Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers ...is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.
Significance It is established that glucose tolerance decreases from the morning to the evening, and that shift work is a risk factor for diabetes. However, the relative importance of the endogenous ...circadian system, the behavioral cycle (including the sleep/wake and fasting/feeding cycles), and circadian misalignment on glucose tolerance is unclear. We show that the magnitude of the effect of the endogenous circadian system on glucose tolerance and on pancreatic β-cell function was much larger than that of the behavioral cycle in causing the decrease in glucose tolerance from morning to evening. Also, independent from circadian phase and the behavioral cycle, circadian misalignment resulting from simulated night work lowered glucose tolerance—without diminishing effects upon repeated exposure—with direct relevance for shift workers.
Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show—by using two 8-d laboratory protocols—in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.
The human circadian system regulates hunger independently of behavioral factors, resulting in a trough in the biological morning and a peak in the biological evening. However, the role of the only ...known orexigenic hormone, ghrelin, in this circadian rhythm is unknown. Furthermore, although shift work is an obesity risk factor, the separate effects of the endogenous circadian system, the behavioral cycle, and circadian misalignment on ghrelin has not been systematically studied. Here we show-by using two 8-day laboratory protocols-that circulating active (acylated) ghrelin levels are significantly impacted by endogenous circadian phase in healthy adults. Active ghrelin levels were higher in the biological evening than the biological morning (fasting +15.1%, P = 0.0001; postprandial +10.4%, P = 0.0002), consistent with the circadian variation in hunger (P = 0.028). Moreover, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial active ghrelin levels (+5.4%; P = 0.04). While not significantly influencing hunger (P > 0.08), circadian misalignment increased appetite for energy-dense foods (all P < 0.05). Our results provide possible mechanisms for the endogenous circadian rhythm in hunger, as well as for the increased risk of obesity among shift workers.
Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of ...Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.
Shift work causes circadian misalignment and is a risk factor for obesity. While some characteristics of the human circadian system and energy metabolism differ between males and females, little is ...known about whether sex modulates circadian misalignment effects on energy homeostasis. Here we show—using a randomized cross-over design with two 8-d laboratory protocols in 14 young healthy adults (6 females)—that circadian misalignment has sex-specific influences on energy homeostasis independent of behavioral/environmental factors. First, circadian misalignment affected 24-h average levels of the satiety hormone leptin sex-dependently (P < 0.0001), with a ∼7% decrease in females (P < 0.05) and an ∼11% increase in males (P < 0.0001). Consistently, circadian misalignment also increased the hunger hormone ghrelin by ∼8% during wake periods in females (P < 0.05) without significant effect in males. Females reported reduced fullness, consistent with their appetite hormone changes. However, males reported a rise in cravings for energy-dense and savory foods not consistent with their homeostatic hormonal changes, suggesting involvement of hedonic appetite pathways in males. Moreover, there were significant sex-dependent effects of circadian misalignment on respiratory quotient (P < 0.01), with significantly reduced values (P < 0.01) in females when misaligned, and again no significant effects in males, without sex-dependent effects on energy expenditure. Changes in sleep, thermoregulation, behavioral activity, lipids, and catecholamine levels were also assessed. These findings demonstrate that sex modulates the effects of circadian misalignment on energy metabolism, indicating possible sex-specific mechanisms and countermeasures for obesity in male and female shift workers.
Context:
Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and ...24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown.
Objective:
The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects.
Design:
A randomized, crossover study with two 3-day laboratory visits.
Setting:
Center for Clinical Investigation at Brigham and Women's Hospital.
Patients:
Healthy chronic shift workers.
Intervention:
The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment).
Main Outcome Measures:
Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols.
Results:
Postprandial glucose was 6.5% higher at 8:00 pm than 8:00 am (circadian phase effect), independent of behavioral effects (P = .0041). Circadian misalignment increased postprandial glucose by 5.6%, independent of behavioral and circadian effects (P = .0042). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic β-cell function (18% lower early and late phase insulin; both P ≤ .011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late phase insulin; P = .015) without change in early-phase insulin (P = .38).
Conclusions:
Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers.
Hematopoietic stem cells (HSCs) undergo rapid expansion in response to stress stimuli. Here we investigate the bioenergetic processes which facilitate the HSC expansion in response to infection. We ...find that infection by Gram-negative bacteria drives an increase in mitochondrial mass in mammalian HSCs, which results in a metabolic transition from glycolysis toward oxidative phosphorylation. The initial increase in mitochondrial mass occurs as a result of mitochondrial transfer from the bone marrow stromal cells (BMSCs) to HSCs through a reactive oxygen species (ROS)-dependent mechanism. Mechanistically, ROS-induced oxidative stress regulates the opening of connexin channels in a system mediated by phosphoinositide 3-kinase (PI3K) activation, which allows the mitochondria to transfer from BMSCs into HSCs. Moreover, mitochondria transfer from BMSCs into HSCs, in the response to bacterial infection, occurs before the HSCs activate their own transcriptional program for mitochondrial biogenesis. Our discovery demonstrates that mitochondrial transfer from the bone marrow microenvironment to HSCs is an early physiologic event in the mammalian response to acute bacterial infection and results in bioenergetic changes which underpin emergency granulopoiesis.
Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates ...that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium‐catalyzed C−H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane‐protected phosphine). A complimentary catalyst system (quinoline‐based silane ligand with (COD)IrOMe2) was optimal for biphenyl‐based phosphines. Selective polyborylation was also shown providing bis‐ and tris‐borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.
Phosphine‐directed C−H borylation: A series of commonly used phosphines undergo iridium‐catalyzed C−H borylation, providing a range of ambiphilic phosphine boronates. The unexpected cationic iridium catalyst overcomes limited reactivity, allowing a large range of phosphines to be selectively functionalized, including selective polyborylation of several phosphines.
The primary goal of this study was to examine developmental patterns among the relations between components of executive function (EF; working memory WM, inhibitory control, shifting), and academic ...outcomes (reading, mathematics, language) in elementary school-age children. These relations were examined within the context of the development of EF and of academic skills utilizing an extension of the unity and diversity, intrinsic cognitive load, and dual process theories. Using meta-analytic methods, we summarized results from 299 studies from 293 articles/dissertations, representing 65,605 elementary school-age children (42-191 months old M = 101 months, SD = 24.49 months). Results indicated that accounting for general EF (by including the correlations among EF tasks in meta-analytic path models and accounting for effects between all three EF components and academic outcomes simultaneously) produced weaker relations between EF and academic skills than the bivariate relations which have been reported in prior meta-analytic reviews. However, although reduced, all relations between EF and academic outcomes remained significant throughout elementary school. Whereas WM was consistently moderately associated with reading, math, and oral language across development, the developmental trends for the relations between inhibitory control and shifting with academic outcomes varied based upon the academic skill examined. On the academic side, whereas the relations between reading and language skills with EF components varied throughout elementary school, few developmental changes were found in the relations between EF components and math skills across elementary school. Future directions and implications of findings for the conceptualization of the impact of EF on academics are discussed within the context of relevant theoretical models.
Public Significance StatementThis study demonstrated that executive function skills have moderate relations with reading, oral language, and mathematics. These relations are strongest for working memory. Results suggest that to better understand the relations between EF and academics and how these relations vary across development, a more complex and nuanced model, which takes into account developmental trajectories of EF and academics and specific task demands, is needed.
PDF
