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.

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).

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.

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.