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  1. 1. WRITING REQUIREMENTS OF EDITORIAL1 Title: Title should be less than 12 words.2 Running Title: A short running title of less than 6 words should be provided.3 Authorship: Authorship credit should be in accordance with the standard proposed byInternational Committee of Medical Journal Editors, based on (1) substantial contributions toconception and design, acquisition of data, or analysis and interpretation of data; (2) drafting thearticle or revising it critically for important intellectual content; and (3) final approval of the versionto be published. Authors should meet conditions 1, 2, and 3.4 Received: Fill out by S-editor; Revised: Fill out by S-editor; Accepted: Fill out by S-editor; Publishedonline: Fill out by E-editor.5 Abstract: An informative, structured abstracts of no more than 480 words should accompany eachmanuscript. Abstracts for original contributions should be structured into the following sections.AIM (no more than 20 words): Only the purpose should be included. Please write the aim as the formof “To investigate/study/…; MATERIALS AND METHODS (no more than 140 words); RESULTS(nomore than 294 words): You should present P value where necessary and must provide relevant datato illustrate how it is obtained, e.g. 6.92 ± 3.86 vs 3.61 ± 1.67, P < 0.001; CONCLUSION(no more than26 words).6 Keywords: Please list 5-10 key words for each manuscript, selected mainly from Index Medicus,which reflect the content of the study. Each key word is separated by a semicolon.7 Peer reviewer: Fill out by S-editor.8 Tables and illustrations: Each table or illustration should be made on a separate sheet and shouldbe “self-explanatory” (sufficient to be intelligible without reference to the text). Avoid repetitions ofdata in the text, tables, and illustration. Explain tersely the symbols, letters, or number used. Indicatethe number and character of observations and subjects. Identify statistical significance bysuperscripts in front of the probabilities (P), e.g. aP<0.05, bP<0.01 vs A; cP<0.05, dP<0.01 vs B; etc.8.1 Figures: You should provide decomposable figures with a size of 5 : 7 (height : width) in general. 1
  2. 2. The curves or straight lines should be clear. Freehand or typewritten lettering is unacceptable. Unitscan not be omitted. Combine related curves in a single figure when possible. A composite of curveswill save space and convey more information. Standard symbols (e.g. ○, ●, ×, □, ■, △, ▲) should beused when there are multiple curves.8.2 Photographs, Images and Legends8.2.1 The photographs supplied should be no smaller than 85 mm in height and 126 mm in width,and at a resolution of 300 dpi as TIFF format. The colour photos should be saved in TIFF format at aresolution of 300 dpi; each photo in a separate file, and no smaller than 86 mm × 50mm.8.2.2 Images submitted should be those which uniquely display the data. Figures are not limited, butmust be thoroughly justified. For figures that have multiple panels, the labels should be set inuppercase Helvetica or Arial letters and should not contain periods or parentheses. Please be sure toembed all fonts. Micrographs should be provided with a scale bar, if appropriate, instead ofmagnification. Figures should be should be either Photoshop or Illustrator files (in tiff, psd, eps, ai,pdf, or JPEG formats) at 300 dpi resolution (for a figure no smaller than 50 mm in height and 86 mmin width). Our professional in-house illustrator will work with authors to ensure the highest qualityand clarity of published figures. Please provide only one legend for each photo or figure that containsall the pertinent information. Figures or photos should be grouped according to their themes. Forexample, Figure 1 Pathological changes of atrophic gastritis tissue before and after treatment. A: …;B: …; C: …; D: …; E: …; F: …. Explain the symbols, arrows, numbers, or letters in the illustrations.Identify the method of staining and magnification of the photomicrographs (eg, HE stain, ×900). Forthose including methodology, the legend should be no more than 100 words (no more than 500words in total). For those not including methodology, the legend should be no more than 300 words(no more than 800 words in total). Letters in photos or figures should be lowercased while the firstone be capitalized. An interval should be inserted between numbers and units. Photos or figures thatare obtained at different time or places must not be grouped into one, unless those photos or figuresare arranged in a time order. There are intervals between photos or figures of the same group.Photographs or figures should be put in an independent file.8.2.3 Authors should list the names of tools they use to obtain and edit the image file. Images must beedited equally and contrast must be reasonable. Editing that is far beyond the contents is forbidden. 2
  3. 3. It is not allowed to over-emphasize the difference between experiment data and control data, or over-emphasize a certain part of the photos by ignoring some other parts. (A) Electrophoresis and blottingimages: must include negative, positive controls and molecular Marker; provide the reference of theidentified antibodies; explain the specificity and active spectrum of the agents not identified; bandshould be clear; important bands must not be deleted; leave six-band space around the blottingbands; we suggest not use high-contrast blotting, for over-display may conceal the other bands.Authors should try to exhibit the bands on the gray background. Black frame may be used if thebackground is weak. (B) Microscopic or endoscopic images: cells from different field must not be putin the same field; images should be adjusted at a whole; avoid pseudo-color and nonlinearadjustment (e.g. γ transformation), and give an explanation in the legend if necessary.8.3 Tables: A decomposable table is required. Each table should be put in an independent page, witha bold title no more than a row long. Tables should be put at the end of the article.9 References: Pleased provide PubMed citation numbers to the reference list, e.g. PMID and DOI,which can be found at http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed andhttp://www.crossref.org/SimpleTextQuery/, respectively. The numbers will be used in E-version ofthis journal. Thanks very much for your co-operation.10 S- Editor, L- Editor and E- Editor: Fill out by responsible person. 3
  4. 4. Format for EDITORIALMs. wjg/2009/000000 EDITORIALChanging face of irritable bowel syndromeQuigley EMM. Irritable bowel syndromeEamonn MM QuigleyEamonn MM Quigley, Alimentary Pharmabiotic Centre, Department of Medicine,Clinical Sciences Building, Cork University Hospital, IrelandAuthor contributions: Quigley EMM solely contributed to this paper.Supported by 4
  5. 5. Correspondence to: Eamonn MM Quigley, MD, FACG, Professor of Medicine andHuman Physiology, Head of the Medical School, National University of Ireland, Cork,Ireland. e.quigley@ucc.ieTelephone: +353-21-490-1228 Fax: +353-21-490-1289Received: Revised: Accepted: Published online:AbstractRecent years have witnessed tremendous progress in our understanding of irritablebowel syndrome (IBS). It is evident that this is a truly global disease associated withsignificant symptoms and impairments in personal and social functioning for afflictedindividuals. Advances in our understanding of gut flora-mucosal interactions, theenteric nervous system and the brain-gut axis have led to substantial progress in thepathogenesis of symptoms in IBS and have provided some hints towards the basicetiology of this disorder, in some subpopulations, at the very least. We look forward to atime when therapy will be addressed to pathophysiology and perhaps, even to primaryetiology. In the meantime, a model based on a primary role for intestinal inflammationserves to integrate the various strands, which contribute to the presentation of IBS. 5
  6. 6. © 2006 The WJG Press. All rights reserved.Key words: Irritable bowel syndrome; Functional gastrointestinal disease; IntestinalinflammationPeer reviewer:Quigley EMM. Changing face of irritable bowel syndrome. World J Gastroenterol2006 ;12(1):1-5Available from: URL: http://www.wjgnet.com/1007-9327/12/0000.aspDOI: http://dx.doi.org/10.3748/wjg.12.0000EPIDEMIOLOGYIn recent years, the true prevalence of irritable bowel syndrome (IBS) has beendocumented in many parts of the world. What is truly remarkable is how common IBSis, no matter where you look! It is absolutely clear, for example, that IBS is a commondisorder, not only in North America and Western Europe but throughout Asia and LatinAmerica and even in parts of Africa[1]. However, caution needs to be exerted in the 6
  7. 7. interpretation of such studies. Typically, community or hospital-based surveys of IBSprevalence have utilized some iteration of Rome or Manning criteria as their diagnosticinstrument; whether these diagnostic tools, developed in the West, are equally valid inemerging nations, where confusion with symptoms related to chronic parasiticinfestations, for example, may be an issue. Clearly, we have much to learn from theepidemiology and natural history of IBS or IBS-like symptoms in this context.DIAGNOSISDiagnostic confusion has also emerged as an issue in the West. Here, still the debatecontinues regarding potential overlap between IBS, inflammatory bowel disorders (IBD)and celiac sprue[2]. Do reported instances of celiac sprue among patients with “typical”IBS, or the occurrence of IBS-type symptoms among IBD patients in apparent remission,reflect a true association between these disorders and, thereby, the effects of low gradeinflammation on enteric nerve and muscle function, or does such apparent overlapsimply serve to emphasize the non-specificity of many gastrointestinal symptoms?Explaining it simply, the gut has a limited symptomatic repertoire which may not allowus to differentiate between those complaints which are consequent upon continuing (butotherwise undetected) inflammation in IBD or in the non-compliant celiac and thosewhich arise from a functional disorder, per se. Progress in this contentious area mustawait readily applicable measures of disease activity which are sufficiently sensitive andaccurate to provide a true definition of remission. In the meantime, how should the clinician interpret these dilemmas? It is evident, thatthe majority of celiacs now present later in life and usually with vague and non-specificgastrointestinal symptomatology; celiac disease must, therefore, be considered in all newIBS patients, especially in areas of high prevalence and regardless of the nature ofpresenting symptoms[3].ASSOCIATED DISEASES 7
  8. 8. Over the years, IBS has been associated with a wide variety of intestinal and extra-intestinal symptoms and syndromes. Recent community surveys have confirmed howfrequently IBS, functional dyspepsia (FD) and gastroesophageal reflux disease (and non-erosive reflux disease (NERD), in particular) overlap; a phenomenon that maycomplicate clinical trials as well as diagnostic and therapeutic strategies. My own beliefis that we should be “lumpers” and not “splitters” here; I contend that efforts to separateIBS from FD and NERD are clinically unrealistic and unhelpful. IBS has also beenassociated with a variety of psychological disorders; here, in contrast, the evidence for atrue association is less firm, more recent analyses suggest that the occurrence of suchsymptomatology in IBS is largely the preserve of those who seek further referral aloneand is not a feature of IBS in the community. Psychopathology should be viewed,therefore, not as a fundamental prerequisite for the development of IBS, but, rather, as aco-factor which, if present, will modify the individual’s response to IBSsymptomatology. IBS patients commonly complain of fatigue and tiredness; theseappear to be real entities in IBS, yet have been scarcely acknowledged in the assessmentof IBS activity or response to therapy. Urinary and gynecological symptoms are alsocommon; the basis for these associations is less clear. Aware of the prominence ofsmooth muscle hyper-reactivity in both conditions, parallels have been drawn betweenIBS and asthma; whether these conditions are linked remains to be defined.PATHOPHYSIOLOGYGenetic factorsWhile IBS patients commonly give a positive family history, the relative roles of“nature” and “nurture” in this intra-familial aggregation of functional disorders havereceived little attention. For example, in a recent community survey almost 20% of IBSsufferers reported abdominal symptoms in a first degree relative; a relative risk of 2.5 [4].Whether this association reflects reporting bias, shared environmental factors or a truegenetic basis has been addressed in two recent twin studies which both identified a 8
  9. 9. genetic component to IBS[5,6]. This is not the whole answer by any means; thus in thestudy by Levy and colleagues, while the concordance for IBS was twice as high inmonozygotic than in dizygotic twins (15.2% vs 6.7%), a history of IBS in a parent was amore potent predictor of IBS in a twin than was the presence of IBS in the other twin [6].These findings suggest a relatively minor role for genetic factors in the basicpathogenesis of IBS. Genetic factors may, however, influence disease expression andtherapeutic response, as evidenced by recent studies of G-protein subunit, IL-10, CCK-1receptor, alpha 2 adrenoceptor and serotonin transporter genotypes among IBSpatients[7-11]. These are complex studies but may pave the way for real progress in ourunderstanding of the true diversity of IBS [12].Gastrointestinal motor dysfunctionDysmotility has long been considered a major factor in the pathophysiology of IBS, asindicated by the use, in the past, of such terms as the “spastic colon” to describe what isnow referred to as IBS. Accordingly, it was suggested that gut spasm or other abnormalcontractile activities led to the development of symptoms in IBS. There are, indeed,several reports of abnormal motor patterns in many parts of the gastrointestinal tract inIBS. The specificity of many of these abnormalities for IBS is, however, unclear [13]. Incontrast, and of particular interest, are very recent observations on the handling of gasby the intestine in IBS[14,15]. Whereas gas infused into the small intestine was rapidlyevacuated through the gut in normal volunteers, a similar infusion resulted in gasretention, symptoms and an increase in abdominal girth in IBS patients [14]; all reversibleby administration of a prokinetic agent[15]. Distension, often the most distressing “gas”-related symptom in IBS, has, until recently, been assumed to represent a disturbance ofperception, as apparently objective tests of abdominal volume failed to detect anyincrease in IBS[16]. This assumption has now been questioned[17] and it may well come topass that more detailed studies of changes in distension over time[18] may detectsignificant diurnal variations in girth in IBS. While the balance of evidence suggests thatintestinal gas production is not abnormal in IBS, one can visualize how relatively local 9
  10. 10. changes in the gas content could lead to symptoms, given the aforementioned intrinsicabnormality of gas transport[19] and the hypersensitivity to intraluminal gas that areknown to occur in IBS[20].Visceral hypersensitivity and hyperalgesiaRecently, there has been considerable interest in these phenomena, not only in IBS, butalso in functional disorders, in general[7]. The phenomenon of visceral hypersensitivity,to distention and other intra-luminal stimuli, appears to be common in patients withnon-cardiac pain, FD and the irritable bowel, alike. Recently, it has been suggested thatvisceral hyperalgesia, the phenomenon whereby stimuli normally not experienced aspainful become so, is highly specific for IBS[21]. Visceral hypersensitivity, visceralhyperalgesia and viscero-somatic referral (the phenomenon whereby stimuli are referredover wide areas) have, indeed, been confirmed, in IBS, in more recent studies, using avariety of methodologies and under controlled experimental conditions[22]. Whilevisceral hyperalgesia has been postulated as being highly specific for IBS, it alone or inassociation with other manifestations of hypersensitivity cannot explain all of IBS; eventhe most celebrated enthusiasts for the sensory hypothesis concede that sensation isnormal in some patients. There are several possible anatomical locations for sensory abnormalities in IBS,ranging from sensory receptors on the gut wall, primary sensory afferent neurons, to thespinal cord and the brain itself. Research in this area in man is notoriously difficult;however, advances in functional brain imaging provided by such techniques as cerebralevoked potentials (CEP), positron emission tomography (PET),magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI),have provided insights into the brain’s response to visceral stimuli. These and otherstudies have advanced the concept of an abnormal (or hypervigilant) central nervoussystem (CNS), in IBS, which records an exaggerated, inappropriate or aberrantperception of visceral events[23]. Other pieces of evidence support this concept. These 10
  11. 11. include the conscious perception, by IBS patients, of intestinal motor events which areusually sub-conscious and evidence of abnormal psycho-neuro-hormonal responses,often implicating an abnormal hypothalamico-pituitary axis (HPA). Motility and sensation may not be the most fundamental causes of IBS; it is clear,however, that these phenomena play a significant role in symptom generation.Infection, inflammation, immunity and IBSIt may come as a real surprise to many to hear that infection and inflammation are nowseen as potential factors in the etiology of IBS. With regard to infection, we are nowbeginning to see the real data to directly support the concept of post-infective or post-dysenteric IBS.Infection and IBS: First reported by McKendrick and Read[24], the occurrence of IBSfollowing bacteriologically-confirmed gastroenteritis has now been documented inseveral studies[25-30]. The risk of developing IBS following an episode of gastroenteritis isin the order of 4%-23%, with females, those with a more severe initial illness and pre-morbid psychopathology being most at risk[25,26,28,30]. One of these studies went on toestablish a direct link between prior exposure to an infectious agent, persisting low-grade inflammation and IBS[28]. In this study, an increase in the number of chronicinflammatory cells in the rectal mucosa was seen only among those exposed patientswho had developed IBS. Others have demonstrated a persisting increase in rectalmucosal enteroendocrine cells, T lymphocytes and gut permeability in patients withpost-dysenteric IBS[29,30]. Post-infectious IBS may explain only a minority of cases of IBSbut does represent a clear link between exposure to an environmental agent,inflammation and IBS, in predisposed individuals[31].Inflammation and IBS: Direct and compelling evidence was first provided by Chadwick 11
  12. 12. and colleagues for a role of inflammation in IBS, in general. They evaluated 77 IBSpatients of whom 55% would be considered as diarrhea predominant; none had aconfirmed infectious origin for their IBS[32]. All had colonic biopsies taken forconventional histology and immunohistology. Thirty-eight had normal histology, 31demonstrated microscopic inflammation and 8 fulfilled the criteria for lymphocyticcolitis. However, in the group with “normal” histology, immunohistology revealedincreased intraepithelial lymphocytes as well as an increase in CD3+ and CD25+ cells inthe lamina propria; all, therefore, showed evidence of immune activation. These featureswere even more evident in the microscopic inflammation group who, in addition,revealed increased neutrophils, mast cells and natural killer cells. All of theseaforementioned immunopathological abnormalities were most evident in thelymphocytic colitis group who, alone, also demonstrated HLA-DR staining in crypts andincreased CD8+ cells in the lamina propria. Interestingly, taking the group of IBSpatients as a whole, CD3+ cell number was higher among those with diarrhea thanamong alternators or those with predominant constipation. In contrast, in the non-inflamed IBS group the presence of mast cells was a predictor of constipation.Surprisingly, given the aforementioned description of a direct relationship betweensymptoms and chronic inflammation among patients with post-infectious IBS, theseauthors did not find an association between either the nature of disease onset or diseaseduration and immunological findings. In an accompanying editorial, Collins suggestedthat the increased presence of CD25+ cells may have indicated “auto- or exogenousantigen challenge in these patients, and that the CD25+ cells are preventing theprogression to a more florid inflammatory response”[33]. That IBS patients may bepredisposed to an, albeit contained, inflammatory response to luminal triggers is alsosupported by the finding, of Gonsalkorale and colleagues, of a reduced frequency of thehigh-producer phenotype for the anti-inflammatory cytokine interleukin-10 (IL-10)among IBS patients[9]. A direct linkage between immune activation and symptoms hasbeen provided by the work of Barbara and colleagues who demonstrated, not only anincreased prevalence of mast cell degranulation in the colon in IBS, but also a direct 12
  13. 13. correlation between the proximity of mast cells to neuronal elements and painseverity[34]. While the inflammatory hypothesis in IBS is in its infancy, there is already someevidence for the extension of the inflammatory process beyond the confines of themucosal compartment. Tornblom and colleagues addressed this issue in ten patientswith severe IBS by examining full-thickness jejunal biopsies obtained at laparoscopy [35].In nine, they found low-grade infiltration of lymphocytes in the myenteric plexus; fourof these had an associated increase in intraepithelial lymphocytes and six demonstratedevidence of neuronal degeneration. Nine patients had longitudinal muscle hypertrophyand seven had abnormalities in the number and size of interstitial cells of Cajal.Interestingly, three of their patients reported an acute onset of their IBS; in two, possiblyprecipitated by gastroenteritis. The finding of intraepithelial lymphocytosis is consistentwith the reports of Chadwick and colleagues[32], in the colon and of Wahnschaffe andcolleagues, in the duodenum[36]. Most recently, in a group of 78 unselected IBS patients,we demonstrated, in peripheral blood mononuclear cells, an alteration in the ratiobetween the cytokines IL10 and IL12 which became skewed towards a Th1, pro-inflammatory profile[37]. With regard to the pathophysiology of the mucosal inflammatory changes, Spillerproposed that these changes could represent a response to an initial bacterial infectionamong individuals who are rendered susceptible by a relative deficiency of anti-inflammatory cytokines[38]. Alternately, could this low-grade inflammation representeither an abnormal reaction to the normal flora or a contained response to qualitative orquantitative changes in the intrinsic flora? Whether IBS is accompanied by quantitativeor qualitative changes in the bacterial flora of the small or large intestine remains acontentious issue; while some have described bacterial overgrowth in the smallintestine[39,40] and qualitative alterations in the fecal flora[41-43] and increased bacterialfermentation[44], in IBS, others have failed to replicate these findings[45]. The description ofefficacy for certain probiotics, and bifidobacterium, in particular, in IBS [37] could alsosupport a role of gut flora-mucosal interaction in IBS[46]. Bacterial overgrowth could also 13
  14. 14. explain some of the proposed overlap between IBS and celiac sprue[47].MANAGEMENTMany IBS patients relate the onset of symptoms to intake of food and often incriminatespecific food items. However, the role of food intolerance or food allergy in IBS hasremained undefined. While most would agree that there is scant evidence for classicalfood allergy in IBS, Whorwell and colleagues suggest that testing for food intolerance,utilizing IgG antibodies, can lead to a successful dietary modification regime[48]. In recent years, much interest has been generated by serotonin and the potential roleof serotonergic drugs in IBS[49]. Tegaserod, a 5HT4 agonist, is effective in the therapy offemale patients with constipation-predominant IBS and has demonstrated efficacyagainst some previously “resistant” symptoms, such as bloating[50,51]. Alosetron, a 5HT3agonist, is effective in females with diarrhea-predominant IBS, but its prescription isnow limited due to reports on ischemic colitis[52]. Cilansetron, a 5HT3 agonist, is effectivein both males and females with diarrhea-predominant IBS[53]; here the specter of ischemiccolitis has again become an issue with regulators, in the US. Indeed, ischemic colitis hasbecome an issue for all of these agents, though it appears that many reports ofassociation probably reflect diagnostic confusion ab initio between IBS and ischemiccolitis rather than an effect of serotonergic agents, per se[54]. Given the explosion that has occurred in our understanding of the enteric nervoussystem, and of the pathways that link it to the CNS, it should come as no surprise thatmany agonists and antagonists of other putative neurotransmitters andneuromodulators are under study in IBS and related disorders. Given the potential role of infection and inflammation in at least some instances ofIBS, efforts have been made to address this aspect of pathophysiology in IBS. In thisregard, a probiotic, bifidobacterium infantis has proved to be a very successful agent inunselected IBS patients[37]. Clearly, this is an area of increasing interest. 14
  15. 15. CONCLUSIONOur understanding of IBS has come a long way. This is a global disease associated withsignificant symptoms and impairments in personal and social functioning for afflictedindividuals. Advances in our understanding of gut flora-mucosal interactions, theenteric nervous system and the brain-gut axis have led to substantial progress in thepathogenesis of symptoms in IBS and have provided some hints towards the basicetiology of this disorder, in some subpopulations, at the very least. We look forward to atime when therapy will be addressed to pathophysiology and, perhaps, even to primaryetiology. In the meantime, as illustrated in Figure 1, I would suggest that a model basedon a primary role for intestinal inflammation serves to integrate the various strandswhich contribute to the presentation of IBS. 15
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  20. 20. PMID:1575739454 Walker AM, Bohn RL, Cali C, Cook SF, Ajene AN, Sands BE. Risk factors for colon ischemia. Am J Gastroenterol 2004; 99: 1333-1337 doi:10.1111/j.1572-0241.2004.21436.x PMID:15233674 S-Editor L-Editor E-Editor Psyche Environmental stress Abnormal perception Dysmotility Infection Visceral hypersensitivity 20
  21. 21. Inflammation Abnormal flora Normal floraFigure 1 Interactions between the gut, the brain and the external and internalenvironments in IBS; the Iinflammation hypothesis (a personal view). Bacterial orviral infection, a disturbed flora or an abnormal response to a normal flora leads tomucosal Iinflammation which in turn can disrupt motility and augment visceralsensation. Centrally, perception is abnormal, thereby, contributing to symptomdevelopment. Central output can in turn influence motor events in the periphery.While not central to causation, psychological factors, either spontaneously or inresponse to environmental stressors, can influence motor and sensory events andimmune activity in the gut. 21