Ken Sugimoto

IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis

Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22-binding protein. Treatment with IL-22-binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium-induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene-delivery system for treating UC.

The impact of visit-to-visit variability in blood pressure on renal function.

Hypertension is an important risk factor for cardiovascular diseases such as chronic kidney disease. It is still not fully understood how blood pressure impacts the kidneys. In this study, we aimed to establish the significance of visit-to-visit variability in blood pressure for renal function. We analyzed 143 consecutive patients undergoing renal Doppler ultrasonography in our hospital ward and measured blood pressure at outpatient visits six or more times. We analyzed the correlation between visit-to-visit variability in blood pressure and multiple clinical parameters, including albuminuria and resistive index evaluated by renal Doppler ultrasonography, which is thought to be a good indicator of renal vascular resistance. Subjects with higher variability in systolic blood pressure showed a significantly higher prevalence rate of clinical albuminuria and microalbuminuria, and showed significantly higher resistive index. Stepwise multiple regression analysis showed that variability in systolic blood pressure was a significant risk factor for higher resistive index, independent of other renal risk factors. Visit-to-visit variability in blood pressure correlates significantly with renal function and renal arteriosclerotic change. This parameter could provide additional information about renal arteriosclerotic change independent of estimated glomerular filtration rate and albuminuria, and should be considered a therapeutic target for renal protection.

Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype.

Acid inhibitory effects of proton pump inhibitors (PPIs) are influenced by CYP2C19 genotype. In contrast, the potent acid inhibition of vonoprazan is not influenced by CYP2C19 genotype.

Evidence for the critical role of interleukin-12 but not interferon-γ in the pathogenesis of experimental colitis in mice

Background and Aims: The imbalance between helper T (Th)1/Th2 cytokines has been observed in human inflammatory bowel disease and various animal models. Because interleukin (IL)‐12 and interferon‐γ (IFN‐γ) productions are known to be a hallmark of Th1‐dominant intestinal inflammation such as 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis, we strictly addressed the roles of IFN‐γ and IL‐12 in the development of colitis, employing knockout mice with IFN‐γ receptor (IFN‐γR) or IL‐12 p40 gene disruptions and mice administered with neutralizing monoclonal antibodies (mAbs) against IFN‐γ or IL‐12.

A patient with undifferentiated carcinoma of gallbladder presenting with hemobilia.

Abstract: Hemobilia is relatively rare among hemorrhages in the digestive tract, and hemobilia caused by tumors of the biliary tract is particularly rare. We treated a 74-year-old-man with undifferentiated carcinoma of the gallbladder presenting with hemobilia. During hospitalization for neurogenic bladder at the Department of Urology, he showed progressive anemia. Since hemorrhage in the digestive tract was suspected, endoscopy of the upper gastrointestinal tract was performed, and bleeding from the papilla of Vater was observed. On ultrasound examination, findings were indicative of cholecystic cancer, and hemorrhage from the cystic duct was found on percutaneous transhepatic cholangioscopy. On perioral cholecystoscopy, however, masses of coagulated blood were found only in the gallbladder. Abnormalities such as dense staining of tumors or extravasation were not found on angiography. The patient died of hepatic failure due to rapid invasion of the liver by the tumor, associated with biliary infection and disseminated intravascular coagulation. At autopsy, a nodal tumor was found in the gallbladder, and the cavity of the gallbladder was filled with coagulated masses of blood. Direct invasion of the tumor to the liver, diaphragm, and transverse colon was found. The histopathological diagnosis was undifferentiated carcinoma (pleomorphic large-cell type).

Accumulation of common polymorphisms is associated with development of hypertension: a 12-year follow-up from the Ohasama study.

Hypertension is a complex multi-factorial and polygenic disorder. Nevertheless, most studies have focused on single-gene effects. Furthermore, a majority of these studies have been cross-sectional and diagnosed hypertension using conventional blood pressure (BP) measurements, which are known to be subject to biases, including the so-called white-coat effect. Thus, we performed a longitudinal association study to clarify the effects of polymorphism accumulation on the development of hypertension that is defined on the basis of self-measured BP at home (home BP). In 403 Japanese aged 40–79 years with home normotension (home BP <135/85 mm Hg, and not treated with antihypertensive medication at baseline), we examined the associations of 51 single-nucleotide polymorphisms (SNPs) classically nominated or reported to be associated with hypertension in the Japanese Millennium Genome Project for Hypertension with a 12-year risk of progression to home hypertension (home BP ⩾135/85 mm Hg, or start of antihypertensive medication). Out of 51 SNPs, four significantly and independently predicted the risk of progression of home hypertension, even after adjustment for possible confounding factors, including baseline home BP value. These were rs3767489 near the regulator of G-protein signaling 2 (RGS2), rs4961 in adducin 1 (ADD1), rs2236957 in the calcium channel, voltage-dependent, α-2/δ-subunit 2 (CACNA2D2) and rs769214 in catalase (CAT). Accumulation of these SNPs significantly improved the predictive values for the development of home hypertension. In conclusion, this longitudinal study, which was based on home BP measurement, showed that accumulation of common polymorphisms reliably predicted the risk of future hypertension in the Japanese general population.

Twice‐daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice‐daily omeprazole, rabeprazole or lansoprazole

Twice‐daily dosing of proton pump inhibitors (PPIs) is used to treat Helicobacter pylori or acid‐related diseases, such as gastro‐oesophageal reflux disease (GERD) refractory to standard dose of a PPI. Genetic polymorphisms of CYP2C19 are involved to different extents in the metabolism of four kinds of PPIs (omeprazole, lansoprazole, rabeprazole and esomeprazole) available in Japan.

Efficacy of Tailored Helicobacter pylori Eradication Treatment Based on Clarithromycin Susceptibility and Maintenance of Acid Secretion

Insufficient acid inhibition during Helicobacter pylori eradication treatment and bacterial resistance to antibiotics often causes eradication failure. Four times daily dosing (q.i.d.) of a proton‐pump inhibitor (PPI) achieves potent acid inhibition, suggesting its potential usefulness as a regimen for eradicating H. pylori infection. Therefore, a tailored eradication regimen based on antibiotic susceptibility and maintenance of acid inhibition should have a high success rate. We investigated the efficacy of such treatment based on clarithromycin (CAM) susceptibility.

The Ulcerative Colitis Endoscopic Index of Severity More Accurately Reflects Clinical Outcomes and Long-term Prognosis than the Mayo Endoscopic Score.

BACKGROUND AND AIMS The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo endoscopic score (Mayo ES) are used to evaluate ulcerative colitis (UC) severity. This study compared UCEIS and the Mayo ES for evaluating UC severity and outcomes in patients undergoing remission induction during routine clinical practice with the aim of predicting medium- to long-term prognosis. METHODS Forty-one UC patients who received colonoscopy before and after tacrolimus remission induction therapy were included. An index of clinical activity and endoscopic findings scored by both the UCEIS and the Mayo ES were determined. Changes in UCEIS and Mayo ES before and after induction therapy were compared. RESULTS The mean UCEIS improved from 6.2±0.9 to 3.4±2.1 (p < 0.001). Based on the UCEIS, a significant reduction was reached in both the response and the remission groups. In contrast, the Mayo ES did not reflect a significant change in the response group. The discrepancy appeared to be due to ulcers becoming smaller and shallower during the early stages of mucosal healing; the Mayo ES seems to miss these early changes. In other words, whereas the UCEIS indicates improvements when ulcers shrink, the Mayo ES does not distinguish deep ulcers from shallow ulcers and is 3 (severe UC) for both deep and shallow ulcers. Additionally, better UCEIS strata after induction therapy were associated with lower incidences of colectomy (p = 0.0001) or relapse (p = 0.0008). CONCLUSIONS The UCEIS accurately reflects clinical outcomes and predicts the medium- to long-term prognosis in UC patients undergoing induction therapy. These findings should support decision-making in clinical practice settings.

Sitafloxacin-based third-line rescue regimens for Helicobacter pylori infection in Japan.

Quinolone‐based regimens have been used as the rescue for eradication of Helicobacter pylori. Sitafloxacin is known to have low minimum inhibitory concentration for H. pylori. Here, we compared two sitafloxacin‐based eradication regimens as rescue for the eradication of H. pylori.