012-01-01

Background and Aims Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn’s Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis. Methods We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI;0.1 mg/mouse), or high dose indomethacin (HDI;1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype. Results Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% Gram + Firmicutes to >95% Gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2−/−, and reduced dysbiosis in ileitis-resistant CCR2−/− mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion. Conclusions Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD. PMID:22848538

Identifying cell and molecular stress after radiation in a three-dimensional (3-D) model of oral mucositis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lambros, Maria Polikandritou, E-mail: mlambros@westernu.edu; Parsa, Cyrus; Mulamalla, HariChandana

2011-02-04

Research highlights: {yields} We irradiated a 3-D human oral cell culture of keratinocytes and fibroblasts with 12 and 2 Gy. {yields} 6 h after irradiation the histopathology and apoptosis of the 3-D culture were evaluated. Microarrays were used to assess the gene expression in the irradiated 3-D tissue. {yields} 12 Gy induced significant histopathologic changes and cellular apoptosis. {yields} 12 Gy significantly affected genes of the NF-kB pathway, inflammatory cytokines and DAMPs. -- Abstract: Mucositis is a debilitating adverse effect of chemotherapy and radiation treatment. It is important to develop a simple and reliable in vitro model, which can routinelymore » be used to screen new drugs for prevention and treatment of mucositis. Furthermore, identifying cell and molecular stresses especially in the initiation phase of mucositis in this model will help towards this end. We evaluated a three-dimensional (3-D) human oral cell culture that consisted of oral keratinocytes and fibroblasts as a model of oral mucositis. The 3-D cell culture model was irradiated with 12 or 2 Gy. Six hours after the irradiation we evaluated microscopic sections of the cell culture for evidence of morphologic changes including apoptosis. We used microarrays to compare the expression of several genes from the irradiated tissue with identical genes from tissue that was not irradiated. We found that irradiation with 12 Gy induced significant histopathologic effects including cellular apoptosis. Irradiation significantly affected the expression of several genes of the NF-kB pathway and several inflammatory cytokines, such as IL-1B, 1L-8, NF-kB1, and FOS compared to tissue that was not irradiated. We identified significant upregulation of several genes that belong to damage-associated molecular patterns (DAMPs) such as HMB1, S100A13, SA10014, and SA10016 in the 3-D tissues that received 12 Gy but not in tissues that received 2 Gy. In conclusion, this model quantifies radiation damage and this is an important first step towards the development 3-D tissue as a screening tool.« less

Haemophilus is overrepresented in the nasopharynx of infants hospitalized with RSV infection and associated with increased viral load and enhanced mucosal CXCL8 responses.

PubMed

Ederveen, Thomas H A; Ferwerda, Gerben; Ahout, Inge M; Vissers, Marloes; de Groot, Ronald; Boekhorst, Jos; Timmerman, Harro M; Huynen, Martijn A; van Hijum, Sacha A F T; de Jonge, Marien I

2018-01-11

While almost all infants are infected with respiratory syncytial virus (RSV) before the age of 2 years, only a small percentage develops severe disease. Previous studies suggest that the nasopharyngeal microbiome affects disease development. We therefore studied the effect of the nasopharyngeal microbiome on viral load and mucosal cytokine responses, two important factors influencing the pathophysiology of RSV disease. To determine the relation between (i) the microbiome of the upper respiratory tract, (ii) viral load, and (iii) host mucosal inflammation during an RSV infection, nasopharyngeal microbiota profiles of RSV infected infants (< 6 months) with different levels of disease severity and age-matched healthy controls were determined by 16S rRNA marker gene sequencing. The viral load was measured using qPCR. Nasopharyngeal CCL5, CXCL10, MMP9, IL6, and CXCL8 levels were determined with ELISA. Viral load in nasopharyngeal aspirates of patients associates significantly to total nasopharyngeal microbiota composition. Healthy infants (n = 21) and RSV patients (n = 54) display very distinct microbial patterns, primarily characterized by a loss in commensals like Veillonella and overrepresentation of opportunistic organisms like Haemophilus and Achromobacter in RSV-infected individuals. Furthermore, nasopharyngeal microbiota profiles are significantly different based on CXCL8 levels. CXCL8 is a chemokine that was previously found to be indicative for disease severity and for which we find Haemophilus abundance as the strongest predictor for CXCL8 levels. The nasopharyngeal microbiota in young infants with RSV infection is marked by an overrepresentation of the genus Haemophilus. We present that this bacterium is associated with viral load and mucosal CXCL8 responses, both which are involved in RSV disease pathogenesis.

Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

PubMed

Bleier, Benjamin S; Kohman, Richie E; Feldman, Rachel E; Ramanlal, Shreshtha; Han, Xue

2013-01-01

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

Permeabilization of the Blood-Brain Barrier via Mucosal Engrafting: Implications for Drug Delivery to the Brain

PubMed Central

Bleier, Benjamin S.; Kohman, Richie E.; Feldman, Rachel E.; Ramanlal, Shreshtha; Han, Xue

2013-01-01

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson’s disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS. PMID:23637885

Biodegradable polymeric microsphere-based vaccines and their applications in infectious diseases.

PubMed

Lin, Chi-Ying; Lin, Shih-Jie; Yang, Yi-Chen; Wang, Der-Yuan; Cheng, Hwei-Fang; Yeh, Ming-Kung

2015-01-01

Vaccination, which provides effective, safe infectious disease protection, is among the most important recent public health and immunological achievements. However, infectious disease remains the leading cause of death in developing countries because several vaccines require repeated administrations and children are often incompletely immunized. Microsphere-based systems, providing controlled release delivery, can obviate the need for repeat immunizations. Here, we review the function of sustained and pulsatile release of biodegradable polymeric microspheres in parenteral and mucosal single-dose vaccine administration. We also review the active-targeting function of polymeric particles. With their shield and co-delivery functions, polymeric particles are applied to develop single-dose and mucosally administered vaccines as well as to improve subunit vaccines. Because polymeric particles are easily surface-modified, they have been recently used in vaccine development for cancers and many infectious diseases without effective vaccines (e.g., human immunodeficiency virus infection). These polymeric particle functions yield important vaccine carriers and multiple benefits.

Effects of commercially produced almond by-products on chemotherapy-induced mucositis in rats

PubMed Central

Whittaker, Alexandra L; Zhu, Ying; Howarth, Gordon S; Loung, Chi S; Bastian, Susan E P; Wirthensohn, Michelle G

2017-01-01

AIM To determine if almond extracts reduce the severity of chemotherapy-induced mucositis as determined through biochemical, histological and behavioural markers. METHODS Intestinal mucositis is a debilitating condition characterized by inflammation and ulceration of the gastrointestinal mucosa experienced by cancer patients undergoing chemotherapy. Certain bioactive plant products have shown promise in accelerating mucosal repair and alleviating clinical symptoms. This study evaluated almond extracts for their potential to reduce the severity of chemotherapy-induced mucositis in Dark Agouti rats. Female Dark Agouti rats were gavaged (days 3-11) with either PBS, almond hull or almond blanched water extract at two doses, and were injected intraperitoneally with 5-fluorouracil (5-FU-150 mg/kg) or saline on day 9 to induce mucositis. Burrowing behavior, histological parameters and myeloperoxidase activity were assessed. RESULTS Bodyweight was significantly reduced in rats that received 5-FU compared to saline-treated controls (P < 0.05). Rats administered 5-FU significantly increased jejunal and ileal MPO levels (1048%; P < 0.001 and 409%; P < 0.001), compared to healthy controls. Almond hull extract caused a pro-inflammatory response in rats with mucositis as evidenced by increased myeloperoxidase activity in the jejunum when compared to 5-FU alone (rise 50%, 1088 ± 96 U/g vs 723 ± 135 U/g, P = 0.02). Other extract-related effects on inflammatory activity were minimal. 5-FU significantly increased histological severity score compared to healthy controls confirming the presence of mucositis (median of 9.75 vs 0; P < 0.001). The extracts had no ameliorating effect on histological severity score in the jejunum or ileum. Burrowing behavior was significantly reduced in all chemotherapy-treated groups (P = 0.001). The extracts failed to normalize burrowing activity to baseline levels. CONCLUSION Almond extracts at these dosages offer little beneficial effect on mucositis severity. Burrowing provides a novel measure of affective state in studies of chemotherapy-induced mucositis. PMID:29184703

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence.

PubMed

O'Regan, Kevin; Breen, Micheál; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J; Hodi, F Stephen; Van den Abbeele, Annick D

2013-12-30

Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38-76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin.

Close association between oral Candida species and oral mucosal disorders in patients with xerostomia.

PubMed

Shinozaki, S; Moriyama, M; Hayashida, J-N; Tanaka, A; Maehara, T; Ieda, S; Nakamura, S

2012-10-01

Heightened interest in oral health has lead to an increase in patients complaining of xerostomia, which is associated with various oral mucosal disorders. In this study, we investigated the relationship between Candida species and oral mucosal disorders in patients with xerostomia. We evaluated whole salivary flow rate and presence of oral mucosal disorders in 48 patients with xerostomia and 15 healthy controls. The number of Candida species was measured as colony-forming units after propagation on selective medium. Identification of Candida at the species level was carried out by polymerase chain reaction and restriction fragment length polymorphism analysis. We then examined the relationship between Candida species and oral mucosal symptoms. Compared with controls, patients with xerostomia exhibited significantly decreased whole salivary flow rate, increased rate of oral mucosal symptoms, and higher numbers of Candida. Salivary flow rate negatively correlated with the number Candida. Among patients with oral candidiasis, Candida albicans was isolated from the tongue mucosa and Candida glabrata was isolated from the angle of the mouth. These results suggest that particular Candida species are involved in the pathogenesis of oral mucosal disorders in patients with xerostomia. © 2012 John Wiley & Sons A/S.

Morphometric study of uninvolved rectal mucosa 10 cm and 20 cm away from the malignant tumor.

PubMed

Despotović, Sanja Z; Milićević, Novica M; Milosević, Dragoslav P; Despotović, Nebojsa; Erceg, Predrag; Bojić, Bozidar; Bojić, Danijela; Svorcan, Petar; Mihajlović, Gordana; Dorđević, Jelena; Lalić, Ivana M; Milićević, Zivana

2014-02-01

Recently, many details of the interplay between tumor cells and tumor-associated stromal elements leading to the progression of malignant disease were elucidated. In contrast, little is known about the role of uninvolved stromal tissue in the remote surrounding of the malignant tumor. Therefore, we performed a computer-aided morphometric study of rectal mucosa in samples taken 10 cm and 20 cm away from the malignant tumor during endoscopic examination of 23 patients older than 60 years. The samples of rectal mucosa from 10 healthy persons of corresponding age subjected to diagnostic rectoscopy during active screening for asymptomatic cancer were used as control. All structural elements of the rectal mucosa were studied and the number of nucleated cells in the lamina propria per 0.1 mm² of tissue was assessed. Our study revealed a reduced number of cells in the lamina propria of the rectal mucosa 10 cm and 20 cm away from the tumor lesion in both male and female patients. The decreased mucosal height and increased crypt number were registered in female patients 10 cm away from the tumor. The connective tissue of lamina propria showed a disorderly organization: the collagen fibers were frail, loosely arranged and signs of tissue edema were present. Small blood vessels and capillaries were much more frequently seen than in healthy tissue. Our results demonstrate the complex interactions between the cancer and remote mucosal tissue of the affected organ.

Numerical modeling of turbulent and laminar airflow and odorant transport during sniffing in the human and rat nose.

PubMed

Zhao, Kai; Dalton, Pamela; Yang, Geoffery C; Scherer, Peter W

2006-02-01

Human sniffing behavior usually involves bouts of short, high flow rate inhalation (>300 ml/s through each nostril) with mostly turbulent airflow. This has often been characterized as a factor enabling higher amounts of odorant to deposit onto olfactory mucosa than for laminar airflow and thereby aid in olfactory detection. Using computational fluid dynamics human nasal cavity models, however, we found essentially no difference in predicted olfactory odorant flux (g/cm2 s) for turbulent versus laminar flow for total nasal flow rates between 300 and 1000 ml/s and for odorants of quite different mucosal solubility. This lack of difference was shown to be due to the much higher resistance to lateral odorant mass transport in the mucosal nasal airway wall than in the air phase. The simulation also revealed that the increase in airflow rate during sniffing can increase odorant uptake flux to the nasal/olfactory mucosa but lower the cumulative total uptake in the olfactory region when the inspired air/odorant volume was held fixed, which is consistent with the observation that sniff duration may be more important than sniff strength for optimizing olfactory detection. In contrast, in rats, sniffing involves high-frequency bouts of both inhalation and exhalation with laminar airflow. In rat nose odorant uptake simulations, it was observed that odorant deposition was highly dependent on solubility and correlated with the locations of different types of receptors.

[Analysis of HIV antibody positive cases in Peking University Hospital of Stomatology during 9 years].

PubMed

Ding, Jian-fen; Qiu, Juan; Shen, Shu-ming

2016-02-01

To investigate the prevalence and characteristics of HIV patients found in Peking University Hospital of Stomatology during 9 years, and provide management strategy for early diagnosis and control of HIV in Stomatology Hospital. A retrospective study of the HIV positive patients diagnosed by HIV antibody screening was carried out. The related information about these patients found in Peking University School of Stomatology during 2005-2013 was obtained from China Disease Control Information System. 68,562 patients accepted HIV antibody screening in Peking University Hospital of Stomatology during 2005-2013. Thirty one patients were found HIV antibody positive. The ratio of HIV antibody positive was about 0.045%, which was composed of 25 males and 6 females. 61.29% patients aged between 20-40 years, and their career was mainly commercial service with a education level of junior high school. The proportion of sexual route of transmission was about 74.91%, and 34.78% of them were male homosexuality. Most of the patients with HIV antibody positive were found in the out-patient clinic, especially in the department of oral mucosal diseases, accounting for 70.97%. HIV antibody positive rate in Peking University School of Stomatology was slightly lower than that in general hospitals. Medical staff should increase their awareness of AIDS prevention and control, for higher HIV risk departments, such as oral mucosal diseases and periodontal disease, efforts should be made to increase HIV screening, expand the scope of screening, and promote provider-initiated HIV testing and counseling.

A single intranasal immunization with a subunit vaccine formulation induces higher mucosal IgA production than live respiratory syncytial virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garg, Ravendra

Respiratory syncytial virus (RSV) causes serious respiratory illness in infants and elderly. RSV infection induces short-lived immunity, which leaves people prone to re-infection. In contrast, the RSV fusion (F) protein formulated with a novel adjuvant (∆F/TriAdj) elicits long term protective immunity. A comparison of RSV-immunized mice to mice vaccinated with a single dose of ∆F/TriAdj showed no difference in IgG1 and IgG2a production; however, local IgA secreting memory B cell development and B cell IgA production were significantly lower in RSV vaccinated mice than in ∆F/TriAdj-immunized mice. This indicates a potential reason as to why long-term immunity is not inducedmore » by RSV infection. The comparison also revealed that germinal center lymphocyte populations were higher in ∆F/TriAdj-vaccinated mice. Furthermore, ∆F/TriAdj induced higher gene expression of activation-induced cytidine deaminase (AID), as well as IL-6, IL-21, TGF-β cytokines, which are key players in IgA class switch recombination, ultimately leading to a sustained long-term memory response. - Highlights: •Immune responses to adjuvanted RSV F protein, ∆F/TriAdj, and RSV were compared. •∆F/TriAdj stimulates more local IgA production than RSV. •∆F/TriAdj induces more local IgA secreting memory B cells than RSV. •Germinal center lymphocyte populations are higher in ∆F/TriAdj-vaccinated mice. •∆F/TriAdj induces higher gene expression of AID, IL-6, IL-21, and TGF-β than RSV.« less

Gastrointestinal microbiota and mucosal immune gene expression in neonatal pigs reared in a cross-fostering model.

PubMed

Maradiaga, Nidia; Aldridge, Brian; Zeineldin, Mohamed; Lowe, James

2018-05-06

Cross fostering is employed to equalize the number of piglet between litters ensuring colostrum intake for their survival and growth. However, little is known about the impact of cross fostering on the intestinal microbiota and mucosal immune gene expression of the neonatal pig. The objective of this study was to determine the influence of maternal microbial communities on the gastrointestinal (GI) microbiota and mucosal immune gene expression in young pigs reared in a cross-fostering model. Piglets were given high quality colostrum from birth dam or foster dam upon birth. Twenty-four piglets were randomly assigned at birth to 1 of 3 treatments according to colostrum source and postcolostral milk feeding during, as follow: treatment 1 (n = 8), received colostrum and post-colostral milk feeding from their own dam; treatment 2 (n = 8), received colostrum from foster dam and returned to their own dam for post-colostral milk feeding; and treatment 3 (n = 8), received colostrum and post-colostral milk feeding from foster dam. Genomic DNA was extracted, and the V1-V3 hypervariable region of the bacterial 16S rRNA gene was amplified and sequenced using the Illumina MiSeq platform. Quantitative real-time PCR analysis was also performed to quantify the expression of toll-like receptors (TLR) 2, TLR 4, TLR 10, tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and interleukin (IL) 4 and IL 10. Data analysis revealed that microbial communities were varied according to the GI biogeographical location, with colon being the most diverse section. Bacterial communities in both maternal colostrum and vaginal samples were significantly associated with those present in the fecal samples of piglets. Cross-fostering did not affect bacterial communities present in the piglet GI tract. However, the mRNA expression of TLR and inflammatory cytokines changed (P < 0.05) with biogeographical location in the GI tract. Higher mRNA expression of TLR and inflammatory cytokines was observed in ileum and ileum associated lymph tissues. This study suggests an impact of colostrum and maternal microbial communities on the microbiota development and mucosal immune gene expression in the newly born piglet. This study revealed novel information about the distribution and expression patterns of TLR and inflammatory cytokines in the GI tract of the young pig. Future studies are needed to determine the role and clinical importance of the mucosal microbiota and mucosal gene expression in health, productivity, and susceptibility to the development of GI disease, in piglets. Published by Elsevier Ltd.

Colonization and effector functions of innate lymphoid cells in mucosal tissues

PubMed Central

Kim, Myunghoo; Kim, Chang H.

2016-01-01

Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. PMID:27365193

Analysis of TSC1 mutation spectrum in mucosal melanoma.

PubMed

Ma, Meng; Dai, Jie; Xu, Tianxiao; Yu, Sifan; Yu, Huan; Tang, Huan; Yan, Junya; Wu, Xiaowen; Yu, Jiayi; Chi, Zhihong; Si, Lu; Cui, Chuanliang; Sheng, Xinan; Kong, Yan; Guo, Jun

2018-02-01

Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma. We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1. The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007). Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.

KIT amplification and gene mutations in acral/mucosal melanoma in Korea.

PubMed

Yun, Jina; Lee, Jeeyun; Jang, Jiryeon; Lee, Eui Jin; Jang, Kee Taek; Kim, Jung Han; Kim, Kyoung-Mee

2011-06-01

Mucosal and acral melanomas have demonstrated different genetic alterations and biological behavior compared with more common cutaneous melanomas. It was recently reported that gain-of-function KIT mutations and/or copy number increases are more common in mucosal and acral melanomas. Thus, we studied the frequency and pattern of KIT aberrations in mucosal and acral melanomas in Korea. We analyzed 97 patients who were pathologically confirmed with mucosal or acral melanoma between 1997 and 2010 at Samsung Medical Center. Of the 97 melanoma patients, 92 were screened for mutations in KIT exons 11, 13, 17, and 18, BRAF and NRAS genes. KIT copy number was assessed by quantitative, real-time PCR. Of the 97 patients, 55 (56.7%) were mucosal, 40 (41.2%) were acral melanoma, and two were of unknown primary origin. Among seven cases with KIT mutation, five (60.0%) occurred in exon 11, one (20.0%) in exon 17, and one (20.0%) in exon 13. Point mutations were the most common, resulting in substitutions in exon 11 (K558R, T574A, L576P, and V559A), exon 13 (N655K), and exon 17 (N822K). A novel Thr574Ala (c.1720A>G) KIT mutation, which has not been reported in melanoma or other tumor types, was identified in one genital melanoma case. Of the 97 mucosal or acral melanoma specimens, 49 were tested for KIT gene copy number changes using quantitative PCR. Increased KIT copy number was identified in 15 patients: seven (40%) of 20 acral melanomas and eight (31%) of 26 mucosal melanomas. Our study implicates that a significant proportion of acral and mucosal melanomas have KIT mutations in Asian population. © 2011 The Authors. APMIS © 2011 APMIS.

Beneficial Effects of Adjuvant Melatonin in Minimizing Oral Mucositis Complications in Head and Neck Cancer Patients Receiving Concurrent Chemoradiation.

PubMed

Onseng, Kittipong; Johns, Nutjaree Pratheepawanit; Khuayjarernpanishk, Thanut; Subongkot, Suphat; Priprem, Aroonsri; Hurst, Cameron; Johns, Jeffrey

2017-12-01

Oral mucositis is a major cause of pain and delayed cancer treatment leading to poor survival in head and neck cancer patients receiving concurrent chemoradiation. The study evaluated the effect of adjuvant melatonin on minimizing oral mucositis complications to reduce these treatment delays and interruptions. A randomized, double-blind, double dummy, placebo-controlled clinical trial. Ubon Ratchathani Cancer Hospital, Thailand. Thirty-nine head and neck cancer patients receiving concurrent chemoradiation (5 days/week of radiation plus chemotherapy three or six cycles). Patients were randomized to receive 20 mg melatonin gargle (or matched placebo) before each irradiation, and 20 mg melatonin capsules (or matched placebo) taken nightly during 7 weeks of concurrent chemoradiation. Endpoints were oral mucositis events (incidence and time to grade 3 mucositis or grade 2 xerostomia), pain medication consumption and quality of life (QOL). Melatonin group reported lower incidence of grade 3 oral mucositis (42% vs. 55%) and grade 2 xerostomia (20% vs. 21%); no statistical significance was detected. Melatonin regimen delayed onset of grade 3 mucositis (median 34 days vs. 50 days; p = 0.0318), allowing median time of 16 more patient visits before its onset and fewer interrupted treatments due to oral mucositis were reported (n = 1 vs. n = 5). There was no difference of grade 2 xerostomia (median 32 days vs. 50 days; p = 0.624). Morphine consumption was also reduced (median 57 mg vs. 0 mg; p = 0.0342), while QOL was comparable during the study period. Adjuvant melatonin delayed the onset of oral mucositis, which enables uninterrupted cancer treatment and reduced the amount of morphine used for pain treatment.

Leptin accelerates enterocyte turnover during methotrexate-induced intestinal mucositis in a rat.

PubMed

Sukhotnik, Igor; Mogilner, Jorge G; Shteinberg, Dan; Karry, Rahel; Lurie, Michael; Ure, Benno M; Shaoul, Ron; Coran, Arnold G

2009-05-01

Gastrointestinal mucositis occurs as a consequence of cytotoxic treatment. In the present study, we tested whether leptin can protect gut epithelial cells from methotrexate (MTX)-induced intestinal damage. Non-pretreated and pretreated with MTX Caco-2 cells were incubated with increasing concentrations of leptin for 24 h. Cell proliferation and apoptosis were assessed using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-rats were treated with a single dose of MTX, and MTX-LEP rats were also treated with leptin for 3 d. Intestinal mucosal damage (Park score), mucosal structural changes (bowel and mucosal weight, mucosal DNA and protein content, villus height and crypt depth), enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. RT-PCR was used to determine the level of bax and bcl-2 mRNA expression. In the vitro experiment, treatment with leptin of Caco-2 cells pre-treated with MTX resulted in a significant stimulation of cell proliferation and inhibition of cell apoptosis in a dose-dependent manner. In the vivo experiment, MTX-LEP rats demonstrated a greater jejunal and ileal bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, as well as a greater enterocyte proliferation index compared to MTX-animals. MTX-LEP rats also showed a trend toward an increase in enterocyte apoptosis that was accompanied by an increase in bax mRNA and decrease in bcl-2 mRNA expression. In conclusion, leptin enhances proliferation and decreases apoptosis in Caco-2 cells pretreated with MTX. In a rat model of MTX-induced mucositis, treatment with leptin improves intestinal recovery and enhances enterocyte turnover.

The effect of royal jelly on oral mucositis in patients undergoing radiotherapy and chemotherapy.

PubMed

Erdem, Ozden; Güngörmüş, Zeynep

2014-01-01

This study was conducted to evaluate the effect of royal jelly on oral mucositis in patients undergoing radiotherapy and chemotherapy. The study population consisted of 103 patients undergoing radiotherapy and chemotherapy. Oral mucositis was graded according to the World Health Organization criteria, and patients were divided into 2 groups. All patients received mouthwash therapy with benzydamine hydrochloride and nystatin rinses. In addition, patients in the experimental group received royal jelly. The mean resolution time of oral mucositis in the royal jelly group was significantly shorter than that of the control group. As a result, the study results demonstrate that royal jelly administrated by a certain procedure improved the signs and symptoms of oral mucositis and markedly shortened its healing time.

Endobronchial Mucosal Neuroma with Sarcoidosis.

PubMed

Erdem, Ipek; Duman, Dildar; Eroglu, Selma; Agca, Meltem; Erdagi, Aykut; Turker, Hatice; Hazar, Armagan

2018-02-01

A first case of endobronchial mucosal neuroma with sarcoidosis is hereby reported. A 67-year female patient, who was diagnosed as sarcoidosis previously, was admitted to our hospital with symptoms of dyspnea, chest pain and fatigue. Middle lobe atelectasis and endobronchial lesion were observed in thorax computed tomography (CT). Fiberoptic bronchoscopy revealed polypoid lesions and histopathological examination of biopsy material showed clustered nerve bundles consistent with mucosal neuroma and non-necrotising granulomas consistent with sarcoidosis. Mucosal neuromas are pathognomonic features of multiple endocrine neoplasia (MEN) type 2B. But other components of MEN type 2B such as medullary tyroid carcinoma or pheochromocytoma were not detected in our patient. Hence, a diagnosis of solitary mucosal neuroma and sarcoidosis in the bronchi was made.

Treatment of severe mucositis pain with oral ketamine mouthwash.

PubMed

Shillingburg, Alexandra; Kanate, Abraham S; Hamadani, Mehdi; Wen, Sijin; Craig, Michael; Cumpston, Aaron

2017-07-01

Mucositis is a significant complication of intensive chemotherapy or hematopoietic cell transplantation (HCT), with few treatment options. Ketamine mouthwashes have been used for pain relief, but supporting evidence is limited. The primary objective of this study was to assess the reduction in pain intensity of stomatodynia and odynophagia compared to baseline assessment. This open-label, prospective, phase II interventional study (NCT01566448) was conducted from February 2012 through July 2015. Patients with grade 3 or 4 oral mucositis according to the World Health Organization (WHO) scale as a result of chemotherapy were treated with ketamine mouthwash 20 mg/5 mL four times daily and every 4 h as needed. Thirty patients were enrolled and a total of 136 assessments were conducted. A statistically significant reduction in pain scores of 2 and 3 points was achieved after 1 h and 3 days, respectively (p < 0.0001, p = 0.0003). Pain scores were significantly improved while swallowing, reduced 1 and 4 points at 1-h and 3-day assessment, respectively (p = 0.0006, p = 0.0001). No patients developed adverse effects related to ketamine administration. Ketamine mouthwashes resulted in clinically meaningful and statistically significant reduction in pain scores, have an acceptable safety profile, and can be a useful adjunctive treatment in the multi-modal management of severe mucositis.

Correlation between presence of Leishmania RNA virus 1 and clinical characteristics of nasal mucosal leishmaniosis.

PubMed

Ito, Marcos Massayuki; Catanhêde, Lilian Motta; Katsuragawa, Tony Hiroshi; Silva Junior, Cipriano Ferreira da; Camargo, Luis Marcelo Aranha; Mattos, Ricardo de Godoi; Vilallobos-Salcedo, Juan Miguel

2015-01-01

Mucosal leishmaniosis (ML) is a severe clinical form of leishmaniosis. Complex factors related to the parasite and the host are attributed to the development of mucosal lesions. Leishmania RNA virus 1 (LRV1) can disrupt immune response, and may be the main determinant of severity of the disease; it should be investigated. To study the existence of clinical differences between patients with ML with endosymbiosis by LRV1 and. those without it. A cross-sectional cohort study with clinical evaluation, polymerase chain reaction (PCR) detection of Leishmania, species classification, and search of LRV1 was performed. Only patients with confirmed diagnosis of ML by positive PCR and with nasal mucosa injuries were included in this analysis. Out of 37 patients, 30 (81.1%) were diagnosed with Leishmania braziliensis, five (13.5%) with Leishmania guyanensis, and two (5.4%) with mixed infection of L. braziliensis and L. guyanensis. LVR1 virus was present in 26 (70.3%) of the cases. Correlation between clinical phenotype and presence of LRV1 was not observed, although the frequency of the virus is two-fold higher in mucosal lesions than that found in the literature on skin lesions in the same geographical area. Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Role of vitamin D on gut microbiota in cystic fibrosis.

PubMed

Kanhere, Mansi; Chassaing, Benoit; Gewirtz, Andrew T; Tangpricha, Vin

2018-01-01

This review explores the potential for vitamin D to favorably alter the gut microbiota, given emerging evidence of the role of vitamin D in controlling mucosal inflammation in the gut. It will focus on cystic fibrosis (CF) patients, a population with both vitamin D deficiency due to gut malabsorption and an altered gut microbiota composition. Recent evidence shows that vitamin D acts to maintain the integrity of the gut mucosal barrier by enhancement of intercellular junctions that control mucosal permeability and reduction of pro-inflammatory cytokines such as IL-8. In addition, vitamin D receptor-mediated signaling has been shown to inhibit inflammation-induced apoptosis of intestinal epithelial cells. As a result of these effects on the intestinal mucosa, maintenance of sufficient vitamin D status may be essential for the development of a healthy gut microbiota, particularly in conditions defined by chronic mucosal inflammation such as CF. We hypothesize here that high dose vitamin D may be used to favorably manipulate the aberrant mucosa seen in patients with CF. This may result in improved clinical outcomes in association with a low inflammatory environment that allows beneficial bacteria to outcompete opportunistic pathogens. Current evidence is sparse but encouraging, and additional evidence is needed to establish vitamin D as a therapeutic approach for gut microbiota modification. Copyright © 2016 Elsevier Ltd. All rights reserved.

Localized mucosal response to intranasal live attenuated influenza vaccine in adults.

PubMed

Barría, Maria Ines; Garrido, Jose Luis; Stein, Cheryl; Scher, Erica; Ge, Yongchao; Engel, Stephanie M; Kraus, Thomas A; Banach, David; Moran, Thomas M

2013-01-01

Influenza virus infection is a major public health burden worldwide. Available vaccines include the inactivated intramuscular trivalent vaccine and, more recently, an intranasal live attenuated influenza vaccine (LAIV). The measure of successful vaccination with the inactivated vaccine is a systemic rise in immunoglobulin G (IgG) level, but for the LAIV no such correlate has been established. Seventy-nine subjects were given the LAIV FluMist. Blood was collected prior to vaccination and 3 days and 30 days after vaccination. Nasal wash was collected 3 days and 30 days after vaccination. Responses were measured systemically and in mucosal secretions for cytokines, cell activation profiles, and antibody responses. Only 9% of subjects who received LAIV seroconverted, while 33% of patients developed at least a 2-fold increase in influenza virus-specific immunoglobulin A (IgA) antibodies in nasal wash. LAIV induced a localized inflammation, as suggested by increased expression of interferon-response genes in mucosal RNA and increased granulocyte colony-stimulating factor (G-CSF) and IP-10 in nasal wash. Interestingly, patients who seroconverted had significantly lower serum levels of G-CSF before vaccination. Protection by LAIV is likely provided through mucosal IgA and not by increases in systemic IgG. LAIV induces local inflammation. Seroconversion is achieved in a small fraction of subjects with a lower serum G-CSF level.

[Can the prophylactic treatment of mycotic mucositis improve the time of performing radiotherapy in head and neck tumors?].

PubMed

Gava, A; Ferrarese, F; Tonetto, V; Coghetto, F; Marazzato, G; Zorat, P L

1996-04-01

Radiotherapy-related mucositis is the most frequent complication in the patients submitted to irradiation for head and neck cancers. Many such patients may develop mycotic infections which may lead to treatment discontinuation, with possible consequences on the local control of these cancers. In this study, we investigated the efficacy of fluconazole in preventing mycotic mucositis in 80 patients undergoing radiation therapy for head and neck cancers. The patients were randomized to two groups: 41 patients in group A received the supporting treatment we usually administer, plus fluconazole (50 mg/day) starting from the 6th irradiation session throughout the treatment; 39 patients in group B received the same baseline treatment, but were given the drug only when mycotic infections appeared. The clinical characteristics, treated sites, treatment doses and volumes were similar in the two groups of patients. Fluconazole was well tolerated and no early or late toxicity was observed. We had 1 mycotic mucositis and 14 non-scheduled treatment discontinuations in group A, vs. 19 and 30, respectively, in group B. Radiation therapy lasted 52.3 days (mean) in group A and 55.6 days (mean) in group B; the differences were statistically significant. In our experience, fluconazole, used prophylactically from the 6th radiotherapy session on, reduced the number of mycotic infections and improved radiotherapy schedule in our head and neck cancer patients.

Autoimmunity and asthma: The dirt on the hygiene hypothesis.

PubMed

Mannie, Mark D

2010-04-01

Self peptides shape T-cell development through selectional processes in the thymus and secondary lymphoid organs to promote a diverse and balanced repertoire of conventional and regulatory T cells. Foreign proteins and their derivative peptides permeate our mucosal tissues to constitute another diverse array of peptides that may specify and diversify the mucosal T-cell repertoire. Indeed, the distinction between self peptides and environmental foreign peptides may be academic if both are present constantly within the body. The premise here is that the plethora of foreign peptides, present ubiquitously in our environment and body, form homeostatic niches to foster highly diversified repertoires of conventional and regulatory T cells that recognize persistent environmental peptides as self. Highly diversified repertoires that recognize myriads of self and environmental foreign peptides as homeostatic ligands may be critical for adaptive distinctions of friend or foe in mucosal tissues. The change from our agrarian past to the highly sterile environments of today may adversely impact the diversity and concentrations of foreign peptides that shape the mucosal T-cell repertoire. Various hygiene hypotheses postulate that the lack of factors such as infectious pathogens, innate receptor engagement or Th1 bias is key to the marked increase in immunological disease in modern society. In this version of the hygiene hypothesis, highly diverse constellations of innocuous environmental peptides are postulated to be the critical factor for immune balance and homeostasis.

Ocular surface reconstruction with a tissue-engineered nasal mucosal epithelial cell sheet for the treatment of severe ocular surface diseases.

PubMed

Kobayashi, Masakazu; Nakamura, Takahiro; Yasuda, Makoto; Hata, Yuiko; Okura, Shoki; Iwamoto, Miyu; Nagata, Maho; Fullwood, Nigel J; Koizumi, Noriko; Hisa, Yasuo; Kinoshita, Shigeru

2015-01-01

Severe ocular surface diseases (OSDs) with severe dry eye can be devastating and are currently some of the most challenging eye disorders to treat. To investigate the feasibility of using an autologous tissue-engineered cultivated nasal mucosal epithelial cell sheet (CNMES) for ocular surface reconstruction, we developed a novel technique for the culture of nasal mucosal epithelial cells expanded ex vivo from biopsy-derived human nasal mucosal tissues. After the protocol, the CNMESs had 4-5 layers of stratified, well-differentiated cells, and we successfully generated cultured epithelial sheets, including numerous goblet cells. Immunohistochemistry confirmed the presence of keratins 3, 4, and 13; mucins 1, 16, and 5AC; cell junction and basement membrane assembly proteins; and stem/progenitor cell marker p75 in the CNMESs. We then transplanted the CNMESs onto the ocular surfaces of rabbits and confirmed the survival of this tissue, including the goblet cells, up to 2 weeks. The present report describes an attempt to overcome the problems of treating severe OSDs with the most severe dry eye by treating them using tissue-engineered CNMESs to supply functional goblet cells and to stabilize and reconstruct the ocular surface. The present study is a first step toward assessing the use of tissue-engineered goblet-cell transplantation of nonocular surface origin for ocular surface reconstruction. ©AlphaMed Press.

Cryopreservation of Human Mucosal Leukocytes.

PubMed

Hughes, Sean M; Shu, Zhiquan; Levy, Claire N; Ferre, April L; Hartig, Heather; Fang, Cifeng; Lentz, Gretchen; Fialkow, Michael; Kirby, Anna C; Adams Waldorf, Kristina M; Veazey, Ronald S; Germann, Anja; von Briesen, Hagen; McElrath, M Juliana; Dezzutti, Charlene S; Sinclair, Elizabeth; Baker, Chris A R; Shacklett, Barbara L; Gao, Dayong; Hladik, Florian

2016-01-01

Understanding how leukocytes in the cervicovaginal and colorectal mucosae respond to pathogens, and how medical interventions affect these responses, is important for developing better tools to prevent HIV and other sexually transmitted infections. An effective cryopreservation protocol for these cells following their isolation will make studying them more feasible. To find an optimal cryopreservation protocol for mucosal mononuclear leukocytes, we compared cryopreservation media and procedures using human vaginal leukocytes and confirmed our results with endocervical and colorectal leukocytes. Specifically, we measured the recovery of viable vaginal T cells and macrophages after cryopreservation with different cryopreservation media and handling procedures. We found several cryopreservation media that led to recoveries above 75%. Limiting the number and volume of washes increased the fraction of cells recovered by 10-15%, possibly due to the small cell numbers in mucosal samples. We confirmed that our cryopreservation protocol also works well for both endocervical and colorectal leukocytes. Cryopreserved leukocytes had slightly increased cytokine responses to antigenic stimulation relative to the same cells tested fresh. Additionally, we tested whether it is better to cryopreserve endocervical cells on the cytobrush or in suspension. Leukocytes from cervicovaginal and colorectal tissues can be cryopreserved with good recovery of functional, viable cells using several different cryopreservation media. The number and volume of washes has an experimentally meaningful effect on the percentage of cells recovered. We provide a detailed, step-by-step protocol with best practices for cryopreservation of mucosal leukocytes.

HIV-1 and hijacking of the host immune system: the current scenario.

PubMed

Imran, Muhammad; Manzoor, Sobia; Saalim, Muhammad; Resham, Saleha; Ashraf, Javed; Javed, Aneela; Waqar, Ahmed Bilal

2016-10-01

Human immunodeficiency virus (HIV) infection is a major health burden across the world which leads to the development of acquired immune deficiency syndrome (AIDS). This review article discusses the prevalence of HIV, its major routes of transmission, natural immunity, and evasion from the host immune system. HIV is mostly prevalent in Sub-Saharan Africa and low income countries. It is mostly transmitted by sharing syringe needles, blood transfusion, and sexual routes. The host immune system is categorized into three main types; the innate, the adaptive, and the intrinsic immune system. Regarding the innate immune system against HIV, the key players are mucosal membrane, dendritic cells (DCs), complement system, interferon, and host Micro RNAs. The major components of the adaptive immune system exploited by HIV are T cells mainly CD4+ T cells and B cells. The intrinsic immune system confronted by HIV involves (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) APOBEC3G, tripartite motif 5-α (TRIM5a), terherin, and (SAM-domain HD-domain containing protein) SAMHD1. HIV-1 efficiently interacts with the host immune system, exploits the host machinery, successfully replicates and transmits from one cell to another. Further research is required to explore evasion strategies of HIV to develop novel therapeutic approaches against HIV. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Low level laser therapy in the treatment of oral mucositis in cancer patients: systematic review of literature

NASA Astrophysics Data System (ADS)

El-Sabbagh, Rula Fawzi; Selting, Wayne J.

2016-03-01

Oral mucositis is a debilitating and dose limiting side effect of oncotherapy in cancer patients. Low Level Laser Therapy (LLLT) is a promising new intervention for the treatment of oral mucositis. Aims and objectives: 1. Perform a systematic review of available literature on the therapeutic effect of LLLT on established oral mucositis. 2. Formulate recommendations for future studies based on results of review. Methods: Electronic search oflow level laser therapy in the treatment of oral mucositis was conducted and eligible studies reviewed. Results: Four studies met the inclusion criteria and were analyzed. A total of 109 patients were included, 59 of which received LLLT as a therapeutic measure. An overall success rate of 81.4% success rate was reported in regard to OM. Conclusion: The review demonstrated the positive therapeutic effect of LLLT on oral mucositis. However, the need for future studies with standardized reporting of parameters and methods is needed to increase the level of evidence of this intervention.

[Cryotherapy is useful and safe in the prevention of oral mucositis after high-dose melphalan (L-PAM)].

PubMed

Inagaki, Noriko; Ohue, Yukiko; Shigeta, Hiroe; Tasaka, Taizo

2006-11-01

We prospectively assessed the effectiveness of cryotherapy after high-dose L-PAM to prevent oral mucositis. Cryotherapy with ice tips was commenced 15 minutes before L-PAM administration, and continued until the end of administration. Twenty-six patients were enrolled in this study. Thirteen patients with myeloma were treated with 200 mg/m2 L-PAM followed by autologous peripheral blood stem cell transplantation, and 13 patients (4 AML, 4 MDS, 2 ALL, 2 lymphoma and 1 CML) were treated with 140 mg/m2 L-PAM followed by allogeneic stem cell transplantation. Grade 1 mucositis occurred in four of 13 patients (31%) with 200 mg/m2 L-PAM, and 2 of 13 patients (16%) with 140 mg/m2 L-PAM. Only one patient had grade 2 mucositis, and no grade 3 mucositis were observed. The procedure was well tolerated in all patients. These data suggest that cryotherapy is effective to minimize L-PAM-induced oral mucositis.

Mucosal immunoglobulins at respiratory surfaces mark an ancient association that predates the emergence of tetrapods

PubMed Central

Xu, Zhen; Takizawa, Fumio; Parra, David; Gómez, Daniela; von Gersdorff Jørgensen, Louise; LaPatra, Scott E.; Sunyer, J. Oriol

2016-01-01

Gas-exchange structures are critical for acquiring oxygen, but they also represent portals for pathogen entry. Local mucosal immunoglobulin responses against pathogens in specialized respiratory organs have only been described in tetrapods. Since fish gills are considered a mucosal surface, we hypothesized that a dedicated mucosal immunoglobulin response would be generated within its mucosa on microbial exposure. Supporting this hypothesis, here we demonstrate that following pathogen exposure, IgT+ B cells proliferate and generate pathogen-specific IgT within the gills of fish, thus providing the first example of locally induced immunoglobulin in the mucosa of a cold-blooded species. Moreover, we demonstrate that gill microbiota is predominantly coated with IgT, thus providing previously unappreciated evidence that the microbiota present at a respiratory surface of a vertebrate is recognized by a mucosal immunoglobulin. Our findings indicate that respiratory surfaces and mucosal immunoglobulins are part of an ancient association that predates the emergence of tetrapods. PMID:26869478

Development and pre-clinical evaluation in the swine model of a mucosal vaccine tablet for human influenza viruses: A proof-of-concept study.

PubMed

Busignies, V; Simon, G; Mollereau, G; Bourry, O; Mazel, V; Rosa-Calatrava, M; Tchoreloff, P

2018-03-01

Liquid vaccine formulations present some disadvantages such as stability problems, cold chain requirement or administration by trained personnel. Vaccine formulated as tablets would present a wide range of progress such as an increase stability that would facilitate the administration, the distribution and the storage of vaccine formulations. This work investigates the possibility to develop a mucosal tablet vaccine for human influenza viruses. The tablets were tested in vitro for biological efficacy and stability and in vivo in swine as a model for influenza A virus immunity. First, the ability to produce by compaction a stable vaccine with a preserved antigen was demonstrated. In a second part, vaccine tablets were used to immunize pigs. After positioning the tablets on the buccal mucosa, the animals were challenged by inoculation of the A/H1N1 pandemic virus. The responses were compared to those observed in animals vaccinated intramuscularly with the commercial liquid vaccine. It was observed signs of priming of the pig's immune system with vaccine tablets, even if the immune response stayed lower than vaccination by intramuscular route. Thus, we present attractive results that indicate a promising potential for mucosal vaccine tablets. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional characterization of a novel 3D model of the epithelial-mesenchymal trophic unit.

PubMed

Bucchieri, Fabio; Pitruzzella, Alessandro; Fucarino, Alberto; Gammazza, Antonella Marino; Bavisotto, Celeste Caruso; Marcianò, Vito; Cajozzo, Massimo; Lo Iacono, Giorgio; Marchese, Roberto; Zummo, Giovanni; Holgate, Stephen T; Davies, Donna E

2017-03-01

Epithelial-mesenchymal communication plays a key role in tissue homeostasis and abnormal signaling contributes to chronic airways disease such as COPD. Most in vitro models are limited in complexity and poorly represent this epithelial-mesenchymal trophic unit. We postulated that cellular outgrowth from bronchial tissue would enable development of a mucosal structure that recapitulates better in vivo tissue architecture. Bronchial tissue was embedded in Matrigel and outgrowth cultures monitored using time-lapse microscopy, electrical resistance, light and electron microscopy. Cultures were challenged repetitively with cigarette smoke extract (CSE). The outgrowths formed as a multicellular sheet with motile cilia becoming evident as the Matrigel was remodeled to provide an air interface; cultures were viable for more than one year. Immunofluorescence and electron microscopy (EM) identified an upper layer of mucociliary epithelium and a lower layer of highly organized extracellular matrix (ECM) interspersed with fibroblastic cells separated by a basement membrane. EM analysis of the mucosal construct after repetitive exposure to CSE revealed epithelial damage, loss of cilia, and ECM remodeling, as occurs in vivo. We have developed a robust bronchial mucosal model. The structural changes observed following CSE exposure suggest the model should have utility for drug discovery and preclinical testing, especially those targeting airway remodeling.

Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants.

PubMed

Wright, Peter F; Connor, Ruth I; Wieland-Alter, Wendy F; Hoen, Anne G; Boesch, Austin W; Ackerman, Margaret E; Oberste, M Steven; Gast, Chris; Brickley, Elizabeth B; Asturias, Edwin J; Rüttimann, Ricardo; Bandyopadhyay, Ananda S

2016-12-01

Identification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools. In the FIDEC trial, Latin American infants were randomly assigned to nine groups to assess the efficacy of two schedules of bivalent OPV (bOPV) and IPV and challenge with monovalent type 2 OPV, and stools samples were collected. We selected three groups of particular interest-the bOPV control group (serotypes 1 and 3 at 6, 10, and 14 weeks), the trivalent attenuated OPV (tOPV) control group (tOPV at 6, 10, and 14 weeks), and the bOPV-IPV group (bOPV at 6, 10, and 14 weeks plus IPV at 14 weeks). Neutralising activity and poliovirus type-specific IgA were measured in stool after a monovalent OPV type 2 challenge at 18 weeks of age. Mucosal immunity was measured by in-vitro neutralisation of a type 2 polio pseudovirus (PV2). Neutralisation titres and total and poliovirus-type-specific IgG and IgA concentrations in stools were assessed in samples collected before challenge and 2 weeks after challenge from all participants. 210 infants from Guatemala and Dominican Republic were included in this analysis. Of 38 infants tested for mucosal antibody in the tOPV group, two were shedding virus 1 week after challenge, compared with 59 of 85 infants receiving bOPV (p<0·0001) and 53 of 87 infants receiving bOPV-IPV (p<0·0001). Mucosal type 2 neutralisation and type-specific IgA were noted primarily in response to tOPV. An inverse correlation was noted between virus shedding and both serum type 2 neutralisation at challenge (p<0·0001) and mucosal type 2 neutralisation at challenge (p<0·0001). Mucosal type-2-specific antibodies can be measured in stool and develop in response to receipt of OPV type 2 either in the primary vaccine series or at challenge. These mucosal antibodies influence the amount of virus that is shed in an established infection. Bill & Melinda Gates Foundation. Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.

Autonomic regulation of mucociliary transport rate in the oesophagus of the frog, Rana temporaria.

PubMed Central

Morley, J; Sanjar, S

1984-01-01

Transport of lead particles along the mucosal surface of the frog oesophagus has been measured by direct observation with the aid of video recording. Electrical stimulation of the vagus nerve increased the rate of particle transport. This acceleration was suppressed by atropine or by hexamethonium. Acetylcholine and other parasympathomimetic agents accelerated particle transport rate. Such acceleration was abolished by atropine. Nicotine increased the rate of particle transport and this effect was suppressed by hexamethonium or by atropine. Atropine did not significantly alter basal particle transport rate. Neither basal particle transport rate nor the response to vagal nerve stimulation were affected by eserine. Adrenaline, noradrenaline or isoprenaline did not affect basal particle transport rate. Adrenaline or noradrenaline were without effect on the increased particle transport rate due to electrical stimulation of the vagus. PMID:6332901

Preventive Effect of Glycyrrhiza Glabra Extract on Oral Mucositis in Patients Under Head and Neck Radiotherapy: A Randomized Clinical Trial

PubMed Central

Najafi, Shamsolmolok; Koujan, Soraiya Ebrahimpour; Manifar, Soheila; Kharazifard, Mohammad Javad; Kidi, Saba

2017-01-01

Objectives: About two-thirds of cancer patients undergo radiotherapy. Oral mucositis represents a major complication of radiotherapy, causing morbidity and mortality and decreasing the quality of life of patients. This study aimed to assess the preventive effect of Glycyrrhiza aqueous extract on oral mucositis in cancer patients under head and neck radiotherapy. Materials and Methods: In this double-blind clinical trial, 37 head and neck cancer patients were divided into intervention (n=19) group receiving Glycyrrhiza aqueous extract and control (n=18) group receiving placebo. Patients in the test group used Glycyrrhiza aqueous extract topically twice a day from the first day of starting radiotherapy until the end of the second week. Patients were examined in the first day of radiotherapy for any type of wound before treatment and those with oral ulcers before radiotherapy were excluded from the study. The grade of mucositis was determined using the classification by the World Health Organization. ANCOVA was performed to assess any difference between the two groups with regard to oral mucosal irritation and wound size after the intervention while controlling for the covariates such as sex and age. Results: Significant differences were found in the maximum grade of mucositis and oral mucosal irritation between the intervention and control groups (P<0.001). Conclusions: This study showed that aqueous extract of Glycyrrhiza can be effective for decreasing the severity of oral mucositis in head and neck cancer patients undergoing radiotherapy. PMID:29296112

Induction of pneumococcal polysaccharide-specific mucosal immune responses by oral immunization.

PubMed

VanCott, J L; Kobayashi, T; Yamamoto, M; Pillai, S; McGhee, J R; Kiyono, H

1996-04-01

Liposome and cholera toxin (CT) are considered to be effective antigen delivery vehicles and adjuvants for mucosal vaccines. The effect of these antigen delivery systems on adjuvant responses to mucosally administered pneumococcal polysaccharide (Pnup) was investigated in this study. Both mucosal (e.g. oral) and systemic (i.p.) immunization of mice with purified preparations of Pnup type 23F induced antigen-specific IgM responses in sera. Interestingly, oral immunization of as little as 10 micrograms of Pnup type 23F was sufficient to induce systemic IgM responses. Pnup-specific IgM antibodies peaked by day 7 and no booster responses were evident after a second dose on day 14. In order to examine whether IgG and IgA Pnup-specific immune responses are induced by mucosal immunization, the mucosal adjuvant CT was mixed with Pnup type 23 as an oral vaccine. Co-oral administration of CT and Pnup type 23F resulted in the induction of Pnup-specific faecal IgA antibodies. These results were confirmed by detecting antigen-specific IgA-spot-forming cells in mononuclear cell suspensions prepared from the intestine of immunized mice. These findings suggest that oral immunization with Pnup in the presence of mucosal adjuvants, such as CT, could induce Pnup-specific IgA responses whereas Pnup alone did not. In an attempt to further enhance antigen-specific antibody responses, Pnup type 23F was encapsulated in liposomes and used as mucosal vaccine. However, immunogenicity of Pnup was not improved.

Evaluation of Mucosal and Systemic Immune Responses Elicited by GPI-0100- Adjuvanted Influenza Vaccine Delivered by Different Immunization Strategies

PubMed Central

Liu, Heng; Patil, Harshad P.; de Vries-Idema, Jacqueline; Wilschut, Jan; Huckriede, Anke

2013-01-01

Vaccines for protection against respiratory infections should optimally induce a mucosal immune response in the respiratory tract in addition to a systemic immune response. However, current parenteral immunization modalities generally fail to induce mucosal immunity, while mucosal vaccine delivery often results in poor systemic immunity. In order to find an immunization strategy which satisfies the need for induction of both mucosal and systemic immunity, we compared local and systemic immune responses elicited by two mucosal immunizations, given either by the intranasal (IN) or the intrapulmonary (IPL) route, with responses elicited by a mucosal prime followed by a systemic boost immunization. The study was conducted in BALB/c mice and the vaccine formulation was an influenza subunit vaccine supplemented with GPI-0100, a saponin-derived adjuvant. While optimal mucosal antibody titers were obtained after two intrapulmonary vaccinations, optimal systemic antibody responses were achieved by intranasal prime followed by intramuscular boost. The latter strategy also resulted in the best T cell response, yet, it was ineffective in inducing nose or lung IgA. Successful induction of secretory IgA, IgG and T cell responses was only achieved with prime-boost strategies involving intrapulmonary immunization and was optimal when both immunizations were given via the intrapulmonary route. Our results underline that immunization via the lungs is particularly effective for priming as well as boosting of local and systemic immune responses. PMID:23936066

Immunogenic Properties of Lactobacillus plantarum Producing Surface-Displayed Mycobacterium tuberculosis Antigens

PubMed Central

Kleiveland, Charlotte R.; Minic, Rajna; Moen, Lars F.; Øverland, Lise; Tjåland, Rannei; Carlsen, Harald; Lea, Tor; Eijsink, Vincent G. H.

2016-01-01

ABSTRACT Tuberculosis (TB) remains among the most deadly diseases in the world. The only available vaccine against tuberculosis is the bacille Calmette-Guérin (BCG) vaccine, which does not ensure full protection in adults. There is a global urgency for the development of an effective vaccine for preventing disease transmission, and it requires novel approaches. We are exploring the use of lactic acid bacteria (LAB) as a vector for antigen delivery to mucosal sites. Here, we demonstrate the successful expression and surface display of a Mycobacterium tuberculosis fusion antigen (comprising Ag85B and ESAT-6, referred to as AgE6) on Lactobacillus plantarum. The AgE6 fusion antigen was targeted to the bacterial surface using two different anchors, a lipoprotein anchor directing the protein to the cell membrane and a covalent cell wall anchor. AgE6-producing L. plantarum strains using each of the two anchors induced antigen-specific proliferative responses in lymphocytes purified from TB-positive donors. Similarly, both strains induced immune responses in mice after nasal or oral immunization. The impact of the anchoring strategies was reflected in dissimilarities in the immune responses generated by the two L. plantarum strains in vivo. The present study comprises an initial step toward the development of L. plantarum as a vector for M. tuberculosis antigen delivery. IMPORTANCE This work presents the development of Lactobacillus plantarum as a candidate mucosal vaccine against tuberculosis. Tuberculosis remains one of the top infectious diseases worldwide, and the only available vaccine, bacille Calmette-Guérin (BCG), fails to protect adults and adolescents. Direct antigen delivery to mucosal sites is a promising strategy in tuberculosis vaccine development, and lactic acid bacteria potentially provide easy, safe, and low-cost delivery vehicles for mucosal immunization. We have engineered L. plantarum strains to produce a Mycobacterium tuberculosis fusion antigen and to anchor this antigen to the bacterial cell wall or to the cell membrane. The recombinant strains elicited proliferative antigen-specific T-cell responses in white blood cells from tuberculosis-positive humans and induced specific immune responses after nasal and oral administrations in mice. PMID:27815271

Immunogenic Properties of Lactobacillus plantarum Producing Surface-Displayed Mycobacterium tuberculosis Antigens.

PubMed

Kuczkowska, Katarzyna; Kleiveland, Charlotte R; Minic, Rajna; Moen, Lars F; Øverland, Lise; Tjåland, Rannei; Carlsen, Harald; Lea, Tor; Mathiesen, Geir; Eijsink, Vincent G H

2017-01-15

Tuberculosis (TB) remains among the most deadly diseases in the world. The only available vaccine against tuberculosis is the bacille Calmette-Guérin (BCG) vaccine, which does not ensure full protection in adults. There is a global urgency for the development of an effective vaccine for preventing disease transmission, and it requires novel approaches. We are exploring the use of lactic acid bacteria (LAB) as a vector for antigen delivery to mucosal sites. Here, we demonstrate the successful expression and surface display of a Mycobacterium tuberculosis fusion antigen (comprising Ag85B and ESAT-6, referred to as AgE6) on Lactobacillus plantarum The AgE6 fusion antigen was targeted to the bacterial surface using two different anchors, a lipoprotein anchor directing the protein to the cell membrane and a covalent cell wall anchor. AgE6-producing L. plantarum strains using each of the two anchors induced antigen-specific proliferative responses in lymphocytes purified from TB-positive donors. Similarly, both strains induced immune responses in mice after nasal or oral immunization. The impact of the anchoring strategies was reflected in dissimilarities in the immune responses generated by the two L. plantarum strains in vivo The present study comprises an initial step toward the development of L. plantarum as a vector for M. tuberculosis antigen delivery. This work presents the development of Lactobacillus plantarum as a candidate mucosal vaccine against tuberculosis. Tuberculosis remains one of the top infectious diseases worldwide, and the only available vaccine, bacille Calmette-Guérin (BCG), fails to protect adults and adolescents. Direct antigen delivery to mucosal sites is a promising strategy in tuberculosis vaccine development, and lactic acid bacteria potentially provide easy, safe, and low-cost delivery vehicles for mucosal immunization. We have engineered L. plantarum strains to produce a Mycobacterium tuberculosis fusion antigen and to anchor this antigen to the bacterial cell wall or to the cell membrane. The recombinant strains elicited proliferative antigen-specific T-cell responses in white blood cells from tuberculosis-positive humans and induced specific immune responses after nasal and oral administrations in mice. Copyright © 2016 American Society for Microbiology.

Mucosal immune response in broilers following vaccination with inactivated influenza and recombinant Bacillus subtilis

USDA-ARS?s Scientific Manuscript database

Mucosal and systemic immunity were observed in broilers vaccinated with mannosylated chitosan adjuvated (MCA) inactivated A/Turkey/Virginia/158512/2002 (H7N2) and administered with and without recombinant Bacillus subtilis to elicit heterologous influenza strain protection. Previously, mucosal immu...

Relationship between lesion formation and permeability of rat gastric mucosa to H+ and other cations.

PubMed

Bunce, K T; McCarthy, J J; Spraggs, C F; Stables, R

1982-02-01

The relationship between lesion formation and ionic permeability has been investigated in rat gastric mucosa in vivo. Changes in these parameters were measured in the mucosa treated topically with prostaglandins E2 and A2 and/or aspirin. Particular attention was paid to the net flux of H+ ions across the gastric mucosa. The effect of aspirin concentrations of 5 mM, 20 mM and '40 mM' (the latter, a suspension in a saturated solution) was investigated. Aspirin concentrations of 20 mM and '40 mM' produced a marked increase in lesion formation and increased the net mucosal to serosal flux of H+ ions. Aspirin 5 mM produced a significant increase in lesion formation but did not cause a significant change in net H+ ion flux. This result suggests that aspirin can have a direct irritant effect on the gastric mucosa and that the back diffusion of H+ ions is not a pre-requisite for the development of overt mucosal ulceration. The effect of topically applied prostaglandin E2 (PGE2) on aspirin-induced gastric mucosal damage was investigated. Concentrations of PGE2 of 10(-5) M and 10(-4) M ameliorated aspirin-induced damage, but these changes were not necessarily accompanied by a significant reduction in net H+ ion flux. Again, this result is not consistent with a direct relationship between lesion formation and mucosal permeability to H+ ions. Since PGA2 did not ameliorate aspirin-induced mucosal damage, the protective effect of PGE2 could not be attributed to its conversion to PGA2 in the acidic environment of the gastric lumen. 5 Changes in gastric mucosal potential difference (p.d.) and net fluxes of Na+ and K+ ions may occur without a concomitant change in the permeability of the gastric mucosa to acid back-diffusion. Thus, the assumption cannot be made that a change in the permeability of the gastric mucosa to one particular ion reflects a general increase in ionic permeability.

Colonization and effector functions of innate lymphoid cells in mucosal tissues.

PubMed

Kim, Myunghoo; Kim, Chang H

2016-10-01

Innate lymphoid cells (ILCs) protect mucosal barrier tissues to fight infection and maintain tissue integrity. ILCs and their progenitors are developmentally programmed to migrate, differentiate and populate various mucosal tissues and associated lymphoid tissues. Functionally mature ILC subsets respond to diverse pathogens such as bacteria, viruses, fungi and parasites in subset-specific manners. In this review, we will discuss how ILCs populate mucosal tissues and regulate immune responses to distinct pathogens to protect the host and maintain tissue integrity. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Vigilance or Subversion? Constitutive and Inducible M Cells in Mucosal Tissues.

PubMed

Lo, David D

2018-03-01

Microfold (M) cells are epithelial cells present in mucosal tissues and specialized for the capture of luminal microparticles and their delivery to underlying immune cells; thus, they are crucial participants in mucosal immune surveillance. Multiple phenotypic subsets of M cells have now been described, all sharing a unique apical morphology that provides clues to their ability to capture microbial particles. The existence of diverse M cell phenotypes, especially inflammation-inducible M cells, provides an intriguing puzzle: some variants may augment luminal surveillance to boost mucosal immunity, while others may promote microbial access to tissues. Here, I consider the unique induction requirements of each M cell subset and functional differences, highlighting the potentially distinct consequences in mucosal immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacokinetics of flomoxef in mucosal tissue of the middle ear and mastoid following intravenous administration in humans.

PubMed

Saito, H; Kimura, T; Takeda, T; Kishimoto, S; Oguma, T; Shimamura, K

1990-01-01

The pharmacokinetics of flomoxef in serum and in the mucosal tissue of the middle ear and mastoid were studied in 9 patients undergoing tympanoplasties. All patients received 1 g of flomoxef intravenously. Flomoxef levels in serum and in mucosal tissue were determined by a bioassay method. The peak value of mean concentrations of flomoxef in the mucosal tissue was 30.3 +/- 11.7 micrograms/ml at 10 min after the administrations. Pharmacokinetic analyses showed that the concentration of flomoxef in the mucosal tissue was over 1.56 micrograms/ml (which is the MIC90 for the common pathogens of otitis media) for more than 2 h and decreased parallel with serum concentration with a half-life of about 40 min.

Dietary L-arginine supplementation reduces Methotrexate-induced intestinal mucosal injury in rat.

PubMed

Koppelmann, Tal; Pollak, Yulia; Mogilner, Jorge; Bejar, Jacob; Coran, Arnold G; Sukhotnik, Igor

2012-04-30

Arginine (ARG) and nitric oxide maintain the mucosal integrity of the intestine in various intestinal disorders. In the present study, we evaluated the effects of oral ARG supplementation on intestinal structural changes, enterocyte proliferation and apoptosis following methotrexate (MTX)-induced intestinal damage in a rat. Male rats were divided into four experimental groups: Control rats, CONTR-ARG rats, were treated with oral ARG given in drinking water 72 hours before and 72 hours following vehicle injection, MTX rats were treated with a single dose of methotrexate, and MTX-ARG rats were treated with oral ARG following injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. RT-PCR was used to determine bax and bcl-2 mRNA expression. MTX-ARG rats demonstrated greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in jejunum and ileum and crypt depth in ileum, compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-ARG rats (vs MTX) was accompanied by decreased bax mRNA and protein expression and increased bcl-2 protein levels. Treatment with oral ARG prevents mucosal injury and improves intestinal recovery following MTX- injury in the rat.

Sodium alginate inhibits methotrexate-induced gastrointestinal mucositis in rats.

PubMed

Yamamoto, Atsuki; Itoh, Tomokazu; Nasu, Reishi; Kajiwara, Eiji; Nishida, Ryuichi

2013-01-01

Gastrointestinal mucositis is one of the most prevalent side effects of chemotherapy. Methotrexate is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukemia and other malignancies. Through its effects on normal tissues with high rates of proliferation, methotrexate treatment leads to gastrointestinal mucositis. In rats, methotrexate-induced gastrointestinal mucositis is histologically characterized by crypt loss, callus fusion and atrophy, capillary dilatation, and infiltration of mixed inflammatory cells. The water-soluble dietary fiber sodium alginate (AL-Na) is derived from seaweed and has demonstrated muco-protective and hemostatic effects on upper gastrointestinal ulcers. In the present study, we evaluated the effects of AL-Na on methotrexate-induced small intestinal mucositis in rats. Animals were subcutaneously administered methotrexate at a dosage of 2.5 mg/kg once daily for 3 d. Rats were treated with single oral doses of AL-Na 30 min before and 6 h after methotrexate administration. On the 4th day, small intestines were removed and weighed. Subsequently, tissues were stained with hematoxylin-eosin and bromodeoxyuridine. AL-Na significantly prevented methotrexate-induced small intestinal mucositis. Moreover, AL-Na prevented decreases in red blood cell numbers, hemoglobin levels, and hematocrit levels. These results suggest the potential of AL-Na as a therapy for methotrexate-induced small intestinal mucositis.

Mucosal Cysts of the Maxillary Sinus in Solid Organ Transplant Population: Computerised Tomography Follow-Up Results

PubMed Central

Aydın, Erdinç; Yerli, Hasan; Tanrıkulu, Suna; Hizal, Evren

2013-01-01

Background: The clinical significance of maxillary sinus mucosal cysts in liver and kidney transplant recipients remains unclear. Aim: To investigate the course of maxillary mucosal cysts in liver and kidney transplantation patients. Study Design: Retrospective clinical study Methods: Paranasal sinus computed tomography scans of 169 renal and 43 hepatic transplant recipients were reviewed. The incidence, size and growth characteristics of maxillary mucosal cysts in the renal and hepatic transplant population were noted. Results: Overall incidence of maxillary sinus mucosal cyst in transplantation patients was found to be 24.5%, with a male to female ratio of 2:1 (p<0.05). Follow-up views of 26 patients showed that the size of the cysts increased in 19, decreased in 4, and remained the same in 3 patients. Mean growth rate of the cysts was calculated to be 6.30 ± 7.02 mm2 per month. Most of the cysts were located on the inferior wall of the maxillary sinus. Conclusion: Incidence of the maxillary mucosal cysts in renal and hepatic transplant recipients does not differ from general population, but these cysts have a greater tendency to grow. Specific measures are not needed for isolated, asymptomatic maxillary mucosal cysts in transplant populations. PMID:25207125

Effect of dietary fat on the distribution of mucosal mass and cell proliferation along the small intestine.

PubMed Central

Jenkins, A P; Thompson, R P

1992-01-01

This study investigated how substitution of long chain triglycerides for glucose in a mixed diet affects the overall small intestinal mucosal mass and the distribution of mucosal mass and cell proliferation along the small intestine. Four groups of eight female Wistar rats (180-200 g) were isocalorically fed mixed diets containing the essential fatty acid rich oil Efamol substituted for glucose at concentrations of 1.2%, 10%, 25%, and 50% total calories for 20 to 23 days. The small intestine was divided into three equal length segments and whole gut weights, mucosal weights, protein and DNA determined. Cell proliferation was estimated from the two hour accumulation of vincristine arrested metaphases in microdissected crypts at points 0%, 17%, 33%, 50%, 66%, and 100% small intestinal length. There were no differences between groups in parameters of overall small intestinal or distal segment mucosal mass. With increasing levels of fat, however, there was a significant trend for the mucosal mass of the proximal segment to fall and that of the middle segment to rise. The pattern of two hour metaphase accumulation reflected these changes. These regional changes in mucosal mass and cell proliferation may reflect differences in the sites of absorption of fat and glucose. PMID:1541418

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence

PubMed Central

O’Regan, Kevin; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J.; Stephen Hodi, F.; Van den Abbeele, Annick D.

2013-01-01

Abstract Purpose: Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. Materials and methods: This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38–76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. Results: At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Conclusion: Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin. PMID:24434078

Targeted next generation sequencing of mucosal melanomas identifies frequent NF1 and RAS mutations.

PubMed

Cosgarea, Ioana; Ugurel, Selma; Sucker, Antje; Livingstone, Elisabeth; Zimmer, Lisa; Ziemer, Mirjana; Utikal, Jochen; Mohr, Peter; Pfeiffer, Christiane; Pföhler, Claudia; Hillen, Uwe; Horn, Susanne; Schadendorf, Dirk; Griewank, Klaus G; Roesch, Alexander

2017-06-20

Mucosal melanoma represents ~1% of all melanomas, frequently having a poor prognosis due to diagnosis at a late stage of disease. Mucosal melanoma differs from cutaneous melanoma not only in terms of poorer clinical outcome but also on the molecular level having e.g. less BRAF and more frequent KIT mutations than cutaneous melanomas. For the majority of mucosal melanomas oncogenic driver mutations remain unknown. In our study, 75 tumor tissues from patients diagnosed with mucosal melanoma were analyzed, applying a targeted next generation sequencing panel covering 29 known recurrently mutated genes in melanoma. NF1 and RAS mutations were identified as the most frequently mutated genes occurring in 18.3% and 16.9% of samples, respectively. Mutations in BRAF were identified in 8.4% and KIT in 7.0% of tumor samples. Our study identifies NF1 as the most frequently occurring driver mutation in mucosal melanoma. RAS alterations, consisting of NRAS and KRAS mutations, were the second most frequent mutation type. BRAF and KIT mutations were rare with frequencies below 10% each. Our data indicate that in mucosal melanomas RAS/NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors.

Targeted next generation sequencing of mucosal melanomas identifies frequent NF1 and RAS mutations

PubMed Central

Cosgarea, Ioana; Ugurel, Selma; Sucker, Antje; Livingstone, Elisabeth; Zimmer, Lisa; Ziemer, Mirjana; Utikal, Jochen; Mohr, Peter; Pfeiffer, Christiane; Pföhler, Claudia; Hillen, Uwe; Horn, Susanne; Schadendorf, Dirk

2017-01-01

Purpose Mucosal melanoma represents ~1% of all melanomas, frequently having a poor prognosis due to diagnosis at a late stage of disease. Mucosal melanoma differs from cutaneous melanoma not only in terms of poorer clinical outcome but also on the molecular level having e.g. less BRAF and more frequent KIT mutations than cutaneous melanomas. For the majority of mucosal melanomas oncogenic driver mutations remain unknown. Experimental Design and Results In our study, 75 tumor tissues from patients diagnosed with mucosal melanoma were analyzed, applying a targeted next generation sequencing panel covering 29 known recurrently mutated genes in melanoma. NF1 and RAS mutations were identified as the most frequently mutated genes occurring in 18.3% and 16.9% of samples, respectively. Mutations in BRAF were identified in 8.4% and KIT in 7.0% of tumor samples. Conclusions Our study identifies NF1 as the most frequently occurring driver mutation in mucosal melanoma. RAS alterations, consisting of NRAS and KRAS mutations, were the second most frequent mutation type. BRAF and KIT mutations were rare with frequencies below 10% each. Our data indicate that in mucosal melanomas RAS/NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors. PMID:28380455

Elemental Diet Accelerates the Recovery From Oral Mucositis and Dermatitis Induced by 5-Fluorouracil Through the Induction of Fibroblast Growth Factor 2.

PubMed

Harada, Koji; Ferdous, Tarannum; Kobayashi, Hiroaki; Ueyama, Yoshiya

2018-06-01

Mucositis and dermatitis induced by anticancer agents are common complications of anticancer therapies. In this study, we evaluated the efficacy of Elental (Ajinomoto Pharmaceutical Ltd, Tokyo, Japan), an elemental diet with glutamine in the treatment of 5-fluorouracil (5-FU)-induced oral mucositis and dermatitis in vivo and tried to clarify the underlying mechanisms of its action. Oral mucositis and dermatitis was induced through a combination of 5-FU treatment and mild abrasion of the cheek pouch in hamsters and the dorsal skin in nude mice respectively. These animals received saline, dextrin or Elental suspension (18 kcal/100 g) by a gastric tube daily until sacrifice. Elental reduced oral mucositis and dermatitis more effectively than dextrin in the animal model. Moreover, growth facilitating effects of Elental on HaCaT cells were examined in vitro. MTT assay, wound healing assay, and migration assay revealed that Elental could enhance the growth, invasion, and migration ability of HaCaT. ELISA and Western blotting showed upregulated FGF2 in Elental-treated HaCaT. These findings suggest that Elental is effective for the treatment of mucositis and dermatitis, and may accelerate mucosal and skin recovery through FGF2 induction and reepithelization.

Effect of dietary fat on the distribution of mucosal mass and cell proliferation along the small intestine.

PubMed

Jenkins, A P; Thompson, R P

1992-02-01

This study investigated how substitution of long chain triglycerides for glucose in a mixed diet affects the overall small intestinal mucosal mass and the distribution of mucosal mass and cell proliferation along the small intestine. Four groups of eight female Wistar rats (180-200 g) were isocalorically fed mixed diets containing the essential fatty acid rich oil Efamol substituted for glucose at concentrations of 1.2%, 10%, 25%, and 50% total calories for 20 to 23 days. The small intestine was divided into three equal length segments and whole gut weights, mucosal weights, protein and DNA determined. Cell proliferation was estimated from the two hour accumulation of vincristine arrested metaphases in microdissected crypts at points 0%, 17%, 33%, 50%, 66%, and 100% small intestinal length. There were no differences between groups in parameters of overall small intestinal or distal segment mucosal mass. With increasing levels of fat, however, there was a significant trend for the mucosal mass of the proximal segment to fall and that of the middle segment to rise. The pattern of two hour metaphase accumulation reflected these changes. These regional changes in mucosal mass and cell proliferation may reflect differences in the sites of absorption of fat and glucose.

A Judgement Bias Test to Assess Affective State and Potential Therapeutics in a Rat Model of Chemotherapy-Induced Mucositis.

PubMed

George, Rebecca P; Barker, Timothy H; Lymn, Kerry A; Bigatton, Dylan A; Howarth, Gordon S; Whittaker, Alexandra L

2018-05-29

Chemotherapy-induced mucositis is an extremely painful condition that occurs in 40-60% of patients undergoing chemotherapy. As mucositis currently has no effective treatment, and due to the self-limiting nature of the condition, the major treatment aims are to manage symptoms and limit pain with significance placed on improving patient quality of life. Rodent models are frequently used in mucositis research. These investigations typically assess pathological outcomes, yet fail to include a measure of affective state; the key therapeutic goal. Assessment of cognitive biases is a novel approach to determining the affective state of animals. Consequently, this study aimed to validate a cognitive bias test through a judgement bias paradigm to measure affective state in a rat model of chemotherapy-induced intestinal mucositis. Rats with intestinal mucositis demonstrated a negative affective state, which was partially ameliorated by analgesic administration, whilst healthy rats showed an optimistic response. This study concluded that the judgement bias test was able to evaluate the emotional state of rats with chemotherapy-induced mucositis. These findings provide a foundation for future refinement to the experimental design associated with the animal model that will expedite successful transitioning of novel therapeutics to clinical practice, and also improve humane endpoint implementation.

IL-9-producing cells in the development of IgE-mediated food allergy.

PubMed

Shik, Dana; Tomar, Sunil; Lee, Jee-Boong; Chen, Chun-Yu; Smith, Andrew; Wang, Yui-Hsi

2017-01-01

Food allergy is a harmful immune reaction driven by uncontrolled type 2 immune responses. Considerable evidence demonstrates the key roles of mast cells, IgE, and TH2 cytokines in mediating food allergy. However, this evidence provides limited insight into why only some, rather than all, food allergic individuals are prone to develop life-threatening anaphylaxis. Clinical observations suggest that patients sensitized to food through the skin early in life may later develop severe food allergies. Aberrant epidermal thymic stromal lymphopoietin and interleukin (IL) 33 production and genetic predisposition can initiate an allergic immune response mediated by dendritic cells and CD4 + TH2 cells in inflamed skin. After allergic sensitization, intestinal IL-25 and food ingestion enhance concerted interactions between type 2 innate lymphoid cells (ILC2s) and CD4 + TH2 cells, which perpetuate allergic reactions from the skin to the gut. IL-4 and cross-linking of antigen/IgE/FcεR complexes induce emigrated mast cell progenitors to develop into the multi-functional IL-9-producing mucosal mast cells, which produce prodigious amounts of IL-9 and mast cell mediators to drive intestinal mastocytosis in an autocrine loop. ILC2s and TH9 cells may also serve as alternative cellular sources of IL-9 to augment the amplification of intestinal mastocytosis, which is the key cellular checkpoint in developing systemic anaphylaxis. These findings provide a plausible view of how food allergy develops and progresses in a stepwise manner and that atopic signals, dietary allergen ingestion, and inflammatory cues are fundamental in promoting life-threatening anaphylaxis. This information will aid in improving diagnosis and developing more effective therapies for food allergy-triggered anaphylaxis.

IL-9–producing cells in the development of IgE-mediated food allergy

PubMed Central

Shik, Dana; Tomar, Sunil; Lee, Jee-Boong; Chen, Chun-Yu; Smith, Andrew; Wang, Yui-Hsi

2016-01-01

Food allergy is a harmful immune reaction driven by uncontrolled type-2 immune responses. Considerable evidence demonstrates the key roles of mast cells, IgE, and TH2 cytokines in mediating food allergy. However, this evidence provides limited insight into why only some, rather than all, food allergic individuals are prone to develop life-threatening anaphylaxis. Clinical observations suggest that patients sensitized to food through the skin early in life may later develop severe food allergies. Aberrant epidermal thymic stromal lymphopoietin and interleukin (IL) 33 production and genetic predisposition can initiate an allergic immune response mediated by dendritic cells and CD4+TH2 cells in inflamed skin. After allergic sensitization, intestinal IL-25 and food ingestion enhance concerted interactions between type-2 innate lymphoid cells (ILC2s) and CD4+TH2 cells, which perpetuate allergic reactions from skin to the gut. IL-4 and crosslinking of antigen/IgE/FcεR complexes induce emigrated mast cell progenitors to develop into the multi-functional IL-9–producing mucosal mast cells, which produce prodigious amounts of IL-9 and mast cell mediators to drive intestinal mastocytosis in an autocrine loop. ILC2s and TH9 cells may also serve as alternative cellular sources of IL-9 to augment the amplification of intestinal mastocytosis, which is the key cellular checkpoint in developing systemic anaphylaxis. These findings provide a plausible view of how food allergy develops and progresses in a stepwise manner and that atopic signals, dietary allergen ingestion, and inflammatory cues are fundamental in promoting life-threatening anaphylaxis. This information will aid in improving diagnosis and developing more effective therapies for food allergy–triggered anaphylaxis. PMID:27909880

Relieving Oral Mucositis - Palifermin Discovery

Cancer.gov

Painful mouth and throat sores can be a side effect of intensive cancer treatments for many patients. Learn how NCI scientists developed the drug, Palifermin, which vastly improves the quality of life for cancer patients.

Nutrition status and Helicobacter pylori infection in patients receiving hemodialysis.

PubMed

Sugimoto, Mitsushige; Yasuda, Hideo; Andoh, Akira

2018-04-21

Chronic kidney disease (CKD) patients receiving hemodialysis (HD) often develop gastrointestinal abnormalities over their long treatment period. In general, prognosis in such patients is poor due to the development of protein-energy wasting (PEW). Therefore, it is important to clarify the etiology of PEW and to establish better strategies to deal with this condition. Chronic Helicobacter pylori ( H. pylori ) infection in the gastric mucosa has a close association with not only the development of peptic ulcer disease and gastric cancer, but is also associated with abnormal plasma and gastric mucosal ghrelin levels that are seen in malnutrition. It is unclear whether H. pylori infection of the gastric mucosa is directly associated with prognosis in HD patients by affecting ghrelin levels. Recent studies show that the prevalence of H. pylori infection in HD patients is significantly lower than in subjects with normal renal function. In the natural history of H. pylori infection in HD patients, the prevalence of infection decreases as the length of time on HD increases. The severity of gastric mucosal atrophy has been suggested as the major determinant of ghrelin levels in these patients, and eradication therapy of H. pylori improves nutritional status by increasing serum cholinesterase and cholesterol levels, especially in patients with mild-to-moderate gastric mucosal atrophy. Prompt H. pylori eradication to inhibit the progress of gastric atrophy may be required to prevent this decrease in ghrelin levels and subsequent PEW and improve the prognosis of HD patients by improving their nutritional status.

Correlation of Nasal Mucosal Temperature With Subjective Nasal Patency in Healthy Individuals

PubMed Central

Bailey, Ryan S.; Casey, Kevin P.; Pawar, Sachin S.; Garcia, Guilherme J. M.

2016-01-01

Importance Historically, otolaryngologists have focused on nasal resistance to airflow and minimum airspace cross-sectional area as objective measures of nasal obstruction using methods such as rhinomanometry and acoustic rhinometry. However, subjective sensation of nasal patency may be more associated with activation of cold receptors by inspired air than with respiratory effort. Objective To investigate whether subjective nasal patency correlates with nasal mucosal temperature in healthy subjects. Design, Setting, and Participants Twenty-two healthy adults were recruited for this study. Subjects first completed the Nasal Obstruction Symptom Evaluation (NOSE) and a unilateral visual analog scale (VAS) to quantify subjective nasal patency. A miniaturized thermocouple sensor was then used to record nasal mucosal temperature bilaterally in two locations along the nasal septum: at the vestibule and across from the inferior turbinate head. Results The range of temperature oscillations during the breathing cycle, defined as the difference between end-expiratory and end-inspiratory temperatures, was greater during deep breaths (ΔTexp-insp = 6.2 ± 2.6°C) than during resting breathing (ΔTexp-insp = 4.2 ± 2.3°C) in both locations (p < 10−13). Mucosal temperature measured at the right vestibule had a statistically significant correlation with both right-side VAS score (Pearson r = −0.55, p=0.0076) and NOSE score (Pearson r = −0.47, p=0.028). No other statistically significant correlations were found between mucosal temperature and subjective nasal patency scores. Nasal mucosal temperature was lower in the first cavity to be measured, which was the right cavity in all subjects. Conclusions and Relevance The greater mucosal temperature oscillations during deep breathing is consistent with the common experience that airflow sensation is enhanced during deep breaths, thus supporting the hypothesis that mucosal cooling plays a central role in nasal airflow sensation. A possible correlation was found between subjective nasal patency scores and nasal mucosal temperature, but our results were inconsistent. The higher temperature in the left cavity suggests that the sensor irritated the nasal mucosa, affecting the correlation between patency scores and mucosal temperature. Future studies should consider non-contact temperature sensors to prevent mucosa irritation. PMID:27918749

Effects of ε-viniferin, a dehydrodimer of resveratrol, on transepithelial active ion transport and ion permeability in the rat small and large intestinal mucosa.

PubMed

Karaki, Shin-Ichiro; Ishikawa, Junji; Tomizawa, Yuka; Kuwahara, Atsukazu

2016-05-01

ε-Viniferin is a dehydrodimer of resveratrol, a polyphenol synthesized in many plants, including grapevine. The present study investigated the effects of ε-viniferin and resveratrol on epithelial secretory and barrier functions in isolated rat small and large intestinal mucosa. Mucosa-submucosa tissue preparations of various segments of the rat large and small intestines were mounted on Ussing chambers, and short-circuit current (Isc) and tissue conductance (Gt) were continuously measured. The mucosal addition of ε-viniferin (>10(-5) mol/L) and resveratrol (>10(-4) mol/L) to the cecal mucosa, which was the most sensitive region, induced an increase in Isc and a rapid phase decrease (P-1) followed by rapid (P-2) and broad (P-3) peak increases in Gt in concentration-dependent manners. Mucosal ε-viniferin (10(-4) mol/L), but not resveratrol (10(-4) mol/L), increased the permeability of FITC-conjugated dextran (4 kDa). The mucosal ε-viniferin-evoked changes in Isc (Cl(-) secretion), but not in Gt, were attenuated by a selective cyclooxygenase (COX)-1 inhibitor and a selective EP4 prostaglandin receptor. The mucosal ε-viniferin-evoked increase in Isc was partially attenuated, and P-2, but not P-1 or P-3, change in Gt was abolished by a transient receptor potential cation channel, subfamily A, member 1 (TRPA1) inhibitor. Moreover, the mucosal ε-viniferin concentration-dependently attenuated the mucosal propionate (1 mmol/L)-evoked increases in Isc and Gt Immunohistochemical studies revealed COX-1-immunoreactive epithelial cells in the cecal crypt. The present study showed that mucosal ε-viniferin modulated transepithelial ion transport and permeability, possibly by activating sensory epithelial cells expressing COX-1 and TRPA1. Moreover, mucosal ε-viniferin decreased mucosal sensitivity to other luminal molecules such as short-chain fatty acids. In conclusion, these results suggest that ε-viniferin modifies intestinal mucosal transport and barrier functions. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Distinct shifts in the oral microbiota are associated with the progression and aggravation of mucositis during radiotherapy.

PubMed

Hou, Jin; Zheng, HuiMin; Li, Pan; Liu, HaiYue; Zhou, HongWei; Yang, XiaoJun

2018-05-04

Oral mucositis remains one of the most common complications of radiation therapy for patients with head and neck cancer. This study aimed to investigate the dynamic shifts in the oral mucosal microbiota and their association with the progression and aggravation of mucositis in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. In this study, oropharyngeal mucosa of patients were examined regularly, and sampled longitudinally in eight stages of their radiation treatment program: before radiation, and then after 10, 20, 30, 40, 50, 60, and 70 Gy. Based on 16S rRNA gene sequencing and bioinformatics analysis, the characteristics of dynamic variations in oral microbiota during their treatment were investigated. The results showed that the mucosal bacterial alpha diversity (richness and evenness) did not change significantly during the entire course of these patient treatments. Notwithstanding 20 genera were found to be significantly positively associated with their radiation dose, whereas 10 genera were negatively associated with it. Notably, two bacterial co-abundance groups (CAG 1 and 2) were identified and the majority of bacteria clustered within the CAG 2 were indeed periodontal disease-associated genera. Most strikingly, many of them, especially Prevotella, Fusobacterium, Treponema and Porphyromonas, showed obvious dynamic synchronous variations in their abundances throughout the course of radiation therapy, where their peaks frequently coincided with the onset of severe mucositis. Our results suggest that dysbiosis of oral mucosal microbiota may contribute to exacerbating the severity of mucositis in patients undergoing radiotherapy for nasopharyngeal carcinoma. Copyright © 2018 Elsevier B.V. All rights reserved.

Initiation of ART during Early Acute HIV Infection Preserves Mucosal Th17 Function and Reverses HIV-Related Immune Activation

PubMed Central

Schuetz, Alexandra; Deleage, Claire; Sereti, Irini; Rerknimitr, Rungsun; Phanuphak, Nittaya; Phuang-Ngern, Yuwadee; Estes, Jacob D.; Sandler, Netanya G.; Sukhumvittaya, Suchada; Marovich, Mary; Jongrakthaitae, Surat; Akapirat, Siriwat; Fletscher, James L. K.; Kroon, Eugene; Dewar, Robin; Trichavaroj, Rapee; Chomchey, Nitiya; Douek, Daniel C.; O′Connell, Robert J.; Ngauy, Viseth; Robb, Merlin L.; Phanuphak, Praphan; Michael, Nelson L.; Excler, Jean-Louis; Kim, Jerome H.; de Souza, Mark S.; Ananworanich, Jintanat

2014-01-01

Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation. PMID:25503054

Mucosal immunogenicity of plant lectins in mice

PubMed Central

Lavelle, E C; Grant, G; Pusztai, A; Pfüller, U; O’Hagan, D T

2000-01-01

The mucosal immunogenicity of a number of plant lectins with different sugar specificities was investigated in mice. Following intranasal (i.n.) or oral administration, the systemic and mucosal antibody responses elicited were compared with those induced by a potent mucosal immunogen (cholera toxin; CT) and a poorly immunogenic protein (ovalbumin; OVA). After three oral or i.n. doses of CT, high levels of specific serum antibodies were measured and specific IgA was detected in the serum, saliva, vaginal wash, nasal wash and gut wash of mice. Immunization with OVA elicited low titres of serum IgG but specific IgA was not detected in mucosal secretions. Both oral and i.n. delivery of all five plant lectins investigated [Viscum album (mistletoe lectin 1; ML‐1), Lycospersicum esculentum (tomato lectin; LEA), Phaseolus vulgaris (PHA), Triticum vulgaris (wheat germ agglutinin (WGA), Ulex europaeus I (UEA‐1)] stimulated the production of specific serum IgG and IgA antibody after three i.n. or oral doses. Immunization with ML‐1 induced high titres of serum IgG and IgA in addition to specific IgA in mucosal secretions. The response to orally delivered ML‐1 was comparable to that induced by CT, although a 10‐fold higher dose was administered. Immunization with LEA also induced high titres of serum IgG, particularly after i.n. delivery. Low specific IgA titres were also detected to LEA in mucosal secretions. Responses to PHA, WGA and UEA‐1 were measured at a relatively low level in the serum, and little or no specific mucosal IgA was detected. PMID:10651938

Effects of n-3 polyunsaturated fatty acids and vitamin E on colonic mucosal leukotriene generation, lipid peroxidation, and microcirculation in rats with experimental colitis.

PubMed

Shimizu, T; Igarashi, J; Ohtuka, Y; Oguchi, S; Kaneko, K; Yamashiro, Y

2001-01-01

We investigated the effect of n-3 polyunsaturated fatty acids (PUFAs) on mucosal levels of leukotrienes (LTs) and lipid peroxide (LPO), and on mucosal microcirculation, in rats with experimental colitis induced by dextran sulfate sodium (DSS). We fed Wistar rats a perilla oil-enriched diet containing alpha-linolenic acid (63.2% of total fatty acids) with various doses of vitamin E for 4 weeks, with 4% DSS added to the drinking water during the last week. Control rats were fed a diet produced from soybean oil containing alpha-linolenic acid (5.1% of total fatty acids). Colonic mucosal blood flow was measured with a laser Doppler flowmeter. The mucosal level of arachidonic acid was significantly lower and that of eicosapentaenoic acid was significantly higher in the experimental group. The mucosal level of LPO in the experimental group fed a trace or ordinary dose of vitamin E was significantly higher than that of the controls. The production of LTB(4) and LTC(4) from the colonic mucosa in the experimental group was significantly lower than that in controls. However, only the experimental group fed a vitamin E dose 4-fold higher than that given to the controls showed a significant increase in mucosal blood flow. These results suggest that n-3 PUFAs increase mucosal blood flow by inhibiting LT production when there is sufficient vitamin E to inhibit lipid peroxidation in rats with experimental colitis. Copyright 2001 S. Karger AG, Basel

Oral Human Immunoglobulin for Children with Autism and Gastrointestinal Dysfunction: A Prospective, Open-Label Study

ERIC Educational Resources Information Center

Schneider, Cindy K.; Melmed, Raun D.; Barstow, Leon E.; Enriquez, F. Javier; Ranger-Moore, James; Ostrem, James A.

2006-01-01

Immunoglobulin secretion onto mucosal surfaces is a major component of the mucosal immune system. We hypothesized that chronic gastrointestinal (GI) disturbances associated with autistic disorder (AD) may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI…

Branch pattern of starch internal structure influences the glucogenesis by mucosal Nt-maltase-glucoamylase

USDA-ARS?s Scientific Manuscript database

To produce sufficient amounts of glucose from food starch, both alpha-amylase and mucosal alpha-glucosidases are required. We found previously that the digestion rate of starch is influenced by its susceptibility to mucosal alpha-glucosidases. In the present study, six starches and one glycogen were...