Experimental evidence of heparanase, Hsp70 and NF-κB gene expression on the response of anti-inflammatory drugs in TNBS-induced colonic inflammation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of clinical, ultrasonographic and hysteroscopic parameters in the differentiation of endometrial polyps and cancer of endometrium

Study Objective: To evaluate the diagnostic accuracy of transvaginal ultrasound and office hysteroscopy in the differentiation between endometrial polyps and endometrial adenocarcinoma. Design: This is a prospective 100 women longitudinal study, 24 to 80 years, submitted to hysteroscopic polypectomy (n = 80) or surgery due to endometrial adenocarcinoma (n = 20), from january 2010 to December 2011. Clinical, ultrasonographic and hysteroscopic parameters were analyzed and compared with histopathologic find. Statistical analysis were performed utilizing the Tukey, Kruskal-Wallis, Dunn and Mann-Whitney test, with a confidence interval of 95% and p\0, 05 statiscally significant. Setting: Botucatu Medical School. Intervention: Prospective analysis of clinical, ultrasonographic and hysteroscopic parameters in patients with diagnosis suspected of endometrial polyps and adenocarcinoma of endometrium were performed. According to the diagnosis, hysteroscopic polypectomy or pan hysterectomy with lymph node sampling was realized. After the surgery and histopathological study, statistical analysis of parameters was performed and the results were compared between groups. It was Research Ethics Committee approved. Measurements and Main Results: There were no differences between age, BMI, menopause, TH use and associated diseases among groups. The main symptom of endometrial cancer was the postmenopausal bleeding, affecting 84,2% of women against 34,8% of polypectomy group. The majority of women with endometrial polyps were asymptomatic. Transvaginal ultrasonography showed no ability to differentiate cases of endometrial cancer compared with the cases of endometrial polyps, considering the presence of endometrial thickness and blood flow on color Doppler. Office hysteroscopy showed significant changes in 75% of the adenocarcinoma cases, especially the presence of diffuse hypervascularity with atypical vessels. Conclusion: Still remains an inability to establish clinical parameters and reliable ultrasound imaging to differentiate endometrial polyps and cancer of endometrium. Attention should be given to hysteroscopic exams presenting diffuse endometrial hypervascularization with architectural distortion of the vessels. The recommendation of our service remains the systematic removal of all endometrial polyps.

Antiproliferative Effects of Fluoxetine on Colon Cancer Cells and in a Colonic Carcinogen Mouse Model

The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as models. Fluoxetine increased the percentage of HT29 cells in the G(0)/G(1) phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy.

High-fat diet causes an imbalance in the colonic serotonergic system promoting adipose tissue enlargement and dysplasia in rats

A high-fat (HF) diet, the serotonergic system and stromal elements have all been implicated in colon carcinogenesis. We investigated whether the colonic serotonergic system could play a main role in the development of colonic dysplasia and stromal reactivity in carcinogen-treated rats under HF diet. For this, dimethylhydrazine-treated rats were fed with standard diet and a HF diet. Fat distribution was quantified by computerized tomography exam, serotonergic activity was analyzed by high-performance liquid chromatography, gene expression, and immunohistochemistry, which along with histopathological technique enabled us to enumerate dysplasia, microvessels density, cell proliferation and COX-2 expression. We found that the HF diet induced an increase in the amount of viscera! adipose tissue, even without expressive changes in the average body weight. This was correlated with a loss of serotonergic balance in colon tissue. Moreover, the HF diet promoted dysplasia and microvessel density in association with increased proliferation and COX-2 expression within pericryptal colonic stroma. Our current findings suggest that a HF diet promotes the enlargement of adipose tissue via loss of control in colon serotonergic activity, which enhances colonic dysplasia by supporting microvessel development. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Why do we not find polyps in the lungs? Bronchial mucosa as a model in the treatment of polyposis

The link between lower and upper airways has been reported since the beginning of 1800s. They share the same pseudostratified ciliated columnar epithelium lining and the concept of one airway, one disease is quite well widespread. Nasal polyposis and asthma share basically the same inflammatory process: predominant infiltration of eosinophils, mucus cell hyperplasia, edema, thickened basal membrane, polarization for Th2 cell immune response, similar pro-inflammatory mediators are increased, for example cysteinyl leukotrienes. If the lower and upper airways share a lot of common epithelial structural features so why is the edema in the nasal mucosa able to increase so much the size of the mucosa to the point of developing polyps? The article tries to underline some differences between the nasal and the bronchial mucosa that could be implicated in this aberrant change from normal mucosa to polyps. This paper creates the concept that there are no polyps with the features of nasal polyposis disease in the lower airway and through it is developed the hypothesis of the nasal polyps origin could partially lie on the difference between the upper and lower airway histology. (C) 2012 Elsevier Ltd. All rights reserved.

EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists

The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also propose definitions for 'difficult to treat' rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between the upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists.

Suppression of Inflammatory Cytokine Secretion by an NF-kappa B Inhibitor DHMEQ in Nasal Polyps Fibroblasts

Background: NF-kappa B is an essential transcription factor strongly associated to inflammatory response in chronic rhinosinusitis with nasal polyps (CRSwNP). DHMEQ is a NF-kappa B inhibitor that has been previously described with a greatpotential indecreasing inflammation in diseases other than CRSwNP. The aim of study isto evaluate the ability of DHMEQ to reducethe inflammatory recruiters on CRSwNP and to compare its anti-inflammatory profile as a single-agent or in association with fluticasone propionate (FP). Methods: nasal polyp fibroblasts were cultured in TNF-alpha enriched media. Cells were submitted to three different concentrations (1, 10 and 100nM) of either FP, DHMEQ or both. Inflammatory response was accessed by VCAM-1, ICAM-1 and RANTES expression (by RTQ-PCR) and protein levels by ELISA. Nuclear translocation of NF-kappa B was also evaluated. Results: both FP and DHMEQ inhibited inflammatory recruiters' production and NF-kappa B nuclear translocation. Interestingly, the anti-inflammatory effect from the association steroids plus DHMEQ was more intense than of each drug in separate. Conclusion: DHMEQ seems efficient in modulating the inflammatory process in CRSwNP. The synergic anti-inflammatory effect of DHMEQ and steroids may be a promising strategy to be explored, particularly in the setting of steroid-resistant NP. Copyright (c) 2012 S. Karger AG, Basel

Clostridium difficile toxins facilitate bacterial colonization by modulating the fence and gate function of colonic epithelium

The contribution of Clostridium difficile toxin A and B (TcdA and TcdB) to cellular intoxication has been extensively studied, but their impact on bacterial colonization remains unclear. By setting-up two- and three-dimensional in vitro models of polarized gut epithelium, we investigated how C. difficile infection is affected by host cell polarity and whether TcdA and TcdB contribute to such events. Indeed, we observed that C. difficile adhesion and penetration of the epithelial barrier is substantially enhanced in poorly polarized or EGTA-treated cells, indicating that bacteria bind preferentially to the basolateral cell surface. In this context, we demonstrated that sub-lethal concentrations of C. difficile TcdA are able to alter cell polarity by causing redistribution of plasma membrane components between distinct surface domains. Taken together, the data suggest that toxin-mediated modulation of host cell organization may account for the capacity of this opportunistic pathogen to gain access to basolateral receptors leading to a successful colonization of the colonic mucosa.

Paediatric traffic accident and obstructive sleep apnoea by antrochoanal polyps: case report and literature review

Antrochoanal polyps are hyperplasias of the nasal mucosa, which have their origin in the maxillary sinus and extend through the nasal cavity and the choanae into the naso- and oropharynx. In children antrochoanal polyps represent one of the more frequent manifestations of paediatric nasal polyposis. Most studies on antrochoanal polyps in children report only on nasal obstruction, hyponasal speech and snoring, which are also encountered in the most common cause of obstructive sleep apnoea syndrome; i.e. adenoid or tonsillar hyperplasia. Only very few studies report on additional health hazards by antrochoanal polyps ranging from obstructive sleep apnoea syndrome to swallowing disorders and cachexia. We present the case of an 8 year old girl with a bicycle accident caused by excessive daytime sleepiness and obstructive sleep apnoea syndrome due to an extensive antrochoanal polyp. After a transnasal polypectomy and meatotomy type II the obstructive sleep apnoea and day time sleepiness resolved completely. Awareness of this additional health hazard is important and correct evaluation and timely diagnosis of a potential antrochoanal polyp is mandatory because minimally invasive rhinosurgery is highly curative in preventing further impending problems.

High salt intake down-regulates colonic mineralocorticoid receptors, epithelial sodium channels and 11β-hydroxysteroid dehydrogenase type 2

Besides the kidneys, the gastrointestinal tract is the principal organ responsible for sodium homeostasis. For sodium transport across the cell membranes the epithelial sodium channel (ENaC) is of pivotal relevance. The ENaC is mainly regulated by mineralocorticoid receptor mediated actions. The MR activation by endogenous 11β-hydroxy-glucocorticoids is modulated by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Here we present evidence for intestinal segment specific 11β-HSD2 expression and hypothesize that a high salt intake and/or uninephrectomy (UNX) affects colonic 11β-HSD2, MR and ENaC expression. The 11β-HSD2 activity was measured by means of 3H-corticosterone conversion into 3H-11-dehydrocorticosterone in Sprague Dawley rats on a normal and high salt diet. The activity increased steadily from the ileum to the distal colon by a factor of about 3, an observation in line with the relevance of the distal colon for sodium handling. High salt intake diminished mRNA and protein of 11β-HSD2 by about 50% (p<0.001) and reduced the expression of the MR (p<0.01). The functionally relevant ENaC-β and ENaC-γ expression, a measure of mineralocorticoid action, diminished by more than 50% by high salt intake (p<0.001). The observed changes were present in rats with and without UNX. Thus, colonic epithelial cells appear to contribute to the protective armamentarium of the mammalian body against salt overload, a mechanism not modulated by UNX.

Amphotericin B nasal spray has no effect on nasal polyps

Nasal polyps and chronic rhinosinusitis are the products of an inflammatory process. Recently, fungal involvement has been thought to stimulate the development of polyps, and administration of antifungal agents was therefore considered a potential treatment. Several studies have been published indicating amphotericin B as an effective treatment for nasal polyps and chronic rhinosinusitis. The aim of our investigation was to evaluate the efficacy of intranasal applied amphotericin B on the growth of nasal polyps in a three-month, prospective, open trial. Our results show that nasal amphotericin B spray is not effective for nasal polyps and may even cause deterioration.

Prospective study on bright lumen magnetic resonance colonography in comparison with conventional colonoscopy

The aim of this prospective trial was to evaluate sensitivity and specificity of bright lumen magnetic resonance colonography (MRC) in comparison with conventional colonoscopy (CC). A total of 120 consecutive patients with clinical indications for CC were prospectively examined using MRC (1.5 Tesla) which was then followed by CC. Prior to MRC, the cleansed colon was filled with a gadolinium-water solution. A 3D GRE sequence was performed with the patient in the prone and supine position, each acquired during one breathhold period. After division of the colon into five segments, interactive data analysis was carried out using three-dimensional post-processing, including a virtual intraluminal view. The results of CC served as a reference standard. In all patients MRC was performed successfully and no complications occurred. Image quality was diagnostic in 92% (574/620 colonic segments). On a per-patient basis, the results of MRC were as follows: sensitivity 84% (95% CI 71.7-92.3%), specificity 97% (95% CI 89.0-99.6%). Five flat adenomas and 6/16 small polyps (< or =5 mm) were not identified by MRC. MRC offers high sensitivity and excellent specificity rates in patients with clinical indications for CC. Improved MRC techniques are needed to detect small polyps and flat adenomas.