Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial.

INTRODUCTION: Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity. METHODS: This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points. RESULTS: In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 ( P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 ( P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep. DISCUSSION: In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease.

Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis.

BACKGROUND: Disruption of central circadian rhythms likely mediated by changes in microbiota and a decrease in gut-derived metabolites like short chain fatty acids (SCFAs) negatively impacts colonic barrier homeostasis. We aimed to explore the effects of isolated peripheral colonic circadian disruption on the colonic barrier in a mouse model of colitis and explore the mechanisms, including intestinal microbiota community structure and function. METHODS: Colon epithelial cell circadian rhythms were conditionally genetically disrupted in mice: TS4Cre-BMAL1lox (cBMAL1KO) with TS4Cre as control animals. Colitis was induced through 5 days of 2% dextran sulfate sodium (DSS). Disease activity index and intestinal barrier were assessed, as were fecal microbiota and metabolites. RESULTS: Colitis symptoms were worse in mice with peripheral circadian disruption (cBMAL1KO). Specifically, the disease activity index and intestinal permeability were significantly higher in circadian-disrupted mice compared with control animals (TS4Cre) (P < .05). The worsening of colitis appears to be mediated, in part, through JAK (Janus kinase)-mediated STAT3 (signal transducer and activator of transcription 3), which was significantly elevated in circadian-disrupted (cBMAL1KO) mice treated with DSS (P < .05). Circadian-disrupted (cBMAL1KO) mice also had decreased SCFA metabolite concentrations and decreased relative abundances of SCFA-producing bacteria in their stool when compared with control animals (TS4Cre). CONCLUSIONS: Disruption of intestinal circadian rhythms in colonic epithelial cells promoted more severe colitis, increased inflammatory mediators (STAT3 [signal transducer and activator of transcription 3]), and decreased gut microbiota-derived SCFAs compared with DSS alone. Further investigation elucidating the molecular mechanisms behind these findings could provide novel circadian directed targets and strategies in the treatment of inflammatory bowel disease.

Disruption of peripheral circadian rhythms of the colon epithelium results in worse colitis and increased intestinal permeability in mice when given dextran sulfate sodium. This may be mediated through alterations in microbiota, butyrate levels, and STAT3.

Disrupted Circadian Rest-Activity Cycles in Inflammatory Bowel Disease Are Associated With Aggressive Disease Phenotype, Subclinical Inflammation, and Dysbiosis.

Patients with inflammatory bowel disease (IBD)-Crohn's disease (CD), and ulcerative colitis (UC), have poor sleep quality. Sleep and multiple immunologic and gastrointestinal processes in the body are orchestrated by the circadian clock, and we recently reported that a later category or chronotype of the circadian clock was associated with worse IBD specific outcomes. The goal of this study was to determine if circadian misalignment by rest-activity cycles is associated with markers of aggressive disease, subclinical inflammation, and dysbiosis in IBD. A total of 42 patients with inactive but biopsy-proven CD or UC and 10 healthy controls participated in this prospective cohort study. Subjects were defined as having an aggressive IBD disease history (steroid dependence, use of biologic or immunomodulator, and/or surgery) or non-aggressive history. All participants did two weeks of wrist actigraphy, followed by measurement of intestinal permeability and stool microbiota. Wrist actigraphy was used to calculate circadian markers of rest-activity- interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). Aggressive IBD history was associated with decrease rest-activity stability (IS) and increased fragmentation compared to non-aggressive IBD and health controls at 0.39 ±.15 vs. 0.51 ± 0.10 vs. 0.55 ± 0.09 (P < 0.05) and 0.83 ± 0.20 vs. 0.72 ± 0.14 (P < 0.05) but not HC at 0.72 ± 0.14 (P = 0.08); respectively. There was not a significant difference in RA by IBD disease history. Increased intestinal permeability and increased TNF-α levels correlated with an increased rest activity fragmentation (IV) at R = 0.35, P < 0.05 and R = 0.37, P < 0.05, respectively; and decreased rest-activity amplitude (RA) was associated with increased stool calprotectin at R = 0.40, P < 0.05. Analysis of intestinal microbiota showed a significant decrease in commensal butyrate producing taxa and increased pro-inflammatory bacteria with disrupted rest-activity cycles. In this study, different components of circadian misalignment by rest-activity cycles were associated with a more aggressive IBD disease history, increased intestinal permeability, stool calprotectin, increased pro-inflammatory cytokines, and dysbiosis. Wrist activity allows for an easy non-invasive assessment of circadian activity which may be an important biomarker of inflammation in IB.

Characterization of long-term prognosis in acute pancreatitis: An explorative analysis.

BACKGROUND/OBJECTIVES: Severity classification systems of acute pancreatitis (AP) assess inpatient morbidity and mortality without predicting outpatient course of AP. To provide appropriate outpatient care, determinants of long-term prognosis must also be identified. The aim of this study was to define clinical groups that carry long-term prognostic significance in AP. METHODS: A retrospective study that included patients admitted with AP was conducted. Determinants of long-term prognosis were extracted: These included Revised Atlanta and Determinant Based Classification (RAC), Charlson Comorbidity Index (CCI), Modified CT Severity Index (MCTSI), etiology, and local complications (LCs). Seven surrogates of morbidity up to 1 year after discharge were also collected and subsequently imputed into a clustering algorithm. The algorithm was set to produce three categories and multinomial regression analysis was performed. RESULTS: 281 patients were included. The incidences of morbidity endpoints were similar among the 3 RAC categories. Three clusters were identified that carried long-term prognostic significance. Each cluster was given a name to reflect prognosis. The limited AP had the best prognosis and included patients without LCs with a low co-morbidity burden. The brittle AP had a low co-morbidity burden and high MCTSI (LCs 94%). It ran a very morbid course but had excellent survival. The high-risk AP had the worst prognosis with the highest mortality rate (28%). They had a high co-morbidity burden without local complications. CONCLUSION: Categories that carry long-term prognostic significance in AP have been developed. This study could help formulate appropriate follow-up and ultimately improve AP outcomes.

Rates of Prevalent Colorectal Cancer Occurrence in Persons 75 Years of Age and Older: A Population-Based National Study.

BACKGROUND/AIMS: There is a lack of studies describing the epidemiology of colorectal cancer (CRC) in patients aged 75 years and older (elderly). Current guidelines recommend against routine screening colonoscopies in this population. We sought to describe the epidemiology of CRC in the elderly, utilizing a large, population-based database as this may impact screening guidelines in this population. METHODS: Utilizing a commercial database (Explorys Inc, Cleveland, OH), we identified a cohort of patients with a first-ever diagnosis of CRC between 2012 and 2017 based on the Systematized Nomenclature of Medicine-Clinical Terms. We calculated the rate of first-ever CRC occurrence in the elderly, described age, race, and gender-based rates of new CRC diagnoses, and identified associated conditions for new CRC in the elderly. RESULTS: The rate of first-ever CRC in the elderly (aged 75 and above) was 102.6/100,000 persons. The rate of new CRC was higher in males than females and in African Americans than Caucasians and Asians. There was a higher prevalence of right than left colon cancer. The rate of new CRC was higher in elderly with certain comorbidities. CONCLUSION: The rate of new CRC diagnosis in the elderly was substantially greater compared to the overall population. Screening would be justified especially if a patient's life expectancy warrants it particularly if the patient has specific associated conditions that increase the risk for CRC.

The annular ligament-revisited.

BACKGROUND: Studies investigating the annular ligament have presented confusing information about its anatomy and nomenclature. Cadaver elbow dissections were used to clarify the anatomy and terminology of the annular ligament. METHODS: Nineteen elbows were dissected (7 fresh frozen and 12 embalmed). Target structures were identified, photographed, and measured by independent observers. RESULTS: There are 3 layers to the lateral elbow ligaments: the superficial lateral ulnar collateral and radial collateral ligament; a deeper layer of the superior oblique band (SOB) and inferior oblique band (IOB) of the annular ligament; and the deepest capsular layer. The annular ligament measured 9.5 ± 1.4 mm anteriorly. The SOB (15/19) was 3.9 ± 1.0 mm wide by 10.5 ± 3.8 mm long. The IOB (13/19) was 3.6 ± 1.1 mm wide by 11.4 ± 4.2 mm long. The IOB inserts onto the anterior proximal ulna rather than the supinator crest. The anterior oblique band (8/19) was 3.8 ± 1.7 mm wide. CONCLUSION: The SOB and IOB were present in the majority of specimens. The previously described accessory lateral collateral ligament is a localized thickening on the lateral ligament complex arising from the supinator insertion independent of the IOB that attaches to the annular ligament inferiorly and distally and attaches onto the proximal anterior ulna at the bicipital fossa floor, medial to the supinator crest.