A novel PDHK inhibitor restored cognitive dysfunction and limited neurodegeneration without affecting amyloid pathology in 5xFAD mouse, a model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid ß slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation. METHODS: In the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice. RESULTS: Compound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid ß deposits. CONCLUSIONS: These results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD.

Characteristic endoscopic findings in Helicobacter pylori diagnosis in clinical practice.

INTRODUCTION: Helicobacter pylori is a major risk factor for gastric cancer. In addition to eradication therapy, early-phase detection of gastric cancer through screening programs using high-vision endoscopy is also widely known to reduce mortality. Although European and US guidelines recommend evaluation of atrophy and intestinal metaplasia by high-vision endoscopy and pathological findings, the guideline used in Japan - the Kyoto classification of gastritis - is based on endoscopic evaluation, and recommends the grading of risk factors. This system requires classification into three endoscopic groups: H. pylori-negative, previous H. pylori infection (inactive gastritis), and current H. pylori infection (active gastritis). Major endoscopic findings in active gastritis are diffuse redness, enlarged folds, nodularity, mucosal swelling, and sticky mucus, while those in H pylori-related gastritis - irrespective of active or inactive status - are atrophy, intestinal metaplasia, and xanthoma. AREAS COVERED: This review describes the endoscopic characteristics of current H. pylori infection, and how characteristic endoscopic findings should be evaluated. EXPERT OPINION: Although the correct evaluation of endoscopic findings related to H. pylori remains necessary, if findings of possible infection are observed, it is important to diagnose infection by detection methods with high sensitivity and specificity, including the stool antigen test and urea breath test.

Characteristics of Helicobacter pylori Eradication Therapy in Patients 80 Years or Older Living in a Metropolitan Area: A Multicenter Retrospective Study.

BACKGROUND: The situation of Helicobacter pylori eradication therapy has been changing over time, owing to increases in antimicrobial-resistant strains, lifestyle improvements, and changes in indications for eradication. In Japan, eradication therapy is now available to all H. pylori-positive patients under the medical insurance system, and the potassium-competitive acid blocker vonoprazan has been used for eradication from 2015. Recently, with the aging of society, opportunities to provide eradication to elderly patients are increasing, but the current status and effectiveness of eradication in elderly patients remains unclear. Therefore, we aimed to investigate the trends of H. pylori eradication in a metropolitan area to determine the factors associated with successful H. pylori eradication in elderly patients older than 80 years. METHODS: Trends in the eradication rates of patients who received first- or second-line eradication at 20 hospitals in the Tokyo metropolitan area from 2013 to 2023 were investigated. RESULTS: The eradication rates in the per-protocol analysis were 82.3% (95% confidence interval [CI]: 81.2%-83.2%) for the first-line treatment (n = 6481), and 87.9% (86.9%-88.9%) for the second-line treatment (n = 4899). Multivariate analysis showed that independent factors for successful eradication in the first-line treatment were an age of older than 80 years (OR: 0.606; 95% CI: 0.448-0.822), peptic ulcers (vs. atrophic gastritis: 3.817; 3.286-4.433), and vonoprazan (vs. proton pump inhibiters (PPIs), 3.817; 3.286-4.433), and an age of older than 80 years (0.503; 0.362-0.699) and vonoprazan (1.386; 1.153-1.667) in the second-line treatment. CONCLUSION: After 2015, the eradication rate of both first- and second-line therapies were maintained at a higher level than before 2015, owing to the use of vonoprazan. As the H. pylori eradication rate in patients older than 80 years was low, an effective strategy for these patients needs to be developed in the future.

Risk of map-like redness development after eradication therapy for Helicobacter pylori infection.

BACKGROUND: Map-like redness is a newly identified endoscopic risk factor for gastric cancer in patients who received Helicobacter pylori eradication therapy. However, the incidence rate of map-like redness in patients who received eradication, and the risk factors for the development of map-like redness remain unclear. We hence aimed to investigate the incidence rate of map-like redness at 1-year post H. pylori eradication, and evaluated its associations with map-like redness and gastric cancer in relation with gastric condition. MATERIALS AND METHODS: Endoscopic severity of gastritis and map-like redness were retrospectively evaluated according to the Kyoto Classification of Gastritis in patients who had undergone endoscopy before and after H. pylori eradication therapy. RESULTS: The incidence rate of map-like redness for all 328 patients at a mean of 1.2 ± 0.6 years after eradication was 25.3% (95% confidence interval [CI]: 20.7%-30.4%). Patients who developed map-like redness were older, had more severe atrophy and intestinal metaplasia, a higher total score of the Kyoto Classification of Gastritis both before and after eradication, and a higher rate of gastric cancer history than patients who did not have map-like redness. On multivariate analysis, risk of map-like redness was increased in patients with intestinal metaplasia (odds ratio [OR]: 2.794, 95% CI: 1.155-6.757) and taking acid inhibitors (OR: 1.948, 95% CI: 1.070-3.547). Characteristics of H. pylori-positive patients with gastric cancer history were patients who were older (OR: 1.033, 95% CI: 1.001-1.066), taking acid inhibitors (OR: 4.456, 95% CI: 2.340-8.484), and with occurrence of map-like redness after eradication therapy (OR: 2.432, 95% CI: 1.264-4.679). CONCLUSIONS: Map-like redness is observed in one fourth of patients at 1-year post eradication. Patients who developed map-like redness were found to have severe intestinal metaplasia and taking acid inhibitors, and hence such patients require increased attention at surveillance endoscopy.

Eradication Therapy for Helicobacter pylori Infection in Patients Receiving Hemodialysis: Review.

Patients receiving hemodialysis (HD) often develop gastrointestinal diseases. Recently, although in general population, clinical guidelines for Helicobacter pylori have strongly recommended its eradication in patients to prevent gastric cancer, optimal eradication regimen and optimal dosage of drugs for patients receiving HD have not been established, due to possible incidence of adverse events. Some antimicrobial agents used in eradication therapy, particularly amoxicillin, can exacerbate renal dysfunction. Given the delayed pharmacokinetics of drugs in patients receiving HD compared with those in healthy individuals, drug regimen and dosage should be considered to minimize adverse effects. Although previous studies have investigated the benefits of eradication therapy for patients receiving HD, because most studies were small in terms of the number of enrolled patients, it is hard to show evidence. The numbers of eradication in HD patients have recently increased, and it is important to provide an optimal regimen. The consideration of eradication in patients undergoing HD with a reduction in the drug dose by 1/2-1/3 may prevent adverse events. Additionally, another important consideration is whether adverse events can be prevented while maintaining a similar eradication rate with reduced drug dosages. Recent meta-analysis findings indicate comparable eradication rates in patients receiving HD and healthy individuals, both with the same dosage regimen and at a reduced dosage regimen, with no significant differences (relative risk [RR] for successful eradication: 0.85 [95% confidence interval (CI): 0.48-1.50]). Unlike with the same dosage regimen (RR for adverse events: 3.15 [95% CI: 1.93-5.13]), the adverse events in the dosage reduction regimen were similar to those in healthy individuals (RR: 1.26 [95% CI: 0.23-6.99]). From a pharmacological perspective, the eradication regimen in patients receiving HD should consider the dosage (1/2-1/3 dosage), dosing number (bid), dosing timing of drugs (after HD), and susceptibility to antimicrobial agents.

Intragastric bacterial infection and endoscopic findings in Helicobacter pylori-negative patients.

In the present study, the authors examined the association between gastric bacterial infection and gastric endoscopic findings in Helicobacter pylori (H. pylori)-negative patients. The subjects were 105 H. pylori-negative patients. The mean age was 72.8 ±â€…9.1 years. Endoscopy and gastric juice culture were performed. The presence or absence of endoscopic findings was checked according to the Kyoto classification of gastritis. Culture was positive in 69 patients (65.7%), with Streptococcus α-hemolytic being the most common (51 patients), followed by Neisseria sp. (43 patients). According to the univariate analysis, there was a significant difference between the results of culture and background factors in the use of gastric antisecretory drugs and between the results of culture and various endoscopic findings in atrophic gastritis, intestinal metaplasia, regular arrangement of collecting venule, mucosal swelling, sticky mucus, hyperplastic polyps, hematin, and gastric cobblestone-like lesions. Furthermore, multivariate analysis revealed significant differences in background factors such as the use of gastric antisecretory drugs and endoscopic findings only in patients with mucosal swelling. Endoscopic findings of non-H. pylori bacteria-positive gastritis differed from endoscopic findings of H. pylori-infected gastritis in several respects. In conclusion, our results suggest that non-H. pylori bacteria may infect the stomach and cause gastric inflammation, especially in patients who long term use gastric antisecretory drugs.

Long-term endoscopic gastric mucosal changes up to 20 years after Helicobacter pylori eradication therapy.

Helicobacter pylori eradication therapy reduces the risk of gastric cancer. However, it is unclear whether the severity of risk factors for gastric cancer such as atrophy and intestinal metaplasia are reduced after eradication in the long term. We aimed to study long-term changes in endoscopic risk factors for gastric cancer up to 20 years post-eradication. The endoscopic severity of gastritis according to the Kyoto Classification of Gastritis in 167 patients was retrospectively evaluated over an average follow-up 15.7 years. A significant improvement in mean total gastric cancer risk score (4.36 ± 1.66 to 2.69 ± 1.07, p < 0.001), atrophy (1.73 ± 0.44 to 1.61 ± 0.49, p = 0.004), and diffuse redness (1.22 ± 0.79 to 0.02 ± 0.13, p < 0.001) was observed compared to baseline in the Eradication group. However, there was no change in the never infection and current infection groups. The frequency of map-like redness increased over time until 15 years (3.6% to 18.7%, p = 0.03). The Cancer group had significantly higher risk scores at all time points. Endoscopic atrophy significantly improved in eradicated patients over long-term, suggested that eradication is one of the key elements in gastric cancer prevention. Individualized surveillance strategies based on endoscopic gastritis severity before eradication may be important for those at risk of gastric cancer.

Investigation of the relationship between colonoscopy insertion difficulty factors and endoscope shape using an endoscopic position detection unit.

In this study, we investigated the relationship between the cecal intubation time (CIT) and the form and method used for passing through the sigmoid/descending colon junction (SDJ) and the hepatic flexure using an endoscopic position detection unit (UPD), with reference to various factors [age, sex, body mass index (BMI), history of abdominal and pelvic surgery, and diverticulum]. A total of 152 patients underwent colonoscopy with UPD. The mean age was 66.9 ±â€…12.4 years, and the male to female ratio was 3.6:1. The average CIT time was 14.3 ±â€…8.2 min. Age, number of experienced endoscopies, history of abdominal and pelvic surgery, BMI, and diverticulum were associated with prolonged CIT; SDJ passage pattern was straight: 8.6 ±â€…5.0, alpha loop: 11.8 ±â€…5.6, puzzle ring-like loop: 20.2 ±â€…5.0, reverse alpha loop: 22.4 ±â€…9.7, and other loop: 24.7 ±â€…10.5. The hepatic flexure passing method was in the following order: right rotation maneuver: 12.6 ±â€…6.6, push maneuver: 15.1 ±â€…5.9, and right rotation with positional change maneuver: 20.5 ±â€…7.2. In conclusion, colonoscopy with UPD revealed an association between CIT and SDJ passage pattern and hepatic flexure passing method.

Advanced diagnostic endoscopy in the upper gastrointestinal tract: Review of the Japan Gastroenterological Endoscopic Society core sessions.

The Japan Gastroenterological Endoscopy Society (JGES) held four serial symposia between 2021 and 2022 on state-of-the-art issues related to advanced diagnostic endoscopy of the upper gastrointestinal tract. This review summarizes the four core sessions and presents them as a conference report. Eleven studies were discussed in the 101st JGES Core Session, which addressed the challenges and prospects of upper gastroenterological endoscopy. Ten studies were also explored in the 102nd JGES Core Session on advanced upper gastrointestinal endoscopic diagnosis for decision-making regarding therapeutic strategies. Moreover, eight studies were presented during the 103rd JGES Core Session on the development and evaluation of endoscopic artificial intelligence in the field of upper gastrointestinal endoscopy. Twelve studies were also discussed in the 104th JGES Core Session, which focused on the evidence and new developments related to the upper gastrointestinal tract. The endoscopic diagnosis of upper gastrointestinal diseases using image-enhanced endoscopy and AI is one of the most recent topics and has received considerable attention. These four core sessions enabled us to grasp the current state-of-the-art in upper gastrointestinal endoscopic diagnostics and identify future challenges. Based on these studies, we hope that an endoscopic diagnostic system useful in clinical practice is established for each field of upper gastrointestinal endoscopy.

Degenerate oligonucleotide primer MIG-seq: an effective PCR-based method for high-throughput genotyping.

Next-generation sequencing (NGS) library construction often involves using restriction enzymes to decrease genome complexity, enabling versatile polymorphism detection in plants. However, plant leaves frequently contain impurities, such as polyphenols, necessitating DNA purification before enzymatic reactions. To overcome this problem, we developed a PCR-based method for expeditious NGS library preparation, offering flexibility in number of detected polymorphisms. By substituting a segment of the simple sequence repeat sequence in the MIG-seq primer set (MIG-seq being a PCR method enabling library construction with low-quality DNA) with degenerate oligonucleotides, we introduced variability in detectable polymorphisms across various crops. This innovation, named degenerate oligonucleotide primer MIG-seq (dpMIG-seq), enabled a streamlined protocol for constructing dpMIG-seq libraries from unpurified DNA, which was implemented stably in several crop species, including fruit trees. Furthermore, dpMIG-seq facilitated efficient lineage selection in wheat and enabled linkage map construction and quantitative trait loci analysis in tomato, rice, and soybean without necessitating DNA concentration adjustments. These findings underscore the potential of the dpMIG-seq protocol for advancing genetic analyses across diverse plant species.

JTT-654, an 11-beta hydroxysteroid dehydrogenase type 1 inhibitor, improves hypertension and diabetic kidney injury by suppressing angiotensinogen production.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of 11ß-HSD1 in mouse adipose tissue causes a metabolic syndrome-like phenotype, leading to hypertension. Although, many 11ß-HSD1 inhibitors have been studied, few have shown a clear ameliorative effect against hypertension. We investigated whether JTT-654, a novel 11ß-HSD1 inhibitor, ameliorated hypertension and elucidated the underlying mechanisms. JTT-654 showed inhibitory effects on angiotensinogen production in cortisone-treated 3T3-L1 adipocytes and in a rat model. JTT-654 improved hypertension not only in cortisone-treated rats and spontaneously hypertensive rats (SHR), but also in SHR/NDmcr-cp rats. In the SHR study, JTT-654 and losartan showed the same degree of antihypertensive efficacy. In addition, JTT-654 ameliorated diabetic nephropathy by suppressing renal angiotensinogen production in SHR/NDmcr-cp rats. These effects of JTT-654 were independent of its insulin-sensitizing effects, and similar effects were not observed for pioglitazone, an insulin sensitizer. Moreover, JTT-654 did not affect normotension or hypothalamus-pituitary-adrenal (HPA) axis function in normal Sprague-Dawley rats. Our results indicate that JTT-654 ameliorates hypertension and diabetic nephropathy by inhibiting 11ß-HSD1 in the adipose tissue, liver, and kidney.

Multicenter study of invasive gastric cancer detected after 10 years of Helicobacter pylori eradication in Japan: Clinical, endoscopic, and histopathologic characteristics.

Objectives: Gastric cancer can be diagnosed even in patients long after Helicobacter pylori eradication. Most cases involve intramucosal lesions; however, some are invasive and require surgery. To clarify appropriate long-term surveillance methods, this study compared invasive gastric cancer diagnosed ≥10 and <10 years after eradication. Methods: This retrospective multicenter study included 14 institutions. We included 377 patients with gastric cancer with submucosal or deep invasion after surgical or endoscopic resection. Ordered logistic regression analysis was used to explore the factors contributing to the pathological stage and histological type. Results: Invasive gastric cancer was detected in 84 patients (Group L) and 293 patients (Group S) ≥10 and <10 years after H. pylori eradication, respectively. Endoscopic mucosal atrophy at the time of cancer detection was similar in both groups; 50% of the patients had severe atrophy. Annual endoscopy correlated with early pathological stage (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.14-0.54, p < 0.001). Group L exhibited an independent correlation with the advanced pathological stage (OR 2.27, 95% CI 1.06-4.88, p = 0.035) and the undifferentiated type (OR 2.12, 95% CI 1.16-3.90, p = 0.015). The pure differentiated type and early pathological stage significantly (p = 0.001) correlated with severe mucosal atrophy in Group S but not in Group L. Conclusions: Invasive cancers diagnosed ≥10 years after H. pylori eradication were likely to be more malignant in histological type and pathological stage. Gastric cancer surveillance should continue regardless of endoscopic atrophy, particularly ≥10 years after eradication.

Identifying predictors for comorbidities related mortality versus pancreatic cancer related mortality in patients with intraductal papillary mucinous neoplasm.

BACKGROUNDS: Few data are available for surveillance decisions focusing on factors related to mortality, as the primary outcome, in intraductal papillary mucinous neoplasm (IPMN) patients. AIMS: We aimed to identify imaging features and patient backgrounds associated with mortality risks by comparing pancreatic cancer (PC) and comorbidities. METHODS: We retrospectively conducted a multicenter long-term follow-up of 1864 IPMN patients. Competing risk analysis was performed for PC- and comorbidity-related mortality. RESULTS: During the median follow-up period of 5.5 years, 14.0% (261/1864) of patients died. Main pancreatic duct ≥5 mm and mural nodules were significantly related to all-cause and PC-related mortality, whereas cyst ≥30 mm did not relate. In 1730 patients without high-risk imaging features, 48 and 180 patients died of PC and comorbidity. In the derivation cohort, a prediction model for comorbidity-related mortality was created, comprising age, cancer history, diabetes mellitus complications, chronic heart failure, stroke, paralysis, peripheral artery disease, liver cirrhosis, and collagen disease in multivariate analysis. If a patient had a 5 score, 5- and 10-year comorbidity-related mortality is estimated at 18.9% and 50.2%, respectively, more than 7 times higher than PC-related mortality. The model score was also significantly associated with comorbidity-related mortality in a validation cohort. CONCLUSIONS: This study demonstrates main pancreatic duct dilation and mural nodules indicate risk of PC-related mortality, identifying patients who need periodic examination. A comorbidity-related mortality prediction model based on the patient's age and comorbidities can stratify patients who do not require regular tests, especially beyond 5 years, among IPMN patients without high-risk features. CLINICAL TRIAL REGISTRATION: T2022-0046.

Rebleeding Risk of Acute Hemorrhagic Rectal Ulcer: A Multicenter Retrospective Study.

Objective Acute hemorrhagic rectal ulcer (AHRU) is characterized by sudden, painless, and massive bleeding from rectal ulcers. To date, few studies have analyzed the risk factors for AHRU rebleeding. In this study, we clarified the risk factors of rebleeding after initial hemostasis of AHRU through a multicenter study. Methods A total of 149 patients diagnosed with AHRU between January 2015 and May 2020 at 3 medical centers were enrolled. We retrospectively investigated the following factors: age, sex, body mass index (BMI), performance status (PS), Charlson Comorbidity Index (CCI), comorbidities, medications, laboratory examinations, endoscopic findings, view of the entire rectum on endoscopy, hemostasis method, blood transfusion history, shock, instructions for posture change after initial hemostasis, and clinical course. Results Rebleeding was observed in 35 (23%) of 149 patients. A multivariate analysis showed that significant factors for rebleeding were PS 4 [odds ratio (OR), 5.23; 95% confidence interval (CI), 1.97-13.9; p=0.001], a blood transfusion history (OR, 3.66; 95% CI, 1.41-9.51; p=0.008), low an estimated glomerular filtration rate (eGFR) levels (OR, 0.98; 95% CI, 0.97-0.99; p=0.001), poor view of the whole rectum on endoscopy (OR, 0.33; 95% CI, 0.12-0.90; p=0.030), and use of monopolar hemostatic forceps (OR, 4.89; 95% CI, 1.37-17.4; p=0.014). Conclusion Factors associated with rebleeding of AHRU were a poor PS (PS 4), blood transfusion, a low eGFR, poor view of the whole rectum on endoscopy, and the use of monopolar hemostatic forceps.

Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (Tmax), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs. METHODS: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and Tmax. RESULTS: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and Tmax varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and Tmax (OR, 6.056; 95% CI, 1.094-33.529; P = .039). CONCLUSIONS: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.