Study on Pyridine-Boryl Radical-Promoted, Ketyl Radical-Mediated Carbon-Carbon Bond-Forming Reactions.

Ketyl radicals are synthetically versatile reactive species, but their applications have been hampered by harsh generation conditions employing highly reducing metals. Recently, the pyridine-boryl radical received wide attention as a promising organic reductant because of its mildness as well as convenience in handling. While probing the utility of the pyridine-boryl radical, our group observed facile pinacol coupling reactivity that had not been known at that time. This serendipitous finding was successfully rendered into a practical synthesis of tetraaryl-1,2-diols in up to 99% yield within 1 h. Subsequently, upon examinations of various reaction manifolds, a diastereoselective ketyl-olefin cyclization was accomplished to produce cycloalkanols such as trans-2-alkyl-1-indanols. Compared to the previous methods, the stereocontrolling ability was considerably enhanced by taking advantage of the structurally modifiable boryl group that would be present near the bond-forming site. In this full account, our synthetic efforts with the O-boryl ketyl radicals are disclosed in detail, covering the discovery, optimization, scope expansion, and mechanistic analysis, including density functional theory (DFT) calculations.

Effect of bile reflux on gastric juice microbiota in patients with different histology phenotypes.

BACKGROUND/AIMS: Bile reflux (BR) can influence the gastric environment by altering gastric acidity and possibly the gastric microbiota composition. This study investigated the correlation between bile acids and microbial compositions in the gastric juice of 50 subjects with differing gastric pathologies. METHODS: This study included 50 subjects, which were categorized into three groups based on the endoscopic BR grading system. The primary and secondary bile acid concentrations in gastric juice samples were measured, and microbiota profiling was conducted using 16 S rRNA gene sequencing. RESULTS: Significant differences were observed in each bile acid level in the three endoscopic BR groups (P < 0.05). The Shannon index demonstrated a significant decrease in the higher BR groups (P < 0.05). Analysis of the ß-diversity revealed that BR significantly altered the gastric microbiota composition. The presence of neoplastic lesions and the presence of H. pylori infection impacted the ß-diversity of the gastric juice microbiota. The abundance of the Streptococcus and Lancefielfdella genera exhibited positive correlations for almost all bile acid components(P < 0.05). In addition, the abundance of Slobacterium, Veillonella, and Schaalia showed positive correlations with primary unconjugated bile acids (P < 0.05). CONCLUSION: Changes in microbial diversity in the gastric juice were associated with BR presence in the stomach. This result suggests that the degree of BR should be considered when studying the gastric juice microbiome.

Diagnosis of Chronic Constipation.

Patients with chronic constipation (CC) usually complain of mild to severe symptoms, including hard or lumpy stools, straining, a sense of incomplete evacuation after a bowel movement, a feeling of anorectal blockage, the need for digital maneuver to assist defecation, or reduced stool frequency. In clinical practice, healthcare providers need to check for 'alarm features' indicative of a colonic malignancy, such as bloody stools, anemia, unexplained weight loss, or new-onset symptoms after 50 years of age. In the Seoul Consensus on the diagnosis and treatment of chronic constipation, the Bristol stool form scale, colonoscopy, and digital rectal examination are useful for objectively evaluating the symptoms and making a differential diagnosis of the secondary cause of constipation. If patients with CC improve to lifestyle modification or first-line therapies, the effort to determine the subtypes of CC is usually not considered. On the other hand, if conventional therapeutic strategies fail, diagnostic testing needs to be considered to distinguish between the different subtypes of functional constipation (normal-transit constipation, slow transit constipation, or defecatory disorder) because these subtypes of constipation have different therapeutic implications and a correct diagnosis is critical. In the Seoul consensus, physiological testing is recommended for patients with functional constipation who have failed to respond to treatment with available laxatives (for a minimum of 12 weeks and recommended a therapeutic regimen) or who are strongly suspected of having a defecatory disorder. The Seoul consensus contains statements of physiological testing, including balloon expulsion test, anorectal manometry, defecography, and colon transit time.

Associations of urinary polycyclic aromatic hydrocarbon (PAH) metabolites and their mixture with thyroid hormone concentration during pregnancy in the LIFECODES cohort: A repeated measures study.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine disruptors resulting from incomplete combustion. Pregnancy represents a particularly vulnerable period to such exposures, given the significant influence of hormone physiology on fetal growth and pregnancy outcomes. Maternal thyroid hormones play crucial roles in fetal development and pregnancy outcomes. However, limited studies have examined gestational PAH exposure and maternal thyroid hormones during pregnancy. METHODS: Our study included 439 women enrolled in the LIFECODES birth cohort in Boston, aiming to explore the relationship between urinary PAH metabolites and thyroid hormones throughout pregnancy. Urine samples for PAH metabolite analysis and plasma samples for thyroid hormone were measured up to four visits throughout gestation. Single pollutant analyses employed linear mixed effect models to investigate individual associations between each PAH metabolite and thyroid hormone concentration. Sensitivity analyses were conducted to assess potential susceptibility windows and fetal-sex-specific effects of PAH exposure. Mixture analyses utilized quantile g-computation to evaluate the collective impact of eight PAH metabolites on thyroid hormone concentrations. Additionally, Bayesian kernel machine regression (BKMR) was employed to explore potential non-linear associations and interactions between PAH metabolites. Subject-specific random intercepts were incorporated to address intra-individual correlation of serial measurements over time in both single pollutant and mixture analyses. RESULTS: Our findings revealed positive trends in associations between PAH metabolites and thyroid hormones, both individually and collectively as a mixture. Sensitivity analyses indicated that these associations were influenced by the study visit and fetal sex. Mixture analyses suggested non-linear relationships and interactions between different PAH exposures. CONCLUSIONS: This comprehensive investigation underscores the critical importance of understanding the impact of PAH exposures on thyroid hormone physiology during pregnancy. The findings highlight the intricate interplay between environmental pollutants and human pregnancy physiology, emphasizing the need for targeted interventions and public health policies to mitigate adverse outcomes associated with prenatal PAH exposure.

Prenatal per- and polyfluoroalkyl substances (PFAS) and maternal oxidative stress: Evidence from the LIFECODES study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals linked to adverse pregnancy outcomes. Although their underlying biological mechanisms are not fully understood, evidence suggests PFAS may disrupt endocrine functions and contribute to oxidative stress (OS) and inflammation. OBJECTIVE: We examined associations between early pregnancy PFAS exposure and OS biomarkers, exploring potential effect modifications by fetal sex and maternal race. METHODS: We used data from 469 LIFECODES participants with measured plasma PFAS (median 10 weeks gestation) and repeated measures (median 10, 18, 26, and 35 weeks gestation) of urinary OS biomarkers [8-iso-prostaglandin-F2α (8-isoprostane) and 8-hydroxydeoxyguanosine (8-OHdG)]. Protein damage biomarkers (chlorotyrosine, dityrosine, and nitrotyrosine) were additionally measured in plasma from a subset (N = 167) during the third visit. Associations between each PFAS and OS biomarkers were examined using linear mixed-effects models and multivariable linear regressions, adjusting for potential confounders, including maternal age, race, education level, pre-pregnancy BMI, insurance status, and parity. Effect modifications were evaluated by including an interaction term between each PFAS and fetal sex or maternal race in the models. RESULTS: We observed significant positive associations between PFOS and 8-isoprostane, with a 9.68% increase in 8-isoprostane levels (95% CI: 0.10%, 20.18%) per interquartile range increase in PFOS. In contrast, PFUA was negatively associated [9.32% (95% CI: -17.68%, -0.11%)], while there were suggestive positive associations for MPAH and PFOA with 8-isoprostane. The associations of several PFAS with 8-OHdG varied by fetal sex, showing generally positive trends in women who delivered females, but negative or null in those who delivered males. No significant effect modification by maternal race was observed. CONCLUSIONS: This study provides evidence linking PFAS exposure to OS during pregnancy, with potential sex-specific effects of certain PFAS on 8-OHdG. Further research should explore additional OS/inflammatory biomarkers and assess the modifying effects of dietary and behavioral patterns across diverse populations.

Blocking Microglial Proliferation by CSF-1R Inhibitor Does Not Alter the Neuroprotective Effects of Adoptive Regulatory T Cells in 3xTg Alzheimer's Disease Mice.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes cognitive impairment. Neuroinflammation induced by activated microglia exacerbates AD. Regulatory T cells (Tregs) play roles in limiting neuroinflammation by converting microglial polarization. Therefore, adoptive Treg therapy is considered an attractive option for neurodegenerative disorders. However, the mechanism underlying Treg therapy via microglial modulation is not fully understood. In this study, we sought to determine whether adoptively transferred Tregs were effective when microglia proliferation was inhibited by using GW2580, which is an inhibitor of CSF1R. We found that inhibition of microglial proliferation during Treg transfer did not alter the therapeutic effects of Tregs on cognitive deficits and the accumulation of Aß and pTAU in 3xTg-AD mice. The expression of pro- and anti-inflammatory markers in the hippocampus of 3xTg mice showed that GW2580 did not affect the inhibition of neuroinflammation by Treg transfer. Additionally, adoptively transferred Tregs were commonly detected in the brain on day 7 after transfer and their levels decreased slowly over 100 days. Our findings suggest that adoptively transferred Tregs can survive longer than 100 days in the brain, suppressing microglial activation and thus alleviating AD pathology. The present study provides valuable evidence to support the prolonged efficacy of adoptive Treg therapy in AD.

Associations of maternal blood metal concentrations with plasma eicosanoids among pregnant women in Puerto Rico.

BACKGROUND/AIM: Heavy metals are known to induce oxidative stress and inflammation, and the association between metal exposure and adverse birth outcomes is well established. However, there lacks research on biomarker profiles linking metal exposures and adverse birth outcomes. Eicosanoids are lipid molecules that regulate inflammation in the body, and there is growing evidence that suggests associations between plasma eicosanoids and pregnancy outcomes. Eicosanoids may aid our understanding of etiologic birth pathways. Here, we assessed associations between maternal blood metal concentrations with eicosanoid profiles among 654 pregnant women in the Puerto Rico PROTECT birth cohort. METHODS: We measured concentrations of 11 metals in whole blood collected at median 18 and 26 weeks of pregnancy, and eicosanoid profiles measured in plasma collected at median 26 weeks. Multivariable linear models were used to regress eicosanoids on metals concentrations. Effect modification by infant sex was explored using interaction terms. RESULTS: A total of 55 eicosanoids were profiled. Notably, 12-oxoeicosatetraenoic acid (12-oxoETE) and 15-oxoeicosatetraenoic acid (15-oxoETE), both of which exert inflammatory activities, had the greatest number of significant associations with metal concentrations. These eicosanoids were associated with increased concentrations of Cu, Mn, and Zn, and decreased concentrations of Cd, Co, Ni, and Pb, with the strongest effect sizes observed for 12-oxoETE and Pb (ß:-33.5,95 %CI:-42.9,-22.6) and 15-oxoETE and Sn (ß:43.2,95 %CI:11.4,84.1). Also, we observed differences in metals-eicosanoid associations by infant sex. Particularly, Cs and Mn had the most infant sex-specific significant associations with eicosanoids, which were primarily driven by female fetuses. All significant sex-specific associations with Cs were inverse among females, while significant sex-specific associations with Mn among females were positive within the cyclooxygenase group but inverse among the lipoxygenase group. CONCLUSION: Certain metals were significantly associated with eicosanoids that are responsible for regulating inflammatory responses. Eicosanoid-metal associations may suggest a role for eicosanoids in mediating metal-induced adverse birth outcomes.

Factors associated with gastric and duodenal neuroendocrine tumors: A multicenter case-control study.

BACKGROUND AND AIMS: The incidence of gastric and duodenal neuroendocrine tumors (GNET and DNET, respectively) is increasing, however associated factors of these diseases are not well known. Here, we investigated the factors associated with GNET and DNET. METHODS: Patients with GNET and DNET presenting at eight tertiary referral centers between 2001 and 2020 were included and compared with healthy controls who underwent upper endoscopic screening. Clinical factors and laboratory data were analyzed to determine associated factors of GNET and DNET. RESULTS: Overall, 396 patients with GNET and 193 patients with DNET were included and compared with 1725 healthy controls. Multivariate analysis showed that age (odds ratio [OR] 0.98), diabetes (OR 1.72), hypertension (OR 1.97), low serum high-density lipoprotein cholesterol (HDL-C) levels (OR 2.54), and past/present H. pylori infection (OR 1.46) were significantly associated with GNET. In contrast, DNET was significantly associated with diabetes (OR 1.80), hypertension (OR 1.68), low serum HDL-C levels (OR 2.29), and past/present H. pylori infection (OR 5.42). In the sex-based subgroup analysis in GNET, current smoking was strongly associated in women (OR 9.85), but not in men. CONCLUSIONS: This study identified several common metabolic factors associated with GNET and DNET. Additionally, some factors had sex-specific associations.

Therapeutic Effects of Aß-Specific Regulatory T Cells in Alzheimer's Disease: A Study in 5xFAD Mice.

The aging global population is placing an increasing burden on healthcare systems, and the social impact of Alzheimer's disease (AD) is on the rise. However, the availability of safe and effective treatments for AD remains limited. Adoptive Treg therapy has been explored for treating neurodegenerative diseases, including AD. To facilitate the clinical application of Treg therapy, we developed a Treg preparation protocol and highlighted the therapeutic effects of Tregs in 5xFAD mice. CD4+CD25+ Tregs, isolated after Aß stimulation and expanded using a G-rex plate with a gas-permeable membrane, were adoptively transferred into 5xFAD mice. Behavioral analysis was conducted using Y-maze and passive avoidance tests. Additionally, we measured levels of Aß, phosphorylated tau (pTAU), and nitric oxide synthase 2 (NOS2) in the hippocampus. Real-time RT-PCR was employed to assess the mRNA levels of pro- and anti-inflammatory markers. Our findings indicate that Aß-specific Tregs not only improved cognitive function but also reduced Aß and pTAU accumulation in the hippocampus of 5xFAD mice. They also inhibited microglial neuroinflammation. These effects were observed at doses as low as 1.5 × 103 cells/head. Collectively, our results demonstrate that Aß-specific Tregs can mitigate AD pathology in 5xFAD mice.

Gestational glyphosate exposure and early childhood neurodevelopment in a Puerto Rico birth cohort.

INTRODUCTION: N-(phosphonomethyl)glycine, or glyphosate, is a non-selective systemic herbicide widely used in agricultural, industrial, and residential settings since 1974. Glyphosate exposure has been inconsistently linked to neurotoxicity in animals, and studies of effects of gestational exposure among humans are scarce. In this study we investigated relationships between prenatal urinary glyphosate analytes and early childhood neurodevelopment. METHODS: Mother-child pairs from the PROTECT-CRECE birth cohort in Puerto Rico with measures for both maternal urinary glyphosate analytes and child neurodevelopment were included for analysis (n = 143). Spot urine samples were collected 1-3 times throughout pregnancy and analyzed for glyphosate and aminomethylphosphonic acid (AMPA), an environmental degradant of glyphosate. Child neurodevelopment was assessed at 6, 12, and 24 months using the Battelle Developmental Inventory, 2nd edition Spanish (BDI-2), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. We used multivariable linear regression to examine associations between the geometric mean of maternal urinary glyphosate analytes across pregnancy and BDI-2 scores at each follow-up. Results were expressed as percent change in BDI-2 score per interquartile range increase in exposure. RESULTS: Prenatal AMPA concentrations were negatively associated with communication domain at 12 months (%change = -5.32; 95%CI: 9.04, -1.61; p = 0.007), and communication subdomain scores at 12 and 24 months. At 24 months, four BDI-2 domains were associated with AMPA: adaptive (%change = -3.15; 95%CI: 6.05, -0.25; p = 0.038), personal-social (%change = -4.37; 95%CI: 7.48, -1.26; p = 0.008), communication (%change = -7.00; 95%CI: 11.75, -2.26; p = 0.005), and cognitive (%change = -4.02; 95%CI: 6.72, -1.32; p = 0.005). Similar trends were observed with GLY concentrations, but most confidence intervals include zero. We found no significant associations at 6 months. CONCLUSIONS: Our results suggest that gestational exposure to glyphosate is associated with adverse early neurodevelopment, with more pronounced delays at 24 months. Given glyphosate's wide usage, further investigation into the impact of gestational glyphosate exposure on neurodevelopment is warranted.

Evaluation of the Efficacy and Safety of DW1903 in Patients with Gastritis: A Randomized, Double-Blind, Noninferiority, Multicenter, Phase 3 study.

Background/Aims: H2 receptor antagonists (H2RA) have been used to treat gastritis by inhibiting gastric acid. Proton pump inhibitors (PPIs) are more potent acid suppressants than H2RA. However, the efficacy and safety of low-dose PPI for treating gastritis remain unclear. The aim was to investigate the efficacy and safety of low-dose PPI for treating gastritis. Methods: A double-blind, noninferiority, multicenter, phase 3 clinical trial randomly assigned 476 patients with endoscopic erosive gastritis to a group using esomeprazole 10 mg (DW1903) daily and a group using famotidine 20 mg (DW1903R1) daily for 2 weeks. The full-analysis set included 319 patients (DW1903, n=159; DW1903R1, n=160) and the per-protocol set included 298 patients (DW1903, n=147; DW1903R1, n=151). The primary endpoint (erosion improvement rate) and secondary endpoint (erosion and edema cure rates, improvement rates of hemorrhage, erythema, and symptoms) were assessed after the treatment. Adverse events were compared. Results: According to the full-analysis set, the erosion improvement rates in the DW1903 and DW1903R1 groups were 59.8% and 58.8%, respectively. According to the per-protocol analysis, the erosion improvement rates in the DW1903 and DW1903R1 groups were 61.9% and 59.6%, respectively. Secondary endpoints were not significantly different between two groups except that the hemorrhagic improvement rate was higher in DW1903 with statistical tendency. The number of adverse events were not statistically different. Conclusions: DW1903 of a low-dose PPI was not inferior to DW1903R1 of H2RA. Thus, lowdose PPI can be a novel option for treating gastritis (ClinicalTrials.gov Identifier: NCT05163756).

Perceptions of and Practices for the Management of Constipation: Results of a Korean National Survey.

Background/Aims: Although guidelines exist regarding the evaluation and management of patients with chronic constipation (CC), little is known about real-world clinical practice patterns. This study aimed to evaluate the various practices used to manage CC patients in various clinical settings in South Korea. Methods: A nationwide web-based survey was conducted, randomly selecting gastroenterologists and non-gastroenterologists. The 25-item questionnaire included physicians' perceptions and practices regarding the available options for diagnosing and managing CC patients in Korea. Results: The study participants comprised 193 physicians (86 gastroenterologists, 44.6%) involved in the clinical management of CC patients. The mean clinical experience was 12 years. Only 21 of 193 respondents (10.9%) used the Rome criteria when diagnosing CC. The Bristol Stool Form Scale was used by 29% of the respondents (56/193), while the digital rectal examination was performed by 11.9% of the respondents (23/193). Laboratory testing and colonoscopies were performed more frequently by gastroenterologists than by non-gastroenterologists (both p=0.001). Physiologic testing was used more frequently by gastroenterologists (p=0.046), physicians at teaching hospitals, and physicians with clinical experience ≤10 years (both p<0.05). There were also significant differences in the preference for laxatives depending on the type of hospital. Conclusions: There were discrepancies in the diagnosis and management of CC patients depending on the clinical setting. The utilization rates of the Bristol Stool Form Scale and digital rectal examination by physicians are low in real-world clinical practice. These results imply the need for better and more practical training of physicians in the assessment and management of CC.

Efficacy and safety of CKD-495 in acute and chronic gastritis: A Phase III superiority clinical trial.

BACKGROUND: Despite the availability of numerous treatment options, many patients with gastritis experience only partial symptom relief. CKD-495, a newly developed product with the active ingredient extracted from Cinnamomum cassia Presl., has demonstrated anti-inflammatory and antioxidant activity in vitro and an in vivo protective effect against gastric damage by stimulating mucus secretion. This study compared the efficacy and safety of CKD-495 with Artemisiae argyi folium (AAF) for the treatment of acute and chronic gastritis. AAF, a gastric mucosa protective agent that promotes gastric mucosa regeneration, has been used clinically for about 20 years. METHODS: This phase III multicenter, randomized, double-blind, parallel-group trial (ClinicalTrials.gov; NCT04255589) assigned 242 patients with endoscopically-proven gastric mucosal erosions to receive CKD-495 75 mg (n = 122) or AAF 60 mg (n = 120), respectively, with placebo (for double-blind purposes) 3 times a day for 2 weeks. The primary efficacy endpoint was the erosion improvement rate. Secondary endpoints included erosion cure rates, and improvement rates for edema, redness, hemorrhage, and gastrointestinal (GI) symptoms. Drug-related adverse events were evaluated. RESULTS: The erosion improvement rate was significantly higher in the CKD-495 group than in the AAF group for both the full analysis set (55.9% vs 39.4%, P = .0063) and per-protocol set (54.6% vs 38.2%, P = .0084). In addition, the erosion improvement rate in patients with acute or chronic gastritis showed that the CKD-495 group had better improvement of erosion than the AAF group, especially in patients with chronic gastritis. Analysis of secondary endpoints, which included erosion cure rate and the improvement rates of edema, redness, hemorrhage, and GI symptoms, showed that the CKD-495 group was more effective than the AAF group. There were no significant between-group differences in safety profiles. No serious adverse events or adverse drug reactions occurred. CONCLUSIONS: These results demonstrate that CKD-495 75 mg is superior to AAF 60 mg in terms of the endoscopic improvement rate of erosions in patients with acute or chronic gastritis. This new mucoprotective agent, CKD-495, can be considered the therapy of choice for symptomatic relief and healing of gastritis.

Relationship between plasma leucine-rich α-2-glycoprotein 1 and urinary albumin excretion in patients with type 2 diabetes.

Aims: To explore the relationship between plasma leucine-rich α-2-glycoprotein 1 (LRG1) level and the degree of urinary albumin excretion in patients with type 2 diabetes. Methods: We evaluated 332 patients with type 2 diabetes in a cross-sectional study. Result: The plasma LRG1 level differed significantly according to the quartiles of urinary albumin excretion (Q1 [<7.7 mg/g], 17.1 µg/mL; Q2 [7.7-15.0 mg/g], 17.5 µg/mL; Q3 [15.1-61.4 mg/g], 18.6 µg/mL; Q4 [≥61.5 mg/g], 22.3 µg/mL; p for trend = 0.003) under adjustment with other covariates. A positive correlation was found between plasma LRG1 level and urinary albumin excretion (ρ = 0.256, p <0.001). According to a multivariate model, the association between LRG1 and urinary albumin excretion remained significant, under adjustment for confounding factors (ß = 0.285, p <0.001). Conclusion: Plasma LRG1 level was independently associated with urinary albumin excretion in patients with type 2 diabetes. This study suggests that LRG1 may be associated with increased excretion of urinary albumin in the early stages of diabetic nephropathy.

Risk factors for patients hospitalized with recurrent colon diverticular bleeding: a single center experience.

Background/aims: Colonic diverticular bleeding (CDB) is a common cause of acute lower gastrointestinal bleeding. Patients with CDB are at increased risk for recurrence. Here, we aimed to evaluate the clinical course of patients with CDB and identify risk factors for recurrent CDB (rCDB). Methods: We included patients who were hospitalized at a single tertiary center for management of CDB between January 2005 and March 2020. A Cox proportional hazards regression analysis was performed to evaluate the risk factors of patients with rCDB as follows: model 1 adjusted by age, Charlson comorbidity index (CCI), and presence of bilateral colon diverticula; model 2 adjusted by age, CCI, and presence of left side colon diverticula; model 3 adjusted by age, CCI, and presence of sigmoid colon diverticula. Results: Among 219 patients (mean age, 68.0 years; 55 females), 56 and 163 had definite and presumptive CDB, respectively. During the median period of 506 days, 62 patients (28.3%) experienced rCDB. CCI score ≥ 4 was independently associated with rCDB in models 1, 2 and 3 (all p < 0.05). Age ≥ 75 years was independently associated with rCDB in models 1 and 2 (both p < 0.05). The presence of bilateral colon and sigmoid colon diverticula were independently associated with rCDB in models 1 and 3, respectively (both p < 0.05). Conclusion: rCDB frequently occurred at any time in patients with previous CDB. High CCI scores and distribution of colon diverticula were associated with rCDB. Clinicians should consider a possible rCDB for a patient considering age, comorbidity, and distribution of colon diverticula.

Constipation in Patients With Chronic Kidney Disease.

Constipation is a frequent symptom in patients with chronic kidney disease (CKD). This review outlines the mechanisms and management of constipation in patients with CKD from a physician's perspective. Common causes of constipation in patients with CKD include concomitant medications, low dietary fiber intake, water-restricted diet, lack of physical activity, altered gut microbiota, and reduced gastrointestinal motility. Constipation has a negative impact on overall health, and, in particular, the presence of constipation has been associated with worsening kidney function and increased risk of developing advanced stages of CKD. Although lifestyle and dietary modifications may not always be practical for patients with CKD, they are recommended because they are beneficial as they lower mortality in patients with CKD. The use of laxatives containing magnesium salts, bulking agents, and osmotic laxatives may have insufficient efficacy and may be associated with adverse effects. In contrast, lactulose and lubiprostone have been shown to exhibit reno-protective effects. Linaclotide and plecanatide have very limited systemic absorption and appear safe in patients with CKD. Tenapanor reduces paracellular intestinal phosphate absorption in addition to blocking sodium uptake by enterocytes, and provides additional benefit in patients patients with CKD who have hyperphosphatemia and constipation. Prucalopride leads to improvements in bowel function and constipation-related symptoms in cases in which response to conventional laxatives are inadequate. However, the dose of prucalopride should be reduced to 1 mg once daily for patients with CKD. In conclusion, there are important advances on the impact and treatment of constipation in patients with CKD.

On-demand Versus Continuous Maintenance Treatment With a Proton Pump Inhibitor for Mild Gastroesophageal Reflux Disease: A Prospective Randomized Multicenter Study.

Background/Aims: It remains unclear which maintenance treatment modality is most appropriate for mild gastroesophageal reflux disease (GERD). We aimed to compare on-demand treatment with continuous treatment using a proton pump inhibitor (PPI) in the maintenance treatment for patients with non-erosive GERD or mild erosive esophagitis. Methods: Patients whose GERD symptoms improved after 4 weeks of standard dose PPI treatment were prospectively enrolled at 25 hospitals. Subsequently, the enrolled patients were randomly assigned to either an on-demand or a continuous maintenance treatment group, and followed in an 8-week interval for up to 24 weeks. Results: A total of 304 patients were randomized to maintenance treatment (continuous, n = 151 vs on-demand, n = 153). The primary outcome, the overall proportion of unwillingness to continue the assigned maintenance treatment modality, failed to confirm the non-inferiority of on-demand treatment (45.9%) compared to continuous treatment (36.1%). Compared with the on-demand group, the GERD symptom and health-related quality of life scores significantly more improved and the overall satisfaction score was significantly higher in the continuous treatment group, particularly at week 8 and week 16 of maintenance treatment. Work impairment scores were not different in the 2 groups, but the prescription cost was less in the on-demand group. Serum gastrin levels significantly elevated in the continuous treatment group, but not in the on-demand group. Conclusions: Continuous treatment seems to be more appropriate for the initial maintenance treatment of non-erosive GERD or mild erosive esophagitis than on-demand treatment. Stepping down to on-demand treatment needs to be considered after a sufficient period of continuous treatment.

Alpha-Synuclein-Specific Regulatory T Cells Ameliorate Parkinson's Disease Progression in Mice.

Parkinson's disease (PD) is a long-term neurodegenerative disease characterized by dopaminergic neuronal loss and the aggregation of alpha-synuclein (α-syn) in the brain. Cell therapy using regulatory T cells (Tregs) has therapeutic potential on PD progression in a mouse model; however, several challenges were associated with its applications. Here, we propose a strategy for α-syn specific Treg expansion (α-syn Treg). We presented α-syn to T cells via dendritic cells. This method increased the mobility of Tregs towards the site of abundant α-syn in vitro (p < 0.01; α-syn Tregs versus polyclonal Tregs (poly Tregs)) and in vivo. Consequently, α-syn Tregs showed noteworthy neuroprotective effects against motor function deficits (p < 0.05, p < 0.01; α-syn Tregs versus poly Tregs), dopaminergic neuronal loss (p < 0.001; α-syn Tregs versus poly Tregs), and α-syn accumulation (p < 0.05; α-syn Tregs versus poly Tregs) in MPTP-induced PD mice. Furthermore, the adoptive transfer of α-syn Tregs exerted immunosuppressive effects on activated microglia, especially pro-inflammatory microglia, in PD mice. Our findings suggest that α-syn presentation may provide a significant improvement in neuroprotective activities of Tregs and suggest the effective clinical application of Treg therapy in PD.

Real-World Epidemiology, Treatment Patterns, and Disease Burden of Chronic Hepatitis B and HDV Co-Infection in South Korea.

INTRODUCTION: Long-term complications of chronic hepatitis B (CHB) viral infection, such as cirrhosis, hepatocellular carcinoma (HCC), and liver failure, cause a large disease burden. This study aimed to describe the epidemiology, clinical outcomes, and treatment patterns of CHB infection and co-infection with hepatitis D virus (HDV) in South Korea. METHODS: The retrospective, observational study used existing data from the Health Insurance Review and Assessment Service (HIRA) database. Confirmed cases of (CHB) and HBV/HDV co-infection were identified between 2013 and 2019. Hepatitis C virus co-infections and acute HBV infections were excluded. Incident cases diagnosed between 2015 and 2018 with no prior disease history up to 2 years were included. Patient characteristics, clinical outcomes, economic burden, and healthcare-resource utilization were described. RESULTS: The estimated 7-year prevalence of CHB and HBV/HDV co-infection were 0.9% and 0.0024%, respectively. The prevalence was higher among 45-54 years old (CHB: 1.6%, HBV/HDV: 0.0049%) and males (1.1%, 0.0035%). The 5-year cumulative incidences of compensated cirrhosis, decompensated cirrhosis, HCC, and liver transplantation were 13.3%, 7.1%, 8.4%, and 0.7%, respectively. Hyperlipidemia (40.6%), hypertension (23.5%), and peptic ulcer (23.7%) were the more prevalent comorbidities. Among CHB patients, 48.1% received ≥ 1 prescribed anti-HBV drug including interferon or nucleos(t)ide analogues and 64.4% had ≥ 1 hospitalization compared to 80.4% and 79.4% HBV/HDV patients. Estimated total healthcare costs for CHB and HBV/HDV were US$786 million and $62 million, respectively. CONCLUSIONS: These findings provide insights to the epidemiology, clinical burden, treatment patterns, and healthcare costs of CHB and HBV/HDV co-infection in South Korea.

Successful Simultaneous Treatment of Benign Stricture and Colonic Neoplasm Arising from Colonic Interposition after Esophagectomy: A Case Report.

Colonic interposition is the main procedure used in esophageal reconstruction. We report a rare case of simultaneous treatment of an anastomotic site stricture and a neoplasm in the interpositioned colon. A 69-year-old female visited our outpatient clinic with symptoms of progressive dysphagia for 1 year. At the age of 30 years, the patient underwent esophagectomy with retrosternal colonic interposition because of severe esophageal burns after chemical ingestion. Upper gastrointestinal endoscopy revealed stricture at the anastomosis site and a 10-mm flat elevated high-grade dysplasia in the interpositioned colon. First, through-the-scope balloon dilatation was performed for strictures. However, stenosis was observed during the second upper gastrointestinal endoscopy session. Therefore, a second session of through-the-scope balloon dilatation was performed, and simultaneously, endoscopic submucosal dissection was also successfully performed. After 2 months of follow-up, stenosis persisted; consequently, balloon dilatation was performed. No recurrence of neoplasm was confirmed endoscopically. Through-the-scope balloon dilatation of the stricture site and simultaneous endoscopic submucosal dissection of the neoplasm in the interpositioned colon were successfully performed.