尿胰蛋白酶抑制剂对鼠溃疡性结肠炎结肠组织中蛋白酶活性的抑制作用

目的 :确定尿胰蛋白酶抑制剂 (UTI)对鼠溃疡性结肠炎 (UC)结肠组织中蛋白酶的作用。方法 :用 18%的DNBS乙醇溶液 0 .2 5ml灌肠 ,在Wistar大鼠上建立UC模型 ;经尾静脉注射UTI ;用明胶酶谱法测定病变结肠组织中的蛋白酶活性。结果 :经UTI处理后 ,鼠UC结肠组织中蛋白酶活性仅为对照组的 1/3。结论 :UTI能显著降低鼠UC结肠组织中蛋白酶活性。

中医综合治疗方案治疗溃疡性结肠炎的临床疗效分析

目的观察中医综合治理方案治疗溃肠性结肠炎的临床效果。方法对来我院就诊的50例溃肠性结肠炎患者随机分为治疗组和观察组进行治疗,其中治疗组主要采用中医综合治疗方案进行治疗,对照组采用西医治疗方案进行治疗。结果通过临床治疗可以得出:中医综合治疗方案与西医治疗两组治疗效果均比治疗前有明显的改善;中医综合治疗有效率达到93.3%,而西医治疗的有效率达到85.0%,中医综合治疗方案优于西医治疗方案,差异有统计学意义(P<0.05),中医综合治疗比西医治疗效果显著。结论中医综合治疗方案治疗溃肠性结肠炎临床疗效显著。

中医综合治疗溃疡性结肠炎随机对照临床研究

[目的]探讨中医综合治疗溃肠性结肠炎临床效果。[方法]对我院2008年2月至2010年10月共收治60例溃肠性结肠炎患者,随机分为治疗组和对照组,每组30例。治疗组采用中医综合治疗,对照组采用西药治疗,治疗2个疗程进行判定疗效。[结果]治疗组总有效率93.33%,对照组总有效率83.33%,治疗组临床疗效优于对照组(P<0.05)。[结论]中医综合治疗溃疡性结肠炎效果显著,值得临床推广使用。

Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases

Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.

Effect of Berberine Chloride on Experimental Murine Colitis Induced by Dextran Sulfate Sodium

Aim To investigate the effect in berberine chloride （BER） on experimental ulcerative colitis in mice. Methods BALB/C mice in 6 groups were allowed to drink either 4% dextran sulfate sodium （DSS） solution or distilled water freely with different doses of BER （15 mg·kg^-1, 45 mg·kg^-1, 150 mg·kg^-1） or sallcylazosulfapyridine （SASP, 520 mg·kg^-1）, and solvent （0. 2 mL/10 mg Wt） once a day for 7 d, respectively. The symptom of ulcerative colitis was evaluated by disease activity index （DAI）. Myeloperoxidase （MPO） and superoxide dismutase （SOD） activities and malondialdehyde （MDA） content were determined by HE staining and immunohistochemistry of expressions of NF-κB p65 and intercellular adhesion molecule 1 （ ICAM-1 ） proteins to observe the damage to colon tissues and possible mechanisms. Results DAI, MPO activity, MDA content and expressions of ICAM-1 and NF-κB p65 were markedly increased, while SOD activity decreased in DSS-treated mice. Treatment of mice with different doses of BER or SASP significantly decreased DAI, MPO activity and MDA content, improved histological changes of colon tissues, blunted the expressions of NF-κB p65 and ICAM-1 proteins, and enhanced SOD activity. Conclusion Berberine chloride has excellent therapeutic effect on ulcerative colitis caused by DSS in mice. The possible mechanism may be related to its antioxidant and anti-inflammatory activities associated with inhibiting the NF-κB activation and ICAM-1 expression.

Study on TCM syndrome-typing of chronic ulcerative colitis

AIMS To study the relationship between the modern clinical and pathohistological classification and TCM Syndrome-Typing of chronic ulcerative colitis (CUC). METHODS Totally 452 patients with CUC were clas- sified according to the standards of TCM Syndrome- Typing set up in the Conference of the Combination of the Chinese-Western Medicine on Digestive Diseases in Linfen. The relevant changes between both classifica- tions were analyzed and compared through the colonofiberscopic and pathohistological examination. RESULTS The type of retention of damp-heat in inte- rior is more commonly seen in the patients with initial onset of disease (P<0.01). There is no significant difference among other TCM Syndrome-Typing groups in patients with chronic persistent and recurrent disease (P>0.05). The congestion,edema,reduction of goblet cells and the infiltration of neutrophils are patho- logically common to all TCM Syndrome-Typing groups. Mucosal ulcer is dominant in damp-heat syndrome while crypt ulcer is dominant in the types of spleen-stomach asthenia and spleen-kidney Yang deficiency (P< 0.01). CONCLUSIONS There appears a certain relation- ship between the TCM syndrome typing and pathohis- tological changes of the colonal mucosa of CUC.

Effects of four regulating-intestine prescriptions on pathology and ultrastructure of colon tissue in rats with ulcerative colitis

AIM: To observe different histomorphologic changes of ulcerative colitis (UC) rats that were treated with four regulating-intestine prescriptions (FRIP), to investigate the curative effects of FRIP and to analyze their treatment mechanism.METHODS: The UC rat model was made by the method of 2,4-dinitro chloro benzene (DNCB) immunity and acetic acid local enema. Ninety-eight SD rats were randomly divided into seven groups, namely, the normal control group, model group, salicylazosulfapyridine (SASP) group,Wumeiwan (WMW) group, Baitouwengtang (BTWT) group,Senglingbaishusan (SLBSS) group, and Tongxieyaofang (TXYF) group. Each group had 14 rats (with equal ratio of male and female). The six animal model groups of UC-SASP, TXYF, WMW, BTWT, SLBSS, TXYF-were treated by distilled water except the normal control group. Changes of the rat's general conditions after treatment were respectively observed, the colon tissue damage scores were given out, the pathology of colonic mucosa and changes of ultrastructure were analyzed.RESULTS: Different pathological changes on histology were shown after treatment by FRIP. The colon tissue damage score in model group was higher than that of FRIP groups and SASP group (q = 4.59, 4.77, P＜0.05 or q = 5.48,6.25, 5.97, P＜0.01). The scores of WMW group, BTWT group and SLBSS group were lower than that of SASP (q = 4.13, P＜0.05 or q = 5.31, 5.12, P＜0.01). There was no remarkable difference between the damage score of TXYF group and SASP group (q = 3.75, P＞0.05). In addition, some apoptosis cells were found in the pathologic control group.CONCLUSION: The model made with DNCB and acetic acid was successful, and FRIP had better curative effect and WMW was the best curative effect, BTW, SLBSS and TXYF were similar to SASP, and we discovered that apoptosis was possibly related to UC.

Effect of smoking on inflammatory bowel disease: Is it disease or organ specific?

Smoking is an important environmental factor in inflammatory bowel disease （IBD） with differing effects in ulcerative colitis （UC） and Crohn＇s disease （CD）. Never smoking and formerly smoking increase the risk of UC, whereas smoking exacerbates the course of CD. The potential mechanisms involved in this dual relationship are yet unknown. A reasonable assumption is that smoking has different effects on the small and large intestine. This assumption is based on animal and human studies that show that the effects of smoking/nicotine on CD and UC depend on the site of inflammation and not on the type of disease.

Aquaporin-8 expression is reduced in ileum and induced in colon of patients with ulcerative colitis

AIM： To study susceptibility genes which may play a potential role in the pathogenesis and etiology of inflammatory bowel disease （IBD）. METHODS： To identify potential susceptibility genes we performed global gene expression profiling in patients with IBD and control specimens. For determination of an intrinsic gene expression profile in ulcerative colitis （UC） and Crohn＇s disease （CD） compared to normal subjects, mucosal biopsies of non-inflamed regions of the colon and the terminal ileum were subjected to DNA microarray analysis. Real-time RT-PCR and immunohistochemistry were used for verification of selected regulated candidate genes and a genetic analysis was performed. RESULTS： We could show that aquaporin-8 （AQP8） mRNA and protein levels were significantly increased in the colon of UC patients compared to controls. Genetic analysis of the six exons and the promoter region of AQPS, however, revealed no mutations or polymorphisms in IBD patients. CONCLUSION： Our results suggest that upregulation of AQP8 in the colon of UC patients represents a secondary phenomenon which may, due to altered water exchange of the distal intestinal mucosa, disturb the physiologic colonic mucus barrier and thus lead to chronic inflao mmation and ulceration.

Treatment of inflammatory bowel disease:A review of medical therapy

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.

Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis

Ulcerative colitis （UC） and Crohn＇s disease （CD） are the major forms of idiopathic inflammatory bowel disease （IBD）. Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor （TNF）-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin （IL）-Iβ, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages （GH） are major sources. Further, in IBD, peripheral GHs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GH by receptor-mediated adsorption （GHA）. Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid nai＇ve patients （the best responders）, GHA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GHA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.

Maintenance of remission with infliximab in inflammatory bowel disease: Effi cacy and safety long-term follow-up

AIM: To evaluate the safety and efficacy of a long- term therapy with infliximab in Crohn’s disease (CD) and ulcerative colitis (UC) patients retrospectively. METHODS: The medical charts of 50 patients (40 CD and 10 UC), who received after a loading dose of 3 infl iximab infusions scheduled re-treatments every 8 wk as a maintenance protocol, were reviewed. RESULTS: Median (range) duration of treatment was 27 (4-64) mo in CD patients and 24.5 (6-46) mo in UC patients. Overall, 32 (80%) CD and 9 (90%) UC patients showed a sustained clinical response or remission throughout the maintenance period. Three CD patients shortened the interval between infusions. Eight (20%) CD patients and 1 UC patient underwent surgery for flare up of disease. Nine out of 29 CD and 4 out of 9 UC patients, who discontinued infliximab scheduled treatment, are still relapse-free after a median of 16 (5-30) and 6.5 (4-16) mo following the last infusion, respectively. Ten CD patients (25%) and 1 UC patient required concomitant steroid therapy during maintenance period, compared to 30 (75%) and 9 (90%) patients at enrolment. Of the 50 patients, 16 (32%) experienced at least 1 adverse event and 3 patients (6%) were diagnosed with cancer during maintenance treatment. CONCLUSION: Scheduled infl iximab strategy is effective in maintaining long-term clinical remission both in CD and UC and determines a marked steroid sparing effect. Long-lasting remission was observed following infliximab withdrawal.

New serological biomarkers of inflammatory bowel disease

Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and surveillance. This review summarizes both old and new biomarkers in IBD, but focuses on the development and character-ization of new serological biomarkers (identifi ed since 2007). These include fi ve new anti-glycan antibodies, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA), and antibod-ies against chemically synthesized (∑) two major oligomannose epitopes, Man α-1,3 Man α-1,2 Man (∑Man3) and Man α-1,3 Man α-1,2 Man α-1,2 Man (∑Man4). These new biomarkers serve as valuable complementary tools to existing biomarkers not only in differentiating Crohn's disease (CD), ulcerative colitis (UC), normal and other non-IBD gut diseases, but also in predicting disease involvement (ileum vs colon), IBD risk (as subclinical biomarkers), and disease course (risk of complication and surgery). Interestingly, the prevalence of the antiglycan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), ALCA and AMCA, was found to be associated with single nucleotide polymorphisms (SNPs) of IBD susceptible genes such as NOD2/CARD15, NOD1/CARD4, toll-likereceptors (TLR) 2 and 4, and β-defensin-1. Further-more, a gene dosage effect was observed: anti-glycan positivity became more frequent as the number of NOD2/CARD15 SNPS increased. Other new serum/ plasma IBD biomarkers reviewed include ubiquitination factor E4A (UBE4A), CXCL16 (a chemokine), resistin, and apolipoprotein A-IV. This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics, fourier transform near-infrared spectroscopy, and mul-tiplex enzyme-linked immunosorbent assay (ELISA)'s (with an emphasis on cytokine/chemokine profiling). Finally, the prospects of developing more clinically use-ful novel diagnostic algorithms by incorporating new technologies in serological biomarker profiling and integrating multiple biomarkers with bioinformatics analysis/modeling are also discussed.

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.

Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease

AIM： To evaluate fecal calprotectin （FC） as a surrogate marker of treatment outcome of relapse of inflammatory bowel disease （IBD） and, to compare FC with fecal myeloperoxidase （MPO） and fecal eosinophil protein X （EPX）. METHODS： Thirty eight patients with IBD, comprising of 27 with ulcerative colitis （UC） and 11 with Crohn＇s disease （CD） were investigated before treatment （inclusion）, and after 4 and 8 wk of treatment. Treatment outcomes were evaluated by clinical features of disease activity and endoscopy in UC patients, and disease activity in CD patients. In addition, fecal samples were analyzed for FC by enzyme-linked immunosorbent assay （ELISA）, and for MPO and EPX with radioimmunoassay （RIA）. RESULTS： At inclusion 37 of 38 （97%） patients had elevated FC levels （〉 94.7 μg/g）. At the end of the study, 31 of 38 （82%） patients fulfilled predefined criteria of a complete response IUC 21/27 （78%）; CD 10/11 （91%）]. Overall, a normalised FC level at the end of the study predicted a complete response in 100% patients, whereas elevated FC level predicted incomplete response in 30%. Normalised MPO or EPX levels predicted a complete response in 100% and 90% of the patients, respectively. However, elevated MPO or EPX levels predicted incomplete response in 23% and 22%, respectively. CONCLUSION： A normalised FC level has the potential to be used as a surrogate marker for successful treatment outcome in IBD patients. However, patients with persistent elevation of FC levels need further evaluation. FC and MPO provide superior discrimination than EPX in IBD treatment outcome.

Clinical significance of plasma D-dimer and von Willebrand factor levels in patients with ulcer colitis

AIM: To investigate the levels of D-dimer(DD) and von Willebrand factor(vWF) and the relationship between DD and vWF in ulcerative colitis(UC) patients. METHODS: A total of 29 plasma specimens were obtained from patients with ulcerative colitis (male 13, female 16) aged 21-47 years (33+/-11). Disease activity was assessed by Truelove-Writeria. Patients with a score of above 5 were regarded as having active colitis. Twenty healthy people(male 12, female 8) aged 19-53 years(31+/-14) served as normal controls. Blood samples were taken from an antecubital vein puncture. Blood(1.8 mL) was injected into the tubes containing sodium citrate (0.13 mmol/L). The plasma was obtained by centrifugation at 3000 r.min(-1) for 10 min, and stored at -80 degrees until assayed by ELISA. RESULTS: The mean plasma levels of DD and vWF in active UC patients were significantly higher than those of the controls (0.69+/-0.41 vs 0.27+/-0.11, P【0.01 143+/-46 vs 103+/-35, P【0.01). The mean plasma levels of DD in the patients with active disease were higher than those with inactive disease(0.69+/-0.41 vs 0.48+/-0.29 P【0.05). The levels of vWF were not different between active and inactive patients. DD levels were positively related to vWF levels( r =0.574, P【0.01). There was no significant difference between levels of DD and vWF and the scope of disease and sex of the patients. CONCLUSION: vWF is an important feature and a good marker of UC intravascular thrombus and endothelial cell dysfunction were found in UC patients and the combined test of DD and vWF is helpful to distinguish the activity of the UC patients.

Use of mycophenolate mofetil in inflammatory bowel disease

AIM:To assess the efficacy and safety of mycophenolate mofetil(MMF)prospectively in inflammatory bowel disease(IBD)patients intolerant or refractory to conventional medical therapy.METHODS:Crohn's disease(CD)or ulcerative colitis/ IBD unclassified(UC/IBDU)patients intolerant or refractory to conventional medical therapy received MMF(500-2000 mg bid).Clinical response was assessed by the Harvey Bradshaw index(HBI)or colitis activity index(CAI)after 2,6 and 12 mo of therapy,as were steroid usage and adverse effects.RESULTS:Fourteen patients(9 CD/5 UC/IBDU;8M/6F;mean age 50.4 years,range 28-67 years)were treated and prospectively assessed for their response to oral MMF.Of the 11 patients who were not in remission on commencing MMF,7/11(63.6%)achieved remission by 8 wk.All 3 patients in remission on commencing MMF maintained their remission.Ten patients were still on MMF at 6 mo with 9/14(64.3%)in remission,while of 12 patients followed for 12 mo,8 were in remission without dose escalation(66.7%).Three patients were withdrawn from the MMF due to drug intolerance.There were no serious adverse events attributed due to the medication.CONCLUSION:MMF demonstrated efficacy in the management of difficult IBD.MMF appeared safe,well tolerated and efficacious for both short and long-term therapy,without the need for dose escalation.Further evaluation of MMF comparing it to conventional immunosuppressants is required.

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.