Bowel preparation with linaclotide and 1 L polyethylene glycol plus ascorbic acid prior to colonoscopy in chronic constipated patients.

BACKGROUND AND AIMS: Information on effective bowel preparation (BP) methods for patients with constipation is limited. We recently reported the efficacy of 1 L polyethylene glycol plus ascorbic acid (PEG-Asc) combined with senna for BP; however, this regimen was insufficient in patients with constipation. We hypothesized that the addition of linaclotide, which is approved for the treatment of chronic constipation, to 1 L PEG-Asc would yield results superior to those of senna in patients with constipation. METHODS: This was a retrospective, single-center study that included outpatients with constipation who underwent BP prior to colonoscopy between March and December 2019 (receiving 1 L PEG-Asc with 24 mg senna) and between January and October 2020 (receiving 1 L PEG-Asc with 500 mg linaclotide). RESULTS: A total of 543 patients with constipation were included, of whom 269 received linaclotide and 274 received senna. The rate of inadequate BP was significantly lower (11% vs 20%, p < 0.01) and the adenoma detection rate was significantly higher (54% vs 45%, p = 0.04) in the linaclotide group than in the senna group. Multivariate analysis revealed that the linaclotide regimen significantly reduced the risk of inadequate BP (odds ratio = 0.36, 95% confidence interval = 0.21-0.60, p < 0.01). CONCLUSIONS: The linaclotide regimen significantly increased BP efficacy and the adenoma detection rate compared with the senna regimen without reducing tolerability and is therefore a promising new option for BP in patients with constipation.

Importance of Bowel Habits in Predicting Inadequate Bowel Preparation: A Prospective Observational Study.

OBJECTIVES: Inadequate bowel preparation (BP) negatively affects the efficacy and quality of colonoscopy. Although constipation has already been reported as one of the most important predictors of inadequate BP, there is limited information on the relation between inadequate BP and bowel habits including constipation-related symptoms, medications, and severity of constipation. METHODS: This single-center, prospective observational study was conducted between August 2019 and May 2020. All participants answered questionnaires regarding personal bowel habits and received low-volume polyethylene glycol plus ascorbic acid for outpatient colonoscopy. Severity of constipation was evaluated by constipation scoring system. Bowel preparation cleansing was evaluated using Boston Bowel Preparation Scale (BBPS). Potential predictors of inadequate BP were analyzed using multivariate logistic regression models. RESULTS: Overall, 1054 patients were enrolled, of which, 105 (10%) had inadequate BP (total BBPS ≤ 6 or any segmental BBPS < 2). The risk of inadequate BP increased with constipation severity (P = 0.01). Multivariate analysis showed that frequent straining (> 25% of defecations) (OR 2.09, 95% CI: 1.33-3.28) and chronic use of stimulant laxatives (OR 2.57, 95% CI: 1.59-4.17) were significant predictors of inadequate BP, among personal bowel habits. CONCLUSION: Frequent straining and chronic use of stimulant laxatives were predictors of inadequate BP. An intensified preparation regimen should be considered for severely constipated patients with straining and chronic use of stimulant laxatives.

Bidirectional Elongation Strategy Using Ambiphilic Radical Linchpin for Modular Access to 1,4-Dicarbonyls via Sequential Photocatalysis.

Organic molecules that can be connected to multiple substrates by sequential C-C bond formations can be utilized as linchpins in multicomponent processes. While they are useful for rapidly increasing molecular complexity, most of the reported linchpin coupling methods rely on the use of organometallic species as strong carbon nucleophiles to form C-C bonds, which narrows the functional group compatibility. Here, we describe a metal-free, radical-mediated coupling approach using a formyl-stabilized phosphonium ylide as a multifunctional linchpin under visible-light photoredox conditions. The present method uses the ambiphilic character of the phosphonium ylide, which serves as both a nucleophilic and an electrophilic carbon-centered radical source. The stepwise and controllable generation of these radical intermediates allows sequential photocatalysis involving two mechanistically distinct radical additions, both of which are initiated by the same photocatalyst in one pot with high functional group tolerance. The methodology enables a bidirectional assembly of the linchpin with two electronically differentiated alkene fragments and thus offers rapid and modular access to 1,4-dicarbonyl compounds as versatile synthetic intermediates.

Emergence of [GAR+ ] cells in yeast from sake brewing affects the fermentation properties.

In the traditional (kimoto) method of sake (Japanese rice wine) brewing, Saccharomyces cerevisiae yeast cells are exposed to lactate, which is produced by lactic acid bacteria in the seed mash. Lactate promotes the appearance of glucose-repression-resistant [GAR+ ] cells. Herein, we compared the resistance to glucose repression among kimoto, industrial, and laboratory yeast strains. We observed that the frequencies of the spontaneous emergence of [GAR+ ] cells among the kimoto strains were higher than those among the industrial and laboratory strains. The fermentation ability of a kimoto yeast (strain U44) was lower than that of an industrial strain (K701), as [GAR+ ] cells generally showed slower ethanol production. The addition of lactate decreased the fermentation abilities of the K701 strain by increasing the number of [GAR+ ] cells, but it did not affect those of the U44 strain. These results suggest that lactate controlled fermentation by promoting the appearance of [GAR+ ] cells in the industrial sake strains but not in the kimoto strains.

Efficacy and tolerability of 1 L polyethylene glycol plus ascorbic acid with senna versus 2 L polyethylene glycol plus ascorbic acid for colonoscopic bowel preparation: Prospective, randomized, investigator-blinded trial.

OBJECTIVES: Low-volume polyethylene glycol plus ascorbic acid (PEG-Asc) reduces the dosage of colonoscopic bowel preparation (BP) solution, but is still poorly tolerated. Adding laxatives to the BP solution reduces the volume of fluid required, without affecting quality. This study aimed to compare 1 L PEG-Asc plus 24 mg senna (1L-PEG/AS) and conventional 2 L PEG-Asc (2L-PEG/A) regimens on BP quality and patient tolerability. METHODS: A single-center, randomized, investigator-blinded, noninferiority trial was performed between June and August 2022. Outpatients scheduled for colonoscopy were randomized (1:1) to the 1L-PEG/AS or 2L-PEG/A group. The Boston Bowel Preparation Scale (BBPS) was used to evaluate BP quality. Adverse events and tolerability were surveyed using questionnaires. RESULTS: Overall, 344 patients received 1L-PEG/AS or 2L-PEG/A regimens. The baseline characteristics and adverse events of the two groups were comparable. The 1L-PEG/AS group showed noninferior adequate BP rates compared with the 2L-PEG/A group (88% vs. 89%, P = 1.00); overall BBPS was 7.1 ± 1.5 and 7.2 ± 1.5, respectively (P = 0.39). Higher willingness to repeat the BP was observed in the 1L-PEG/AS group (85% vs. 62%, P < 0.01). CONCLUSIONS: The 1L-PEG/AS regimen was comparable to the 2L-PEG/A regimen in terms of BP adequacy, requiring lower BP solution volumes, with better patient tolerance. Thus, it may be a suitable alternative to the conventional BP solution for colonoscopy. The Japan Registry of Clinical Trials (jRCT1051220043).

Analysis of the Factors Affecting Static In Vitro Pepsinolysis of Food Proteins.

In this meta-analysis, we collected 58 publications spanning the last seven decades that reported static in vitro protein gastric digestion results. A number of descriptors of the pepsinolysis process were extracted, including protein type; pepsin activity and concentration; protein concentration; pH; additives; protein form (e.g., 'native', 'emulsion', 'gel', etc.); molecular weight of the protein; treatment; temperature; and half-times (HT) of protein digestion. After careful analysis and the application of statistical techniques and regression models, several general conclusions could be extracted from the data. The protein form to digest the fastest was 'emulsion'. The rate of pepsinolysis in the emulsion was largely independent of the protein type, whereas the gastric digestion of the native protein in the solution was strongly dependent on the protein type. The pepsinolysis was shown to be strongly dependent on the structural components of the proteins digested-specifically, ß-sheet-inhibited and amino acid, leucine, methionine, and proline-promoted digestion. Interestingly, we found that additives included in the digestion mix to alter protein hydrolysis had, in general, a negligible effect in comparison to the clear importance of the protein form or additional treatment. Overall, the findings allowed for the targeted creation of foods for fast or slow protein digestion, depending on the nutritional needs.

The C-type lectin receptor Clec1A plays an important role in the development of experimental autoimmune encephalomyelitis by enhancing antigen presenting ability of dendritic cells and inducing inflammatory cytokine IL-17.

Clec1A, a member of C-type lectin receptor family, has a carbohydrate recognition domain in its extracellular region, but no known signaling motif in the cytoplasmic domain. Clec1a is highly expressed in endothelial cells and weakly in dendritic cells. Although this molecule was reported to play an important role in the host defense against Aspergillus fumigatus by recognizing 1,8-dihydroxynaphthalene-melanin on the fungal surface, the roles of this molecule in un-infected animals remain to be elucidated. In this study, we found that Clec1a-/- mice develop milder symptoms upon induction of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The maximum disease score was significantly lower, and demyelination and inflammation of the spinal cord were much milder in Clec1a-/- mice compared to wild-type mice. No abnormality was detected in the immune cell composition in the draining lymph nodes and spleen on day 10 and 16 after EAE induction. Recall memory T cell proliferation after restimulation with myelin oligodendrocyte glycoprotein peptide (MOG35-55) in vitro was decreased in Clec1a-/- mice, and antigen presenting ability of Clec1a-/- dendritic cells was impaired. Interestingly, RNA-Seq and RT-qPCR analyses clearly showed that the expression of inflammatory cytokines including Il17a, Il6 and Il1b was greatly decreased in Clec1a-/- mice after induction of EAE, suggesting that this reduced cytokine production is responsible for the amelioration of EAE in Clec1a-/- mice. These observations suggest a novel function of Clec1A in the immune system.

Chronic constipation is negatively associated with colonic diverticula.

OBJECTIVES: Constipation has been considered the key risk factor for diverticulosis occurrence, but the underlying mechanism is unclear. We investigated the factors associated with diverticulosis, focusing on the association of constipation severity with the localization and number of diverticula. MATERIALS AND METHODS: We analyzed consecutive patients who underwent colonoscopy between March and December 2019. Chronic constipation was diagnosed as constipation meeting Rome IV criteria or as that requiring laxative therapy for more than 6 months. The degree of constipation was scored using the Constipation Scoring System (CSS). RESULTS: We assessed 1014 patients. Multivariate analysis revealed that age, alcohol consumption, and hypertension were positively associated with diverticulosis, whereas chronic constipation was negatively associated with diverticulosis (odds ratio [OR] = 0.74; 95% confidence interval [CI], 0.55-0.99). When assessed according to the location of diverticula, right-sided diverticula were significantly associated with a lower incidence of constipation (OR = 0.94; 95% CI, 0.89-0.98), whereas neither left-sided nor bilateral diverticula was associated with constipation. This negative association of diverticula with constipation was stronger in patients with a high CSS score. In stratified analysis, the number of diverticula decreased with increasing degree of constipation (p for trend <.01), and a high CSS score was associated with a decreased prevalence of ≥3 diverticula (OR = 0.64; 95% CI, 0.44-0.99). CONCLUSIONS: Chronic constipation was negatively associated with colonic diverticulosis. The association increased with the degree of constipation and was strong only in cases with right-sided diverticula and those with ≥3 diverticula.

A 25 mg rectal dose of diclofenac for prevention of post-ERCP pancreatitis in elderly patients.

OBJECTIVES: A 50-100 mg rectal dose of diclofenac or indomethacin is recommended for prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP); however, limited data are available regarding the appropriate dose to prevent PEP in elderly patients. We aimed to evaluate the efficacy and safety of 25 mg diclofenac in preventing PEP in elderly patients. Material and methods: Overall, 276 patients with naive papilla, aged over 75 years, were included in the present study between April 2013 and March 2020. We retrospectively evaluated the risk of PEP in patients over 75 years, administered with or without 25 mg diclofenac 30 min before ERCP using inverse probability of treatment weighting (IPTW) analysis. Results: Patients were categorized into the diclofenac group (83 patients) or non-diclofenac group (193 patients). The incidence rate of PEP in the diclofenac group was significantly lower than that in the non-diclofenac group (4% vs. 14%, p = .01). Multivariate analysis revealed that 25 mg diclofenac was an independent protective factor against PEP in elderly patients aged over 75 years (odds ratio [OR] = 0.17; 95% confidence interval [CI] = 0.04-0.67; p = 0.01). This protective effect of diclofenac against PEP remained robust after IPTW analysis (OR = 0.11; 95% CI = 0.03-0.40; p = .001). No adverse events related to diclofenac were observed. Conclusion: Diclofenac (25 mg) was considered effective and safe for preventing PEP in elderly patients. Our results may provide a new strategy for preventing PEP in elderly patients.

Assessment of finger motor function that reflects the severity of cognitive function.

OBJECTIVES: We conducted a finger tapping movement test using a finger tapping device with magnetic sensors (UB-2) and performed multiple regression analyses using a number of finger movements parameters to estimate the severity of cognitive impairment. METHODS: The subjects of this study were 64 patients, including 44 diagnosed with Alzheimer's disease (AD) (mean age: 73.8±7.0 years) and 20 diagnosed with mild cognitive impairment (MCI) (mean age: 76.7±4.2 years). For the finger-tapping movement tasks, we tested single-hand (left and right) tapping, simultaneous tapping of both hands, and alternate tapping between hands. After measurement, multiple regression analysis adjusted for age and sex was performed to predict the Mini-Mental State Examination (MMSE) score from the calculated hand parameters. RESULTS: Relatively high standardized partial regression coefficients were observed for the following two parameters: standard deviation (SD) of distance rate of velocity peak in extending movement and the SD of contact duration. The coefficients of determination (R2) ranged between 0.1 to 0.28. CONCLUSIONS: Our results suggest the possibility that these parameters may be used to assess cognitive function. We shall obtain large-scale data from older people to examine the possibility of these parameters to be used as an early diagnostic tool for dementia patients.

Effect of Genetic Polymorphisms of Human SLC22A3 in the 5'-flanking Region on OCT3 Expression and Sebum Levels in Human Skin.

BACKGROUND: Human organic cation transporter 3 (OCT3,SLC22A3) mediates the uptake of many important endogenous substances and basic drugs, and has been identified as one of the transporters that are highly expressed in human skin. However, the mechanisms responsible for variability in mRNA expression, and the role of SLC22A3 in human skin is not clear. OBJECTIVE: We examined the effects of the single nucleotide polymorphisms ofSLC22A3 on the variability in SLC22A3 expression and sebum levels in humans. METHODS: Immunostaining of OCT3 in human skin was performed. We analyzed the association of promoter variants with the SLC22A3 mRNA expression levels in human skins. Luciferase, knockdown, chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay were employed to investigate transcriptional regulation of SLC22A3 expression. Effects of the identified variant on sebum levels were evaluated in healthy volunteers. RESULTS: Immunohistochemistry revealed marked expressions of OCT3 in the basal epidermis, sebaceous glands, hair follicles, and sweat glands of human skin. SLC22A3 mRNA levels were significantly lower in skin samples with homozygotes for -1603A/A than in those for -1603 G/G. The analysis of p53 binding to -1603 G > A in the promoter ofSLC22A3 suggested that -1603 G > A down-regulates SLC22A3 gene expression by decreased p53 binding in the vicinity of the -1603 site. In humans, squalene levels in samples from the back at the baseline were significantly lower in homozygotes for -1603A/A than in those for -1603 G/G. CONCLUSION: These results suggest that the genetic variant contributes to the variability of expression and activities of OCT3 in human skin.

Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells.

The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anticancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function to suppress harmful immune responses. Here we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell surface molecules. GC-induced up-regulation of PD-1 depended on transactivation of PD-1 transcription mediated through the glucocorticoid receptor. We further found that a GC response element 2525 bp upstream of the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level.

Differences among patients with Alzheimer's disease, older adults with mild cognitive impairment and healthy older adults in finger dexterity.

AIM: We have developed a smart terminal device for screening finger function, and investigated the capability of this tool for detecting abnormalities of finger dexterity. METHODS: Finger dexterity was measured for 31 patients with Alzheimer's disease (AD group), 15 people diagnosed with mild cognitive impairment (MCI group) and 48 family members (healthy older adult group) as the control. Cognitive function was assessed using the Mini-Mental State Examination. RESULTS: There were significant differences between the AD and control group in response time, rhythm and contact duration (P ≤ 0.05), and a negative correlation was identified between contact duration and Mini-Mental State Examination score (-0.36 to -0.5; P ≤ 0.05). Also, there were significant differences between the AD and MCI group in response time and contact duration (P ≤ 0.05). DISCUSSION: These results show that declines in finger dexterity can reflect declining cognitive function, and that measurement of finger dexterity using our smart terminal device can facilitate screening of large groups for MCI or AD. Geriatr Gerontol Int 2018; 18: 907-914.

Interindividual Differences in the Expression of ATP-Binding Cassette and Solute Carrier Family Transporters in Human Skin: DNA Methylation Regulates Transcriptional Activity of the Human ABCC3 Gene.

The identification of drug transporters expressed in human skin and interindividual differences in gene expression is important for understanding the role of drug transporters in human skin. In the present study, we evaluated the expression of ATP-binding cassette (ABC) and solute carrier (SLC) transporters using human skin tissues. In skin samples, ABCC3 was expressed at the highest levels, followed by SLCO3A1, SLC22A3, SLC16A7, ABCA2, ABCC1, and SLCO2B1. Among the quantitated transporters, ABCC3 accounted for 20.0% of the total mean transporter mRNA content. The expression of ABCC3 mRNA showed large interindividual variability (9.5-fold). None of the single nucleotide polymorphisms tested (-1767G>A, -1328G>A, -1213C>G, -897delC, -260T>A, and -211C>T) in the promoter region of the ABCC3 gene showed a significant change in ABCC3 mRNA levels. ABCC3 expression levels negatively correlated with the methylation status of the CpG island (CGI) located approximately 10 kilobase pairs upstream of ABCC3 (Rs: -0.323, P < 0.05). The reporter gene assay revealed a significant increase in transcriptional activity in the presence of CGI. ABCC3 mRNA was upregulated in HaCaT cells by the demethylating agent 5-aza-2'-deoxycytidine. Furthermore, the deletion of the region surrounding CGI using the clustered regularly interspaced short palindromic repeat/Cas9 system resulted in significantly lower ABCC3 mRNA levels than those in control clones in HaCaT cells. Herein, we demonstrated large interindividual differences in the expression of drug transporters in human skin. CGI may function as an enhancer of the transcription of ABCC3, and methylation levels in CGI contribute to the variability of ABCC3 expression in human skin.