Role of bile acids in inflammatory liver diseases

Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases

The RT-18: a new screening tool to assess young adult risk-taking behavior

Risk-taking behavior is a major determinant of health and plays a central role in various diseases. Therefore, a brief questionnaire was developed to assess risk taking among young adults with known different levels of risk-taking behavior (social drinkers and recreational drug users). In Study 1, N = 522 university students completed the RT-18 risk taking questionnaire. N = 100 students were retested after 2 to 4 weeks and performed the Cambridge Gambling Task (CGT). Mean RT-18 score was 7.69 and Cronbach’s alpha was 0.886. The test-retest reliability was r = 0.94. Significant correlation was found between the RT-18 score and CGT scores of risk taking, bet proportion, and risk adjustment. In Study 2, N = 7834 young adult social drinkers, and recreational drug users, mean RT-18 score was 9.34 and Cronbach’s alpha was 0.80. Factor analysis showed that the RT-18 comprises two factors assessing level of risk-taking behavior and risk assessment. Men scored significantly higher than women on the RT-18. Recreational drug users had significantly higher scores when compared to social drinkers. In Study 3 of N = 1000 students, construct validity was confirmed by showing that the RT-18 outcome correlates significantly with scores on the Stimulating-Instrumental Risk Inventory. In conclusion, the RT-18 is a valid and reliable screening tool to differentiate levels of risk-taking behavior. This short scale is quick and practical to administer, imposing minimal demands on participants. The RT-18 is able to differentiate risk taking and risk assessment which can help target appropriate intervention strategies

Cost-effectiveness of laser Doppler imaging in burn care in the Netherlands

textabstractBackground: Early accurate assessment of burn depth is important to determine the optimal treatment of burns. The method most used to determine burn depth is clinical assessment, which is the least expensive, but not the most accurate.Laser Doppler imaging (LDI) is a technique with which a more accurate (>95%) estimate of burn depth can be made by measuring the dermal perfusion. The actual effect on therapeutic decisions, cli

Cost-effectiveness of laser Doppler imaging in burn care in the Netherlands

Background: Early accurate assessment of burn depth is important to determine the optimal treatment of burns. The method most used to determine burn depth is clinical assessment, which is the least expensive, but not the most accurate.Laser Doppler imaging (LDI) is a technique with which a more accurate (>95%) estimate of burn depth can be made by measuring the dermal perfusion. The actual effect on therapeutic decisions, cli

Face-to-face vs telephone pre-colonoscopy consultation in colorectal cancer screening; A randomised trial

Background: A pre-colonoscopy consultation in colorectal cancer (CRC) screening is necessary to assess a screenees general health status and to explain benefits and risks of screening. The first option allows for personal attention, whereas a telephone consultation does not require travelling. We hypothesised that a telephone consultation would lead to higher response and participation in CRC screening compared with a face-to-face consultation. Methods:A total of 6600 persons (50-75 years) were 1: 1 randomised for primary colonoscopy screening with a pre-colonoscopy consultation either face-to-face or by telephone. In both arms, we counted the number of invitees who attended a pre-colonoscopy consultation (response) and the number of those who subsequently attended colonoscopy (participation), relative to the number invited for screening. A questionnaire regarding satisfaction with the consultation and expected burden of the colonoscopy (scored on five-point rating scales) was sent to invitees. Besides, a questionnaire to assess the perceived burden of colonoscopy was sent to participants, 14 days after the procedure.Results:In all, 3302 invitees were allocated to the telephone group and 3298 to the face-to-face group, of which 794 (24%) attended a telephone consultation and 822 (25%) a face-to-face consultation (P=0.41). Subsequently, 674 (20%) participants in the telephone group and 752 (23%) in the face-to-face group attended colonoscopy (P=0.018). Invitees and responders in the telephone group expected the bowel preparation to be more painful than those in the face-to-face group while perceived burden scores for the full screening procedure were comparable. More subjects in the face-to-face group than in the telephone group were satisfied by the consultation in general: (99.8% vs 98.5%, P=0.014).Conclusion:Using a telephone rather than a face-to-face consultation in a population-based CRC colonoscopy screening progr

What determines individuals' preferences for colorectal cancer screening programmes? A discrete choice experiment.

INTRODUCTION: In many countries uptake of colorectal cancer (CRC) screening remains low. AIM: To assess how procedural characteristics of CRC screening programmes determine preferences for participation and how individuals weigh these against the perceived benefits from participation in CRC screening. METHODS: A discrete choice experiment was conducted among subjects in the age group of 50-75 years, including both screening-naive subjects and participants of a CRC screening programme. Subjects were asked on their preferences for aspects of CRC screening programmes using scenarios based on pain, risk of complications, screening location, preparation, duration of procedure, screening interval a

Colorectal Cancer Stage Distribution at First and Repeat Fecal Immunochemical Test Screening

Background &amp; Aims: For colorectal cancer (CRC) screening to be effective, it is important that screen-detected cancers are found at an early stage. Studies on stage distribution of screen-detected CRC at repeat screening of large population-based fecal immunochemical test (FIT)-based screening programs and the impact of FIT cut-off values on staging currently are lacking. Methods: We obtained data for FIT-positive participants (FIT cut-off, 47 μg hemoglobin/g feces) at their first or second (ie, repeat) screening from the Dutch National Screening Database from 2014 to 2018. Tumor characteristics were acquired through linkage with The Netherlands Cancer Registry. We compared stage at diagnosis (I–II vs III–IV) of CRCs detected at a first or second screening. In addition, we analyzed the hypothetical yield and stage distribution of CRC for different FIT cut-off values up to 250 μg hemoglobin/g feces.Results: At the first and second screenings, respectively, 15,755 and 3304 CRCs were detected. CRCs detected at the first or second screening were equally likely to be stages I to II (66.5% vs 67.7%; relative risk, 1.02; 95% CI, 1.00–1.05). A hypothetical increase of the FIT cut-off value from 47 μg to 250 μg resulted in a reduction of detected CRCs by 88.3% and 79.0% at the first or second screening, respectively. Even then, the majority of detected CRCs (63%–64%) still would be diagnosed at stages I to II. Conclusions: FIT-based screening is effective in downstaging CRC, and also at repeat screening. Increasingly, the FIT cut-off level has a limited impact on the stage distribution of detected CRCs, although it greatly affects CRC detection and thus is important to keep low.</p

A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S]

Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. Cytochrome P450 family 2 subfamily c polypeptide 70 (CYP2C70) was recently proposed to catalyze the formation of rodent-specific muricholic acids (MCAs). With CRISPR/Cas9-mediated somatic genome editing, we generated an acute hepatic Cyp2c70 knockout mouse model (Cyp2c70ako) to clarify the role of CYP2C70 in BA metabolism in vivo and evaluate whether its activity modulates effects of pharmacologic FXR activation on cholesterol homeostasis. In Cyp2c70ako mice, chenodeoxycholic acid (CDCA) increased at the expense of βMCA, resulting in a more hydrophobic human-like BA pool. Tracer studies demonstrated that, in vivo, CYP2C70 catalyzes the formation of βMCA primarily by sequential 6β-hydroxylation and C7-epimerization of CDCA, generating βMCA as an intermediate metabolite. Physiologically, the humanized BA composition in Cyp2c70ako mice blunted the stimulation of fecal cholesterol disposal in response to FXR activation compared with WT mice, predominantly due to reduced stimulation of transintestinal cholesterol excretion. Thus, deletion of hepatic Cyp2c70 in adult mice translates into a human-like BA pool composition and impacts the response to pharmacologic FXR activation. This Cyp2c70ako mouse model may be a useful tool for future studies of BA signaling and metabolism that informs human disease development and treatment

A cluster of blood-based protein biomarkers associated with decreased cerebral blood flow relates to future cardiovascular events in patients with cardiovascular disease

Biological processes underlying decreased cerebral blood flow (CBF) in patients with cardiovascular disease (CVD) are largely unknown. We hypothesized that identification of protein clusters associated with lower CBF in patients with CVD may explain underlying processes. In 428 participants (74% cardiovascular diseases; 26% reference participants) from the Heart-Brain Connection Study, we assessed the relationship between 92 plasma proteins from the Olink® cardiovascular III panel and normal-appearing grey matter CBF, using affinity propagation and hierarchical clustering algorithms, and generated a Biomarker Compound Score (BCS). The BCS was related to cardiovascular risk and observed cardiovascular events within 2-year follow-up using Spearman correlation and logistic regression. Thirteen proteins were associated with CBF (ρSpearman range: −0.10 to −0.19, pFDR-corrected &lt;0.05), and formed one cluster. The cluster primarily reflected extracellular matrix organization processes. The BCS was higher in patients with CVD compared to reference participants (pFDR-corrected &lt;0.05) and was associated with cardiovascular risk (ρSpearman 0.42, p &lt; 0.001) and cardiovascular events (OR 2.05, p &lt; 0.01). In conclusion, we identified a cluster of plasma proteins related to CBF, reflecting extracellular matrix organization processes, that is also related to future cardiovascular events in patients with CVD, representing potential targets to preserve CBF and mitigate cardiovascular risk in patients with CVD.</p