Naohiko Harada

TGF-β1 Plays an Important Role in the Mechanism of CD4 + CD25 + Regulatory T Cell Activity in Both Humans and Mice

In previous studies, we have shown that murine CD4+CD25+ regulatory T cells produce high levels of TGF-β1 in a cell surface and/or secreted form, and blockade of such TGF-β1 by anti-TGF-β curtails the ability of these cells to suppress CD25− T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-β1 in suppression by CD4+CD25+ T cells, we show in this study that another TGF-β1-blocking molecule, recombinant latency-associated peptide of TGF-β1 (rLAP), also reverses suppression by mouse CD4+CD25+ T cells as well as their human counterparts, CD4+CD25high T cells. In addition, we show that CD25− T cells exposed to CD4+CD25+ T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF-β-inducible surface integrin. In further studies, we show that while CD4+CD25+ T cells from TGF-β1-deficient mice can suppress CD25− T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4+LAP+, but not CD4+LAP− T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-β1 produced by CD4+CD25+ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.

Intraductal papillary-mucinous tumors of the pancreas: differential diagnosis between benign and malignant tumors by endoscopic ultrasonography.

Intraductal papillary-mucinous tumors of the pancreas: Differential diagnosis between benign and malignant tumors by endoscopic ultrasonography

Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol.

Objective. The onset and progression of non-alcoholic fatty liver disease (NAFLD) seem to be affected by nutritive intake; however, detailed examinations have not been performed in non-obese NAFLD patients. The purpose of this study was to identify potential nutritive factors that affect NAFLD and its related nutritional problems. Material and methods. We investigated the distribution of abdominal fat, dietary intake, and biochemical data in patients with NAFLD and compared non-obese with obese patients. Results. There was no significant difference in the percentage of patients with diabetes or dyslipidemia between the obese and non-obese groups. Waist circumference, total abdominal fat levels, and subcutaneous fat levels were significantly higher in the obese group, while visceral fat levels were not significantly different between the two groups. Immunoreactive insulin (IRI) and homeostasis model assessment-insulin resistance (HOMA-IR) were significantly lower in the non-obese group, suggesting that the non-obese patients were not overtly insulin resistant. Although serum adiponectin and TNF-α levels were similar in both groups, leptin levels were significantly higher in the obese group. Total energy and carbohydrate intake tended to be higher in the obese group. A characteristic feature was that dietary cholesterol intake was significantly higher, while the intake of polyunsaturated fatty acids (PUFAs) was significantly lower in the non-obese group. Conclusions. In non-obese NAFLD patients: 1) although visceral fat was increased, insulin resistance and/or dysregulated secretion of adipocytokines was not necessarily shown; 2) intakes of total energy and carbohydrates were not excessive, although dietary cholesterol was superabundant and dietary PUFAs were significantly lower compared with those in obese patients; and 3) characteristic fat intake may be associated with the formation of NAFLD.

An Inverse Correlation of Human Peripheral Blood Regulatory T Cell Frequency with the Disease Activity of Ulcerative Colitis

Evidence suggests that CD4+CD25+ regulatory T cells play a crucial role in the suppression of intestinal inflammation. However, their role in the suppression of inflammatory bowel disease has not yet been addressed. We examined the proportion of regulatory T cells in inflammatory bowel disease. First, we isolated CD4+CD45RO+CD25+ T cells from the peripheral blood of healthy persons and showed that these cells suppressed T cell proliferation profoundly and expressed FoxP3 abundantly, revealing that they are regulatory cells. Then the proportion of CD45RO+CD25+ in peripheral blood CD4+ T cells was analyzed in patients and healthy controls by flow cytometry. CD4+CD45RO+CD25+ T cell frequency was significantly lower in active ulcerative colitis than in the control and inactive ulcerative colitis. CD4+CD45RO+CD25+ T cell frequency was inversely correlated with the clinical and endoscopic severity of ulcerative colitis. These results suggest that a deficiency of regulatory T cells is associated with the progression of ulcerative colitis.

T helper 1‐inducing property of IL‐27/WSX‐1 signaling is required for the induction of experimental colitis

Background: WSX‐1, a component of the interleukin (IL)‐27 receptor, is a novel class I cytokine receptor with homology to the IL‐12 receptor &bgr;2 chain. Initially, WSX‐1 signaling was reported to play an important role in the promotion of T helper‐1 responses, but recent reports have revealed an anti‐inflammatory property in WSX‐1 signaling. In the present study, we investigated the role of IL‐27/WSX‐1 signaling in a murine colitis model, dextran sulfate sodium (DSS) colitis, by using WSX‐1 knockout (KO) mice. Methods: First, we observed whether WSX‐1 KO mice developed colitis spontaneously. Second, we induced DSS colitis in WSX‐1 KO and wild‐type (WT) mice. Results: WSX‐1 KO mice were observed not to develop colitis spontaneously. The severity of DSS colitis was decreased in WSX‐1 KO mice in comparison with WT mice in association with a reduced production of interferon‐&ggr;, IL‐6, and tumor necrosis factor‐&agr; by lamina propria mononuclear cells from WSX‐1 KO mice and the absence of T‐bet expression in the colon from WSX‐1 KO mice. Conclusions: This study revealed the inflammatory property of IL‐27/WSX‐1 signaling in intestinal inflammation. As a result, IL‐27/WSX‐1 signal pathway may thus be a promising candidate for the therapeutic intervention of human inflammatory bowel diseases such as Crohns disease and ulcerative colitis.

Preoperative diagnosis and staging of gallbladder carcinoma by EUS

BACKGROUND EUS has recently been shown to be efficacious for the preoperative assessment of depth of invasion of gallbladder carcinoma. This study assessed the value of EUS for determining T stage (International Union Against Cancer). METHODS Preoperative EUS findings in 41 patients with gallbladder carcinoma were analyzed retrospectively. EUS images were classified according to the shape of the tumor and the adjacent gallbladder wall structure as follows: type A, pedunculated mass with preserved adjacent wall structures; type B, sessile and/or broad-based mass with a preserved outer hyperechoic layer of the gallbladder wall; type C, sessile and/or broad-based mass with a narrowed outer hyperechoic layer; type D, sessile and/or broad-based mass with a disrupted outer hyperechoic layer. EUS and histopathologic findings were compared, including the depth of invasion of the tumor in the resection specimen. RESULTS The 4 categories of EUS images of gallbladder carcinoma correlated with the histologic depth of invasion and T stage. Accuracies for the EUS classification as type A corresponding to pTis, type B to pT1, type C to pT2, and type D to pT3-4 were, respectively, 100%, 75.6%, 85.3%, and 92.7%. CONCLUSIONS Preoperative EUS imaging accurately depicts T stage of gallbladder carcinoma and allows for effective therapeutic decision making.

Clarithromycin Versus Metronidazole as First-line Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Controlled Study in Japan.

Background: Helicobacter pylori eradication rates achieved with a first-line regimen of clarithromycin (CLR) combined with amoxicillin (AMX) and a proton pump inhibitor have recently fallen to ⩽80% because of the increasing incidence of CLR resistance in Japan. This randomized multicenter trial aimed to compare the eradication success of 2 first-line triple therapy regimens: rabeprazole, amoxicillin, and clarithromycin (RAC) versus rabeprazole, amoxicillin, and metronidazole (RAM). Methods: A total of 124 consecutive patients infected with H. pylori were randomized into one of two 7-day therapeutic regimens: RAC (n=60) or RAM (n=64). Eradication was confirmed by the 13C-urea breath test. Adverse effects were also assessed. Results: Intention-to-treat and per protocol H. pylori eradication rates were 73.3%/77.2% in the RAC group and 90.6%/93.5% in the RAM group. The eradication rate of RAM therapy was significantly higher than that of RAC therapy. CLR, metronidazole, and AMX resistance was found in 36.2%, 2.1%, and 0% of patients, respectively. In addition, no relevant differences in adverse effects were observed. Conclusions: Metronidazole-based therapy (RAM) was superior to standard CLR-based therapy (RAC) for first-line H. pylori eradication. This reflects the progressive increase in CLR resistance observed in Japan.

Expression profile of lipid metabolism‐associated genes in hepatitis C virus‐infected human liver

Aim:  Recent studies have shown that lipid metabolic pathways are required for the entry, replication and secretion of hepatitis C virus (HCV). Although little is known about the life cycle of HCV in humans, the activation of cholesterol and fatty acid biosynthesis may be critical for HCV proliferation.

Endosonography probe-guided endoscopic mucosal resection of gastric neoplasms

the stomach following endoscopic volvulus reduction in a poor surgical candidate. This novel approach resulted in persistence of normal gastric position as documented by UGI series 1 year later. Further data is needed on the long-term follow-up of patients with various types of symptomatic volvulus managed endoscopically in regards to the significance and frequency of recurrence. In conclusion, we have described a new maneuver, the alpha-loop technique, for endoscopic reduction of gastric volvulus. We used this technique to successfully reduce gastric volvulus in 7 out of 8 patients with no procedural complications. The major benefit of endoscopic volvulus reduction was to allow time for elective surgical repair of abdominal pathology (paraesophageal hernia) predisposing to volvulus formation. The role of the alpha-loop technique as a definitive therapy in poor surgical candidates and in patients with idiopathic volvulus requires further evaluation.

Interaction between atrial natriuretic peptide and vasoactive intestinal peptide in guinea pig cecal smooth muscle

BACKGROUNDS & AIMS The role of atrial natriuretic peptide (ANP) in gastrointestinal motility is still unclear. The aim of this study was to investigate the relationship between ANP and vasoactive intestinal peptide (VIP) in guinea pig cecal circular smooth muscle cells. METHODS The inhibition of 125I-ANP binding or 125I-VIP binding to cecal smooth muscle cells was assessed using unlabeled peptides (i.e., ANP, ANP fragments, VIP, secretin, and peptide histidine isoleucine); the effect of ANP, ANP fragments, and VIP on muscle contraction stimulated by 1 mumol/L carbachol was assessed; and the inhibitory effects of ANP 1-11 on VIP-induced relaxation, ANP 1-11 and VIP 10-28 (a VIP antagonist) on ANP-induced relaxation, and nitric oxide production inhibitors on ANP-induced relaxation were assessed. RESULTS The specific binding of 125I-ANP was inhibited completely by unlabeled ANP and VIP in a dose-dependent manner but only slightly inhibited by secretin and peptide histidine isoleucine. ANP 1-11 and C-atrial natriuretic factor inhibited the binding of 125I-ANP with a lower affinity than ANP. ANP only partly inhibited 125I-VIP binding. ANP and VIP inhibited 1 mumol/L carbachol-induced contraction in a dose-dependent manner. ANP 1-11 significantly inhibited VIP-induced relaxation. ANP 1-11, VIP 10-28, and NO production inhibitors completely inhibited ANP-induced relaxation. CONCLUSIONS The results of the study showed that ANP 1-11 antagonized ANP-induced relaxation and that ANP stimulated NO production and subsequently induced relaxation via a receptor to which VIP binds.