Interactions between commensals and the host impact the metabolic and immune status of metazoans. Their deregulation is associated with age-related pathologies like chronic inflammation and cancer, ...especially in barrier epithelia. Maintaining a healthy commensal population by preserving innate immune homeostasis in such epithelia thus promises to promote health and longevity. Here, we show that, in the aging intestine of Drosophila, chronic activation of the transcription factor Foxo reduces expression of peptidoglycan recognition protein SC2 (PGRP-SC2), a negative regulator of IMD/Relish innate immune signaling, and homolog of the anti-inflammatory molecules PGLYRP1–4. This repression causes deregulation of Rel/NFkB activity, resulting in commensal dysbiosis, stem cell hyperproliferation, and epithelial dysplasia. Restoring PGRP-SC2 expression in enterocytes of the intestinal epithelium, in turn, prevents dysbiosis, promotes tissue homeostasis, and extends lifespan. Our results highlight the importance of commensal control for lifespan of metazoans and identify SC-class PGRPs as longevity-promoting factors.
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•Age-associated commensal dysbiosis causes intestinal epithelial dysplasia in flies•Dysbiosis is caused by chronic activation of Foxo in aging enterocytes•Foxo perturbs intestinal immune homeostasis by repressing PGRP-SC2•Overexpression of PGRP-SC2 in enterocytes prevents dysbiosis and extends lifespan
Downregulating NF-kB signaling in the aging fly intestine prevents commensal dysbiosis, maintains immune homeostasis, and extends lifespan.
The microtubule motor kinesin-1 plays central roles in intracellular transport. It has been widely assumed that many cellular cargos are moved by multiple kinesins and that cargos with more motors ...move faster and for longer distances; concrete evidence, however, is sparse. Here we rigorously test these notions using lipid droplets in
Drosophila embryos. We first employ antibody inhibition, genetics, biochemistry, and particle tracking to demonstrate that kinesin-1 mediates plus-end droplet motion. We then measure how variation in kinesin-1 expression affects the forces driving individual droplets and estimate the number of kinesins actively engaged per droplet. Unlike in vitro, increased motor number results in neither longer travel distances nor higher velocities. Our data suggest that cargos in vivo can simultaneously engage multiple kinesins and that transport properties are largely unaffected by variation in motor number. Apparently, higher-order regulatory mechanisms rather than motor number per se dominate cargo transport in vivo.
Objective To evaluate whether clinical anxiety in children presenting to a pediatric pain management center is associated with a poorer treatment response for those who completed pain-focused ...cognitive behavioral therapy (CBT). Study design The total sample consisted of 175 children, 40 of whom completed CBT for chronic pain. The Screen for Child Anxiety Related Emotional Disorders was completed at initial evaluation and outcome measures (average pain intensity and the Functional Disability Inventory) were collected during the initial evaluation and at the end of CBT. Group differences in outcomes were examined following CBT. The role of anxiety in CBT initiation and completion was also explored. Results Presence of clinical anxiety was associated with greater initiation and/or completion of pain-focused CBT but also a poorer treatment response. Specifically, the group with subclinical anxiety exhibited a substantial reduction in pain intensity, and the group with clinical anxiety exhibited a more limited response to treatment (F 1, 36 = 13.68 P < .01). A similar effect was observed for Functional Disability Inventory, such that the group with clinical anxiety had a significantly smaller response to treatment (F 1, 38 = 4.33 P < .05). The difference in pain and disability between groups following CBT suggest moderate effects (Cohen d = 0.77 and 0.78, respectively). Conclusions Although youths with clinical anxiety are more likely to start and/or complete pain-focused CBT, anxiety has an adverse impact on CBT treatment response in children with chronic pain. Identification of patients with anxiety and use of tailored behavioral interventions may improve clinical outcomes.
Juvenile-onset fibromyalgia (JFM) is typically diagnosed in adolescence and characterized by widespread pain and marked functional impairment. The long-term impact of JFM into adulthood is poorly ...understood. The objectives of this study were to describe physical and psychosocial outcomes of youth diagnosed with JFM in early adulthood (∼8-year follow-up), examine longitudinal trajectories of pain and depressive symptoms from adolescence to young adulthood, and examine the impact of pain and depressive symptoms on physical functioning over time. Participants were 97 youth with JFM enrolled in a prospective longitudinal study in which pain symptoms, and physical and psychosocial functioning were assessed at 4 time points over approximately 8 years. At the time 4 follow-up (Mage = 24.2 years), the majority continued to suffer from pain and impairment in physical, social, and psychological domains. However, trajectories of pain and emotional symptoms showed varying patterns. Longitudinal analysis using growth mixture modeling revealed 2 pain trajectories (Steady Improvement and Rapid Rebounding Improvement), whereas depressive symptoms followed 3 distinct trajectories (Low-Stable, Improving, and Worsening). Membership in the Worsening Depressive symptoms group was associated with poorer physical functioning over time (P < 0.001) compared with the Low-Stable and Improving groups. This study offers evidence that although JFM symptoms persist for most individuals, pain severity tends to decrease over time. However, depressive symptoms follow distinct trajectories that indicate subgroups of JFM. In particular, JFM patients with worsening depressive symptoms showed decreasing physical functioning and may require more intensive and consistent intervention to prevent long-term disability.
Objectives:
A high degree of sleep disturbance is reported among youth with disorders of gut‐brain interaction (DGBIs). Given that sleep quality impacts a range of pediatric health outcomes including ...somatic sensations (eg, pain) and depressive mood occurs relatively frequently among youth with DGBIs, there is a dire need to disentangle the unique contributions of sleep and depressive mood on the somatic sensations experienced by youth with DGBIs. We aimed to examine whether depressive mood mediates the relations among sleep disturbance and pain intensity, nausea, and fatigue among youth with DGBIs.
Methods:
One hundred eighteen patients aged 8–17 years (Mage = 14.05, SD = 2.88; 70.34% female), 83.05% White/non‐Hispanic recruited at a pediatric neurogastroenterology clinic completed measures of sleep disturbance, nausea, fatigue, pain intensity, and depressive mood. Three mediation models examined the effect of sleep disturbance on nausea, fatigue, and pain, with depressive mood as a mediator.
Results:
Participants reported moderate sleep disturbance. Depressive mood partially mediated the significant, respective relations between greater sleep disturbance and more severe nausea and fatigue. Sleep disturbance was significantly associated with higher pain intensity; however, depressive mood was not a significant mediator of this relation.
Conclusions:
Sleep quality is a major concern among youth with DGBIs. Low sleep quality may worsen nausea and fatigue via co‐occurring increases in depressive mood symptoms. In contrast, sleep disturbance may directly increase pain, regardless of youths’ depressive mood symptoms. Future research should explore these relations through prospective studies leveraging a combination of subjective and objective assessment approaches.
Aims
Glucagon‐like peptide‐1 (GLP‐1) agonists and dipeptidyl peptidase‐4 (DPP‐4) inhibitors are both incretin‐based therapies for type 2 diabetes (T2DM) but have distinct efficacy and side effect ...profiles. We thus performed a systematic review and meta‐analysis to compare the effects of GLP‐1 agonists to DPP‐4 inhibitors on glycaemic control, weight and incidence of adverse events in adults with T2DM. We also sought to determine whether there was any additional effect in switching from DPP‐4 inhibitor to GLP‐1 agonist.
Materials and methods
We systematically searched PubMed, Embase and ClinicalTrials.gov for (1) randomized controlled trials (RCTs) comparing any GLP‐1 agonist to any DPP‐4 inhibitor and (2) interventional studies where a DPP‐4 inhibitor was switched to a GLP‐1 agonist. We assessed pooled data using random‐effects model (CRD42017057115).
Results
The pooled analysis of 13 RCTs (n = 4330) showed that, compared to DPP‐4 inhibitors, GLP‐1 agonists yielded a greater mean reduction in glycated haemoglobin (HbA1c) of −0.41% (95% CI −0.53 to −0.30) and in weight of −2.15 kg (−3.04 to −1.27). GLP‐1 agonists were associated with greater likelihood of gastrointestinal side effects with no increased risk of hypoglycaemia. In 5 interventional studies (n = 433), switching from DPP‐4 inhibitor to GLP‐1 agonist yielded further mean reduction in HbA1c of −0.69% (−1.03 to −0.35) and in weight of −2.25 kg (−3.12 to −1.38).
Conclusions
GLP‐1 agonists yield greater reduction in HbA1c and weight as compared to DPP‐4 inhibitors, with increased incidence of gastrointestinal symptoms but not hypoglycaemia. Replacing a DPP‐4 inhibitor with GLP‐1 agonist provides additional benefits in glycaemic control and weight loss.
We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio‐facio‐cutaneous (CFC) syndrome. A comprehensive, retrospective medical history ...survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.
Hypermobile Ehlers–Danlos syndrome (hEDS) includes physical symptoms of chronic pain, fatigue, gastrointestinal dysfunction, and joint subluxations/dislocations. This study aims to fill a research ...gap regarding the psychosocial well-being in pediatric hEDS by assessing relationships between functional disability, social support, and mental health. Increased functional disability is hypothesized to be associated with increased mental health challenges, specifically anxiety and depression, and general social support is hypothesized to moderate this relationship, such that higher perceived social support will mitigate the negative psychological impacts of functional disability. Gender’s influence on mental health in pediatric hEDS is also explored. Thirty-four youth with pediatric hEDS recruited from a United States Midwest multidisciplinary genetics clinic completed self-report questionnaires. Results demonstrate associations between functional disability and mental health, and social support and mental health independently; however, moderation was not found. Functional disability and social support each have a unique influence on the mental health of children with pediatric hEDS and should each receive clinical attention. Exploratory analyses into the influence of gender provide a groundwork for future studies.
Mobile health (mHealth) apps have the potential to enhance pain management through the use of daily diaries, medication and appointment reminders, education, and facilitating communication between ...patients and providers. Although many pain management apps exist, the extent to which these apps use evidence-based behavior change techniques (BCTs) remains largely unknown, making it nearly impossible for providers to recommend apps with evidence-based strategies. This study systematically evaluated commercially available pain management apps for evidence-based BCTs and app quality. Pain management apps were identified using the search terms "pain" and "pain management" in the App and Google Play stores. Reviewed apps were specific to pain management, in English, for patients, and free. A total of 28 apps were coded using the taxonomy of BCTs. App quality was assessed using the Mobile App Rating Scale. Apps included 2 to 15 BCTs (M = 7.36) and 1 to 8 (M = 4.21) pain management-specific BCTs. Prompt intention formation, instruction, behavioral-health link, consequences, feedback, and self-monitoring were the most common BCTs used in the reviewed apps. App quality from the Mobile App Rating Scale ranged from 2.27 to 4.54 (M = 3.65) out of a possible 5, with higher scores indicating better quality. PainScale followed by Migraine Buddy demonstrated the highest number of overall and pain management BCTs as well as good quality scores. Although existing apps should be assessed through randomized controlled trials and future apps should include capabilities for electronic medical record integration, current pain management apps often use evidence-based pain management BCTs.
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