Social relationship satisfaction and accumulation of chronic conditions and multimorbidity:a national cohort of Australian women

Background Social relationships are associated with mortality and chronic conditions.However,little is known about the effects of social relationship satisfaction on multiple chronic conditions(multimorbidity).Aims To examine whether social relationship satisfaction is associated with the accumulation of multimorbidity.Methods Data from 7694 Australian women who were free from 11 chronic conditions at 45–50 years of age in 1996 were analysed.Five types of social relationship satisfaction(partner,family members,friends,work and social activities)were measured approximately every 3 years and scored from 0(very dissatisfied)to 3(very satisfied).Scores from each relationship type were summed to provide an overall satisfaction score(range:≤5–15).The outcome of interest was the accumulation of multimorbidity in 11 chronic conditions.Results Over a 20-year period,4484(58.3%)women reported multimorbidities.Overall,the level of social relationship satisfaction had a dose–response relationship with the accumulation of multimorbidities.Compared with women reporting the highest satisfaction(score 15),women with the lowest satisfaction(score≤5)had the highest odds of accumulating multimorbidity(odds ratio(OR)=2.35,95%confidence interval(CI):1.94 to 2.83)in the adjusted model.Similar results were observed for each social relationship type.Other risk factors,such as socioeconomic,behavioural and menopausal status,together explained 22.72%of the association.Conclusions Social relationship satisfaction is associated with the accumulation of multimorbidity,and the relationship is only partly explained by socioeconomic,behavioural and reproductive factors.Social connections(eg,satisfaction with social relationships)should be considered a public health priority in chronic disease prevention and intervention.

Fragile X Messenger Ribonucleoprotein 1(FMR1), a novel inhibitor of osteoblast/osteocyte differentiation, regulates bone formation, mass, and strength in young and aged male and female mice

Fragile X Messenger Ribonucleoprotein 1(FMR1)gene mutations lead to fragile X syndrome,cognitive disorders,and,in some individuals,scoliosis and craniofacial abnormalities.Four-month-old(mo)male mice with deletion of the FMR1 gene exhibit a mild increase in cortical and cancellous femoral bone mass.However,consequences of absence of FMR1 in bone of young/aged male/female mice and the cellular basis of the skeletal phenotype remain unknown.We found that absence of FMR1 results in improved bone properties with higher bone mineral density in both sexes and in 2-and 9-mo mice.The cancellous bone mass is higher only in females,whereas,cortical bone mass is higher in 2-and 9-mo males,but higher in 2-and lower in 9-mo female FMR1-knockout mice.Furthermore,male bones show higher biomechanical properties at 2mo,and females at both ages.Absence of FMR1 increases osteoblast/mineralization/bone formation and osteocyte dendricity/gene expression in vivo/ex vivo/in vitro,without affecting osteoclasts in vivo/ex vivo.Thus,FMR1 is a novel osteoblast/osteocyte differentiation inhibitor,and its absence leads to age-,site-and sex-dependent higher bone mass/strength.

Use of an immunocapture device to detect cytokine release in discrete brain regions

Production of proinflammatory cytokines in the central nervous system is a key process in the neuroinflammatory response to trauma,infection,and neurodegenerative diseases(Kumar,2019).These intercellular signaling molecules play multiple roles in the immune response in the central nervous system including the orchestration of the sickness response to innate immune perturbations in the brain(Dantzer et al.,2008).

Effects of Religious vs. Conventional Cognitive-Behavioral Therapy on Inflammatory Markers and Stress Hormones in Major Depression and Chronic Medical Illness: A Randomized Clinical Trial

Background: Depressive disorder is often accompanied by physiological changes that may adversely affect the course of medical illness, including an increase in pro-inflammatory cytokines. Methods: We examine the effects of religious cognitive behavioral therapy (RCBT) vs. conventional CBT (CCBT) on pro-/anti-inflammatory indicators and stress hormones in 132 individuals with major depressive disorder (MDD) and chronic medical illness who were recruited into a multi-site randomized clinical trial. Biomarkers (C-reactive protein and pro-inflammatory cytokines TNF-α, IL-1β, IFN-γ, IL-6, IL-12-p70), anti-inflammatory cytokines (IL1ra, IL-4, IL-10), and stress hormones (urinary cortisol, epinephrine, norepinephrine) were assessed at baseline, 12 weeks, and 24 weeks. Differential effects of baseline religiosity on treatment response were also examined, along with effects of religiosity on changes in biomarkers over time independent of treatment group. Biomarker levels were log transformed where possible to normalize distributions. Mixed models were used to examine trajectories of change. Results: CRP increased and IL-4, IL-10, and epinephrine decreased over time, mostly in the opposite direction expected (except epinephrine). No significant difference between RCBT and CCBT was found on average trajectory of change in any biomarkers. Religiosity interacted with treatment group in effects on IL-6, such that CCBT was more effective than RCBT in lowering lL-6 in those with low religiosity whereas RCBT appeared to be more effective than CCBT in those with high religiosity. Higher baseline religiosity also tended to predict an increase in pro-inflammatory cytokines INF-γ and IL-12 (p70) and urinary cortisol over time. Conclusions: RCBT and CCBT had similar effects on stress biomarkers. CCBT was more effective in reducing IL-6 levels in those with low religiosity, whereas RCBT tended to be more effective in those with high religiosity. Unexpectedly, higher baseline religiosity was associated with an increase in several stress biomarkers.

Quetiapine augmentation of prolonged exposure therapy in veterans with PTSD and a history of mild traumatic brain injury: design and methodology of a pilot study

Background: Selective serotonergic reuptake inhibitors(SSRIs) are first-line pharmacologic treatments for patients with posttraumatic stress disorder(PTSD), but must be given over extended period of time before the onset of action. The use of SSRIs in PTSD patients with mild traumatic brain injury(m TBI) is problematic since SSRIs could exacerbate post-concussion syndrome(PCS) symptoms. VA/DOD guidelines identify trauma-focused psychotherapy as the best evidence-based treatment for PTSD, but overall effectiveness is limited by reduced levels of patient engagement and retention. A previous study from this research group suggested that quetiapine monotherapy, but not risperidone or valproate, could increase engagement in trauma-focused psychotherapy.Methods: We report the study protocol of a pilot study funded under the South-Central Mental Illness Research, Education, and Clinical Center pilot study program from the U.S. Department of Veterans Affairs. This randomized, open-label study was designed to evaluate the feasibility of completing a randomized trial of quetiapine vs. treatment as usual to promote patient engagement in PTSD patients with a history of m TBI.Discussion: We expect that the success of this ongoing study should provide us with the preliminary data necessary to design a full-scale randomized trial. Positive efficacy results in a full-scale trial should inform new VA guidelines for clinical practice by showing that quetiapine-related improvements in patient engagement and retention may be the most effective approach to assure that VA resources achieve the best possible outcome for veterans.Trial registration: NCT04280965.

Hypnosis for burn-related pain:Case studies and a review of the literature

Burn injuries create severe pain and psychological distress that are highly variable between patients. Distinct types of pain during various stages of injury and recovery make treatment complex. Standard pharmacological treatment of pain can have adverse effects and is not effective in treating anxiety and other psychological issues. Researchers have proposed that integrating clinical hypnosis as a complementary therapy can be highly beneficial to burn patients and their healthcare providers. The existing literature is reviewed and specific hypnosis techniques are discussed. Evidence exists indicating that adjunctive hypnosis is effective at reducing pain and procedural anxiety. Implementing a multidisciplinary burn care team that includes clinical hypnosis and focuses on the patients' psychological health as well as pain reduction is likely to result in faster healing and reduced distress for patients and caregivers alike.

A Mindfulness-Based Cognitive Therapy (MBCT) Intervention to Improve Resilience and Mitigate Symptoms of Burnout Syndrome in Critical Care Nurses: Results of a Randomized Trial

Objective: Critical care nurses work in a challenging intensive care (ICU) environment that results in work-related psychological distress. Our objective was to pilot an in-person or virtual mindfulness-based cognitive therapy (MBCT) program enhanced resilience and a similarly designed attention control group. Methods: We randomized ICU nurses with symptoms of burnout syndrome and decreased resilience to an MBCT program or a similarly formatted book club control. Our primary outcome was change in resilience as measured by the Connor-Davidson Resilience Scale (CD-RISC). Results: One-hundred one nurses completed study-related procedures. Overall, 70% had baseline symptoms of anxiety and 26% had symptoms of depression. For the in-person cohorts, there was no statistical difference between intervention and control groups regarding the total number of sessions attended (3.85 days ± 1.4 versus 3.75 days ± 0.15;p = 0.64). Using the Client/Patient Satisfaction Questionnaire-8 (CSQ-8), satisfaction scores were higher in the intervention group for weeks two through four of the program: p = 0.03, 0.0003, 0.007 respectively. There was no difference in the change in CD-RISC scores between the two groups (mean difference: treatment = 5.0, control = 7.0;p = 0.30). The online intervention cohort had greater improvements in the change of their median emotional exhaustion burnout scores when compared to the in-person intervention cohorts (-5 [-8 to -1.5] vs. 2 [-5 to 8], p = 0.049). Conclusions: We developed a feasible and acceptable in-person and online MBCT-ICU intervention that did not increase resilience scores in ICU nurses when compared to an attention control group. These results could help guide the proper design of larger trials to determine the efficacy of other resilience interventions.

Cognitive Functioning and Insulin Regulation in Obese Youth

Background: There are data that suggest adiposity is associated with diminished cognitive functioning in adults and youth, independent of related co-morbidities. Little is known about the pathophysiological mechanisms associated with cognitive function in obese youth. The objective of the present study was to assess the associations among cognitive functioning and insulin regulation in a sample of obese youth. Methods: The sample consisted of 30 obese, non-diabetic youth (BMI > 95th percentile) ages 6-16 years (mean age = 12.60 years) referred to an outpatient pediatric endocrinology clinic. Youth were administered the Wechsler Abbreviated Scale of Intelligence (WASI) and Wide Range Assessment of Memory and Learning (WRAML-2). Results: Verbal memory, attention/concentration, and intelligence scores were similar across obese youth with elevated insulin levels and normal insulin levels. Obese youth with elevated insulin levels had lower scores in visual memory, with a medium effect (effect size = 0.51). Fasting insulin levels were not associated with any of the four cognitive domains in the multiple linear regression analysis (P > 0.05). Conclusions: These data provide preliminary evidence that visual memory may be impacted in obese youth with insulin resistance. Longitudinal studies examining insulin regulation, cognitive functioning, and weight status over time are needed.

Religious Involvement, Inflammatory Markers and Stress Hormones in Major Depression and Chronic Medical Illness

Background: Religious practices/experiences (RPE) may produce positive physiological changes in patients with major depressive disorder (MDD) and chronic medical illness. Here, we report cross-sectional relationships between depressive symptoms, RPE and stress biomarkers (pro-/anti-inflammatory measures and stress hormones), hypothesizing positive associations between depressive symptoms and stress biomarkers and inverse associations between RPE and stress biomarkers. Methods: We recruited 132 individuals with both MDD and chronic illness into a randomized clinical trial. First, stress biomarkers in the baseline sample were compared to biomarker levels from a community sample. Second, relationships between depressive symptoms and biomarkers were examined, and, finally, relationships between RPE and biomarkers were analyzed, controlling for demographics, depressive symptoms, and physical functioning. Results: As expected, inflammatory markers and stress hormones were higher in our sample with MDD compared to community participants. In the current sample, however, depressive symptoms were largely unrelated to stress biomarkers, and were unexpectedly inversely related to proinflammatory cytokine levels (TNF-α, IL-1β). Likewise, while RPE were largely unrelated to stress biomarkers, they were related to the anti-inflammatory cytokine IL-1RA and the stress hormone norepinephrine in expected directions. Unexpectedly, RPE were also positively related to the proinflammatory cytokine IFN-γ and to IFN-γ/IL-4 and IFN-γ/IL-10 ratios. Conclusions: Little evidence was found for a consistent pattern of relationships between depressive symptoms or religiosity and stress biomarkers. Of the few significant relationships, unexpected findings predominated. Future research is needed to determine whether religious interventions can alter stress biomarkers over time in MDD.

套筒制动及扎针对小鼠电针实验中镇痛的贡献

目的 :动物电针镇痛研究大都需要将动物制动和扎针 ,人们难以确定所观察到的镇痛作用中有无制动和扎针带来的应激性镇痛。本实验在观察到 2Hz电针对套筒制动的Swiss Webster小鼠具有镇痛作用的基础上 ,试图分析小鼠电针镇痛实验中套筒制动和扎针对镇痛的贡献。方法 :纸板 /布兜制动的动物作为对照组 (n =8) ,此法对动物的制动作用短暂而轻微。塑料套筒制动的实验组动物根据扎入针灸针有否又分为不扎针 (n =8)和扎针 (n =8)两组。以 48℃热水甩尾潜伏期 (TWL)作为测痛指标。结果 :塑料套筒制动的实验组小鼠 ,无论是不扎针还是扎针 ,其TWL均较纸板 /布兜制动组延长。结论 :电针实验中观察到的镇痛 ,除了来源于电流刺激外 。

Enduring alterations in hippocampal astrocytesynaptic proximity following adolescent alcohol exposure: reversal by gabapentin

Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years.Despite reports of a wide range of effects of adolescent intermittent ethanol(AIE)exposure on brain and behavior,little is known about the mechanisms that may underlie those effects,and even less about treatments that might reverse them.Recent studies from our laboratory have indicated that AIE produced enduring changes in astrocyte function and synaptic activity in the hippocampal formation,suggesting the possibility of an alteration in astrocyte-neuronal connectivity and function.We utilized astrocyte-specific,membrane restricted viral labeling paired with immunohistochemistry to perform confocal single cell astrocyte imaging,three-dimensional reconstruction,and quantification of astrocyte morphology in hippocampal area CA1 from adult rats after AIE.Additionally,we assessed the colocalization of astrocyte plasma membrane labeling with immunoreactivity for AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)glutamate receptor 1,an AMPA receptor subunit and established neuronal marker of excitatory synapses,as a metric of astrocyte-synapse proximity.AIE significantly reduced the colocalization of the astrocyte plasma membrane with synaptic marker puncta in adulthood.This is striking in that it suggests not only an alteration of the physical association of astrocytes with synapses by AIE,but one that lasts into adulthood-well after the termination of alcohol exposure.Perhaps even more notable,the AIE-induced reduction of astrocyte-synapse interaction was reversed by sub-chronic treatment with the clinically used agent,gabapentin(Neurontin),in adulthood.This suggests that a medication in common clinical use may have the potential to reverse some of the enduring effects of adolescent alcohol exposure on brain function.All animal experiments conducted were approved by the Duke University Institutional Animal Care and Use Committee(Protocol Registry Number A159-18-07)on July 27,2018.

Exploring the Nicotinic Acetylcholine Receptor-associated Proteome with iTRAQ and Transgenic Mice

Neuronal nicotinic acetylcholine receptors(nAChRs) containing a4 and b2 subunits are the principal receptors in the mammalian central nervous system that bind nicotine with high affnity.These nAChRs are involved in nicotine dependence,mood disorders,neurodegeneration and neuroprotection.However,our understanding of the interactions between a4b2-containing(a4b2*) nAChRs and other proteins remains limited.In this study,we identifed proteins that interact with a4b2*nAChRs in a gene-dose dependent pattern by immunopurifying b2*nAChRs from mice that differ in a4 and b2 subunit expression and performing proteomic analysis using isobaric tags for relative and absolute quantitation(iTRAQ).Reduced expression of either the a4 or the b2 subunit results in a correlated decline in the expression of a number of putative interacting proteins.We identifed 208 proteins co-immunoprecipitated with these nAChRs.Furthermore,stratifed linear regression analysis indicated that levels of 17 proteins was correlated signifcantly with expression of a4b2 nAChRs,including proteins involved in cytoskeletal rearrangement and calcium signaling.These fndings represent the frst application of quantitative proteomics to produce a b2* nAChR interactome and describe a novel technique used to discover potential targets for pharmacological manipulation of a4b2 nAChRs and their downstream signaling mechanisms.

Electrochemical measurement of serotonin by Au-CNT electrodes fabricated on microporous cell culture membranes

Gut–brain axis(GBA)communication relies on serotonin(5-HT)signaling between the gut epithelium and the peripheral nervous system,where 5-HT release patterns from the basolateral(i.e.,bottom)side of the epithelium activate nerve afferents.There have been few quantitative studies of this gut-neuron signaling due to a lack of real-time measurement tools that can access the basolateral gut epithelium.In vitro platforms allow quantitative studies of cultured gut tissue,but they mainly employ offline and endpoint assays that cannot resolve dynamic molecular-release patterns.Here,we present the modification of a microporous cell culture membrane with carbon nanotube-coated gold(Au-CNT)electrodes capable of continuous,label-free,and direct detection of 5-HT at physiological concentrations.Electrochemical characterization of single-walled carbon nanotube(SWCNT)-coated Au electrodes shows increased electroactive surface area,5-HT specificity,sensitivity,and saturation time,which are correlated with the CNT film drop-cast volume.Two microliters of CNT films,with a 10-min saturation time,0.6μA/μM 5-HT sensitivity,and reliable detection within a linear range of 500 nM–10μM 5-HT,can be targeted for high-concentration,high-time-resolution 5-HT monitoring.CNT films(12.5μL)with a 2-h saturation time,4.5μA/μM 5-HT sensitivity,and quantitative detection in the linear range of 100 nM–1μM can target low concentrations with low time resolution.These electrodes achieved continuous detection of dynamic diffusion across the porous membrane,mimicking basolateral 5-HT release from cells,and detection of cell-released 5-HT from separately cultured RIN14B cell supernatant.Electrode-integrated cell culture systems such as this can improve in vitro molecular detection mechanisms and aid in quantitative GBA signaling studies.

Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling

Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs.Nicotine attenuates the neuroinflammation induced by microglial activation.However,the molecular target(s)underlying anti-inflammatory action of nicotine has not been fully understood.Considering the psychoactive substances morphine,cocaine,and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4(TLR4),here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2(MD2).

Female ticks (Ixodes scapularis) infected with Borrelia burgdorferi have increased overwintering survival, with implications for tick population growth

The tick, Ixodes scapularis, vectors pathogens such as Borrelia burgdorferi, the bacterium that causes Lyme disease. Over the last few decades I. scapularis has expanded its range, introducing a novel health threat into these areas. Warming temperatures appear to be one cause of its range expansion to the north. However, other factors are also involved. We show that unfed adult female ticks infected with B. burgdorferi have greater overwintering survival than uninfected female ticks. Locally collected adult female ticks were placed in individual microcosms and allowed to overwinter in both forest and dune grass environments. In the spring we collected the ticks and tested both dead and living ticks for B. burgdorferi DNA. Infected ticks had greater overwintering survival compared with uninfected ticks every winter for three consecutive winters in both forest and dune grass environments. We discuss the most plausible explanations for this result. The increased winter survival of adult female ticks could enhance tick population growth. Our results suggest that, in addition to climate change, B. burgdorferi infection itself may be promoting the northern range expansion of I. scapularis. Our study highlights how pathogens could work synergistically with climate change to promote host range expansion.

Modeling Pain Using fMRI:From Regions to Biomarkers

Pain is a subjective and complex phenomenon.Its complexity is related to its heterogeneity: multiple component processes, including sensation, affect, and cognition, contribute to pain experience and reporting.These components are likely to be encoded in distributed brain networks that interact to create pain experience and pain-related decision-making. Therefore, to understand pain, we must identify these networks and build models of these interactions that yield testable predictions about pain-related outcomes. We have developed several such models or `signatures' of pain, by(1) integrating activity across multiple systems, and(2) using pattern-recognition to identify processes related to pain experience. One model, the Neurologic Pain Signature, is sensitive and specific to pain in individuals, involves brain regions that receive nociceptive afferents, and shows little effect of expectation or self-regulation in tests to date. Another, the'Stimulus Intensity-Independent Pain Signature',explains substantial additional variation in trial-to-trial pain reports.It involves many brain regions that do not show increased activity in proportion to noxious stimulus intensity, including medial and lateral prefrontal cortex, nucleus accumbens, and hippocampus. Responses in this system mediate expectancy and perceived control effects in several studies.Overall, this approach provides a pathway to understanding pain by identifying multiple systems that track different aspects of pain. Such componential models can be combined in unique ways on a subject-by-subject basis to explain an individual's pain experience.

脊髓和周围神经系统中内源性大麻酚类花生四烯甘油的液相层析-质谱检测(英文)

AIM: To develop a sensitive method for measuring theputative endocannabinoid 2-arachidonylglycerol (2-AG)in the peripheral and ceatral nervous system.METHODS: A method using atmospheric pressurechemical ionization (APCI) liquid chromatography/mass spectrometry (LC/MS ) was developed todetermine the levels of 2-AG in methanol extracts of therat lumar spinal cord, dorsal root ganglion (DRG),and sciatic nerve. RESULTS: 2-AG was detectedwith high sensitivity and minimal sample preparation.The levels in the tissues analyzed were ≤pmol/mg wetweight. Similar levels were found in the spinal

大麻酚类受体-1在脊髓、背角、背根神经节和周围神经的分布(英文)

AIM: The localization of CB1 receptors in the spinalcord, spinal roots, dorsal root ganglion (DRG), andperipheral nerve of the rat was determined.METHODS: We studied the distribution of CB1cannabinoid receptors by immunohistochemistry usingan antibody raised against the N-termina1 of thereceptor. RESULTS: The spinal cord showednumerous transverse fibers labelled for CB1 receptorsthroughout and concentrated in the dorsal horn.Lightly-stained cells were observed throughout thespinal cord gray matter. The DRG also showed cellsand fibers labelled for CB1 receptors. Labelled fiberswere observed in both dorsal and ventral roots as well

3D-Printed electrochemical sensor-integrated transwell systems

This work presents a 3D-printed,modular,electrochemical sensor-integrated transwell system for monitoring cellular and molecular events in situ without sample extraction or microfluidics-assisted downstream omics.Simple additive manufacturing techniques such as 3D printing,shadow masking,and molding are used to fabricate this modular system,which is autoclavable,biocompatible,and designed to operate following standard operating protocols(SOPs)of cellular biology.Integral to the platform is a flexible porous membrane,which is used as a cell culture substrate similarly to a commercial transwell insert.Multimodal electrochemical sensors fabricated on the membrane allow direct access to cells and their products.A pair of gold electrodes on the top side of the membrane measures impedance over the course of cell attachment and growth,characterized by an exponential decrease(~160%at 10Hz)due to an increase in the double layer capacitance from secreted extracellular matrix(ECM)proteins.Cyclic voltammetry(CV)sensor electrodes,fabricated on the bottom side of the membrane,enable sensing of molecular release at the site of cell culture without the need for downstream fluidics.Real-time detection of ferrocene dimethanol injection across the membrane showed a three order-of-magnitude higher signal at the membrane than in the bulk media after reaching equilibrium.This modular sensor-integrated transwell system allows unprecedented direct,real-time,and noninvasive access to physical and biochemical information,which cannot be obtained in a conventional transwell system.