Highly regio- and stereocontrolled preparation of α-(trifluoromethyl)-ß-(phenylthio) enamines by the hydroamination of in situ-synthesized 1-(trifluoromethyl)-2-(phenylthio)ethyne.

Various nitrogen nucleophiles were easily added to in situ-generated 1-(trifluoromethyl)-2-(phenylthio)ethyne to afford the corresponding trifluoromethyl enamines in good-to-high yields and with high regio- and stereocontrol under very mild conditions.

A human cell orthogonal enzyme ß-D-galacturonidase for sensitive detection of antigen proteins.

Enzymes are used to amplify signals for detection of antigen proteins in biological samples. However, the enzymes conventionally used for this purpose have limitations, such as the presence of the same (i.e., endogenous) activity in human cells and difficulty in simultaneous use of multiple enzymes because of differences in their required reaction conditions. In this report, we identify an enzyme that can overcome these problems: ß-D-galacturonidase (GalUAase) from Eisenbergiella tayi. GalUAase activity was confirmed to be absent from human cells. The substrate of GalUAase, galacturonic acid, is highly hydrophilic because of its anionic carboxylate group; high substrate hydrophilicity is an ideal characteristic for the substrate of an enzyme used for detection because it decreases nonspecific adsorption to biological samples. We show that E. tayi GalUAase could be used in the detection of antigen proteins on live human cells with lower background signal than the conventionally used enzyme ß-D-galactosidase. The combinatorial use of GalUAase with ß-D-galactosidase enabled simultaneous detection of two antigens on live cells.

Efficacy of endoscopy under general anesthesia for the detection of synchronous lesions in oro-hypopharyngeal cancer.

BACKGROUND/AIMS: Image-enhanced endoscopy can detect superficial oro-hypopharyngeal squamous cell carcinoma; however, reliable endoscopy of the pharyngeal region is challenging. Endoscopy under general anesthesia during transoral surgery occasionally reveals multiple synchronous lesions that remained undetected on preoperative endoscopy. Therefore, we aimed to determine the lesion detection capability of endoscopy under general anesthesia for superficial oro-hypopharyngeal squamous cell carcinoma. METHODS: This retrospective study included 63 patients who underwent transoral surgery for superficial oropharyngeal squamous cell carcinoma between April 2005 and December 2020. The primary endpoint was to compare the lesion detection capabilities of preoperative endoscopy and endoscopy under general anesthesia. Other endpoints included the comparison of clinicopathological findings between lesions detected using preoperative endoscopy and those newly detected using endoscopy under general anesthesia. RESULTS: Fifty-eight patients (85 lesions) were analyzed. The mean number of lesions per patient detected was 1.17 for preoperative endoscopy and 1.47 for endoscopy under general anesthesia. Endoscopy under general anesthesia helped detect more lesions than preoperative endoscopy did (p<0.001). The lesions that were newly detected on endoscopy under general anesthesia were small and characterized by few changes in color and surface ruggedness. CONCLUSION: Endoscopy under general anesthesia for superficial squamous cell carcinoma is helpful for detecting multiple synchronous lesions.

Thiopurine naivety at tacrolimus induction is a predictor of long-term remission in patients with intractable ulcerative colitis who responded to tacrolimus.

BACKGROUND: The short-term efficacy of tacrolimus (Tac) for steroid-dependent and steroid-resistant refractory ulcerative colitis (UC) has been demonstrated; however, its long-term outcomes have not been well documented. Thus, this study aimed to clarify the long-term outcomes of patients who achieved Tac-induced remission and identify its predictors. METHODS: This study included patients with moderate-to-severe active UC who started receiving Tac at our hospital between July 2004 and December 2016. Short-term treatment response was assessed using the Lichtiger index 3 months after starting Tac, and responding patients were further followed up to assess long-term outcomes. The primary endpoint was the relapse-free survival after Tac-induced remission, and the secondary endpoint was the identification of factors associated with relapse after Tac-induced remission. RESULTS: The cumulative relapse-free survival rate at 10 years after Tac-induced remission was 33.2%. Multivariate analysis revealed that being thiopurine naïve at Tac induction was associated with the absence of relapse (hazard ratio: 0.45; 95% confidence interval: 0.22-0.92). CONCLUSIONS: Approximately one-third of patients who achieved Tac-induced remission maintained long-term remission. Being thiopurine naïve at Tac induction was a predictor of the absence of relapse.

Novel multicellular prokaryote discovered next to an underground stream.

A diversity of prokaryotes currently exhibit multicellularity with different generation mechanisms in a variety of contexts of ecology on Earth. In the present study, we report a new type of multicellular bacterium, HS-3, isolated from an underground stream. HS-3 self-organizes its filamentous cells into a layer-structured colony with the properties of a nematic liquid crystal. After maturation, the colony starts to form a semi-closed sphere accommodating clusters of coccobacillus daughter cells and selectively releases them upon contact with water. This is the first report that shows that a liquid-crystal status of cells can support the prokaryotic multicellular behavior. Importantly, the observed behavior of HS-3 suggests that the recurrent intermittent exposure of colonies to water flow in the cave might have been the ecological context that cultivated the evolutionary transition from unicellular to multicellular life. This is the new extant model that underpins theories regarding a role of ecological context in the emergence of multicellularity.

Risk factors for severity of colonic diverticular hemorrhage.

BACKGROUND/AIMS: Colonic diverticular hemorrhage (DH) was a rare disease until the 1990s, and its incidence has increased rapidly since 2000 in Japan. In recent years, colonic DH has been the most frequent cause of lower gastrointestinal bleeding (LGIB). Nearly all cases of DH are mild, with the bleeding often stopping spontaneously. Some cases, however, require surgery or arterial embolization. In this study, using a cohort at Fukuoka University Chikushi Hospital, we investigated factors associated with severe colonic DH. METHODS: Among patients with LGIB who underwent colonoscopy at our hospital between 1995 and 2013, DH was identified in 273 patients. Among them, 62 patients (22.7%) were defined as having severe colonic DH according to recurrence of bleeding in a short period, and/or the necessity of transfusion, arterial embolization, or surgery. We then evaluated risk factors for severe DH among DH patients in this retrospective cohort. RESULTS: Among the 273 patients with DH, use of non-steroidal anti-inflammatory drugs (NSAIDs) (odds ratio [OR], 2.801; 95% confidence interval [CI], 1.164-6.742), Charlson Risk Index (CRI) ≥2 (OR, 3.336; 95% CI, 1.154-7.353), right-sided colonic DH (OR, 3.873; 95% CI, 1.554-9.653), and symptoms of cerebral hypoperfusion (such as light-headedness, dizziness, or syncope) (OR, 2.926; 95% CI, 1.310-6.535) showed an increased risk of severe DH even after controlling for other factors. CONCLUSIONS: Severe DH occurred in 23% of DH patients, and NSAID use, CRI ≥2, right-sided colonic DH, and symptoms of cerebral hypoperfusion are suggested to be predictors of severe DH.

Trough level of infliximab is useful for assessing mucosal healing in Crohn's disease: a prospective cohort study.

BACKGROUND/AIMS: Decreased trough levels of infliximab (TLI) and antibodies to infliximab (ATI) are associated with loss of response (LOR) in Crohn's disease. Two prospective studies were conducted to determine whether TLI or ATI better correlates with LOR (Study 1), and whether TLI could become a predictor of mucosal healing (MH) (Study 2). METHODS: Study 1 was conducted in 108 patients, including those with LOR and remission to compare ATI and TLI in discriminating the 2 conditions based on receiver operating characteristic (ROC) curve analyses. Study 2 involved 35 patients who were evaluated endoscopically. RESULTS: In Study 1, there were no differences between the 2 assays in ROC curve analyses; the TLI cutoff value for LOR was 2.6 µg/mL (sensitivity, 70.9%; specificity, 79.2%), and the ATI cutoff value was 4.9 µg/mL (sensitivity, 65.5%; specificity, 67.9%). The AUROC (area under the ROC curve) of TLI was greater than that of ATI. AUROC was useful for discriminating between the 2 conditions. In Study 2, the TLI was significantly higher in the colonic MH group than in the non-MH group (2.7 µg/mL vs. 0.5 µg/mL, P=0.032). CONCLUSIONS: TLI is better than ATI for clinically diagnosing LOR, and a correlation was observed between TLI and colonic MH.

Increase in colonic diverticular hemorrhage and confounding factors.

AIM: To classify changes over time in causes of lower gastrointestinal bleeding (LGIB) and to identify factors associated with changes in the incidence and characteristics of diverticular hemorrhage (DH). METHODS: A total of 1803 patients underwent colonoscopy for overt LGIB at our hospital from 1995 to 2013. Patients were divided into an early group (EG, 1995-2006, n = 828) and a late group (LG, 2007-2013, n = 975), and specific diseases were compared between groups. In addition, antithrombotic drug (ATD) use and nonsteroidal anti-inflammatory drug (NSAID) use were compared between patients with and without DH. RESULTS: Older patients (≥ 70 years old) and those with colonic DH were more frequent in LG than in EG (P < 0.01). Patients using ATDs as well as NSAIDs, male sex, obesity (body mass index ≥ 25 kg/m(2)), smoking, alcohol drinking, and arteriosclerotic diseases were more frequent in patients with DH than in those without. CONCLUSION: Incidence of colonic DH seems to increase with aging of the population, and factors involved include use of ATDs and NSAIDs, male sex, obesity, smoking, alcohol drinking, and arteriosclerotic disease. These factors are of value in handling DH patients.

Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.

BACKGROUND AND AIMS: Intestinal complications of stenosis or fistula may occur during the course of Crohn's disease (CD), and surgery is performed in a fair number of patients. The risk factors for initial surgery in a Japanese hospital-based cohort of CD patients were evaluated. METHODS: This study was a single-center, retrospective, cohort study. The subjects were 520 patients who underwent inpatient and outpatient treatment at our hospital, had a definitive diagnosis of CD, and no previous surgery. Three parameters were investigated: (i) cumulative incidence of stenosis and fistula; (ii) cumulative rate of initial surgery for each disease type; and (iii) risk factors at diagnosis for initial surgery. RESULTS: (i) Stenosis and fistula increased with time, with stenosis or fistula appearing in about half of the patients after 5 years. (ii) The cumulative rate of initial surgery was about 50% after 10 years. (iii) The patient factors at diagnosis of current smoker, upper gastrointestinal disease, stricturing, penetrating, moderate to severe stenosis of the jejunum, moderate to severe stenosis of the ileum, and moderate to severe stenosis of the terminal ileum were risk factors for initial surgery. CONCLUSIONS: Stenosis or fistula appeared in about half of the patients after 5 years from diagnosis. When upper gastrointestinal disease or complicated small intestinal lesions are seen at the time of diagnosis, the cumulative rate of initial surgery is significantly higher.

Mucosal healing of ileal lesions is associated with long-term clinical remission after infliximab maintenance treatment in patients with Crohn's disease.

BACKGROUND AND AIM: The aim of the present study was to endoscopically evaluate ileal mucosal healing during maintenance therapy with infliximab in order to investigate the clinical significance of endoscopic examination of ileal lesions in Crohn's disease patients. METHODS: This study retrospectively analyzed 54 patients who mainly had active ulcers of the ileum on endoscopy at baseline who were responsive to infliximab induction and who received infliximab maintenance therapy. Mucosal healing was defined as no ulcer or only ulcer scar. At the time of follow-up endoscopy after starting infliximab, endoscopic score, mucosal healing, and clinical remission were evaluated. On long-term follow up, correlations between mucosal healing and long-term clinical remission, and between mucosal healing and the need for major abdominal surgery, were also evaluated. RESULTS: Ileal mucosal healing and complete mucosal healing were significantly correlated with clinical remission (P = 0.046, P = 0.0001, respectively). The rate of long-term clinical remission was significantly higher in patients with complete mucosal healing (P = 0.025). The rate of major abdominal surgery for strictures was significantly lower in patients with complete mucosal healing (P = 0.044). CONCLUSIONS: Complete mucosal healing after 1-2 years was a predictive factor for long-term clinical remission up to 4 years after starting infliximab. A lack of complete mucosal healing was a predictive factor for major abdominal surgery for strictures. The present study suggests that endoscopic evaluation of ileal lesions is useful for long-term prognosis of Crohn's disease patients.

Cancer risk in Japanese Crohn's disease patients: investigation of the standardized incidence ratio.

BACKGROUND AND AIM: There have been very few reported investigations on the standardized incidence ratio (SIR) of intestinal cancer and all cancers other than intestinal cancer with Crohn's disease (CD) by organ in Japan. This study examined the risk of developing cancer (i.e. SIR) that occurs in association with CD. METHODS: The subjects were 770 CD patients managed at our hospital department, which specializes in inflammatory bowel disease, during the approximately 25 years from July 1985 to August 2010. The number of expected cancer patients in a healthy population matched for sex and age with the CD patients in our hospital was then calculated. The relative risk, or SIR, was also calculated. RESULTS: The total observation period was 10,552 person-years, during which 19 cases (2.5%) of cancer were discovered in 770 subjects. The cancer cases included nine cases of colorectal cancer (CRC), one case of small bowel cancer, one case of stomach cancer, three cases of acute myeloid leukemia, two cases of endometrial cancer, one case of lung cancer, one case of skin cancer, and one case of thyroid cancer. The SIR for cancers in Japan in 2003 was 0.87 (95% confidence interval [CI] 0.52-1.35) for all cancers, 2.79 (95% CI 1.28-5.29) for CRC, and 6.94 (95% CI 1.43-20.3) for leukemia. CONCLUSIONS: Among the cancers in CD patients in our hospital, no significant difference was seen in the risk for all cancers in comparison with the standard population. However, the risks for CRC and leukemia were significantly higher than in the standard population.