A novel T helper (Th) cell lineage, Th17, that exclusively produces the proinflammatory cytokine interleukin 17 (IL17) has been reported to play important roles in various inflammatory diseases. IL23 ...is also focused upon for its potential to promote Th17. Here, the roles of the IL23/IL17 axis in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease (CD) were investigated.
Mucosal samples were obtained from surgically resected specimens (controls, n = 12; UC, n = 17; CD, n = 22). IL17 production by isolated peripheral blood (PB) and lamina propria (LP) CD4(+) cells was examined. Quantitative PCR amplification was performed to determine the mRNA expression levels of IL17, interferon gamma (IFNgamma), IL23 receptor (IL23R) and retinoic acid-related orphan receptor gamma (RORC) in LP CD4(+) cells, and IL12 family members, such as IL12p40, IL12p35 and IL23p19, in whole mucosal specimens. The effects of exogenous IL23 on IL17 production by LP CD4(+) cells were also examined.
IL17 production was higher in LP CD4(+) cells than in PB. Significant IL17 mRNA upregulation in LP CD4(+) cells was found in UC, while IFNgamma was increased in CD. IL23R and RORC were upregulated in LP CD4(+) cells isolated from both UC and CD. IL17 production was significantly increased by IL23 in LP CD4(+) cells from UC but not CD. Upregulated IL23p19 mRNA expression was correlated with IL17 in UC and IFNgamma in CD.
IL23 may play important roles in controlling the differential Th1/Th17 balance in both UC and CD, although Th17 cells may exist in both diseases.
Multiple early gastric cancers (EGCs) may develop in 6-14% of patients even after achieving curative endoscopic submucosal dissection (ESD); however, a useful biomarker for predicting recurrence is ...not available. The present study investigated whether the expression of CD44 variant 9 (CD44v9), a functional cancer stem cell marker, in the primary gastric cancer tissue represents an indicator of recurrence.
Eighty-eight patients who underwent ESD for EGC from 2008 to 2010 were enrolled and monitored for recurrence for 3 years. The expression levels of CD44v9 in the tissue of initial EGCs were evaluated by immunohistochemistry, and the recurrence rate was compared between CD44v9-positive and CD44v9-negative groups. The mucin phenotype and expression of microRNA-21 (miR-21) and programmed cell death protein 4 (PDCD4) were also analysed.
The recurrence rate of EGC was significantly higher in the CD44v9-positive group than in the CD44v9-negative group (hazard ratio (HR), 21.8; 95% confidence interval (CI), 5.71-83.1). However, mucin phenotypes and the expression of miR-21 and PDCD4 did not predict recurrence after ESD. Meanwhile, grade of gastric atrophy was also identified as a significant marker of multiple recurrence (HR, 4.95; 95% CI, 1.30-18.8).
CD44 variant 9 expression represents a potential predictive marker for recurrence in EGC.
Background and aims: Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral ...administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies. Methods: Patients with refractory active UC were randomly assigned to a high trough concentration (10–15 ng/ml) group (HT group) (n = 21), low trough concentration (5–10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension. Results: An improvement in DAI score (⩾4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor. Conclusions: Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy.
Epigenetic therapy using DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors has clinical promise for the treatment of human malignancies. To investigate roles of microRNAs (miRNAs) ...on epigenetic therapy of gastric cancer, the miRNA expression profile was analysed in human gastric cancer cells treated with 5-aza-2'-deoxycytidine (5-Aza-CdR) and 4-phenylbutyric acid (PBA). miRNA microarray analysis shows that most of miRNAs activated by 5-Aza-CdR and PBA in gastric cancer cells are located at Alu repeats on chromosome 19. Analyses of chromatin modification show that DNA demethylation and HDAC inhibition at Alu repeats activates silenced miR-512-5p by RNA polymerase II. In addition, activation of miR-512-5p by epigenetic treatment induces suppression of Mcl-1, resulting in apoptosis of gastric cancer cells. These results suggest that chromatin remodeling at Alu repeats plays critical roles in the regulation of miRNA expression and that epigenetic activation of silenced Alu-associated miRNAs could be a novel therapeutic approach for gastric cancer.
Summary
Background
Significance of monitoring adalimumab trough levels and anti‐adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear.
Aim
To evaluate the ...association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial.
Methods
We performed this study using adalimumab trough levels, AAA at week 26 and 6‐thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity.
Results
There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/mL vs 5.4 ± 4.3 μg/mL: P <.001). Adalimumab trough level of 5.0 μg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut‐off 6TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity.
Conclusion
Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146)
Linked ContentThis article is linked to Domènech et al and Nakase papers. To view
these papers visit https://doi.org/10.1111/apt.14350 and https://doi.org/10.1111/apt.14365.
Background
Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large‐scale, randomized, placebo‐controlled trials of ...rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD).
Methods
FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo‐controlled, parallel‐group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment.
Key Results
Two hundred forty‐seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori‐infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori‐uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori‐positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups.
Conclusions & Inferences
Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954).
This study aimed to determine the efficacy and safety of rikkunshito, a standardized Japanese herbal medicine, for treating functional dyspepsia. The proportion of responders (GPA scores) and the proportion of participants with individual symptom relief (5‐point Likert scales) were compared between the rikkunshito and placebo groups by using the Fisher's exact test. Administration of rikkunshito for 8 weeks reduced dyspepsia (Responder rates: rikkunshito, 33.6%; placebo, 23.8%; p = 0.09), particularly symptoms of epigastric pain (rikkunshito, 44.0%; placebo 30.3%; p = 0.04) and postprandial fullness (rikkunshito, 50.4%; placebo 37.7%; p = 0.06). Weekly changes in these parameters in the two study groups were compared using the log‐rank test as shown here.
Summary
Background
Mesalazine suppositories are recommended and widely used as the standard therapy in induction and maintenance of remission for proctitis.
Aim
To evaluate the efficacy of mesalazine ...suppositories in patients with ulcerative colitis (UC) and rectal inflammation; and in patient groups categorised by the extent of lesions.
Methods
This study was a phase III multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group study. Mild‐to‐moderate UC patients with rectal inflammation were randomly assigned either a 1 g mesalazine or placebo suppository. The suppository was administered in the rectum once daily for 4 weeks. The primary efficacy end point was the rate of endoscopic remission (mucosal score of 0 or 1) after 4 weeks.
Results
The endoscopic remission rates after 4 weeks in the mesalazine and placebo suppository groups were 81.5% and 29.7%, respectively, and the superiority of mesalazine to placebo was confirmed (P < 0.0001, chi‐squared test). For proctitis, the endoscopic remission rates after 4 weeks were 83.8% and 36.1% in the mesalazine and placebo suppository groups, respectively, and the corresponding rates for all other types of UC were 78.6% and 21.4%, respectively. The superiority of mesalazine to placebo was confirmed in both subgroups (P < 0.0001, Fisher's exact test). The percentage of patients without bleeding was significantly higher in the mesalazine group than the placebo group from Day 3 of treatment (P = 0.0001, Fisher's exact test).
Conclusions
The effectiveness of mesalazine suppositories in all types of UC patients with rectal inflammation was confirmed for the first time in a double‐blind, placebo‐controlled, parallel‐group study (JapicCTI‐ 111421).
Management of functional gastrointestinal disorders is hindered by both poor efficacy and adverse effects of traditional pharmacological therapy. Herbal medicine may be an attractive alternative ...based on the perception of its ‘natural’ approach and low risk of side effects; however, the lack of standardization of drug components has limited the ability to perform rigorous clinical studies in Western countries. Japanese herbal medicine (JHM) is a standardized form of herbal medicine with regards to the quality and quantities of ingredients. While extensively studied and widely used in Asia, there is a paucity of data upon which physicians in other parts of the world may draw conclusions regarding the effectiveness of herbal medicine for gastrointestinal disorders. The aim of this study was to summarize the most recent developments in JHM for treatment of functional gastrointestinal disorders. Animal and human studies were systematically reviewed to identify published data of JHM used for treatment of gastrointestinal disorders. The herbal components of JHM were examined. Results describing the physiological and clinical effects of JHM were ed, with an emphasis on functional gastrointestinal disorders. JHM are associated with a variety of beneficial physiological on the gastrointestinal system. Patient‐based clinical outcomes are improved in several conditions. Rikkunnshi‐to reduces symptoms and reverses physiological abnormalities associated with functional dyspepsia, while dai‐kenchu‐to improves symptoms of postoperative ileus and constipation in children. This updated summary of JHM in the field of gastrointestinal disorders illustrates the potential for herbal medication to serve a valuable role in the management of patients with functional gastrointestinal disorders.
The hypothesis of helper T (T(h))1/T(h)2 cytokine balance proposed by Mosmann and Coffman is often invoked to explain the development of inflammatory diseases, including inflammatory bowel diseases ...(IBD). Recently, however, a newly identified class of T(h) cells-T(h)17 cells, which produce T(h)17 family cytokines-has been recognized as an essential subpopulation in the development of almost all kinds of human and animal inflammatory diseases, rather than T(h)1 and T(h)2 cells. A representative T(h)17 family cytokine, interleukin (IL)-17A, is produced by not only T(h)17 cells, but also by other types of cells, such as T-cell receptor γδ T cells, natural killer (NK) T cells, NK cells, myeloid cells, and innate lymphoid cells, which may also be critically involved in the initiation and persistence of IBD. Here we review recent advances in the study of such IL-17A-producing cells in the pathogenesis of IBD.
Video capsule endoscopy has been established in diagnosis of small-bowel disease and has been evaluated for esophageal pathology and recently for colorectal diagnostics. Gastric capsule endoscopy has ...not hitherto been feasible due to the stomach's large surface area and volume. We present the first application of a magnetically navigated capsule in the human stomach.
29 volunteers and 24 patients (men 42, women 11; mean age 47.5 years) were included in a feasibility study. Low-level magnetic fields were used to maneuver the double-sensor video capsule within the human stomach with an air-water interface provided by ingestion of 1300 ml water within 1 hour before examination. Visualization of all parts of the stomach was attempted; time for visualization was recorded, and a subjective assessment of completeness of visualization was documented.
There was technical failure in one individual; thus technical success rate was 98 %. In the 52 remaining cases, examiners assessed that the antrum, body, fundus, and cardia were fully visualized in 98 %, 96 %, 73 % and 75 %, respectively. Mean duration of examinations was 30 minutes (range 8 - 50), with a longer time (mean 37 minutes) for volunteers for study reasons. In total, 30 findings were identified: 14 were detected by both gastroscopy and capsule, 10 lesions were identified by guided capsule examination only, 6 by gastroscopy only. No significant capsule-related adverse events occurred.
Magnetically navigated video capsule endoscopy appears to be feasible and sufficiently accurate for gastric examination. It may permit endoscopic examinations that are more patient-friendly and without sedation. Comparative studies are under way.
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