Mesenchymal stem cells administered in the early phase of tumorigenesis inhibit colorectal tumor development in rats.

To investigate the differences between the effects of mesenchymal stem cells (MSCs) administered in the early and late phases of tumorigenesis, MSCs were isolated from bone marrow and colorectal tumors were produced by exposing 7-week-old F344 rats to 1,2-dimethylhydrazine and dextran sulfate sodium. We evaluated tumor number and volume (week 25), MSC localization, number of aberrant crypt foci (ACF), transforming growth factor (TGF)-ß1 protein levels in the rectum after administration of MSCs (week 5 or 15), and the effects of MSC-conditioned medium on ACL15 cell proliferation. Administered MSCs labeled with PKH26 were observed in the rectum. Administered MSCs in the early phase (week 5) before tumor occurrence (week 12) significantly decreased tumor number and volume (1.5 vs 4 and 21 mm(3) vs 170 mm(3); p<0.01), but not administered MSCs in the late phase (week 15). Administered MSCs in the early phase reduced ACF number on days 14 and 35 (1.9 vs 4.1 and 3.7 vs 7.3; p<0.01). Rectal TGF-ß1 increased 1.3 fold on day 3, and MSC-conditioned medium containing TGF-ß1 abundantly inhibited ACL15 cell proliferation. MSCs administered in the early phase but not late phase inhibited colorectal tumor development in a rat model.

Gastrointestinal endoscopic practice during COVID-19 pandemic: a multi-institutional survey.

Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities.Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities.Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%-50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs.Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff.

Continuous warfarin administration versus heparin bridging therapy in post colorectal polypectomy haemorrhage: a study protocol for a multicentre randomised controlled trial (WHICH study).

BACKGROUND: Endoscopic removal of colorectal adenoma is considered an effective treatment for reducing the mortality rates associated with colorectal cancer. Warfarin, a type of anticoagulant, is widely used for the treatment and prevention of thromboembolism; however, bleeding may increase with its administration after polypectomy. In recent times, a high incidence of bleeding after endoscopic polypectomy has been reported in patients receiving heparin bridge therapy. However, previous studies have not compared the bleeding rate after endoscopic colorectal polypectomy between patients who continued with anticoagulant therapy and those who received heparin bridge therapy. We hypothesised that endoscopic colorectal polypectomy under the novel treatment with continuous warfarin is not inferior to endoscopic colorectal polypectomy under standard treatment with heparin bridge therapy with respect to the rate of postoperative bleeding. This study aims to compare the efficacy of endoscopic colorectal polypectomy with continuous warfarin administration and endoscopic colorectal polypectomy with heparin bridge therapy with respect to the rate of postoperative bleeding. METHODS: We will conduct a prospective multicentre randomised controlled non-inferiority trial of two parallel groups. We will compare patients scheduled to undergo colorectal polypectomy under anticoagulant therapy with warfarin. There will be 2 groups, namely, a standard treatment group (heparin bridge therapy) and the experimental treatment group (continued anticoagulant therapy). The primary outcome measure is the rate of postoperative bleeding. On the contrary, the secondary outcomes include the rate of cumulative bleeding, rate of overt haemorrhage (that does not qualify for the definition of haemorrhage after endoscopic polypectomy), incidence of haemorrhage requiring haemostasis during endoscopic polypectomy, intraoperative bleeding during endoscopic colorectal polypectomy requiring angiography, abdominal surgery and/or blood transfusion, total rate of bleeding, risk factors for postoperative bleeding, length of hospital stay, incidence of thromboembolism, prothrombin time-international ratio (PT-INR) 28 days after the surgery, and incidence of serious adverse events. DISCUSSION: The results of this randomised controlled trial will provide valuable information for the standardisation of management of anticoagulants in patients scheduled to undergo colorectal polypectomy. TRIAL REGISTRATION: UMIN-CTR UMIN000023720 . Registered on 22 August 2016.

[Gastroenterology and FSS].

Functional gastrointestinal disorders (FGIDs) such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are included in functional somatic syndromes (FSS), which are designated as medically unexplained physical symptoms. Pathopysiology of these diseases are characterized by multi-functional disorders of the gastrointestinal (GI) tract including psychosomatic sensation, brain-gut interaction, autonomic nervous systems, motility disorders, local inflammation, and visceral perception. However, the standard therapy for these diseases is not established, since predominant factors among them associated with respective patients are difficult to be identified in a clinical field. In this section, we are going to present the accumulating evidences for the pathophysiology and therapeutic strategy of FD and IBS.

Perfectionism underlying psychological background correlated with the symptoms of functional dyspepsia.

BACKGROUND: Early satiety, bloating, and postprandial distress are common symptoms in patients with functional dyspepsia (FD) and anorexia nervosa (AN). Perfectionism is known to be associated with AN, accompanied by abnormal eating behavior. We analyzed perfectionism in FD as compared with that in AN, and investigated the correlation of perfectionism with abdominal symptoms. METHODS: The study group comprised 168 patients with FD according to the Rome II criteria (65% females, mean age 47.7 years) and 101 with AN according to the DSM-IV criteria (100% females, mean age 23 years). As control, 130 healthy subjects (81% females, mean age 26.2 years) were studied. Frost's Multidimensional Perfectionism Scale (FMPS) was used to evaluate perfectionism. Abdominal symptoms were evaluated on the Gastrointestinal Symptoms Rating Scale (GSRS). RESULTS: All subscale scores except for organization were significantly higher in patients with AN than in controls. The parental criticism (PC) score in patients with FD was also significantly higher than that in controls, but lower than that in patients with AN. PC was significantly correlated with the total GSRS, particularly indigestion scores of FD patients (P = 0.0476 and P = 0.0294). CONCLUSIONS: Perfectionism such as PC underlying the psychological background of FD patients may be correlated with their abdominal symptoms.

Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats.

AIMS: Mesenchymal stem cells (MSCs) may modulate inflammatory responses resulting in improvement in inflammatory diseases, as well as tissue regeneration via cellular differentiation. We examined the therapeutic effects of exogenously administered MSCs in dextran sulfate sodium (DSS)-induced colitis in rats. MAIN METHODS: Experimental colitis was produced in inbred male Lewis rats by administration of 4% DSS in drinking water for 7 days. MSCs (5x10(6) cells) which were isolated from whole marrow cells and cultured in an optimal medium for MSC outgrowth were administered to the treated rats via the tail vein on days 0, 2, and 4. On day 7, we evaluated colon length, histological changes, and colonic various mRNA expressions by RT-PCR. Localization of MSCs was evaluated using a green-fluorescent cell linker dye. To evaluate the anti-inflammatory action of MSCs, we assayed LPS-induced TNF-alpha secretion in a co-culture of MSCs and monocytes (THP-1 cells) using ELISA. KEY FINDINGS: MSCs reduced in bloody stools, weight loss, colon shortening, and microscopic injuries. In the rectum of MSCs-treated rats, mRNA expression of TNF-alpha, IL-1beta, and COX-2 decreased to 40, 15, and 15% of their respective control levels. MSCs significantly suppressed mRNA expression of VEGF, HGF, and b-FGF to 40, 25, and 25% of their respective control levels. Green-fluorescent-labeled MSCs were found only within the lamina propria in inflamed regions. LPS-induced TNF-alpha secretion by THP-1 cells was significantly suppressed by co-culture with MSCs dose-dependently. SIGNIFICANCE: We conclude that exogenous MSCs accumulated in inflamed tissues and ameliorated DSS-induced colitis via a local anti-inflammatory action.

Effect of chronic stress on gastric emptying and plasma ghrelin levels in rats.

Chronic stress is associated with gastrointestinal functional diseases. Although the pathophysiology seems to be associated with gastrointestinal motility, their mechanisms remain unclear. We investigated gastric emptying and chemical mediators under conditions of continuous stress, which were produced using 8-week-old male Wistar rats kept in a cage filled with water to 2 cm height for 5 days. We examined gastric emptying by the phenol red method and chemical mediators at 4, 8, and 24 h and 3 and 5 days after initiation of stress restraint. Plasma ACTH level was significantly higher in the stress throughout the period of measurement. Continuous stress delayed gastric emptying until 24 h: peak delay was observed at 8 h, whereas gastric emptying was accelerated on days 3 and 5. Plasma noradrenalin level was significantly elevated at every time point until 24 h. Guanethidine pretreatment eliminated the delay in gastric emptying at 8 h. Active ghrelin was significantly increased on days 3 and 5 after peak (at 24 h) plasma total and desacyl ghrelin in the stress group. Number of ghrelin-immunoreactive cells and level of preproghrelin mRNA expression in the gastric body increased in parallel with plasma active ghrelin level. Pretreatment with growth hormone secretagogue receptor antagonist at 5 days partially inhibited the stress-induced acceleration of gastric emptying. Delayed gastric emptying at acute phase of continuous stress was mediated via sympathetic pathway, while acceleration at chronic phase was mediated via increased active ghrelin release from the stomach.

Concurrent assessment of reservoir and emptying of the stomach for dyspepsia patients.

BACKGROUND/AIMS: We simultaneously examined the reservoir function of the stomach as well as emptying by one single assessment for gastric emptying, and investigated their association in patients with functional dyspepsia (FD). Next, we examined the interaction between the association and abdominal symptoms. METHODOLOGY: Sixty-one FD patients according to the Rome III criteria were recruited for this study. We measured the radioactive changes of the proximal and the whole stomach by the scintigraphy until 120 min, and assessed the reservoir function and the respective half-emptying time. We assessed the symptoms by the previously validated questionnaires. RESULTS: Disordered emptying was seen in 55.7% (34/61) of patients, delay in 67.6% (23/34), and acceleration in 32.4% (11/34). Impaired reservoir function was found in 49.2% (30/61) of patients, which had an association with delayed (p = 0.025) and disordered (delay+acceleration) emptying (p = 0.027). Through the period, the radioactive decrease was dynamic in the normal, but virtually unchanged in the impaired reservoir function group. Symptoms in the motility disordered group tended to be more severe than in the normal group. CONCLUSIONS: Gastric reservoir function was associated with emptying in FD patients. Abdominal symptoms of FD patients were partly derived from the impairment of coordinated gastric motility.

Primary duodenal lymphoma: successful rituximab treatment and evaluation by FDG-PET.

A 68-year-old woman has been suffering from chronic inactive hepatitis with hepatitis C virus. Upper endoscopic and pathological findings revealed the typical features of duodenal follicular lymphoma and Helicobacter pylori (H. pylori) infection with her stomach was confirmed by the histological and cultural examinations. No other abnormal findings suspicious for tumor formation were observed by the various examinations such as computed tomography, abdominal ultrasonography and 67Ga-citrate scintigraphy. Primary duodenal follicular lymphoma: stage I according to the Modified Ann Arbor classification was diagnosed by these procedures. The eradication therapy was effective for the withdrawal of H. pylori but not for lymphoma. Four months later, abdominal ultrasonography and magnetic resonance imaging showed the progression of abdominal lymph nodes. Positron emission tomography (PET) with 18F-fluorodeoxyglucose showed radioactive uptake in mesenteric lymph nodes. Systemic chemotherapy using rituximab was started, since these findings suggested the clinical progression from stage I to II2. After 2 courses of the therapy, endoscopic and histological improvement of duodenal lymphoma and lower uptake in mesenteric lymph nodes suggested us complete remission. Rituximab may be useful for duodenal follicular lymphoma and PET with 18F-fluorodeoxyglucose has a potential value for the evaluation of mesenteric lymph nodes spread.

Characteristics of Sleep Disturbances in Patients with Gastroesophageal Reflux Disease.

Objective Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances; however, the detailed differences in the characteristics of sleep disturbances between GERD and non-GERD patients are unknown. The aim of the present study was to analyze the clinical characteristics as well as health-related quality of life in GERD and non-GERD patients with sleep disturbances. Methods Three hundred and fifty patients, including 124 patients with GERD and 226 patients without GERD, completed a self-administered questionnaire that evaluated clinical information. The Pittsburg Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS) and 8-item Short-Form Health Survey (SF-8) were also used. Sleep disturbance was considered to be present if the PSQI was >5.5. Results The prevalence of sleep disturbances was significantly higher in the GERD patients (66/124, 53.9%) than in the non-GERD patients (89/226, 39.3%). Depression and anxiety were significantly more common in the subjects with sleep disturbances than in those without sleep disturbances, although there were no differences between the GERD and non-GERD patients. Among the subjects with sleep disturbances, daytime sleepiness was more common in the GERD patients than in the non-GERD patients. The subjects with sleep disturbances had a poorer health-related quality of life. The physical components of quality of life were impaired, particularly in the GERD patients with sleep disturbances. Conclusion GERD patients with sleep disturbances commonly experience daytime sleepiness and an impaired health-related quality of life, especially in terms of physical components.

Effects of esomeprazole on sleep in patients with gastroesophageal reflux disease as assessed on actigraphy.

OBJECTIVE: Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although treatment with proton pump inhibitors (PPIs) helps to improve GERD symptoms and subjective sleep parameters, the effects of PPI therapy on objective sleep parameters are conflicting. The aim of this study was to examine the effects of esomeprazole treatment on GERD symptoms and sleep parameters assessed using actigraphs and questionnaires. METHODS: Thirteen patients with GERD received 20 mg of esomeprazole once daily for two weeks. The patients wore actigraphs from three days before the initiation of PPI treatment to the end of therapy. They were also asked to answer the following self-reported questionnaires: Frequency Scale for the Symptoms of GERD (FSSG), Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Objective sleep parameters were evaluated using actigraphy. RESULTS: Treatment with esomeprazole significantly decreased the total FSSG score, including the scores for reflux and dysmotility, as well as the ESS score, although it had no effect on the PSQI score. After the second week of treatment, esomeprazole significantly decreased the wake time (from 47.5±39.6 min to 36.0±27.1 min) and sleep latency period (from 19.5±19.8 min to 9.9±10.2 min) and increased the percentage of sleep time (from 89.1±8.8% to 91.9±6.3%); however, improvements were not noted in all objective parameters. CONCLUSION: Esomeprazole treatment significantly improves various objective sleep parameters in Japanese patients with GERD. Further placebo-controlled randomized trials are needed to obtain detailed results.

Clinical classification of subgroups according to the Rome III criteria cannot be used to distinguish the associated respective pathophysiology in Japanese patients with functional dyspepsia.

OBJECTIVE: Patients who meet the Rome III criteria for functional dyspepsia (FD) are generally classified into the following two subgroups, those with postprandial distress syndrome (PDS) and those with epigastric pain syndrome (EPS), in order to treat the dyspeptic symptoms caused by the respective pathophysiological conditions. However, whether simple classification of FD can accurately distinguish the pathophysiological differences between PDS and EPS remains to be clarified because the pathophysiology of FD is characterized and complicated by various factors. METHODS: After classifying FD patients who were not receiving medication at the initial visit, we assessed and compared the following pathophysiological factors between the PDS and EPS groups: (1) the gastric reservoir and emptying functions using a radioisotope method (n=75), (2) the autonomic nervous system (ANS) function using electrocardiography (n=45), (3) gastric mucosal atrophy and intestinal metaplasia using histological examinations (n=47), (4) endoscopic findings of the stomach, such as superficial changes, abnormal gastroesophageal flap valves (n=67) and (5) Helicobacter pylori infection (n=48). RESULTS: The FD patients exhibited higher rates of an impaired reservoir function (49.3%), gastric emptying disorders (54.7%) and relative hyperactivity of the sympathetic nervous system (31.9%) than the control subjects. However, endoscopic and histological changes of the stomach were similar in both the FD patients and control subjects. In addition, no differences were observed in the above-mentioned factors between the PDS and EPS groups. CONCLUSION: The simple classification of FD patients into two subgroups according to the Rome III criteria following diagnosis does not indicate any differences in the pathophysiology related to the respective dyspeptic symptoms of FD patients.

Regression of primary low-grade mucosa-associated lymphoid tissue lymphoma of duodenum after long-term treatment with clarithromycin.

A 74-year-old woman was referred to our department because of epigastralgia. Endoscopic findings revealed yellowish bumpy mucosa from the bulbus to the second portion of the duodenum. The patient was admitted to our hospital for further examinations and treatment for this lesion. Endoscopic mucosal resection (EMR) was performed on part of the lesion to obtain the final diagnosis, and then mucosa-associated lymphoid tissue (MALT) lymphoma of the duodenum was diagnosed using this procedure. In this case, no evidence of Helicobacter pylori infection in the patient's stomach was detected by any of the diagnostic examinations used, such as the urea breath test, histological study, culture, and serological antibody. For this reason, the patient's duodenal MALT lymphoma was treated solely with long-term clarithromycin, which had an inhibitory action on lymphocyte activation. The lesion showed slight improved during the first 12 days of treatment, and complete regression was reached after 6 months of treatment. It is suggested that the long-term use of clarithromycin may be effective for diseases of the gastrointestinal tract associated with the lymphocyte proliferation.

Codeine phosphate-induced hypersensitivity syndrome.

OBJECTIVE: To report a case of drug-induced hypersensitivity syndrome related to codeine phosphate. CASE SUMMARY: A 19-year-old Japanese man was prescribed codeine phosphate 10 mg 3 times daily and several other drugs for cold symptoms. About 20 days later, an erythematous, maculopapular rash appeared and progressed to erythroderma; a spiking fever also developed. He had splenomegaly and generalized lymphadenopathy on admission. Laboratory examinations showed atypical lymphocytosis, eosinophilia, and increased liver enzyme values. The platelet count slowly decreased after admission. The increased numbers of megakaryocytes in bone marrow and platelet-associated immunoglobulin (Ig) G antibodies in serum were compatible with a diagnosis of immune thrombocytopenic purpura. A significant increase in IgG antibodies to human herpesvirus 6 (HHV6) and transient viremia were helpful in diagnosing hypersensitivity syndrome. The results of patch tests were positive for codeine phosphate. An objective causality assessment revealed that an adverse drug event was probable. DISCUSSION: Codeine is an opioid analgesic. Severe adverse cutaneous reactions rarely occur. As of March 3, 2004, our case is, to our knowledge, the first report of hypersensitivity syndrome attributed to codeine phosphate. Drug-induced hypersensitivity syndrome is an acute, potentially life-threatening, idiosyncratic adverse reaction caused mainly by aromatic anticonvulsants. It is characterized by the triad of fever, skin rash, and internal organ involvement. Reactivation of HHV6 is involved in the pathogenesis of this syndrome and may have also caused the immune thrombocytopenic purpura in our patient. CONCLUSIONS: Codeine phosphate may rarely be associated with hypersensitivity syndrome. Clinicians should be aware that the potentially fatal syndrome can be caused by various drugs.