Endoscopic Removal of Premalignant Lesions Reduces Long-Term Colorectal Cancer Risk: Results From the Japan Polyp Study.

BACKGROUND & AIMS: To date, no regional evidence of long-term colorectal cancer (CRC) risk reduction after endoscopic premalignant lesion removal has been established. We aimed to analyze this over a long-term follow-up evaluation. METHODS: This was a prospective cohort study of participants from the Japan Polyp Study conducted at 11 Japanese institutions. Participants underwent scheduled follow-up colonoscopies after a 2-round baseline colonoscopy process. The primary outcome was CRC incidence after randomization. The observed/expected ratio of CRC was calculated using data from the population-based Osaka Cancer Registry. Secondary outcomes were the incidence and characteristics of advanced neoplasia (AN). RESULTS: A total of 1895 participants were analyzed. The mean number of follow-up colonoscopies and the median follow-up period were 2.8 years (range, 1-15 y) and 6.1 years (range, 0.8-11.9 y; 11,559.5 person-years), respectively. Overall, 4 patients (all males) developed CRCs during the study period. The observed/expected ratios for CRC in all participants, males, and females, were as follows: 0.14 (86% reduction), 0.18, and 0, respectively, and 77 ANs were detected in 71 patients (6.1 per 1000 person-years). Of the 77 ANs detected, 31 lesions (40.3%) were laterally spreading tumors, nongranular type. Nonpolypoid colorectal neoplasms (NP-CRNs), including flat (<10 mm), depressed, and laterally spreading, accounted for 59.7% of all detected ANs. Furthermore, 2 of the 4 CRCs corresponded to T1 NP-CRNs. CONCLUSIONS: Endoscopic removal of premalignant lesions, including NP-CRNs, effectively reduced CRC risk. More than half of metachronous ANs removed by surveillance colonoscopy were NP-CRNs. The Japan Polyp Study: University Hospital Medical Information Network Clinical Trial Registry: University Hospital Medical Information Network Clinical Trial Registry, C000000058; cohort study: UMIN000040731.

Photoredox-based late-stage functionalization in SAR study for in vivo potent glucosylceramide synthase inhibitor.

Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson's Disease (PD) and lysosomal storage disorders, such as Gaucher's Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel GCS inhibitors. To further improve activity of this chemical series, SAR was investigated on the fused pyridyl ring core of 2a by employing a photoredox reaction that significantly reduced synthetic demand. Herein, we successfully applied the decarboxylation C-H alkylation photoredox reaction to introduce a wide variety of substituents at the 6-position of the fused pyridine core scaffold. This quick SAR acquisition facilitated the swift identification of the potent GCS inhibitors 2b (IC50 = 5.9 nM) and 2g (IC50 = 3.6 nM). Moreover, 2b exhibited superior in vivo potency to that of our previously reported lead compound, T-036.

Appropriate Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension Improves Right Ventricular Ejection Fraction via Lung Perfusion Scan.

Balloon pulmonary angioplasty (BPA) is a robust treatment and has been performed among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). A lung perfusion scan (LPS) is required for inspection in deciding the curative effect judgment and treatment lesion of BPA. Nevertheless, the impact of BPA in the improvement of right heart system function is not well known. We investigated whether BPA improves right heart function alongside other parameters.We studied 20 patients with CTEPH (mean age 63.6 ± 15.9 years, male 30.0%) who underwent BPA. All study sets including right heart catheter, pulmonary angiography, 6-minute walk test (6MWT), blood gas analysis, and LPS were performed before BPA treatment. All parameters using right heart catheter and oxygenation level were measured at room air temperature. Regarding LPS, right ventricular ejection fraction (RVEF) was calculated using the first-pass method. These parameters before BPA were compared with those after BPA.In total, 120 BPAs were performed (mean number of procedures/patient; 6.0 ± 2.4 sessions). Per BPA session, 6.0 ± 2.4 areas and 10.0 ± 4.3 lesions were treated with a volume of 181.3 ± 53.5 mL of contrast media. No complication required an invasive procedure. World Health Organization functional class, 6MWT, pulmonary artery pressure, pulmonary vascular resistance, and oxygenation level were significantly improved after BPA. RVEF via LPS was also significantly improved after BPA (45.0 ± 6.2% to 50.6 ± 2.9%, P < 0.001).In the present study, we found that RVEF via LPS was improved through appropriate BPA alongside the other parameters. It would be useful to be able to evaluate right heart function.

A new brain-penetrant glucosylceramide synthase inhibitor as potential Therapeutics for Gaucher disease.

Gaucher disease (GD), the most common lysosomal storage disorders, is caused by GBA gene mutations resulting in glycosphingolipids accumulations in various tissues, such as the brain. While suppressing glycosphingolipid accumulation is the central strategy for treating peripheral symptoms of GD, there is no effective treatment for the central nervous system symptoms. As glycosphingolipid biosynthesis starts from ceramide glycosylation by glucosylceramide synthase (GCS), inhibiting GCS in the brain is a promising strategy for neurological GD. Herein, we discovered T-036, a potent and brain-penetrant GCS inhibitor with a unique chemical structure and binding property. T-036 does not harbor an aliphatic amine moiety and has a noncompetitive inhibition mode to the substrates, unlike other known inhibitors. T-036 exhibited sufficient exposure and a significant reduction of glucosylsphingolipids in the plasma and brain of the GD mouse model. Therefore, T-036 could be a promising lead molecule for treating central nervous system symptoms of GD.

Randomised comparison of postpolypectomy surveillance intervals following a two-round baseline colonoscopy: the Japan Polyp Study Workgroup.

OBJECTIVE: To assess whether follow-up colonoscopy after polypectomy at 3 years only, or at 1 and 3 years would effectively detect advanced neoplasia (AN), including nonpolypoid colorectal neoplasms (NP-CRNs). DESIGN: A prospective multicentre randomised controlled trial was conducted in 11 Japanese institutions. The enrolled participants underwent a two-round baseline colonoscopy (interval: 1 year) to remove all neoplastic lesions. Subsequently, they were randomly assigned to undergo follow-up colonoscopy at 1 and 3 years (2-examination group) or at 3 years only (1-examination group). The incidence of AN, defined as lesions with low-grade dysplasia ≥10 mm, high-grade dysplasia or invasive cancer, at follow-up colonoscopy was evaluated. RESULTS: A total of 3926 patients were enrolled in this study. The mean age was 57.3 (range: 40-69) years, and 2440 (62%) were male. Of these, 2166 patients were assigned to two groups (2-examination: 1087, 1-examination: 1079). Overall, we detected 29 AN in 28 patients at follow-up colonoscopy in both groups. On per-protocol analysis (701 in 2-examination vs 763 in 1-examination group), the incidence of AN was similar between the two groups (1.7% vs 2.1%, p=0.599). The results of the non-inferiority test were significant (p=0.017 in per-protocol, p=0.001 in intention-to-treat analysis). NP-CRNs composed of dominantly of the detected AN (62%, 18/29), and most of them were classified into laterally spreading tumour non-granular type (83%, 15/18). CONCLUSION: After a two-round baseline colonoscopy, follow-up colonoscopy at 3 years detected AN, including NP-CRNs, as effectively as follow-up colonoscopies performed after 1 and 3 years.

Epstein-Barr virus-positive gastric cancer involves enhancer activation through activating transcription factor 3.

Epstein-Barr virus (EBV) is associated with particular forms of gastric cancer (GC). We previously showed that EBV infection into gastric epithelial cells induced aberrant DNA hypermethylation in promoter regions and silencing of tumor suppressor genes. We here undertook integrated analyses of transcriptome and epigenome alteration during EBV infection in gastric cells, to investigate activation of enhancer regions and related transcription factors (TFs) that could contribute to tumorigenesis. Formaldehyde-assisted isolation of regulatory elements (FAIRE) sequencing (-seq) data revealed 19 992 open chromatin regions in putative H3K4me1+ H3K4me3- enhancers in EBV-infected MKN7 cells (MKN7_EB), with 10 260 regions showing increase of H3K27ac. Motif analysis showed candidate TFs, eg activating transcription factor 3 (ATF3), to possibly bind to these activated enhancers. ATF3 was considerably upregulated in MKN7_EB due to EBV factors including EBV-determined nuclear antigen 1 (EBNA1), EBV-encoded RNA 1, and latent membrane protein 2A. Expression of mutant EBNA1 decreased copy number of the EBV genome, resulting in relative downregulation of ATF3 expression. Epstein-Barr virus was also infected into normal gastric epithelial cells, GES1, confirming upregulation of ATF3. Chromatin immunoprecipitation-seq analysis on ATF3 binding sites and RNA-seq analysis on ATF3 knocked-down MKN7_EB revealed 96 genes targeted by ATF3-activating enhancers, which are related with cancer hallmarks, eg evading growth suppressors. These 96 ATF3 target genes were significantly upregulated in MKN7_EB compared with MKN7 and significantly downregulated when ATF3 was knocked down in EBV-positive GC cells SNU719 and NCC24. Knockdown of ATF3 in EBV-infected MKN7, SNU719, and NCC24 cells all led to significant decrease of cellular growth through an increase of apoptotic cells. These indicate that enhancer activation though ATF3 might contribute to tumorigenesis of EBV-positive GC.

Cardio-ankle vascular index predicts the 1-year prognosis of heart failure patients categorized in clinical scenario 1.

The sudden increase in blood pressure by vascular dysfunction is associated with the development of acute decompensated heart failure (ADHF) categorized in clinical scenario (CS) 1. However, the relationship between vascular function and prognosis in ADHF patients with CS1 is unclear. 3239 consecutive ADHF patients between January 2012 and June 2018 were enrolled. ADHF patients with CS1 undergoing ankle brachial index/cardio-ankle vascular index (CAVI) were included and patients with peripheral artery disease were excluded. Finally, 113 patients were analyzed. The primary endpoint of the present study was composite endpoint at 1 year (the cardiac death or re-hospitalization by ADHF). Cox proportional hazard analysis was conducted to identify independent predictors of composite endpoint. 25 patients (22.1%) were developed composite endpoint. CAVI in patients who have composite endpoint were significantly higher than without non-composite endpoint (composite endpoint group: 9.9 ± 1.3 non-composite endpoint group 8.7 ± 1.7, P = 0.001). The composite endpoint group was elderly and had higher ejection fraction, lower hemoglobin, and less used beta blockers, and renin angiotensin aldosterone system inhibitors. After adjustment by these confounding factors, CAVI was independently associated with the occurrence of composite endpoint (hazard ratio 1.69, 95% CI 1.05-2.73, P = 0.032). A cut-off value of CAVI for predicting composite endpoint was 8.65 (sensitivity 0.444, specificity 0.920, area under the curve 0.724, 95% CI 0.614-0.834). High CAVI was associated with the occurrence of composite endpoint after CS1 ADHF.

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a ß-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.

Comparable effect of tolvaptan in heart failure patients with preserved or reduced ejection fraction.

Background: It is unclear that the difference in efficacy of tolvaptan (TLV) on the length of hospital stay for both heart failure (HF) preserved ejection fraction (EF) (HFpEF) and reduced EF (HFrEF) patients.Methods: We investigated 369 patients who were hospitalized with HF from February 2011 to June 2016 and initiated TLV. Patients who died in hospital, transferred hospital or clinical scenario 4 or 5 were excluded. Finally, we analyzed 108 patients with HFpEF and 96 patients with HFrEF. We evaluated the relationship between the length of hospital stay and the date of TLV initiation. Moreover, we compared the early use (within the median) and delayed use (the median or later) of TLV.Results: The date of TLV initiation was statistically associated with the length of hospital stay in both HFpEF and HFrEF (HFpEF: r = 0.625, P < 0.001, HFrEF: r = 0.618, P < 0.001). In HFpEF, the length of hospital stay in delayed use group was significantly longer than the early use group (22.2 ± 10.7 days and 38.1 ± 22.6 days, P < 0.001). The result was similar in HFrEF (22.0 ± 15.0 days and 32.1 ± 22.0 days, P = 0.008). On the other hand, there were no statistically significant differences in the length of hospital stay after initiation of TLV in both HFpEF and HFrEF. Other findings (including the severity of HF) were similar between the early use group and the delayed group in HFpEF and HFrEF.Conclusions: The time until TLV initiation after hospitalization was related to the length of hospital stay in HFpEF and HFrEF patients.

Bisoprolol transdermal patch improves orthostatic hypotension in patients with chronic heart failure and hypertension.

ß blockers (BBs) play an important role in heart failure (HF) treatment. However, orthostatic hypotension (OH) is sometimes caused by BBs. The bisoprolol transdermal patch works more slowly and is long acting compared with the bisoprolol fumarate tablet. The risk of OH may be reduced by using the bisoprolol transdermal patch. We evaluated 57 consecutive patients who were taking the bisoprolol fumarate tablet for chronic HF with hypertension from November 2016 to September 2017. We switched the patients to the bisoprolol transdermal patch. Because 12 of 57 subjects could not continue using the bisoprolol transdermal patch, we analyzed the remaining 45 patients. We investigated BP, blood tests, and changes in BP from supine to standing positions before and after 6 months of switching from tablet to patch. OH was diagnosed by observing a systolic/diastolic BP drop of at least 20/10 mmHg or an absolute systolic BP (sBP) of <90 mmHg from the standing position. No significant changes were observed in the BP and BPs from supine to standing positions, whereas log brain natriuretic peptide was significantly reduced after switching from patch to tablet (2.102 to 2.070pg/dl, P = .039). OH, which occurred in originally 17 patients, showed improvement and eventually appeared in 4 patients. In these patients, changes in BP from supine to standing positions were also significantly improved (changes in sBP, -11 to -6mmHg, P = .016). This study demonstrated that switching from the bisoprolol fumarate tablet to transdermal patch reduced the morbidity of OH in HF patients.

Prognostic Significance of Serum Indoxyl Sulfate and Albumin for Patients with Cardiovascular Disease.

The progression of renal dysfunction reduces serum albumin and deteriorates the binding capacity of protein-bound uremic toxins. We evaluated the prognostic implications of serum indoxyl sulfate (IS) and albumin levels in patients with cardiovascular disease.We prospectively enrolled 351 consecutive patients undergoing percutaneous revascularization for coronary artery disease or peripheral artery disease. The primary endpoint was all-cause mortality. Patients were assigned to four groups according to the median levels of serum IS (0.1 mg/dL) and albumin (3.9 g/dL).During the median follow-up time of 575 days, 16 patients died. The IS level was significantly higher in nonsurvivors (0.33 versus 0.85 mg/dL, P < 0.05). On the Kaplan-Meier curve, the high IS/low albumin group presented the highest mortality rate (log-rank test, P < 0.01). Cox proportional hazard analysis revealed that high IS/low albumin (hazard ratio (HR): 5.33; 95% confidence interval (CI): 1.71-16.5; P < 0.01), diastolic pressure (HR: 0.94; 95% CI: 0.91-0.98; P < 0.01), prior stroke (HR: 4.54; 95% CI: 1.33-15.4; P = 0.01), and left ventricular ejection fraction (LVEF) (HR: 0.92; 95% CI: 0.88-0.96; P < 0.001) were associated with increased mortality. Furthermore, the combination of IS and albumin levels significantly conferred an additive value to LVEF for predicting mortality (C-statistic: 0.69 versus 0.80; P < 0.001; net reclassification improvement: 0.83; P < 0.001; integrated discrimination improvement: 0.02; P = 0.02).A lower albumin level adds potentiating effects on IS as a prognostic factor for cardiovascular disease.

Fluorine-Substituted Arylphosphine for an NHC-Ni(I) System, Air-Stable in a Solid State but Catalytically Active in Solution.

Monovalent NHC-nickel complexes bearing triarylphosphine, in which fluorine is incorporated onto the aryl groups, have been synthesized. Tris(3,5-di(trifluoromethyl)-phenyl)phosphine efficiently gave a monovalent nickel bromide complex, whose structure was determined by X-ray diffraction analysis for the first time. In the solid state, the Ni(I) complex was less susceptible to oxidation in air than the triphenylphosphine complex, indicating greatly improved solid-state stability. In contrast, the Ni(I) complex in solution can easily liberate the phosphine, high catalytic activity toward the Kumada-Tamao-Corriu coupling of aryl bromides.

The relationship between the time until commencement of tolvaptan and the length of hospital stay in heart failure patients.

The effect of early use of tolvaptan (TLV) for acute decompensated heart failure (ADHF) is unclear. We investigated the relationship between early use of TLV and the length of hospital stay. 369 consecutive ADHF patients who received TLV during hospitalization between February 2011 and June 2016 were initially enrolled. Patients who died in hospital, transferred hospital or clinical scenario 4 or 5 were excluded. We analyzed 247 ADHF patients. We evaluated the relationship between the length of hospital stay and the following findings: blood pressures, heart rate, New York Heart Association classification, and blood tests on admission. Moreover, we also evaluated treated agents and TLV initiated days from admission. TLV initiated days was statistically associated with the length of hospital stay (r = 0.625, P < 0.001). We compared the early use (within 4 days) vs delayed use of TLV (5 days or later), because the median of time until commencement of TLV from hospitalization was 4 days. The length of hospital stay in the delayed use group was significantly longer than early use group (31.9 ± 20.4 and 21.0 ± 12.9 days, P < 0.001). However, there was no difference in the length of hospital stay after initiation of TLV in both groups. Moreover, we investigated the factors related to the long-term hospitalization (hospital stay of median length or more). Multivariate analysis showed that TLV initiated days was independently related to the long-term hospitalization (odds ratio 1.32, 95% confidence interval 1.13-1.53, P < 0.001). Early use of TLV was related to the length of hospital stay for ADHF patients.

Validation study for development of the Japan NBI Expert Team classification of colorectal lesions.

BACKGROUND AND AIM: The Japan narrow-band imaging (NBI) Expert Team (JNET) was organized to unify four previous magnifying NBI classifications (the Sano, Hiroshima, Showa, and Jikei classifications). The JNET working group created criteria (referred to as the NBI scale) for evaluation of vessel pattern (VP) and surface pattern (SP). We conducted a multicenter validation study of the NBI scale to develop the JNET classification of colorectal lesions. METHODS: Twenty-five expert JNET colonoscopists read 100 still NBI images with and without magnification on the web to evaluate the NBI findings and necessity of the each criterion for the final diagnosis. RESULTS: Surface pattern in magnifying NBI images was necessary for diagnosis of polyps in more than 60% of cases, whereas VP was required in around 90%. Univariate/multivariate analysis of candidate findings in the NBI scale identified three for type 2B (variable caliber of vessels, irregular distribution of vessels, and irregular or obscure surface pattern), and three for type 3 (loose vessel area, interruption of thick vessel, and amorphous areas of surface pattern). Evaluation of the diagnostic performance for these three findings in combination showed that the sensitivity for types 2B and 3 was highest (44.9% and 54.7%, respectively), and that the specificity for type 3 was acceptable (97.4%) when any one of the three findings was evident. We found that the macroscopic type (polypoid or non-polypoid) had a minor influence on the key diagnostic performance for types 2B and 3. CONCLUSION: Based on the present data, we reached a consensus for developing the JNET classification.

Effect of Switching from Cilnidipine to Azelnidipine on Cardiac Sympathetic Nerve Function in Patients with Heart Failure Preserved Ejection Fraction.

Cardiac sympathetic nerve activity is known to play a key role in the development and progression of heart failure (HF). Azelnidipine, an L-type calcium channel blocker (CCB), inhibits the sympathetic nerve activity of the central system. In contrast, cilnidipine, an N-type CCB, inhibits the sympathetic nerve activity of the peripheral system. CCBs are recommended as class IIa in patients with HF preserved ejection fraction (HFpEF); however, there are no comparative data on the difference in effect of cilnidipine and azelnidipine in patients with HFpEF and hypertension. We investigated the difference in effect of azelnidipine compared with cilnidipine in patients with HFpEF. Twenty-four consecutive HF patients who received angiotensin II type1a receptor blocker and beta blocker from April 2013 to January 2015 were enrolled. Cilnidipine was switched to azelnidipine during the follow-up period. Blood pressures, heart rate, blood tests, echocardiography, and 123I-metaiodobenzylguanidine (MIBG) cardiac-scintigraphy were measured before and after 6 months from azelnidipine administration. B-type natriuretic peptide tended to decrease after switching to azelnidipine; however, there were no significant differences between the pre-state and post-state (pre-state: 118.5 pg/mL and post-state: 78.4 pg/mL, P = 0.137). Other laboratory findings, including catecholamine, also did not change significantly. In echocardiography, there were no significant differences in systolic and diastolic functions at the pre-state and post-state. As for MIBG, there were no significant changes in heart/mediastinum ratio. However, washout rate was significantly reduced (pre-state: 42.9 and post-state: 39.6, P = 0.030). Azelnidipine improved the dysfunction of cardiac sympathetic nerve activity compared with cilnidipine in patients with HFpEF.

Short-Term Subcutaneous Fondaparinux and Oral Edoxaban for Acute Venous Thromboembolism.

BACKGROUND: No studies have compared treatment efficacy between subcutaneous (SC) fondaparinux and oral edoxaban, which are categorized as factor Xa inhibitors, for venous thromboembolism (VTE) in the acute phase, and only a limited number of imaging-based quantitative studies have evaluated treatment.Methods and Results:In this open-label, randomized study, 50 patients with acute non-massive pulmonary embolism (PE) and/or deep-vein thrombosis (DVT) were assigned to fondaparinux or edoxaban groups. Lower-limb venous ultrasonography (US), and chest computed tomography (CT) were compared before and 7 days after treatment. Thrombus volume in DVT was calculated using quantitative ultrasound thrombosis (QUT) score on US. For evaluation of PE thrombus volume, lung perfused blood volume (PBV) on CT was calculated. The measurements before and after treatment, respectively, were as follows: QUT score: fondaparinux, 8.1±7.3 to 4.1±4.5; edoxaban, 7.7±6.3 to 4.4±4.3, both significant decreases (P=0.001, P<0.001, respectively); lung PBV: fondaparinux, 32.0±7.8 to 32.1±8.2 HU; edoxaban, 34.2±8.6 to 38.5±11.8 HU (P=0.732, P=0.426, respectively). On subjective CT-based evaluation, all pulmonary artery-related filling defects decreased/disappeared after treatment in both groups (P=NS). CONCLUSIONS: Both SC fondaparinux and oral edoxaban are effective in acute VTE. Effects on thrombus regression on imaging-based quantitative measurement did not differ between the 2 drugs.

Regional colorectal cancer screening program using colonoscopy on an island: a prospective Nii-jima study.

Objective: Colorectal cancer screening program using fecal immunochemical test had been conducted on an isolated island named Nii-jima. However, the participation rate of the program had been approximately 12%, which was lower than average level of Japan. This study aimed to evaluate the participation rate, safety and efficacy of a colorectal cancer screening program using colonoscopy on the island. Methods: Educational campaigns were actively conducted every month using information bulletins and special propaganda pamphlets. The primary recommended modality was colonoscopy, followed by fecal immunochemical test. The participants of this program were 1671 individuals aged 40­79 years (men, 819; women, 852). Results: A total of 789 (47.2%) individuals provided consent for this screening program, and 89.2% (704/789) of participants chose colonoscopy as the primary screening procedure. The completion rate of total colonoscopy was 99.7%, and there was no complication during this program. Detection rates of invasive cancer, intramucosal cancer, advanced neoplasia and any adenoma were 0.9% (n = 6), 2.4% (n = 17), 11.8% (n = 83) and 50.0% (n = 352), respectively. The adenoma detection rate and incidence of advanced neoplasia were significantly higher in men than in women in all age groups. Conclusions: The colorectal cancer screening program using colonoscopy that was conducted on an island achieved considerably higher participation rate than the conventional screening program using fecal immunochemical test. Completion rate and safety of screening colonoscopy were excellent during this program.

Azelnidipine is a useful medication for the treatment of heart failure preserved ejection fraction.

BACKGROUND: The optimal therapy in patients with heart failure preserved ejection fraction (HFpEF) and hypertension (HT) has not been revealed. The beta blocker (BB) and the renin angiotensin aldosterone system inhibitor (RAAS-I) are recommend as class IIa in patients with HFpEF. The calcium channel blocker (CCB), a major anti-hypertensive drugs in Japan, is also recommend as class IIa in patients with HFpEF. However, the difference between azelnidipine, an L type CCB, and cilnidipine, an N type CCB, is unclear. We investigated the difference between azelnidipine and cilnidipine in patients with HFpEF and HT. METHODS: Twenty-five consecutive HFpEF patients treated with BB and RAAS-I from April 2013 to March 2015 were enrolled. Initially, cilnidipine was used, and then switched to azelnidipine. Age, gender, blood pressure (BP), heart rate (HR), blood tests, echocardiography, and cardiac-scintigraphy (123I-metaiodobenzylguanidine: MIBG) were measured before and after six months from azelnidipine administration. RESULTS: There was no statistically significant difference in BP. B type natriuretic peptides were significantly reduced (pre-state: 195.4 ± 209.7 pg/ml and post-state: 140.7 ± 136.4 pg/ml, p = 0.050). In echocardiography, the TEI index tended to be decreased (pre-state: 0.47 ± 0.15 and post-state: 0.42 ± 0.08, p = 0.057). As for MIBG, there was no significant change in the heart/mediastinum ratio. However, the washout rate was significantly reduced (pre-state: 44.7 ± 12.2 and post-state: 40.7 ± 12.1, p = 0.011). In addition, there was no statistically significant change, although HR tended to decrease by switching to azelnidipine (pre-state: 62.7 ± 11.6 and post-state: 61.8 ± 16.5, p = 0.373). CONCLUSIONS: In patients with HT and HFpEF, azelnidipine improved the severity of HF and cardiac sympathetic nerve activity compared with cilnidipine.

A polymethoxyflavone mixture, extracted from orange peels, suppresses the UVB-induced expression of MMP-1.

Ultraviolet (UV) B is the main cause of skin photoageing, which has characteristic features such as deep wrinkles. UVB increases the expression of matrix metalloproteinases (MMPs) in the skin and can cause wrinkles by disrupting components of the extracellular matrix, such as collagen fibres. We now report that a polymethoxyflavone (PMF) mixture, extracted from orange peels, suppresses the UVB-induced expression of MMP-1 that involves the inhibition of c-jun N-terminal kinase (JNK) activity. Furthermore, the PMF mixture also inhibits the UVB-induced phosphorylation of JNK. Therefore, the results suggest that the PMF mixture suppresses the UVB-induced expression of MMP-1 through the inhibition of JNK phosphorylation and should be useful as an antiphotoageing agent.

An enzyme-linked immunosorbent assay-based system for determining the physiological level of poly(ADP-ribose) in cultured cells.

PolyADP-ribosylation is mediated by poly(ADP-ribose) (PAR) polymerases (PARPs) and may be involved in various cellular events, including chromosomal stability, DNA repair, transcription, cell death, and differentiation. The physiological level of PAR is difficult to determine in intact cells because of the rapid synthesis of PAR by PARPs and the breakdown of PAR by PAR-degrading enzymes, including poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3. Artifactual synthesis and/or degradation of PAR likely occurs during lysis of cells in culture. We developed a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the physiological levels of PAR in cultured cells. We immediately inactivated enzymes that catalyze the synthesis and degradation of PAR. We validated that trichloroacetic acid is suitable for inactivating PARPs, PARG, and other enzymes involved in metabolizing PAR in cultured cells during cell lysis. The PAR level in cells harvested with the standard radioimmunoprecipitation assay buffer was increased by 450-fold compared with trichloroacetic acid for lysis, presumably because of activation of PARPs by DNA damage that occurred during cell lysis. This ELISA can be used to analyze the biological functions of polyADP-ribosylation under various physiological conditions in cultured cells.