Pneumomediastinum is a frequent but minor complication during esophageal endoscopic submucosal dissection.

BACKGROUND AND STUDY AIM: Esophageal perforation caused by endoscopic submucosal dissection (ESD) induces serious pneumomediastinum. In the absence of endoscopically detected perforation, postprocedural pneumomediastinum may occur. The aim of this study was to evaluate the association between the clinical factors/courses and pneumomediastinum revealed by chest computed tomography (CT) with special reference to an exposed muscle layer during esophageal ESD. PATIENTS AND METHODS: A total of 58 patients undergoing ESD for esophageal neoplasms between February 2003 and June 2007 also underwent both chest radiography and chest CT within 1 hour after ESD. We studied the association between findings on CT scan and tumor-related and technical factors of esophageal ESD by uni- and multivariate analyses. We also analyzed the clinical factors/courses experienced by all patients. RESULTS: Pneumomediastinum was detected in 18 / 58 patients (31 %) by chest CT compared with only 1 / 58 patients (1.7 %) by chest radiography. ESD-induced exposure of the muscular layer (32 patients) was the only significant factor for pneumomediastinum (18 / 32; P < 0.0001). Clinical factors such as fever, white blood cell count, and C-reactive protein were significantly increased in the group positive for both endoscopically exposed muscular layer and pneumomediastinum (+/+, n = 18) compared with the (-/-) group (n = 26) in the early phase (day 1) after ESD. However, these factors did not affect the length of the fasting period or the length of hospital stay. CONCLUSIONS: In esophageal ESD, pneumomediastinum detected by chest CT only does not cause clinically significant complication. Endoscopic muscle exposure during ESD is a significant risk factor for pneumomediastinum, which causes mild inflammation in the early post-ESD phase.

STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice.

BACKGROUND AND AIMS: SAMP1/Yit mice spontaneously develops intestinal inflammation. Previously, we demonstrated that the signal transducer and activator of transcription (STAT)-3/suppressor of cytokine signalling (SOCS)-3 pathway is pivotal in human inflammatory bowel disease. In our studies in SAMP1/Yit mice, the aim was to investigate whether STAT3 activation contributes to ileitis and to examine the therapeutic effects of this signal blockade. METHODS: Intestinal expression of phospho-STAT3 in SAMP1/Yit mice and control AKR/J mice was examined by western blotting and immunohistochemistry. SOCS3 and interleukin 6 (IL-6) mRNA were determined by northern blotting and reverse transcription-polymerase chain reaction, respectively. We also examined the effects of intravenously injected hyper-IL-6, an IL-6/soluble IL-6 receptor fusion protein, and of soluble gp130-Fc, a specific inhibitor of soluble IL-6 receptor signalling, on STAT3 phosphorylation and disease severity in SAMP1/Yit mice. RESULTS: Phospho-STAT3 was expressed strongly during the disease course in SAMP1/Yit mice but only transiently in AKR/J mice. Phospho-STAT3 was localised to epithelial and mononuclear cells in the diseased intestine of SAMP1/Yit mice. SOCS3 as well as IL-6 mRNAs were expressed in affected intestine. Administration of hyper-IL-6 caused disease exacerbation and enhancement of STAT3 phosphorylation. In contrast, soluble gp130-Fc administration ameliorated the disease and suppressed STAT3 phosphorylation. CONCLUSION: STAT3 signalling is critical in the development of intestinal inflammation in SAMP1/Yit mice. Blockade of this signalling pathway by soluble gp130-Fc may have therapeutic effects in inflammatory bowel disease.

Activation of c-Jun N-terminal kinase (JNK) signalling in experimentally induced gastric lesions in rats.

The c-Jun N-terminal kinase (JNK) participates in intracellular signalling cascades that mediate inflammatory responses. Therefore, the JNK signalling may be involved in gastric injury and inhibition of this pathway may form the basis of a new strategy for the treatment of gastric injury. The aim of this study was to determine whether JNK participates in the formation of gastric lesions in an experimental model. Acute gastric injury was induced in Sprague-Dawley rats by intragastric administration of 100% ethanol. The amount of phospho-JNK in the rat stomach was determined using immunohistochemistry and Western analysis. Animals received subcutaneous injections of a specific JNK inhibitor SP600125 or vehicle and the extent of mucosal damage in the stomach was determined. Western analysis revealed early phosphorylation of JNK and, to a lesser extent, p38 as well as late phosphorylation of the p42/44 extracellular signal-related kinases during the development of gastric lesions. JNK was phosphorylated in epithelial cells and in occasional mononuclear cells present at lesion sites. These cells were rarely found in samples from control specimens. Treatment with SP600125 significantly reduced the extent of gastric lesions. These findings indicate that experimental gastric injury is associated with activation of the JNK signalling pathway, and also suggest that JNK inhibitors may play a role in the treatment of gastric injury in humans.

Attenuation of experimental colonic injury by thiazolidinedione agents.

OBJECTIVE: We investigated the potential use and action mechanisms of thiazolidinedione (TZD) agonists for peroxisome proliferator-activated receptor-gamma, namely pioglitazone and netoglitazone, during dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Colitis was induced by the drinking of 2.5% DSS for 7 days. In the prophylactic protocol, pioglitazone or netoglitazone was administered 2 days before the first DSS exposure and repeated daily for a total of 10 doses. In the therapeutic protocol, pioglitazone was administered 2 days after the first DSS exposure and repeated daily for a total of 10 doses. The effect of pioglitazone on proinflammatory cytokine signaling was examined both in vivo and in vitro. RESULTS: Colitis was significantly attenuated by both pioglitazone and netoglitazone in the prophylactic protocol and by pioglitazone in the therapeutic protocol. The improvement of colitis by pioglitazone was associated with decreased colonic interleukin-6, and phospho-signal transducer and activator of transcription-3 levels. In vitro experiments revealed that culturing lamina propria mononuclear cells in the presence of pioglitazone down-regulated the production of interleukin-6. CONCLUSIONS: These TZD agents should be considered for use as new therapeutic agents in intestinal inflammation such as inflammatory bowel disease. TZD-induced improvement in inflammation is explained, in part, by down-regulation of proinflammatory cytokine signaling.

A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease.

The presence and the role of soluble gp130, the soluble form of a component of the interleukin (IL)-6 receptor complex, were investigated in inflammatory bowel disease. The serum concentrations of soluble gp130 were increased in ulcerative colitis (active disease, median, 93.5 ng/ml; interquartile range, 26-125 ng/ml; inactive disease, 81 ng/ml, 24.8-137.3 ng/ml) and to a lesser extent in Crohn's disease (active disease, 66 ng/ml, 44.4-87.6 ng/ml; inactive disease, 63 ng/ml, 43.5-82.5 ng/ml) compared to normal controls (43 ng/ml, 27-59 ng/ml). Paired analysis of serum samples showed a decrease of IL-6 and soluble IL-6 receptor concentrations in both diseases and an increase of soluble gp130 concentrations, especially in ulcerative colitis, just after the resolution of disease exacerbation. Size fractionation of the serum revealed that a part of the IL-6 co-eluted with soluble gp130 and soluble IL-6 receptor. The IL-6-induced proliferation of murine B9 hybridoma was enhanced by recombinant soluble IL-6 receptor, whereas the proliferation was inhibited by recombinant soluble gp130. These results indicate that soluble gp130 may function as a natural inhibitor of the IL-6 actions in inflammatory bowel disease.

Diminished cytokine signalling against bacterial components in mononuclear leucocytes from ulcerative colitis patients after leukocytapheresis.

Infiltration by circulating inflammatory cells is a prominent local inflammatory feature of ulcerative colitis (UC). Several trials have suggested that leukocytapheresis by filtration can benefit patients with active UC. We investigated how this therapy might modulate the inflammatory response. Patients with active UC who were beginning repeated filtration leukocytapheresis were studied. Mononuclear cell preparations were obtained from blood before and after the first treatment, and expression of cytokine signalling components and the cell-proliferative response were analysed in vitro. Leukocytapheresis reduced lipopolysaccharide-induced production of proinflammatory cytokines (interleukin-1, -6, -8 and tumour necrosis factor-alpha, P < 0.05 for all) and activation of intracellular signalling components (nuclear factor-kappaB, mitogen-activated protein kinases, and signal transducer and activator of transcription-3), as well as surface expression of toll-like receptor-4 (P < 0.05) in mononuclear cells. The therapy also reduced the cell-proliferative response by mononuclear cells stimulated with sonicated bacterial preparations from autologous intestine (P < 0.05). These results indicate that activated mononuclear cells in the peripheral blood of patients with active UC are removed by leukocytapheresis and replaced by cells with a lower activation status. This replacement may partly explain the therapeutic benefit.

Radiographic observation of a case of gastrointestinal stromal tumor in stomach.

A case of gastrointestinal stromal tumor (GIST) in stomach was presented. Serial barium meal x-ray examinations revealed an enlarging elevated lesion on the fornix of the stomach. Tumor volume doubling time was found to be 299 days. Microscopic and immunohistochemical studies of the resected tumor disclosed GIST, uncommitted type, low grade malignant/potentially malignant. A radiographic feature of this rare type of gastric submucosal tumor was demonstrated in this report.

Optimum treatment strategy for superficial esophageal cancer: endoscopic mucosal resection versus radical esophagectomy.

This study was designed to determine the optimum treatment for a superficial esophageal cancer involving the mucosal or submucosal layer of the esophagus. The subjects were 150 patients with a superficial esophageal cancer who underwent endoscopic mucosal resection (EMR) or esophagectomy in Kurume University Hospital from 1981 to 1997. The mortality and morbidity rates, survival rate, and recurrence rate were retrospectively compared for (1) 35 patients who underwent EMR and 37 patients who underwent esophagectomy for a mucosal esophageal cancer and (2) 45 patients who underwent extended radical esophagectomy and 33 patients who underwent less radical esophagectomy for a submucosal esophageal cancer. Among the 72 patients with a mucosal cancer, lymph node metastasis/recurrence was observed in only one (1%); whereas of 78 patients with a submucosal cancer it was observed in 30 (38%). Among patients with a mucosal cancer the mortality and morbidity rates after EMR were lower than for those after esophagectomy. The survival rate after EMR was the same as that after esophagectomy. No recurrence was observed after either treatment modality. Among the patients with a submucosal cancer, the survival rate was higher and the recurrence rate lower after extended radical esophagectomy; than after less radical esophagectomy; the mortality and morbidity rates after extended radical esophagectomy were the same as those after less radical esophagectomy. Multivariate analysis demonstrated that the treatment modality (EMR versus esophagectomy) did not influence the survival of patients with a mucosal esophageal cancer, whereas it strongly influenced the survival of patients with a submucosal esophageal cancer. We concluded that EMR was the mainstay of treatment for a mucosal esophageal cancer, and extended radical esophagectomy was the mainstay of treatment for a submucosal esophageal cancer.

Transcription factor-targeted therapies in inflammatory bowel disease.

Although the causes of inflammatory bowel disease currently are not fully understood, increasing evidence implicates cytokines as key factors in the development of this disorder. The rationale for cytokine-targeted therapy for inflammatory bowel disease has been refined significantly, and clinical studies have been initiated. Recent investigations have focused on transcription factors that regulate production and activation of cytokines, including the nuclear factor-kappa B, the p38 mitogen-activated protein kinase, the peroxisome proliferator-activated receptor-gamma, and the Janus kinases/signal transducers and activator of transcription pathways. Although their exact role in inflammatory bowel disease is still unknown, further studies may lead to identification of additional possible targets for therapeutic intervention that could improve management of the disease.

CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation.

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activator of transcription (STAT) transcription factors. We recently identified two intrinsic Janus kinase (JAK) inhibitors, JAK binding protein (JAB; also referred to as suppressor of cytokine signaling [SOCS1]/STAT-induced STAT inhibitor [SSI1]) and cytokine-inducible SH2 protein (CIS)3 (or SOCS3/SSI3), which play an essential role in the negative regulation of cytokine signaling. We have investigated the role of STATs and these JAK inhibitors in intestinal inflammation. Among STAT family members, STAT3 was most strongly tyrosine phosphorylated in human ulcerative colitis and Crohn's disease patients as well as in dextran sulfate sodium (DSS)-induced colitis in mice. Development of colitis as well as STAT3 activation was significantly reduced in IL-6-deficient mice treated with DSS, suggesting that STAT3 plays an important role in the perpetuation of colitis. CIS3, but not JAB, was highly expressed in the colon of DSS-treated mice as well as several T cell-dependent colitis models. To define the physiological role of CIS3 induction in colitis, we developed a JAB mutant (F59D-JAB) that overcame the inhibitory effect of both JAB and CIS3 and created transgenic mice. DSS induced stronger STAT3 activation and more severe colitis in F59D-JAB transgenic mice than in their wild-type littermates. These data suggest that hyperactivation of STAT3 results in severe colitis and that CIS3 plays a negative regulatory role in intestinal inflammation by downregulating STAT3 activity.

Epidemiological study on food intake and Helicobacter pylori infection.

We conducted an epidemiological study to investigate the relation of food intake to Helicobacter pylori (H. pylori) infection in an area endemic for H. pylori. In this study, 365 subjects, 104 men and 261 women, were randomly selected from 7,389 adult (over age 20) inhabitants of town A, Japan. The prevalence of immunoglobulin G (IgG) class antibody to H. pylori (anti-H. pylori) was 83.7% and the prevalence of anti-H. pylori increased with age significantly (P < 0.05). Subjects with anamnesis of gastritis, gastroduodenal ulcer and gastric cancer tended to have a higher anti-H. pylori positive ratio (93.5%) than those without (81.0%). But there was no relationship between anti-H. pylori prevalence and sex, blood type, smoking or drinking habits. Daily intake of foods by food groups, nutrients and the concentrations of serum ingredients were compared between 37 anti-H. pylori-positive and 40 negative subjects selected from 365 inhabitants by matching up according to sex and age. The daily intake of cereals, potatoes and starches, and milks tended to be higher in positive than negative subjects, while the daily intake of algae and tea appeared to be a little higher in negative than in positive subjects. The daily zinc intake of antibody-positive subjects was significantly higher (P < 0.05) than in antibody negative subjects. On the other hand, the daily iron intake in negative subjects was significantly higher (P < 0.05) than in positive subjects. The serum concentrations of copper, zinc, and vitamin E tended to be higher in positive than negative subjects. But there were no significant differences in serum ingredients concentrations between antibody negative and positive subjects. Our findings suggest that iron and zinc intakes may effect on H. pylori infection.

High plasma cardiac natriuretic peptides associated with enhanced cyclic guanosine monophosphate production in preascitic cirrhosis.

BACKGROUND/AIMS: The initial abnormalities of renal sodium handling in cirrhosis remain unclear. The aim of this study was to characterize sodium metabolism in preascitic cirrhosis. METHODS: Ten patients with preascitic cirrhosis and ten controls were studied. All subjects ate a diet providing 120 mmol sodium during an equilibration period lasting 5 days and the study day. On the study day, after remaining in bed, plasma levels of atrial natriuretic peptide, brain natriuretic peptide, renin activity, aldosterone, noradrenaline, and cyclic guanosine monophosphate were measured at 7 am. Thereafter, they were instructed to maintain an upright posture until dinner and the measurements were repeated at 9 am and 6 pm. After having dinner, all subjects were asked to remain in bed and the measurements were repeated at 11 pm. To measure renal sodium and cyclic guanosine monophosphate excretion, 24-h urine collections were performed, starting from 7 pm on the day before the experimental day. RESULTS: Plasma levels of atrial natriuretic peptide, brain natriuretic peptide and cyclic guanosine monophosphate in patients with preascitic cirrhosis were significantly elevated compared with those in controls at every sampling time (p=0.03 or less, p= 0.04 or less, and p=0.01 or less). In contrast, plasma renin activities at every sampling time were significantly lower in patients than in controls (p= 0.04 or less). Plasma aldosterone and noradrenaline levels were not significantly different at every sampling time in the two groups. No significant differences in daily renal sodium excretion were found. However, urinary cyclic guanosine monophosphate excretion was significantly higher in patients than in controls (p<0.01). CONCLUSIONS: The initial abnormalities of sodium metabolism in cirrhosis might be characterized by blunted renal responsiveness to natriuretic peptides. The results of the study also provide indirect evidence that the impairment is mainly located at postreceptor levels of signal transduction pathway to the peptides, if the activation of antinatriuretic factors other than renin-angiotensin or sympathoadrenergic systems does not play a role.

Cytokine-targeted therapeutic approaches for inflammatory bowel disease.

Although the causes of inflammatory bowel disease currently are not fully understood, increasing evidence implicates cytokines as key factors in the development of this disorder. The rationale for cytokine-targeted therapy for inflammatory bowel disease has been refined significantly and clinical studies have been initiated. Efficacy of therapy with antitumor necrosis factor-alpha antibody has already been established and clinical trials of recombinant interleukin-10 and interleukin-11 are in progress. Recent investigations have also focused on intracellular signaling pathways and transcription factors that regulate production and activation of cytokines. Further elucidation of the immune response and the role of cytokines in inflammatory bowel disease may lead to identification of additional possible targets for therapeutic intervention that could improve management of the disease.

Indication for endoscopic resection of submucosal colorectal carcinoma: special reference to lymph node metastasis.

We investigated the relationship between histological factors and lymph node metastasis in 77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria for lesions in which endoscopic treatment alone results in cure of malignancy. There were positive correlations between histological factors, including the level of invasion, the histologic grade, presence or absence of lymphatic invasion, presence or absence of budding, and lymph node metastasis (p < 0.05, p < 0.05, p < 0.005, p < 0.01). The presence or absence of venous invasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph node dissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors. In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph node dissection by laparoscopic surgery should be directly performed without endoscopic resection.In treating submucosally invasive colorectal carcinomas, the level of invasion can be clinically diagnosed, consequently endoscopic resection should be initially performed when lesions are evaluated as sm1 prior to resection. When histological investigation reveals sm1 carcinoma with histologic grade I (well-differentiated) or II (moderately-differentiated), and the absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient.

Polyarthritis nodosa with mesenteric aneurysms demonstrated by angiography: report of a case and successful treatment of the patient with prednisolone and cyclophosphamide.

Polyarteritis nodosa is a necrotizing angitis that predominantly affects small and medium-sized arteries. The prognosis of untreated polyarteritis nodosa is very poor. Since symptoms are diverse and no serologic test is specific for polyarteritis nodosa, the diagnosis is difficult and often delayed. We describe a patient with polyarteritis nodosa who had gastrointestinal involvement with multiple aneurysms of the inferior mesenteric artery; only abdominal angiography provided a conclusive diagnosis. Alleviation of symptoms and regression of aneurysms were observed after combination therapy of an immunosuppressive agent, cyclophosphamide, and prednisolone. We emphasize the importance of early diagnosis by angiography and aggressive therapy in patients in whom physical signs indicating definite polyarteritis nodosa are not present.

Butyrate from bacterial fermentation of germinated barley foodstuff preserves intestinal barrier function in experimental colitis in the rat model.

BACKGROUND AND AIMS: The consumption of germinated barley foodstuff (GBF) prevents inflammation and diarrhoea in a colitis model. In this study we investigated the mechanism of the preventative effect of GBF on experimental colitis in rats, in view of production of bacterial butyrate and preservation of intestinal barrier function. METHODS: Sprague-Dawley rats administered with diets supplemented with 3.5% dextran sodium sulphate were used as an experimental colitis model. Butyrate was given to rats orally or intracaecally. Intestinal barrier function was estimated by light microscopic observation of the mucosa, intestinal permeability and bacterial translocation. RESULTS: Mucosal damage was reduced by intracaecal administration of butyrate, but not by oral administration. Bacterial butyrate production and reduction of mucosal damage depended on the dose of GBF in diets. The action of endogenous bacterial butyrate, including the reduction of intestinal permeability and bacterial translocation, was inhibited by administration of an inhibitor of beta-oxidation of short-chain fatty acids. CONCLUSIONS: The feeding of GBF promotes bacterial butyrate production and improves intestinal barrier function in rats, resulting in mitigation of experimental colitis.