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Don't feel confused when teachers assign you to write a review essay. This paper is always based on other published articles and it doesn't report any original research. The basic purpose of writing a review paper is to generally sum up existing literature on the chosen topic to explain to the audience its current understanding. Review essays form valuable literature because they sum up interesting findings and let other people form a better idea about the existing knowledge on a particular subject without reading all published works in this field. All students need to complete this academic assignment and they get a number of benefits in return. Review papers allow them to find out about a specific subject matter while acing comprehensive exams. However, writing them is a big job, which requires a detailed guide to do it successfully.
Basic review paper FAQ
What is a review essay? You won't be able to submit a good paper if you don't know the right answer to this question. Your review paper can be the following:
- A scientific text that relies on previously published sources and data (no new information from your experiments are presented);
- Constructive and critical analysis of other sources in a specific subject through a summary, analysis, classification, and comparison;
- A stand-alone publication.
For example, literature reviews are important parts of doctoral and master theses or grant proposals.
What is the main purpose served by review papers? They have the following purposes:
- Evaluate specific literature;
- Organize all primary and secondary sources;
- Synthesize data;
- Identify specific trends and patterns in literature;
- Determine existing research gaps and advise new research fields.
Who are future readers? They can be novice researchers, other students, decision-makers, experts in specific areas, professors, etc.
What re important review paper functions?
All review papers are targeted at a few groups, including the extended explanations of subjects. They are certain meta-analyses or critical evaluations of the materials that have already been published. By integrating, organizing, and evaluating them, you think about the progress of current research towards clarifying a given issue or matter. In some sense, your review paper is a tutorial because you need to do the following:
- Clarify and identify a particular problem;
- Sum up previous investigations to inform readers of the current research state;
- Determine contradictions, links, inconsistencies, and gaps in available sources;
- Suggest new steps in solving this problem.
Which types of review papers exist?
When writing a review paper, you should understand that there are different types and they're classified based on a few methods. Types classified by a methodological approach include:
- Systematic reviews that statistically analyze findings from different individual studies by strict procedures (meta-analyses can be used to pool these results);
- Narrative reviews summarize and compare selected studies based on existing theories, models, and experiences (all results are based on a qualitative level instead of the quantitative one);
- Best-evidence review combined the focus of selected studies with the systematic methods of result exploration and study selection.
Types classified by their objective include:
- History reviews focused on the development of a specific field over time;
- Status-quo reviews present the latest research for a given field or topic;
- Model or theory reviews introduce a new model or theory in a given field of research;
- Issue reviews investigate a particular issue in a certain area.
Review paper types can be categorized based on their mandate:
- Commissioned reviews are the formal contracts of authors with customers;
- Invited reviews involved experiences authors;
- Unsolicited submissions where authors develop their ideas for a review and submit them.
How long should your review paper be? This assignment varies in its length considerably, and everything depends on prompts. Read them attentively or talk to professionals if you have any questions.
Review paper elements
Everything starts with a title that helps readers decide if they want to keep reading a review paper or not. There are certain criteria that your title should fit. For example, it should be informative and indicate that a given text is a review paper. Make sure that it contains all important terms and the main message.
Your title should be short, so keep it concise and catchy. When it comes to choosing the right tense, it's worth remembering that the past tense indicates that results are not any established knowledge, while the present tense highlights their overall validity and shows what you want to achieve with your review paper. You can write a title as a question only if it remains unanswered at the time of writing your review essay.
Your authorship and abstract
It declares your intellectual ownership of a particular text while providing personal and contact data. The abstract of your paper can either inform the audience about the main goals and results if it's informative or indicate a specific text structure if it's descriptive.
If you need to write a descriptive abstract, it's like a table of contents in a paragraph form, so include a description of all the subjects covered with no specific details in the present tense.
When writing an informative abstract, which suits best-evidence and systematic review papers, you need to include the following elements:
- In objectives, describe the main intention and context of your essay in a few brief sentences;
- In methods and materials, provide readers with an overall picture of your chosen methodological approach in short;
- In results, describe the main outcomes in a few sentences;
- In conclusions, present your conclusion linked to the main objectives of your review paper.
A table of contents
This element shows the audience the organization of the entire text while helping them stay oriented among all sections. You should note that some teachers may ask you to print a table of contents at the very beginning of your review paper, while others don't. In most cases, this element is necessary for all extensive narrative reviews, so talk to instructors to make sure that you need to include it in your assignment.
Your introductory paragraph
The introduction of your review paper provides readers with more information about its context while indicating your key motivation when writing it, researching a given question, explaining the entire structure, and defining the main focus. There are certain elements that should be included in this paragraph, such as:
- A subject background that briefly describes a general issue, topic, or area of concern and illustrates the main context;
- A given problem, new perspectives, trends, conflicts, and gaps;
- Your justification, motivation, or reasoning to review specific sources and a description of the organization and approach of your text.
Use the present tense when writing an introductory paragraph and feel free to include a few expert citations (make sure that they are short). Its length should be about 10-20% of the entire text. Your goal is to have an explicit subject matter and a narrow focus in this section because they need to be indicated clearly. You also need to provide readers with both practical and theoretical justification for the need for writing a review paper.
Methods and materials
Systematic and best-evidence review papers have a special methods section that enables motivated students repeat a review in the future. The narrative ones don't have this section, but it's still necessary to include some basic information about your applied methods at the end of an introductory paragraph. This paragraph should contain specific information, such as:
- Search strategies and terms in addition to your selection criteria, like the exclusion or inclusion of studies;
- Data sources or bibliographical databases;
- The number of studies screened and included;
- Statistical methods of your analysis.
It's possible to include a few citations in your methods and materials, such as software used or statistical analyses. Be sure to write this section in the past tense and it should be about 5% of the entire text. Furthermore, all data sources should be clearly identified, and precision is your top priority when writing this paragraph.
The main body
The main body is the main part of your review paper, and a coherent structure of the chosen topic is necessary to end up with the well-written one. Subheadings are important because they reflect the organization of your subject and indicate the content of different paragraphs. You can use different criteria when structuring the main body, including:
- Theories or models;
- Methodological approaches;
- Studies that either agree or disagree with others;
- The extent of support for your thesis;
- Geographical location;
- Chronological order.
When structuring paragraphs in the main body of a review paper, cover one topic idea or aspect in one paragraph and avoid referring to just one study because you need to consider at least a few ones in each section. You should regularly link your discussed findings to the question stated in an introductory paragraph. This is what creates a certain thread of coherence in your essay. Don't forget to link all studies to each other while discussing and comparing their relationships. In the main body, there are 3 tenses commonly used by students:
- The present tense is used to report readers what other authors believe, think, and write while stating information of overall validity and current knowledge;
- Present perfect is used to refer to a specific area with many independent researchers involved;
- Simple past is used to refer to a specific author found or did in a single work.
The length of your main body should be about 70-90% of the core text. Make sure that you organize different facts into a strong line of argument. That's because the right organization of your information has a direct impact on the quality of your review paper. You should focus on writing an idea-driven paper instead of the literature-driven one.
The use of citations
In most cases, citations are indirect, but it's possible to cite directly some relevant and pointed remarks. Integral or direct references indicate that the author's name has a significant grammatical function in the text and they are used to emphasize the contribution of certain people. Non-integral or indirect references are used to emphasize a particular theory, idea, or results instead of people behind it. For example, most references used in biology review papers are non-integral.
A concluding paragraph
The conclusion of your review paper is necessary to answer the question stated in its introduction. There are certain elements that should be covered by this section, such as:
- Interpretations that must be kept separate from factual data;
- Implications of findings;
- Identification of any unresolved questions.
Use the present tense when making conclusions and summarizing. If you need to refer to a specific area or literature, you're allowed to use present perfect. The length of a concluding paragraph should be about 5% of the entire text, and it's not advisable to include any citations. Make a clear message to integrate the main points discussed in your review paper. Its conclusion should never repeat an abstract or an introduction.
Acknowledgements and references
Acknowledgements are written to express your gratitude to people who helped you complete this academic assignment, its writing and structuring. For instance, this brief section of your paper should contain the full names of people and their particular contributions to your writing project. Use the present tense when doing that.
References are necessary to avoid possible plagiarism charges, acknowledge the work of others, and show your readers how to find the sources used and mentioned in a review paper. You need to include each reference cited in your text, but don't include any extra references and avoid online sources. If it's required to use them, find the original sources for online references and be sure to cite them directly and correctly. When writing narrative reviews, focus on including only high-quality studies, while systematic and best-evidence papers require explicit criteria.
Additional elements
When including any illustrations, concept maps are quite helpful in review papers because they visualize your topic while showing existing links between different models, concepts, studies, and theories. If you need to organize data, arrange special boxes with names and terms in a 2-dimensional space. Use arrows to link all boxes and write specifications of their relationships. Any legend describes the content of a concept map, and it must be informative and specific to let other people understand it without reading the entire text. This tool is quite helpful when displaying all complex relationships. A glossary is often provided by students to explain specific terms to reach a broad audience. Boxes are provided to explain different concepts and terms to people who are interesting in studying the chosen topic in depth.
Prepare a review paper in a few basic steps
It's easy to write your review essay in several key steps, including:
- Narrowing the chosen topic and determining important questions or issues;
- Looking for reliable and updated sources of information, researching questions, and refining your topic;
- Reading, classifying, and evaluating all sources while making notes;
- Redefining the main focus and question;
- Writing a preliminary title and developing a basic structure of your paper;
- Determining the best structuring principle for your review, such as a subject matter, chronological, experimental procedure, and so on;
- Creating and outlining and writing headings for all sections;
- Planning the content of every paragraph in your review paper;
- Preparing concept maps, tables, and other important elements;
- Writing the methods section when needed;
- Writing the main body;
- Writing a concluding paragraph;
- Coming up with a great introduction;
- Drafting and revising an abstract;
- Rereading and editing each section of your assignment;
- Revising all references and citations;
- Adjusting the layout of your paper before its further submission;
- Correct any spelling, grammar, punctuation, and other mistakes.
Final words
There are some extra points that should be considered and defined during the preparation stage when writing best-evidence and systematic reviews, including:
- The selection of published data, databases, search strategies, and other resources;
- Statistical procedures to analyze all studies;
- Specific criteria for excluding and including them;
- The treatment of your qualitative research introduced in a review.
All the above-mentioned aspects should be described in methods and materials. Finally, some teachers or instructors may rarely require a detailed review protocol from their students. Ask other people for their competent feedbacks when writing your review paper of any type.
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Revista Española de Enfermedades Digestivas
versión impresa ISSN 1130-0108
Rev. esp. enferm. dig. vol.107 no.2 Madrid feb. 2015
Advances in knowledge on microscopic colitis: From bench to bedside
Avance en el conocimiento de la colitis microscópica: desde el laboratorio a la cabecera de la cama
Danila Guagnozzi1 and Alfredo J. Lucendo2
1 Department of Gastroenterology. Hospital Dr José Molina Orosa. Lanzarote. Spain
2 Department of Gastroenterology. Hospital General de Tomelloso. Tomelloso, Ciudad Real. Spain
Microscopic colitis (MC) is a general term that describes a family of chronic inflammatory bowel diseases, including lymphocytic colitis (LC) and collagenous colitis (CC). The two forms are characterized by chronic watery diarrhea with normal or near normal endoscopic colonic appearance and specific histopathological abnormalities. Data from recent epidemiological studies reported the diagnosis of MC from several different regions in the world, providing that it can be a worldwide condition. The etiopathogenesis of MC still remains unknown but it is generally accepted that MC is a multifactorial disease, probably secondary to an abnormal immune reaction in predisposed individuals, triggered by different luminal factors (infections, drugs, autoimmunity and/or bile acids). Furthermore, some studies show that the epithelial barrier function in the colonic mucosa of MC patients is also impaired. Several mucosal factors of intestinal inflammation have been studied in MC, postulating that an aberrant T-lymphocyte response may lead to a chronic gut inflammatory condition, with the infiltration of colonic mucosa by different proportion of subset of T-lymphocytes. Little is known about the specific inflammatory mediators in MC pathogenesis, but a predominant Th1 type cytokine profile has been demonstrated. Currently, a number of medical treatments have been studied in MC patients, following mainly an empirical treatment approach. Further studies are needed in order to obtain prospective and more evidence-based data. In the future, it will be possible to develop causal treatment approaches after better understanding the molecular mechanisms behind the origin of the disease.
Key words: Microscopic colitis. Lymphocytic colitis. Collagenous colitis. Pathogenesis. Therapeutics. T-lymphocytes.
List of abbreviations:
MC: Microscopic colitis;
LC: Lymphocytic colitis;
CC: Collagenous colitis;
IBS: Irritable bowel syndrome;
BAM: Bile acid malabsorption;
iNOS: Inducible nitric oxide synthase;
NO: Nitric oxide;
EC: Enterochromaffin cells;
CTLs: Cytotoxic T lymphocytes;
IL-2: Interleukin-2;
Treg: Regulatory T-cells;
IL-10: Interleukin-10;
TGF-beta: Transforming growth factor-beta;
IFN-gama: Interferon-gama;
TNF-alpha: Tumor necrosis factor-alpha;
NF-KB: Nuclear factor-KB;
IL-17: Interleukin-17;
HLA: Human leucocyte antigen;
CD: Celiac disease;
IL-6: Interleukin-6;
IL-1b: Interleukin-1b;
IL-1RA: Interleukin-1RA;
5-ASA: 5-aminosalycilic acid.
Microscopic colitis (MC) is a general term, used from 1980 (1) that describes a family of chronic inflammatory bowel diseases, including the two main entities, lymphocytic colitis (LC) and collagenous colitis (CC). The two forms are characterized by chronic or intermittent watery diarrhea, with normal o near normal endoscopic colonic appearance and specific microscopic abnormalities in the colonic mucosa, which allow to distinguish one form to the other. It is not clear whether LC and CC are the same disease entity, or have to be considered as different stages of the same condition (2,3). MC is a fairly new disease that is not always considered in patients with watery chronic diarrhea, because the diagnosis of MC may still be overlooked or misdiagnosed as irritable bowel syndrome (IBS). Epidemiological studies show that MC is diagnosed in up to 10 % of patients investigated for chronic or intermittent watery non-bloody diarrhea and in more than 20 % of patients older than 70 year old, being more frequent in elderly women and smokers (4). Data from recent epidemiological studies reported the diagnosis of MC from several different regions in the world, making it a worldwide condition. Nowadays, after a period of generally rising incidence of MC, data from recent epidemiological studies, show incidence rates ranging between < 1/100.000 to 10.8/100.000 inhabitants for CC and between 2.1/100.000 to 18.9/100.000 inhabitants for LC (5-19) (Table I). The pathogenesis of MC still remains unknown, but it is considered to be multifactorial, showing the importance of an impaired mucosal barrier function and the interaction between luminal content (including from bacteria to drugs) and the mucosal intestinal immune system. A better understanding of the immunological basis of inflammation in the colonic mucosa could lead to better therapeutic options and the design of new strategies to treat MC patients in the future.
This paper reviews the current evidences on the pathogenetic mechanisms underlying MC and its implications in the therapeutic management of the disease. We searched the PubMed, Cochrane, MEDLINE, and Scopus libraries, using the following individual and combined key words: Microscopic colitis; collagenous colitis; lymphocytic colitis; treatment or therapy; etiology; pathophysiology; genetic factors; luminal factors; epithelial barrier function; mediators of intestinal inflammation; budesonide; mesalazine; loperamide; bismuth subsalicylate; probiotics; immunosuppressive therapy; anti-TNF treatment. Reference lists in the articles obtained were also searched in order to identify other potential sources of information. The results were limited only to studies published, written in English.
Etiopathogenetic mechanisms of MC
It is generally accepted that MC is a multifactorial disease, probably secondary to an abnormal immune reaction that appears in predisposed individuals, triggered by different luminal factors (infections, drugs, autoimmunity and/or bile acids). The mechanism by which the alteration of the mucosal immune response generates the dominant symptom of the disease (diarrhea) is still under investigation, with several data showing that the diarrhea in MC patients could have an inflammatory origin. Indeed, the severity of diarrhea seems to be associated with the intensity of inflammation in the lamina propria in LC, while in patients with CC is not correlated to the thickness of the collagenous band (20). Furthermore, in those patients with CC, who had a temporary ileostomy, the recurrence of inflammation in the lamina propria was the first histological change observed in the development of the symptomatic disease (21). Nonetheless, other data indicate that osmotic and secretory components could also contribute to the development of diarrhea in MC patients. In fact, fasting can reduce the diarrhea (22) and some authors have demonstrated that diarrhea can be originated from a reduced Na+ and Cl- absorption, together with an active chloride secretion (23,24). Recently, a study from colonic biopsies from patients with CC and LC has shown that electrogenic sodium transport diminished and the epithelial resistance decreased. Finally, unlike patients with IBS, there are no signs of visceral hypersensitivity in patients with CC, also showing a normal ano-rectal function, despite the presence of rectal inflammation (25). Therefore, a combination of several factors may contribute to the induction and maintenance of an inflammatory response in the colonic mucosa of patients with MC to produce the symptoms of the disease (Fig. 1), which we will describe in detail in the following sections.
Luminal factors
Several luminal factors have been studied as putative triggers, to induce an impaired inflammatory mucosa response in MC patients:
Firstly, an infectious etiology is proposed, despite no specific pathogen has been identified until now. Some studies show the onset of MC following a gastrointestinal infections, as in the case of a Clostridium difficile infection, that can catalyze the inflammatory response to induce the development of CC (26), or the observation that serum antibodies against to Yersinia enterocolitica were more common among CC patients compared to controls, leading to the speculation of a previous Yersinia enterocolitica infection triggering the development of the disease (27). A role for gastrointestinal infections in the pathogenesis of MC is strikingly resembling to the hypothesis of post-infectious IBS (28), with similar clinical presentation, spontaneous regression and similar histological changes (intraepithelial and submucosal infiltration by lymphocytes and mast cells) (29).
Secondly, it is widely known that colonic infusion of bile acids may determine colitis in animal models (30), and in patients with ileal resection, with subsequent bile acid malabsorption (BAM), may have diarrhea (31). Some small retrospective case series have found BAM to be presented in up to 60 % of patients with LC and in up to 44 % of those with CC (32,33). This suggests that, at least in some patients, BAM might have a key role in the development of the disease. However, the evidence on the role of bile acids in the pathogenesis of MC is still conflicting. In fact, small studies conducted with bile acid breath test showed little or no evidence of BAM in MC patients (34-36) and an association between cholecystectomy and MC has not been found (37). On the other hand, some studies investigating the retention of selenium homocholyltaurine have found variable degrees of BAM (31,38) and bile acid binding treatment, such as using cholestyramine, has been shown to be effective in CC patients. Finally, a recent study has shown that a low concentration of dihydroxy bile acids can aggravate the mucosal barrier dysfunction in CC patients by increasing the uptake of non-pathogenic bacteria (39). However, whether BAM is causative or not still remains questionable (40) and on the basis of the new evidence, BAM and MC are probably associated but independent diseases.
Thirdly, drug consumption has been considered as an environmental risk factor causing or triggering MC. The likelihood of a specific drug to trigger MC has been shown in an interesting paper (41); drug imputation was assessed by using a French algorithm and adding the bibliographic score, calculated by the number of previous reports of a similar drug-event association (42). Significant associations were reported between MC and certain drugs with a high likelihood in triggering the disease, including non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), Ranitidine, Sertraline, Clozapine, Acarbose, Aspirin (ASA), Ticlopidine, Flavonoid vein tonic drugs and Entacapone (41). However, it is important to highlight that only by a re-challenge protocol (this is, assessing disease remission after drug withdrawal and recurrence after new expositions) it is possible to truly confirm causality relationships between some drugs and the development of a disease. Data from drug re-challenges are available only for few drugs, including Acarbose, Cyclo 3 forte, Ranitidine, Lansoprazole and Omeprazole (43-47), and some of them are limited to clinical recurrence, with no available histological assessment. Therefore, the possible causative nature of these associations is a matter of ongoing discussion, also because many drugs and their metabolites can produce diarrhea by several different mechanisms. They can affect the colon directly, either through their pharmacological activity, or through idiosyncratic hypersensitivity reactions, or indirectly by altering the colonization of gastrointestinal microorganisms (4). Several drugs thought to be associated with MC are also known to be involved in the development of chronic or recurrent diarrhea as a side effect (48), further confusing the possible causal role of drugs in the development of the disease. In this way the association between the development of MC and drug intake, could be considered as an idiosyncratic drug reaction and should be assessed before starting a specific treatment for MC.
Epithelial barrier dysfunction
The intestinal epithelium is a selective and regulated barrier that permits ions, water and nutrients to be absorbed, but restricts the passage of harmful molecules, bacteria, viruses and other pathogens (49). According with some studies, the colonic epithelial barrier function is impaired in MC patients, while the small bowel mucosa integrity remains still intact (50). In particular, we know that paracellular permeability is increased in CC patients, due to a reduced expression of occludin and claudin-4, which are important tight junction proteins, resulting in a reduction of the epithelial resistance (24). An in vitro study carried out over colonic biopsies from CC patients who were in clinical remission, found a significant dysfunction in the mucosal barrier associated with an increased transmucosal uptake of non-pathogenic bacteria. This worsened in case of an active disease and persisted despite effective treatment with budesonide (51). The diversion of the fecal stream by an ileostomy normalized the mucosal permeability and epithelial degeneration, in parallel with decreasing of the mucosal inflammation in CC patients. The altered mucosal permeability recurred after restoring the bowel continuity, and the thickened collagenous layer latter reappeared (52). Finally, increased levels of both inducible nitric oxide synthase (iNOS) and nitric oxide (NO) are also observed in the colonic mucosa of MC patients, which leads to an increased paracellular transit, by increasing the tight junction permeability (53-55). Some authors postulated that the increased levels of NO are caused by a higher secretion of serotonin from enterochromaffin (EC) cells, as observed in colonic mucosa samples from LC patients (56,57). The increase in colonic serotonin cell density probably results from the interaction between lymphocytes and EC cells. Serotonin accelerates the intestinal motility and promotes water and electrolyte secretion, with a secondary compensatory increased expression in peptide YY, as observed in LC patients (57). It in turn, inhibits prostaglandin E2 and vasoactive intestinal polypeptide activation, stimulating the absorption of water and electrolytes (58-60). This probably explains the intermittent evolution of the diarrhea in MC patients. However, it is not yet clear if mucosal barrier dysfunction is a primary or secondary phenomenon, underlying the mucosal inflammation (Fig. 2).
Impaired mucosal immune system
Several mucosal factors leading to intestinal inflammation have been studied in MC, postulating that an impaired adaptive immune response through aberrant T-cell responses leads to chronic gut inflammatory conditions (61). The number of CD3+ T-lymphocytes in the lamina propria and intraepithelial compartment is increased in LC and CC (62), as it is defined as a hallmark for these diseases. On the basis of immunohistochemical staining and flow cytometric analyses, most of the T lymphocytes are CD4+ within the lamina propria and CD8+ in intraepithelial compartment, carrying the alpha/beta form of the T-cell receptor (62), with a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile (63). The heavy infiltration by CD8+ cytotoxic T-lymphocytes (CTLs) in the colonic mucosa of MC patients has been recently shown to be due to an increased expansion of resident T-cells. It suggests that the activating antigen localizes in the colonic mucosa, such as demonstrated by a reduced T-cell receptor excision circles level with enhanced expression of Ki67+ T-cells in the colonic mucosa of MC patients (61,64). In fact, other studies have also demonstrated an elevated proportion of memory CD8+ T-cells (Ki67+ and CD45RO+ cells) in intraepithelial and lamina propria compartments, being more pronounced in CC than LC and in active disease, compared with the disease in histopathological remission state. It is important to highlight that compared to spleen memory T-cells, memory CD8+ T-cells can be more rapidly reactivated to produce uncontrolled or excessive cytotoxic activity against luminal antigens, developing and maintaining an intestinal chronic inflammatory response (64). Furthermore, CTLs induce proliferation of regulatory T-cells (Treg) through the secretion of interleukin (IL-2), which in turn inhibits CTLs-induced cytotoxic tissue damage, in order to maintain the self-tolerance status by the production of suppressor cytokines (IL-10, transforming growth factor [TGF]-beta) and by cell-to-cell contact-dependent mechanisms (65-68). CD25+FOXP3+ Treg are increased in the lamina propria of MC patients, probably blocking the spoiling effect of CTLs (69,70). In fact, this action is modulated by TGF-beta acting as a suppressive factor for inflammatory cells proliferation and function, with an additional role in causing the accumulation of collagen as observed in CC (71). Several additional factors are being studied as responsible causes in the formation of the thick subepithelial collagen band. Among others, increased numbers of activated subepithelial myofibroblasts (72,73) and vascular endothelial growth factor, which promote the accumulation of immature subepithelial matrix (74). In contrast, patients with LC have significant more CTLs than those with CC and less CD25+FOXP3 Treg than CC patients, although with increased levels compared to normal colonic mucosa (69). These observations support the theory that LC and CC could be considered as different stages of the same condition, with increased numbers of CTLs at the earliest stage (LC) and subepitelial collagen bands and increased CD25+FOXP3+ Treg in the later stage (CC) (69). Besides the lymphocytic infiltration, an increased number of eosinophils can be observed in the colonic mucosa of CC patients (75-77), along with increased levels of eosinophilic cationic protein (77) and degranulation of major basic protein (76), suggesting the involvement of the innate immune system in the pathogenesis of MC.
One report showed a predominant Th1-type cytokine profile, with marked increase in interferon (IFN)-gamma, IL-15 and iNOS expression and with lesser increase in tumor necrosis factor (TNF)-alpha (78). Increased activities of nuclear factor-KB (NF-KB), iNOS, IFN-gamma and COX-2, have been shown in other studies (79-82), especially in CC, where their increases were significantly higher than in LC. An increased expression of interleukin-17 (IL-17) in epithelial and inflammatory cells of MC patients has been recently demonstrated (63,83), which plays an important role in antimicrobial immunity at mucosal barriers and in the amplification of intestinal inflammatory responses.
Genetic factors
Whether genetic predisposition is of importance in MC is unclear. Several aspects in the sparse scientific evidences indicate that a genetic background could play a role in the etiology of MC. Familiar aggregation of MC cases were demonstrated in a Swedish study, which found five families with the occurrence of MC, with a sister-sister relationship, independently of smoking habits (84). Mother-daughter and father-son relationships have also been described (85,86).
Recently, a familial case of CC below 14 years old has been reported in a mother-daughter relationship (87). Unfortunately, until now, no concordance among twins has been reported for MC, pointing out that not only genetic predisposition, but also environmental factors, should also be considered in order to explain the familial occurrence of MC.
In addition, small studies have found an association between MC with various autoimmune-related human leukocyte antigens (HLA) haplotypes. An increasing prevalence of HLA-A1 and a decreased of HLA-A3 haplotypes has been found in LC, with no associated in CC patients (88). Some studies have reported on the association of MC with the HLA-DQ haplotypes predisposing to celiac disease (CD), with a prevalence level of HLA-DQ2 alleles up to 64 % of MC patients (among whom only 4 % had a concomitant CD), compared with only 31 % in control subjects (89). The association of HLA-DQ2 with LC without the association to CD has also been found (90).
Finally, different genetic polymorphisms have been studied in MC patients: the frequency of carriers for the GG allele of the SNP of matrix metalloproteinase was found significantly higher in CC patients than in healthy donors, being the odds ratio for an increased risk of CC 1,9 (95 % confidence interval [CI], 1, 3.5) (91). Unfortunately, the carrier frequencies of the alleles in SNP 8, 12 and 13 of NOD2/CARD15 gene were not different between CC patients and healthy blood donors (92). The IL-6-174 gene polymorphism has also been related with MC, showing that the IL-6 GG and G genotypes were more frequent in patients with MC compared to controls, being the odds ratio of 1.5 (95 % CI 1.041, 2.203) and 1.9 (95 % CI 1.078, 3.495), respectively. An association with other polymorphisms of cytokines IL-1b, IL-1RA, IL-10 and CD14 was not found in the same study (93). The genotypes GG and G of the IL-6 gene are associated with an increased IL-6 production that could contribute to the development of pro-inflammatory responses in the intestinal mucosa. Finally, an association of MC with HLA DR3-DQ2 haplotype and TNF2 allele has also been found (94). Further studies are needed in order to strength the knowledge on the role of genetic factors in the origin of MC.
From bench to bedside: treatment options for MC
The treatment of MC should take into account the severity of symptoms and their impact on the patients' quality of life, the efficacy of the drugs in obtaining clinical remission (accompanied or not with histological remission), and the secondary effects associated to short and long term treatments. Considering the high rate of spontaneous remission and sustained remission after short term therapy, the long-term therapy should be considered preferentially on relapsing or refractory patients, for whom an intermittent therapy should be favored (4). In recent years, a number of randomized controlled trials (RCT) have been provided for a more evidence-based approach to treat MC patients. More evidence is available on the treatment of CC than LC, but there is no reason to treat these two entities differently, because the drugs that seem to be effective in one tend to be effective also in the other disease. Several medical treatments have been studied in MC patients, following empirical approaches. In fact, currently there is no casual treatment approach for MC, although increasing data on the effects of some drugs over pathogenetic mechanisms involved in the development of MC are now available.
Induction of remission and maintenance treatment in patients with active MC
Budesonide is a non-halogenated gluco-corticosteroid with a very high receptor binding affinity and a limited systemic availability, without the significant adverse events that frequently occur in systemic corticosteroids-based treatment. Budesonide is currently the most promising treatment for MC; the strongest evidence on its efficacy, coming from several RCTs. It should be considered the first-line treatment in active MC (4). Three RCT in CC (95-97) and two in LC (98,99) have demonstrated that budesonide therapy (9 mg/day for 6-8 weeks) is effective in inducing the clinical remission and to improve the patients' health-related quality of life. Furthermore, in a recent study, budesonide was significantly superior to mesalazine for inducing clinical remission (80 % vs. 44 %, p = 0.0035) in CC patients (100). Two Cochrane Collaboration systematic reviews with meta-analysis reported a high response rate for achieving a clinical remission compared to placebo, with a pooled response rate of 81 % in CC (101) and an odds ratio of 9 in LC (102), with these last results also confirmed by other recent meta-analysis (103). However, a high rate (61-80 %) of relapse within 2 weeks after stopping the treatment was reported in all trials, which required studying the benefit of a maintenance treatment. In fact, two RCTs have shown that clinical remission and histological response can be maintained with budesonide at a dose of 6 mg/day for 6 months (104,105), and a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in 61.4 % in CC patients vs. only 16.7 % in the placebo group (p < 0.001), with few adverse drug reactions. As a whole, these results suggest the usefulness of maintenance treatment with a low-dose of budesonide, to prevent this high relapse rate (106).
Regarding the mechanism of action of this drug, we know that the glucocorticoid receptor is ubiquitously found in nearly all tissues and its interaction with the cells and mediators plays a key role in the inflammatory cascade, preventing epithelial dysfunction in vitro models of inflammation, by inhibiting the activation of both T-cells and monocytes (107), modulating the inflammatory regulator NF-KB (108) and acting by other different mechanisms (109,110). However, we still lack enough data about what are the exact mechanisms by which budesonide acts in order to produce its therapeutic effect in MC patients. From the few data available, we know that budesonide can modify the different lymphocyte subpopulations infiltrating the intestinal mucosa in MC patients, as showed by immunohistochemical staining and flow cytometric analysis (96,98,111). In fact, budesonide treatment is often associated with the restoration of histology in a majority of LC cases, and with a partial or complete normalization of the inflammatory infiltrate in 30.8 % and 69.2 % CC patients, respectively (112). In contrast, a recent study failed to demonstrate significant reductions in the proportion of total CD8+ intraepithelial T-cells, when T-cells from lamina propria were separately analyzed by flow cytometry in budesonide-treated LC and CC patients (64). In the same study, no differences in the proportion of CD45RO+ or Ki67+ cells, nor CD8+ or CD4+ intrahepitelial and lamina propria T-cells, between untreated and budesonide treated patients with MC were found, except a single LC treated patient showing a declined proportion of these cells. A declined proportion of CD4+8+ lamina propria and IELs cells were only found in CC treated patients, but not in LC patients (64). A reduction in the thickness of the subepithelial collagen band can be seen in treated patients with CC, but it seems to take a longer time than for the resolution of the inflammatory infiltrate (112). Moreover, budesonide treatment can reduce the iNOS mRNA expression that correlates with the inflammatory and the clinical activity of CC patients (113). Finally, the efficacy of budesonide in MC might be in part also due to an increase in the ileal reabsorption of bile acids (114). However, there are some pathogenetic mechanisms on which budesonide has no effect, as demonstrated by the persistent mucosal barrier dysfunction after budesonide treatment (51) despite of the fact of restoring the electrogenic sodium transport impairment (115) and the altered mucosal reactivity (51).
5-Aminosalicylic acid (5-ASA) such as mesalazine has a local anti-inflammatory effect, as demonstrated also in other inflammatory bowel diseases. There are few evidence-based data about its usefulness in MC patients. In retrospective studies 5-ASA have been shown to be effective in about half of the patients at a dose of 2.4-3 g/day, with an effective rate ranging from 86 %-42 % in Spanish studies, to 35-42 % in American and other European studies (116-119). Prospective open-label studies showed one high efficacy of mesalazine for inducing remission in MC (73 % in CC and 85 % in LC), especially when combined with cholestyramine in CC patients (102,120). However, in the unique RCT published, mesalazine resulted less effective than budesonide and placebo to induce clinical remission in CC patients (100). Therefore, the current value of mesalazine for the treatment of MC patients remains unclear and further studies are needed.
Even when cholestiramine has never been assayed in a RCT, evidence from uncontrolled retrospective data shows that this bile acid binder (at a dose of 4 g/day) could be effective in MC, especially in CC patients with a concomitant BAM (121). As stated above, the benefit of cholestyramine is slightly better if combined with mesalazine, as showed in a prospective no placebo-controlled study (120); these data need to be confirmed to clarify the real therapeutic value of this drug. In fact, patients on bile acid binders had no significant changes in histopathology, despite a good effect on their symptoms (122). However, it is important to highlight that its beneficial effect is not only bile acid-specific, as cholestyramine also binds bacterial toxins, which might also contribute to reduce the symptoms in MC patients by a bile acids independent mechanism, which highlights the important role for luminal antigens in the pathogenesis of MC.
Other treatment options
Some drugs could be used to produce symptomatic effect such as loperamide, which does not achieve sustained clinical remission and produces no impact on colonic inflammation. However, loperamide could be reserved to control symptoms in mild cases of MC (123).
Probiotics are other treatment whose potential role in the induction and/or maintenance of clinical remission in MC should also be further investigated. Until now, they have been exclusively investigated in CC patients: In particular, Lactobacillus acidophilus LA-5, Bifidobacterium animalis subspp lactis BB12 and Boswellia serrata extracts did not show benefit, in terms of clinical and histological response or in improvement of quality of life, compared to placebo (124,125). Only the probiotic Escherichia coli strain Nissle 1917 has achieved in an open-label uncontrolled trial a reduction in stool frequency in 64 % of CC patients (126).
Bismuth derivatives
Bismuth subsalicylate, a derivative of salicylic acid with potential anti-inflammatory and antibacterial actions has occasionally been used in America on mild to moderate active MC: A RCT and an additional open-label study showed clinical and histological response in MC patients (127,128), but toxicity concerns have determined that this drug is not available and not used in many countries.
Therapeutical options for refractory MC patients and future prospects
Only a small subset of patients with MC are refractory to steroids treatment, amounting approximately less than 5 % in a population-based cohort study (129). In patients who failed to respond and in patients intolerant to budesonide, the use of immunosuppressive therapies should be considered, once confirmed the histological diagnosis of MC, carried out a correct differential diagnosis, ascertained the compliance to the treatment prescribed and the absence of exposures to high risk medications for MC. However, the experience with immunomodulators in MC is mainly anecdotal, with no RCT available until now, and with its use mainly derived because of the pathogenetic similarities between MC and inflammatory bowel diseases. In particular, Azathioprine or 6-Mercaptopurine, have been demonstrated useful in some MC patients refractory to budesonide with a response rate of 89 %, associating a steroid sparing effect. However, approximately 50 % of MC patients were intolerant to these drugs (129,131). Doses used in MC have been very similar to that of inflammatory bowel disease. Methotrexate (MTX) has also been studied in a retrospective report on CC patients, showing a beneficial effect with oral low-dose (5-25 mg). However, most patients in this report had not been previously treated with budesonide (132). In contrast, a prospective study conducted on patients intolerant or refractory to budesonide who received subcutaneous MTX (15-25 mg) showed no clinical remission (133).
An effective use of anti-TNF therapy (infliximab and adalimumab) has been reported in refractory severe MC patients, as a third-line treatment or "rescue therapy" to avoid surgery (diverting ileostomy or colectomy) in selected intractable cases (134,135). On a pathogenetic point of view, the TNF-alpha released by activated macrophages and T-cells triggers a chain of cellular mediators that causes secondary intestinal damage. Limited data have shown an increased expression of TNF-alpha in the colonic mucosa of MC patients (136,137), although at a very weak level (< 10 % in epithelial and inflammatory cells of MC patients) (83). A putative role for IL-17 in the pathogenesis of MC has been recently proposed, after documenting an increased expression in epithelial and inflammatory cells of MC patients (83). In fact, the regulation of IL-17 appears as a viable future therapeutic option in the treatment of MC patients, since a novel inhibitor of the production of IL-17 in activated lymphocytes (Vidofludimus) has been studied in animal models of chronic intestinal inflammation (138). The better understanding of the molecular mechanisms behind the development and maintenance of colonic inflammation in MC patients will make possible the development of future specific drugs to control disease activity. Evidence-based data deserve further prospective studies to obtain more conclusive data regarding this small subset of patients.
Knowledge about MC has constantly increased since the first description of the disease, to the point that CC and LC have been established as well-defined diseases. MC is currently considered as a worldwide condition, as common as inflammatory bowel disease. However its pathogenesis still remain unknown and the approach to the treatment of MC patients is mainly empirical and not causal, based on very comprehensive evidence. Fundamental advances in the understanding of the pathogenetic mechanisms of the development and maintenance of chronic intestinal inflammation in MC patients are needed, to further allow the development of novel and effective specific therapies.
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93. Castaneda FE, Walia B, Vijay-Kumar M, Patel NR, Roser S, Kolachala VL, et al. Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: Central role of epithelial-derived MMP. Gastroenterology 2005;129:1991-2008. [ Links ]
94. Koskela RM, Karttunen RA, Niemelä SE, Lehtola JK, Bloigu RS, Karttunen RA. Cytokine gene polymorphism in microscopic colitis association with the IL-6-174 GG genotype. Eur J Gastroenterol Hpeatol 2011;23:607-13. [ Links ]
95. Koskela RM, Karttunen TJ, Niemelá SE, Lehtola JK, Llonen J, Karttunen RA. Human leucocyte antigen and TNFα polymorphism association in microscopic colitis. Eur J Gastroenterol Hepatol 2008;20:276-82. [ Links ]
96. Baert F, Schmit A, D'Haens G, Dedeurwaerdere F, Louis E, Cabooter M, et al. Budesonide in collagenous colitis: A double-blind placebo-controlled trial with histologic follow-up. Gastroenterology 2002;122:20-5. [ Links ]
97. Bonderup OK, Hansen JB, Birket-Smith L, Vestergaard V, Teglbjaerg PS, Fallingborg J. Budesonide treatment of collagenous colitis: A randomised, double blind, placebo controlled trial with morphometric analysis. Gut 2003;52:248-51. [ Links ]
98. Miehlke S, Heymer P, Bethke B, Bastlein E, Meier E, Bartram HP, et al. Budesonide treatment for collagenous colitis: A randomized, double-blind, placebo-controlled, multicenter trial. Gastroenterology 2002;123:978-84. [ Links ]
99. Miehlke S, Madisch A, Karimi D, Wonschik S, Kuhlisch E, Beckmann R, et al. Budesonide is effective in treating lymphocytic colitis: A randomized double-blind placebo-controlled study. Gastroenterology 2009;136:2092-100. [ Links ]
100. Pardi DS, Loftus Jr EV, Tremaine WJ, Sandborn WJ. A randomized double-blind, placebo controlled trial of budesonide for the treatment of active lymphocytic colitis. Gastroenterology 2009;136(Supl. 1)(T 1193). [ Links ]
101. Miehlke S, Madisch A, Kupcinskas L, Petrauskas D, Bohm G, Marks HJ, et al. Budesonide is more effective than mesalamine or placebo in short-term treatment of collagenous colitis. Gastroenterology 2014;146:1222-30. [ Links ]
102. Chande N, MacDonald JK, McDonald JW. Interventions for treating microscopic colitis: A Cochrane inflammatory bowel disease and functional bowel disorders review group systematic review of randomized trials. Am J Gastroenterol 2009; 104:235-41. [ Links ]
103. Chande N, McDonald JW, MacDonald JK. Interventions for treating lymphocytic colitis. Cochrane Database Syst Rev 2008 (CD006096)). [ Links ]
104. Stewart MJ, Seow CH, Storr MA. Prednisolone and budesonide for short- and long-term treatment of microscopic colitis: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2011;9:881-90. [ Links ]
105. Bonderup OK, Hansen JB, Teglbjaerg PS, Christensen LA, Fallingborg JF. Long-term budesonide treatment of collagenous colitis: A randomised, double-blind, placebo-controlled trial. Gut 2009;58:68-72. [ Links ]
106. Miehlke S, Madisch A, Bethke B, Morgner A, Kuhlisch E, Henker C, et al. Oral budesonide for maintenance treatment of collagenous colitis: A randomized, double-blind, placebo-controlled trial. Gastroenterology 2008;135:1510-6. [ Links ]
107. Münch A, Bohr J, Miehlke S, Benoni C, Olesen M, Ost A, et al. Low-dose budesonide for maintenance of clinical remission in collagenous colitis: A randomised, placebo-controlled, 12 month trial. Gut 2014; DOI: 10.1136/gutjnl-2014-308363. [ Links ]
108. McKay DM, Brattsand R, Wieslander E, Fung M, Croitoru K, Perdue MH. Budesonide inhibits T cell-initiated epithelial pathophysiology in an in vitro model of inflammation. J Pharmacol Exp Ther 1996;277:403-10. [ Links ]
109. Göke MN, Schneider M, Beil W, Manns MP. Differential glucocorticoid effects on repair mechanisms and NF-kappaB activity in the intestinal epithelium. Regul Pept 2002;30:203-14. [ Links ]
110. Barnes PJ. Molecular mechanisms and cellular effects of glucocorticosteroids. Immunol Allergy Clin North Am 2005;25:451-68. [ Links ]
111. Bloemena E, Weinreich S, Schellekens PT. The influence of prednisolone on the recirculation of peripheral blood lymphocytes in vivo. Clin Exp Immunol 1990;80:460-6. [ Links ]
112. Wagner M, Lampinen M, Sangfelt P, Agnarsdottir M, Carison M. Budesonide treatment of patients with collagenous colitis restores normal eosinophil and T-cell activity in the colon. Inflamm Bowel Dis 2010;16:1118-26. [ Links ]
113. Baert F, Schmit A, D'Haens G, Dedeurwaerdere F, Louis E, Cabooter M, et al. Budesonide in collagenous colitis: A double-blind placebo-controlled trial with histologic follow-up. Gastroenterology 2002;122:20-5. [ Links ]
114. Bonderup OK, Hansen JB, Madsen P, Vestergaard V, Fallingborg J, Teglbjaerg PS. Budesonide treatment and expression of inducible nitric oxide synthase mRNA in colonic mucosa in collagenous colitis. Eur J Gastroenterol Hepatol 2006;18:1095-9. [ Links ]
115. Bajor A, Kilander A, Galman C, Rudling M, Ung KA. Budesonide treatment is associated with increased bile acid absorption in collagenous colitis. Aliment Pharmacol Ther 2006;24:1643-9. [ Links ]
116. Barmeyer C, Erko I, Fromm A, Bojarski C, Allers K, Moos V, et al. Ion transport and barrier function are disturbed in microscopic colitis. Ann N Y Acad Sci 2012;1258:143-8. [ Links ]
117. Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Lymphocytic colitis: A retrospective clinic study of 199 Swedish patients. Gut 2004;53:536-41. [ Links ]
118. Bohr J, Tysk C, Eriksson S, Abrahamsson H, Järnerot G. Collagenous colitis: A retrospective study of clinical presentation and treatment in 163 patients. Gut 1996;39:846-51. [ Links ]
119. Fernández-Bañares F, Salas A, Esteve M, Espinós J, Forné M, Viver JM. Collagenous colitis and lymphocytic colitis. Evaluation of clinical and histological features, response to treatment and long-term follow-up. Am J Gastroenterol 2003;98:340-7. [ Links ]
120. Pardi DS, Ramnath VR, Loftus EV, Tremaine WJ, Sandborn WJ. Lymphocytic colitis: Clinical features, treatment, and outcomes. Am J Gastroenterol 2002;97:2829-33. [ Links ]
121. Calabrese C, Fabbri A, Areni A, Zahlane D, Scialpi C, Di Febo G. Mesalazine with or without cholestyramine in the treatment of microscopic colitis: Randomized controlled trial. J Gastroenterol Hepatol 2007;22:809-14. [ Links ]
122. Ung KA, Gillberg R, Kilander A, Abrahamsson H. role of bile acids and bile acid binding agents in patients with collagenous colitis. Gut 2000;46:170-5. [ Links ]
123. Ung KA, Kilander A, Nilsson O, Abrahamsson H. Long-term course in collagenous colitis and the impact of bile acids malabsorption and bile acid sequestrants on histopathology and clinical features. Scand J Gastroenterol 2001;36:601-9. [ Links ]
124. Park YS, Baek DH, Kim WH, Kim JS, Yang SK, Jung SA, et al. Clinical characteristics of microscopic colitis in Korea: Prospective multicenter study by KASID. Gut Liver 2011;5:181-6. [ Links ]
125. Wildt S, Munck LK, Vinter-Jensen L, Hanse BF, Nordgaard-Lassen I, Christesen S, et al. Probiotic treatment of collagenous colitis: A randomized, double-blind placebo-controlled trial with Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis. Inflamm Bowel Dis 2006;12:395-401. [ Links ]
126. Madisch A, Miehlke S, Eichele O, Mrwa J, Bethke B, Kuhlisch E, et al. Boswellia serrata extract for the treatment of collagenous colitis. A double-blind, randomized, placebo-controlled, multicenter trial. Int J Colorectal Dis 2007;22:1445-51. [ Links ]
127. Tromm A, Niewerth U, Khoury M, Baestlein E, Wilhelms G, Schulze J, et al. The probiotic E. coli strain Nissle 1917 for the treatment of collagenous colitis: First results of an open-label trial. Z gastroenterol 2004;42:365-9. [ Links ]
128. Fine KD, Ogunji F, Lee EL, Lafon G, Tanzi M. Randomized, double-blind, placebo-controlled trial of bismuth subsalicylate for microscopic colitis. Gastroenterology 1999;116:A880. [ Links ]
129. Fine KD, Lee EL. Efficacy of open-label bismuth subsalicylate for the treatment of microscopic colitis. Gastroenterology 1998;114:29-36. [ Links ]
130. Gentile NM, Abdalla AA, Khanna S, Smyrk TC, Tremaine WJ, Faubion WA, et al. Outcomes of patients with microscopic colitis treated with corticosteroids: A population-based study. Am J Gastroenterology 2013;108:256-9. [ Links ]
131. Pardi DS, Loftus EV, Tremaine WJ, Sandborn WJ. Treatment of refractory microscopic colitis with azathioprine and 6-mercaptopurine. Gastroenterology 2001;120:1483-4. [ Links ]
132. Vennamaneni SR, Bonner GF. Use of azathioprine or 6-mercaptopurine for treatment of steroid-dependent lymphocytic and collagenous colitis. Am J Gastroenterol 2001;96:2798-9. [ Links ]
133. Riddell J, Hillman L, Chiragakis L, Clarke A. Collagenous colitis: oral low-dose methotrexate for patients with difficult symptoms: Long term outcomes. J Gastroenterol Hepatol 2007;22:1589-93. [ Links ]
134. Münch A, Bohr J, Vigren L, Tysk C, Ström M. Methotrexate is not effective in budesonide refractory collagenous colitis. Gut 2011;60(Supl. 3):A406. [ Links ]
135. Esteve M, Mahadevan U, Sainz E, Rodríguez E, Salas A, Fernández-Bañares F. Efficacy of anti-TNF therapies in refractory severe microscopic colitis. J Crohns Colitis 2011;5:612-8. [ Links ]
136. Münch A, Ignatova S, Strom M. Adalimumab in budesonide and methotrexate refractory collagenous colitis. Scand J Gastroenterol 2012;47:59-63. [ Links ]
137. Dey I, Beck PL, Chadee K. Lymphocytic colitis is associated with increased pro-inflammatory cytokine profile and up regulation of prostaglandin receptor EP4. PLoS One 2013;8:e61891. [ Links ]
138. Kumawat AK, Strid H, Tysk C, Bohr J, Hörnquist EH. Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile. Mol Immunol 2013;55:355-64. [ Links ]
139. Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006;12:382-8. [ Links ]
Danila Guagnozzi
Department of Gastroenterology.
Hospital Dr José
Molina Orosa.
Ctra. Arrecife-Tinajo, km. 1,300
35550 Arrecife, Las Palmas. Spain
e-mail: firstname.lastname@example.com
Received: 02-01-2015
Accepted: 08-01-2015

subset: commoncrawl


text:
No one begins the process of selling a home hoping they lose money on the deal. Many factors go into the final sale price of a home, and some of these factors are beyond your control. However, there are small things you can do to help reach your goal (or get as close to it as possible). Below we've outlined the top five ways to sell your home for the most money!
1. Understand the financial circumstances
In order to set yourself up for realistic success, you will have to get familiar with the financial side of selling a home. The first thing you'll want to look into is your local real estate market. What are similar properties selling for? Is your area currently in a buyer's or seller's market? Get a decent range on the property values to have a general idea of your initial starting price point. The next number you'll want to look at is the associated fees that go into selling a property. Depending on who you work with to sell your home, there can be anywhere from a 5-10% drop after commission, closing costs, and repairs/maintenance you've done to the property. Once you've got an estimated cost, you'll want to set your home at the right price. It is usually advised to market your home slightly above what your home's true value is. That way, there is room for negotiations and any surprise concessions the buyer will want you to make.
2. Choose the right time to sell
Above, we mentioned checking into whether your area is in a buyer's or seller's market. A buyer's market means that the price of real estate property is lower. This is usually due to a high availability of properties in the area. Potential investors have more options, so they can shop around a bit more for a better deal. Therefore, buyers can typically invest in a home at a lower price. This is great for the buyer, but not so great for the seller. On the other hand, a seller's market means the price of real estate in the area is above the initial value of the home. Opposite of a buyer's market, this is because there is a shortage of available property in the area. There are certain situations where a seller is unable to control when they need to sell. However, if you have the luxury of choice, follow the markets and take advantage of the higher price point during a seller's market!
3. Consider renovations to add value
After studying the markets and properties in your area, you should have a good idea of what the other homes have to offer. This is the point where you need to look at your home and decide if there are any minor repairs or renovations you should make in order to be competitive. While making these decisions, it's important to remember that you don't want to invest more money into the repairs than you anticipate gaining on the sale.
4. Negotiate for the best offer
When you have an interested buyer on the line, you must be open to negotiations. Within the negotiation process, there is more to think about than the price. Sometimes the highest offer isn't the best offer. Things to consider are the timeline of sale, price of repairs (whether by you or the buyer), and any included items aside from the structure (furniture, appliances, etc.). For example, if you are looking to make a quick, profitable sale, you'll want a buyer who is ready to move in so you can move on. If you'll need time to move into your new property, a longer timeline may be part of the negotiations!
5. Determine how you're going to sell
Although this should be one of the first things you decide, we've saved it for last as it is one of the most important. There are a few options for you as you look into selling your home.
You always have the ability to sell a home yourself (for sale by owner - FSBO). In this role, you essentially become the Real Estate Professional. While it's possible, listing your home FSBO is a complicated, time-consuming process.
There is also the more common, traditional real estate process. You will get your home ready, locate a real estate agent, and have them be your guide as you list, show, and negotiate through the selling process.
And finally, our favourite option, a Sweet Sale! At Sweetly, we follow a new and unique business model. When you are ready to sell your home, our company will purchase it for a portion of the expected resale value. This gives you the financial freedom to move on and find your next ideal property. Once you've moved out, we will resell the property and deduct our fee, returning you the balance of your equity in a second payment. A Sweet Sale lets you sell without being listed for sale while living in the home (or you having to do any of the leg-work), and you even get to choose your own moving date.
If you are interested in working with one of our licensed and experienced real estate agents as you prepare to sell your home, reach out! Let us take the stress out of the home sale process. To talk to one of our agents, you can contact us via email at email@example.com or by phone at 780.477.9338. If you have general questions about our process, you can also simply fill out the form on our website. We can't wait to hear from you!


text:
McDSP Revolver is a high-powered convolution reverb for AAX Native, RTAS, AU, and AudioSuite that gives you the power to totally sculpt impulse responses to suit your taste. With dedicated and routable EQ, two syncable delay lines, and specialized stereo imaging, Revolver offers unprecedented control over your mix!McDSP Revolver Convolution Reverb at a Glance
- Includes hundreds of acoustic spaces and reverbs
- Convolution without unnecessary CPU drain
- Record your own spaces
- Includes EQ and delay lines
- Additional controls to shape the sound you want
- 3-band crossover controls reverb tails on the fly
Includes hundreds of acoustic spaces and reverbs
With literally hundreds of sounds from rare, venerable out-of-production reverbs and acoustic spaces, Revolver provides the most compelling impulse library to date. The Revolver plug-in uses convolution to extract and replicate acoustic spaces and other equipment exactly. It combines this extraordinary processing power with the flexibility only found in ultra high-end outboard reverbs.
Convolution without unnecessary CPU drain
Convolution is known to be computationally expensive. McDSP Revolver is a highly optimized convolution engine, and to help maximize the power of your system Revolver provides selectable latency modes and Tail Cut controls to save your computer from having to process signals that are inaudible. When using a higher buffer size and the Low Latency mode output delay can be as low as 0 samples. When the user adjusts the playback buffer size of their DAW, Revolver will also check which latency mode has been selected and automatically choose the best one.
Record your own spaces
Also included with Revolver is a complete tool set to shoot your own rooms and gear. Any acoustic space, outboard gear, or signal path can be modeled in a few minutes with Revolver and the Revolver analysis tools. Other impulse responses can be imported and Revolver will automatically locate the best starting point for the impulse response, and calculate a fade from the noise floor if one is present.
Includes EQ and delay lines
Revolver has two bands of dedicated shelving EQ and three additional bands of routable EQ. The EQ routing system has 18 different insert combinations. Revolver's two programmabdelay lines have five different possible insert combinations. The delay lines are each three seconds long and can be panned and synced to MIDI beat clock independently for a variety of tempo-based effects. Additionally, all parameter adjustments are heard immediately, and the outputs are not muted during any control updates. You don't need to wait while the reverb is "re-rendered."
Additional controls to shape the sound you want
In addition to the usual reverb length, wet and dry mix controls, EQ and delay, Revolver adds positive and negative predelay, controls for the articulation and overall attack of the sampled impulse, as well as other specialized stereo field controls. Separate from the delay lines, Revolver's split delay feature can be used to create an image shift of up to 50 msec, between the left and right channels. The split dampening and selectable diffusion controls can accentuate an image shift in the frequency domain.
3-band crossover controls reverb tails on the fly
Revolver LE's optional 3-band crossover provides control over the specific tonal characteristics of the reverb tail over time, separating out the lows, mids, and highs. This is applied directly to the impulse response, essentially rendering on the fly and saving on system overhead.
- Convolution reverb with hundreds of sampled spaces and processors
- Includes tool set to record your own spaces and gear
- 2-band shelving EQ plus 3-band routable EQ
- Delay lines can sync to MIDI clock
- Positive and negative predelay controls
- Optional 3-band crossover allows control of reverb tail over time
- Maximum sample rate 48kHz
Get Revolver to make your Pro Tools sessions really shine!
Your Paypal account , credit card or debit card will not be charged if your order is not in stock or available with the manufacturer. In stock orders are shipped within 1-2 business days (FEDEX tracking details provided). Un-stocked orders require a special order from the manufacturer and ship within 7-10 business days.
The includes a 1 Year return to base warranty. This warranty applies to all equipment which has developed a manufacturer defect during application. Please contact us to confirm the availability and lowest price for any product. For quotes and price matching requests, contact us and include the competing website address.
|Sealed / New
|Insured Value
Contact us for stock availability , price quotes , expedited shipping quotes or to arrange a return of your (for the full purchase price of ). You may return most new, unopened items within 30 days of delivery for a full refund. AudioDubai are very proud to carry a large selection of gear. You demand quality, reliability, and innovative design from your gear, and we're here to help you find exactly what you need. We're glad to answer any questions you have and you can always depend on AudioDubai to give you the best possible value on musical instruments and accessories with responsive customer service.


text:
Tupelo Honey - Arlington
Beliebte Gerichte
Tupelo Shrimp & Grits
sustainable wild-caught gulf shrimp, peperonata, heirloom grits with goat cheese, chives, griddled lemon
14 Bewertungen
French Toast
whipped butter and powdered sugar
6 Bewertungen
Sweet Potato Pancakes
whipped butter and powdered sugar
5 Bewertungen
Excellent food options; hard to just pick one thing! Great spicy Bloody Mary too. Will definitely return next time I'm in the DC area!
Great place! We definitely plan to come back here frequently.
To start, I have had exceptional service here in the past and ordered takeout multiple times during COVID. We made a mid-afternoon reservation as a late lunch bon voyage to friends. I put in the notes that we would have people coming and going and asked to be seated close to the edge of the patio. This was done but upon arrival, the feted fans were greeted with gruffness to the point that when I arrived they joked not to expect kindness. We ordered cocktails and appetizers and then entrees. Upon ordering dessert, we were told our two hours were up, and we needed to finish quickly as another reservation would be arriving. I understand the business of this, but NOTHING was said as we placed order after order during our less than two hour time frame until the waitress forced us out. (We actually just thought that she wanted to close out the check and were utterly shocked.) I know there is a pandemic, but we were clear on our purpose for lunch and felt quite unappreciated and shocked at the abruptness especially given that we stood on the corner saying good-bye for almost a half hour and then drove by and no one was seated at the table. I don't mind timed sittings, but be up front if we need to rush.
The bourbon ban frozen drink was delicious! So we're my crispy brussel sprouts and chicken/avocado sandwhich. The service was normal but nothing to complain about!
Everything about Tupelo was great except for the fact that they messed up my reservation that I made a week prior. I went for my birthday, so I wanted everyone to be seated closer than we were. Other than that, everything down to the mimosas were great.
Food was wonderful as usual and service was great!
Service was great! They were able to accommodate us earlier than our reservation. Very friendly service and great food that came out quickly.
Took to clients/friends to brunch and TupeloHoney did an awesome job! Food was sophisticated and TASTY, service was great, the atmosphere was wonderful and we all felt safe indoors with the tables far apart.
Good place to have a date or just a quick drink with friends. Great
a quiet, ambient place to have a good lunch during the weekday
Outdoor seating is spaced out pretty well.
We always enjoy going to Tupelo. The food is good and service wonderful. Today's issue is food was not hot. We had to turn back soups and coffee. My dish was lukewarm, but I didn't bother with that.
The food was amazing! I had the sweet potato pancakes with fried chicken. My wife had the fried catfish with Mac and cheese and okra. Everything was great and reasonably priced. We also had the spicy cauliflower for a appetizer. Our tab was under $65 and the service was great!! I will definitely return whenever I'm in downtown Arlington.
Excellent food, good value, fast service, nice outdoor seating.
I love Tupelo Honey brunch. I had the 'Fit to be Tied' Benedict, and I died and went to heaven. So good!
Our table was ready when we got there. Our server was fantastic. She was prompt, courteous and knowledgeable. We ate outside due to covid. The appetizer of avicado toast arrived after our drinks and shortly after we finished our lunch arrived. Perfectly timed. I can't wait to try more menu items.
First Time at TupelWonderful service ... absolutely wonderful and perfectly cooked food. Mimosa's were on point.
Sat outside ... it was absolutely wonderful. Danielle greeted us with a smile and the young man that waited on us was very patient.
Eight of eight satisfied diners. Southern Cobb with fried chicken was the most popular choice with our group, followed by the avocado chicken sandwich.
The food was amazing and I will definitely recommend this restaurant to my friends & family.
Love the food here- always excellent! Ate outside which was ok given the pandemic....
The Sever was friendly and patient. It is a team environment. The team members chip in seamlessly. I enjoyed my time and the ambiance of the establishment. The coffee and mimosas were flowing and brunch options were bar none.
Went for the $2.50 smash burger special, burgers were raw, they'd probably been seared for 30 seconds, even the waiter was in shock when we showed him. Burgers were poorly assembled, some didn't have pickles, and others didn't have cheese even though we ordered standard ones.
Plates were dirty, eewww
The pecan pie was super sweet, If that's your thing you might like it.
Overall the experience was pretty subpar and a waste or time and money.
Great menu and variety to satisfy everyone. The staff is so welcoming.
Delicious food, super helpful & friendly server who went out of her way to accommodate an unusual request.
I go to Tupelo Honey often. It's a nice restaurant and a quick walk from my office. The service is ALWAYS great; wonderful wait staff who are friendly and do everything to make you happy. The food tends to be hit and miss. Today, my guest truly enjoyed his cheeseburger and fried okra, said it was delicious. I had the southern Cobb salad with salmon, and it was just OK. It was an average salad I could get at a chain restaurant, really nothing spectacular. In the past, I have had brunch here that was fantastic, fish that was overcooked, chicken that was too dry, delicious collard greens, fabulous mixed drinks. Like I said, hit and miss. I will still go to Tupelo Honey because, as I said, nice place and a quick walk from the office. Menu is varied enough to to have something on it for everyone.
Food was very good. More vegan menu items or at least be able to more easily modify veggie dishes into vegan would be nice. Service was excellent (Jessyca was our server)!
I really enjoyed their food and ambience. I highly recommend their Mac and cheese, and fried okra! For cocktails, I LOVED their eternal spring so much I ordered it twice. I had their speciality chicken and it was also good. As someone who doesn't like sweet stuff, their honey dust seasoning was alright but I would like to try their spicy version next!
Service started out really good, really like when you feel a server is honest about food and drink suggestions/preferences. Then petered out, perhaps a bit understaffed and bad timing. Apps were really good, then barely warm soup and side of sprouts with no taste and cob salad lacking something. Asked for soup to be warmed, seated outside cold fall night, server said something about microwave and not being able to bring back to the table. Customers don't care about that, just want hot food. She definitely seemed annoyed.
Extremely average
Everything we ordered was delicious! The spacing of the tables put us at ease . Will definitely be coming back
Happy hour is a great deal
This was the perfect place to go to get out after not being in a restaurant for months. The food was great, staff was kind and attentive and it was fun sitting outside! I already want to go back for some fried pickles!
Eat there every Sunday for brunch! Gotta love them biscuits and honey!!
This place was lovely! Our service was great and food/drinks were great too!
Great service and food.
Danielle was Amazing! Came in late but was able to accommodate us with a table!!
Everything was simply amazing! I have been wanting to visit Tupelo Honey for months! The food was delicious and the cocktails were delicious as well!! I'm definitely going back!!
Good food, especially the brunch menu. The expansive bar selection is perfect for a group outing.
Excellent!! I don't think my experience could be any better. Loved every thing from customer service to the outstanding food. This was my first time and i will definitely be back soon. The banana pudding is the best around!
Great food. Great speedy service. Definitely Recommend.
Sie können mit dem 'Online bestellen'-Button die Lieferung direkt bei Tupelo Honey - Arlington bestellen. Tupelo Honey - Arlington bietet Lieferungen auch in Partnerschaft mit Uber Eats an. Tupelo Honey - Arlington bietet auch Takeaways an, die Sie telefonisch beim Restaurant bestellen können: (703) 253-8140.
Tupelo Honey - Arlington wird von 1888 OpenTable‑Gästen mit 4.4 Sternen bewertet.
Ja, Sie können üblicherweise in diesem Restaurant reservieren, indem Sie auf OpenTable Datum, Uhrzeit und Personenzahl wählen. Aufgrund lokaler Einschränkungen nimmt dieses Restaurant derzeit möglicherweise keine Reservierungen entgegen.