超声介导美沙拉嗪肠溶片靶向递送技术对溃疡性结肠炎合并肛肠疾病抗感染的研究

目的:观察超声介导药物靶向递送技术直肠导入美沙拉嗪,结合肛肠疾病手术术后局部换药,治疗轻度、中度溃疡性结肠炎(UC)合并肛肠疾病的临床疗效。方法:选择经内镜检查临床确诊的轻度、中度UC合并肛肠疾病患者200例,随机分为治疗组合和对照组,各100例。治疗组:术后第1天开始,在术后切口常规护理、消毒、局部手术切口换药的基础上,予美沙拉嗪超声介导药物靶向递送技术直肠导入,每日1次,每次30min。对照组:术后第1天开始,在术后切口常规护理、消毒、局部手术切口换药的基础上,予美沙拉嗪口服,疗程均为8周。观察两组患者的总有效率。收集患者治疗前后血清,分别检测CRP、PCT、ESR水平。术中取新鲜的感染组织,避免采集浅表的组织碎屑,术后20d观察创面愈合情况,取创面肉芽组织,行HE染色,及HE染色和免疫组化检测两组患者治疗后组织中CD68、溶菌酶Lyn、血管内皮生长因子VEGF、成纤维细胞生长因子SMA在切口肉芽组织中的表达。结果:治疗组和对照组总有效率为(90%vs80%P<0.05),有统计学差异显著;术后8周治疗组血清CRP、PCT、ESR明显低于对照组,差异有统计学意义(P<0.05);两组切口肉芽组织中CD68、溶菌酶Lyn、血管内皮生长因子VEGF、成纤维细胞生长因子SMA均表达阳性,其中治疗组CD68、VEGF、SMA在切口肉芽组织中阳性细胞率均明显高于对照组,差异有统计学意义(P<0.05)。结论:超声介导药物靶向递送技术直肠导入美沙拉嗪结合肛肠疾病手术术后局部换药治疗轻度、中度溃疡性结肠炎(UC)合并肛肠疾病较单用美沙拉嗪口服结合肛肠疾病手术术后局部换药能更好地改善患者的临床症状,具有更好的临床疗效。

Roles of histamine and its receptors in allergic and inflammatory bowel diseases

Mast cell has a long history of being recognized as an important mediator-secreting cell in allergic diseases, and has been discovered to be involved in IBD in last two decades. Histamine is a major mediator in allergic diseases, and has multiple effects that are mediated by specific surface receptors on target cells. Four types of histamine receptors have now been recognized pharmacologically and the first three are located in the gut. The ability of histamine receptor antagonists to inhibit mast cell degranulation suggests that they might be developed as a group of mast cell stabilizers. Recently, a series of experiments with dispersed colon mast cells suggested that there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. In a word, histamine is an important mediator in allergic diseases and IBD, its antagonists may be developed as a group of mast cell stabilizers to treat these diseases.

Extraintestinal manifestations of inflammatory bowel disease:Do they influence treatment and outcome?

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases that often involve organs other than those of the gastrointestinal tract. Immune-related extraintestinal manifestations (EIMs) are usually related to disease activity, but sometimes may take an independent course. Globally, about one third of patients develop these systemic manifestations. Phenotypic classification shows that certain subsets of patients are more susceptible to developing EIMs, which frequently occur simultaneously in the same patient overlapping joints, skin, mouth, and eyes. The clinical spectrum of these manifestations varies from mild transitory to very severe lesions, sometimes more incapacitating than the intestinal disease itself. The great majority of these EIMs accompany the activity of intestinal disease and patients run a higher risk of a severe clinical course. For most of the inflammatory EIMs, the primary therapeutic target remains the bowel. Early aggressive therapy can minimize severe complications and maintenance treatment has the potential to prevent some devastating consequences.

Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk

AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies. METHODS: DNA samples from 388 patients with Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor: -238 G→A, -308 G→A and -857C→T, using a TaqmanR assay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies. RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, χ2 = 17.36, P < 0.0001) increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, χ2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variant decreased the risk of ileocolonic CD (OR = 0.56, χ2 =4.32, P = 0.037), and the need for a bowel resection (OR = 0.59, χ2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis, (OR = 0.48, χ2 = 4.86, P = 0.028). CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The -857 C/T SNP may decrease IBD risk in certain groups. Pharmaco- or nutrigenomic approaches may be desir- able for individuals with such affected genotypes.

Intestinal inflammation and colorectal cancer:A doubleedged sword?

Chronic inflammation is thought to be the leading cause of many human cancers including colorectal cancer(CRC).Accordingly,epidemiologic and clinical studies indicate that patients affected by ulcerative colitis and Crohn's disease,the two major forms of inflammatory bowel disease,have an increased risk of developing CRC.In recent years,the role of immune cells and their products have been shown to be pivotal in initiation and progression of colitis-associated CRC.On the other hand,activation of the immune system has been shown to cause dysplastic cell elimination and cancer suppression in other settings.Clinical and experimental data herein reviewed,while confirming chronic inflammation as a risk factor for colon carcinogenesis,do not completely rule out the possibility that under certain conditions the chronic activation of the mucosal immune system might protect from colonic dysplasia.

Severe ulcerative colitis: At what point should we define resistance to steroids?

Corticoesteroids are still the first-line treatment for active ulcerative colitis more than 50 years after the publication of trials assessing their beneficial effect, with about a 50% remission rate in cases of severe disease. The mortality related to severe attacks of ulcerative colitis has decreased dramatically, to less than 1%, in experienced centers, due to the appropriate use of intensive therapeutic measures (intravenous steroids, fluids and electrolytes, artificial nutritional support, antibiotics, etc), along with timely decision-making about second-line medical therapy and early identification of patients requiring colectomy. One of the most difficult decisions in the management of severe ulcerative colitis is knowing for how long corticosteroids should be administered before deciding that a patient is a non-responder. Studies assessing the outcome of acute attacks after steroid initiation have demonstrated that, in steroid-sensitive patients, the response generally occurs early on, in the first days of treatment. Different indexes to predict treatment failure, when applied on the third day of treatment, have demonstrated a high positive predictive value for colectomy. In contrast to this resolute approach, which is the most widely accepted, other authors have suggested that in some patients a completeand prolonged response to steroids may take longer. Either way, physicians taking care of these patients need to recognize that severe ulcerative colitis may be life-threatening, and they need to be careful with excessively prolonged medical treatment and delayed surgery.

Chronic fatigue is associated with increased disease-related worries and concerns in inflammatory bowel disease

AIM:To investigate the impact of chronic fatigue on disease-related worries in inflammatory bowel disease (IBD) and the potential multicolinearity between subjective questionnaires.METHODS:Patients in remission or with mild-tomoderate disease activity completed the fatigue questionnaire (FQ),the rating form of IBD patient concerns (RFIPC),the Short-Form 36 (SF-36),and IBD questionnaire (N-IBDQ).In addition,clinical and epidemiological data were obtained.RESULTS:In total,140 patients were included;of which 92 were diagnosed with ulcerative colitis and 48 with Crohn's disease.The mean age of patients with chronic fatigue was 44.2 years (SD=15.8) and for non-fatigued patients was 44.7 years (SD=16.0).Chronic fatigued patients had clinically significantly increased levels of disease-related worries,as measured by Cohen's d effect size.Worries about having an ostomy bag,loss of bowel control,and energy levels were most prominent in both chronic fatigued and non-chronic fatigued IBD patients.Variance inflation factor (VIF) and tolerance indicated that there were no problematic multicolinearity among the FQ,RFIPC,SF-36 and N-IBDQ responses (VIF < 5 and tolerance > 2).CONCLUSION:Chronic fatigue is associated with increased levels of disease-related worries and concerns in IBD.Increased levels of worries were also associated with impaired health-related quality of life.

Family and twin studies in inflammatory bowel disease

Studies examining the inheritance of inflammatory bowel disease （IBD） within different family groups have been the basis for recent molecular advances in the genetics of IBD. The derived heritability in Crohn＇s disease （CD） is higher than in many other complex diseases. The risk of IBD is highest in first-degree relatives of a CD proband, but first-degree relatives of a proband suffering from ulcerative colitis （UC） and more distant relatives are also at increased risk. Disease concordance rates in IBD have been examined in multiplex families and in three large European twin studies.

Rectal administration of d-alpha tocopherol for active ulcerative colitis:A preliminary report

AIM: To investigate the anti-oxidant and anti-neutrophil recruitment effects of rectal d-alpha (d-α) tocopherol administration on mild and moderately active ulcerative colitis (UC). METHODS: Fifteen patients with mild and moderately active ulcerative colitis were enrolled in an open-label study of d-α tocopherol enema (8000 U/d) for 12 wk. All patients were receiving concomitant therapy with 5-aminosalicylic acid derivatives (5-ASA) and/or immunomodulator medications. Endoscopic evaluation was performed at baseline and after 4th and 12th weeks. Disease activity was measured with the Mayo disease activity index (DAI) and remission was defined as DAI of ≤ 2 with no blood in stool. Clinical response was defined as a DAI reduction of ≥ 2. RESULTS: At the end of 12th week,the average DAI score significantly decreased compared to the beginning of the study (2.3 ± 0.37 vs 8 ± 0.48,P < 0.0001). One patient was withdrawn after 3 wk for being unavailable to follow-up. On the 4th week of therapy,12 patients showed clinical response,3 of whom (21.4%) achieving remission. After 12 wk,all 14 patients responded clinically to the therapy and remission was induced in 9 of them (64%). No patient reported adverse events or was hospitalized due to worsened disease activity. CONCLUSION: This preliminary report suggests that rectal d-α tocopherol may represent a novel therapy for mild and moderately active UC. The observed results might be due to the anti-inflammatory and anti-oxidative properties of vitamin E.

Management of inflammatory bowel disease in the pregnant patient

Inflammatory bowel disease (IBD) is a chronic disorder affecting young adults in their reproductive years. Many young women with IBD express concern about the effect their disease will have on fertility, pregnancy course and fetal development. This article presents an approach to management of IBD in the pregnant patient, including counseling and investigation, and summarizes existing data on the safety of medications used to treat IBD in pregnancy and breastfeeding.

Diaphragm disease compared with cryptogenic multifocal ulcerous stenosing enteritis

As the use of drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) increases,so too do gastrointestinal ulcers,bleeding,perforation and obstruction.Diaphragm disease of the small intestine is formed by submucosal fibrosis and destruction of lamina muscularis due to chronic ulceration,which corresponds to the most severe stage of NSAID enteropathy.It may lead to stricture of the small intestine.If such ulcerations and strictures in the small intestine are multiple,differential diagnosis is between diaphragm disease and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE),because the gross findings of diaphragm disease are similar to those of CMUSE.We report a rare case of diaphragm disease caused by NSAID.It has been finally confirmed by capsule endoscopy and the origin of chronic obscure gastrointestinal bleeding was found to be multiple ulcers and strictures in the small intestine.After operation,we diagnosed the patient with diaphragm disease rather than CMUSE.

Fulminant ulcerative colitis associated with steroid-resistant minimal change disease and psoriasis: A case report

A 43-year-old Chinese patient with a history of psoriasis developed fulminant ulcerative colitis after immunosuppressive therapy for steroid-resistant minimal change disease was stopped. Minimal change disease in association with inflammatory bowel disease is a rare condition. We here report a case showing an association between ulcerative colitis, minimal change disease, and psoriasis. The possible pathological link between 3 diseases is discussed.

Venous thromboembolism with inflammatory bowel disease

Venous thrombosis and thromboembolism appear to be increased in patients with inflammatory bowel disease. Although several acquired and genetic risk factors are known, about half that develop a thromboembolic event have no identifiable risk factor. Control of the inflammatory process is thought to be the key factor in risk reduction for thrombotic events. Prophylactic use of anticoagulants is not universally recommended, but possible use should be reviewed in an individual patient after evaluation of the risks, such as hemorrhage, compared to potential benefits. Particular consideration should be given if there has been a prior thrombotic event, if hospitalization will require surgery, or if an underlying coagulation disorder is present.

Defensin expression in chronic pouchitis in patients with ulcerative colitis or familial adenomatous polyposis coli

AIM. Pouchitis develops in ileoanal pouches in up to 50% of patients with ulcerative colitis during the first 10 years after pouch surgery while being rare in patients after proctocolectomy for familial adenomatous polyposis coil （FAP） syndrome. Defensins are major components of the innate immune system and play a significant role in gastrointestinal microbial homeostasis. Pouch defensin and cytokine expression were correlated with states of pouch inflammation to study their role in pouchitis.METHODS： Patients with ulcerative colitis and FAP syndrome were stratified into groups with pouches after surgery, pouches without or with pouchitis. Biopsies from terminal ileum from a healthy intestine or from normal terminal ileum of patients with ulcerative colitis served as controls, mRNA from pouches and controls was analysed for defensin and cytokine expression.RESULTS： Expression of defensins was increased in all pouches immediately after surgery, compared to ileum of controls. Initially, pouches in ulcerative colitis revealed higher defensin expression than FAP pouches. Defensin expression declined in both patient groups and increased again slightly in pouchitis in patients with ulcerative colitis. FAP pouches without pouchitis had strong expression of β-defensin hBD-1, while all other defensins remained at low levels. Cytokine expression in ulcerative colitis pouches was high, while FAP pouches showed moderately elevated cytokines only after surgery.CONCLUSION： Development of pouchitis correlates with decreased defensin expression in ulcerative colitis in addition to high expression of cytokines. The low incidence of pouchitis in FAP pouches correlates with increased expression of hBD-1 β- defensin in association with low cytokine levels.

Propionyl-L-carnitine hydrochloride for treatment of mild to moderate colonic inflammatory bowel diseases

AIM:To assess clinical and endoscopic response to propionyl-L-carnitine hydrochloride(PLC) in colonic inflammatory bowel disease.METHODS:Patients suffering from mild to moderate ulcerative colitis(UC) or Crohn's disease(CD) colitis,with disease activity index(DAI) between 3 and 10 and under stable therapy with oral aminosalicylates,mercaptopurine or azathioprine,for at least 8 wk prior to baseline assessments,were considered suitable for enrollment.Fourteen patients were enrolled to assume PLC 2 g/d(two active tablets twice daily) orally.Clinical-endoscopic and histological activity were assessed by DAI and histological index(HI),respectively,following a colonoscopy performed immediately before and after 4 wk treatment.Clinical response was defined as a lowering of at least 3 points in DAI and clinical remission as a DAI score ≤ 2.Histological response was defined as an improvement of HI of at least 1 point.We used median values for the analysis.Differences pre-and post-treatment were analyzed by Wilcoxon signed rank test.RESULTS:All patients enrolled completed the study.One patient,despite medical advice,took deflazacort 5 d before follow-up colonoscopy examination.No side effects were reported by patients during the trial.After treatment,71%(SE 12%) of patients achieved clinical response,while 64%(SE 13%) obtained remission.Separating UC from CD patients,we observed a clinical response in 60%(SE 16%) and 100%,respectively.Furthermore 60%(SE 16%) of UC patients and 75%(SE 25%) of CD patients were in clinical remission after therapy.The median DAI was 7 [interquartile range(IQR):4-8] before treatment and decreased to 2(IQR:1-3)(P < 0.01) after treatment.Only patients with UC showed a significant reduction of DAI,from a median 6.5(IQR:4-9) before treatment to 2(IQR:1-3) after treatment(P < 0.01).Conversely,in CD patients,although displaying a clear reduction of DAI from 7(IQR:5.5-7.5) before therapy to 1.5(IQR:0.5-2.5) after therapy,differences observed were not significant(P = 0.06).Seventy-nine percent(SE 11%) of patients showed improvement of HI of at least 1 point,while only one CD and two UC patients showed HI stability;none showed HI worsening.Median HI decreased from 1(IQR:1-2),to 0.5(IQR:0-1) at the endoscopic control in the whole population(P < 0.01),while it changed from 1(IQR:1-2) to 0.5(IQR:0-1) in UC patients(P < 0.01) and from 1.5(IQR:1-2) to 0.5(IQR:0-1) in CD patients(P = not significant).The two sample tests of proportions showed no significant differences in clinical and histological response or in clinical remission between UC and CD patients.No side effects were reported during treatment or at 4 wk follow-up visit.CONCLUSION:PLC improves endoscopic and histological activity of mild to moderate UC.Further studies are required to evaluate PLC efficacy in colonic CD patients.

Role of Smad7 in inflammatory bowel diseases

Crohn's disease and ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in man,are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora.There is also evidence that the pathologic process is due to defects in counterregulatory mechanisms,such as those involving the immunosuppressive cytokine transforming growth factor(TGF)-1.Indeed,studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-1 signalling marked by a block in the phosphorylation of Smad3,a signalling molecule associated with the activated TGF-receptor,due to up-regulation of Smad7,an intracellular inhibitor of Smad3 phosphorylation.Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-1/Smad3 signalling,thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis.These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotidebased pharmaceutical compound that is now ready to enter the clinics.In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD.

Prevalence,predictors,and clinical consequences of medical adherence in IBD:How to improve it?

Inflammatory bowel diseases(IBD)are chronic diseases with a relapsing-remitting disease course necessitating lifelong treatment.However,non-adherence has been reported in over 40%of patients,especially those in remission taking maintenance therapies for IBD. The economical impact of non-adherence to medical therapy including absenteeism,hospitalization risk, and the health care costs in chronic conditions,is enormous.The causes of medication non-adherence are complex,where the patient-doctor relationship, treatment regimen,and other disease-related factors play key roles.Moreover,subjective assessment might underestimate adherence.Poor adherence may result in more frequent relapses,a disabling disease course, in ulcerative colitis,and an increased risk for colorectal cancer.Improving medication adherence in patients is an important challenge for physicians.Understanding the different patient types,the reasons given by patients for non-adherence,simpler and more convenient dosage regimens,dynamic communication within the health care team,a self-management package incorporating enhanced patient education and physician-patient interaction,and identifying the predictors of nonadherence will help devise suitable plans to optimize patient adherence.This editorial summarizes the available literature on frequency,predictors,clinical consequences,and strategies for improving medical adherence in patients with IBD.

Current treatment of ulcerative colitis

Ulcerative colitis (UC) is a chronic disease featuring re- current inflammation of the colonic mucosa. The goal of medical treatment is to rapidly induce a steroid-free remission while at the same time preventing complica- tions of the disease itself and its treatment. The choice of treatment depends on severity, localization and the course of the disease. For proctitis, topical therapy with 5-aminosalicylic acid (5-ASA) compounds is used. More extensive or severe disease should be treated with oral and local 5-ASA compounds and corticosteroids to induce remission. Patients who do not respond to this treatment require hospitalization. Intravenous steroids or, when refractory, calcineurin inhibitors (cyclosporine, tacrolimus), tumor necrosis factor-α antibodies (infliximab) or immunomodulators (azathioprine, 6-mercaptopurine) are then called for. Indications for emergency surgery include refractory toxic megacolon, perforation, and continuous severe colorectal bleeding. Close collaboration between gastroenterologist and surgeon is mandatory in order not to delay surgical therapy when needed. This article is intended to give a general, practice-orientated overview of the key issues in ulcerative colitis treatment. Recommendations are based on published consensus guidelines derived from national and international guidelines on the treatment of ulcerative colitis.

Clinical,serological and genetic predictors of inflammatory bowel disease course

Patients with extensive or complicated Crohn's disease(CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines.In patients with localized and uncomplicated CD at diagnosis,early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact.In this context,there is a need for predictors of benign or unfavourable subsequent clinical course,in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions.At diagnosis,an age below 40 years,the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course.The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts.Consequently,the use of these predictors can be integrated into the elements that influence individual decisions.In the CD postoperative context,keeping smoking and history of prior resection are the stron-gest predictors of disease symptomatic recurrence.However,these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice.In ulcerative colitis(UC),extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease,and also with long-term colectomy and colorectal inflammation-associated colorectal cancer.In patients with extensive UC at diagnosis,a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered.At the moment,no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.

Value of colonoscopy for prediction of prognosis in patients with ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by exacerbations and remissions. Some UC patients remain refractory to conventional medical treatment while, in others, the effectiveness of drugs is limited by side-effects. Recently, cyclosporine and leukocyte removal therapy have been used for refractory UC patients. To predict the efficacy of these therapies is important for appropriate selection of treatment options and for preparation for colectomy. Endoscopy is the cornerstone for diagnosis and evaluation of UC. Endoscopic parameters in patients with severe or refractory UC may predict a clinical response to therapies, such as cyclosporine or leukocyte removal therapy. As for the patients with quiescent UC, relapse of UC is difficult to predict by routine colonoscopy. Even when routine colonoscopy suggests remission and a normal mucosal appearance, microscopic abnormalities may persist and relapse may occur later. To more accurately identify disease activity and to predict exacerbations in UC patients with clinically inactive disease is important for deciding whether medical treatment should be maintained. Magnifying colonoscopy is useful for the evaluation of disease activity and for predicting relapse in patients with UC.