Exploring the effect of wound related pain on psychological stress, inflammatory response, and wound healing.

AIMS AND OBJECTIVES: The relationship between pain and poor healing is intricate, potentially mediated by psychological stress and aberrations in inflammatory response. The purpose of this study was to examine the biopsychosocial model of pain by assessing the relationships between pain, stress, inflammation and healing in people with chronic wounds. DESIGN: This was a 4-week prospective observational study to explore the relationship of pain, stress, inflammation and wound healing in a convenience sample of patients with chronic wounds in a chronic care hospital in Canada. METHODS: Only subjects over 18 with chronic wounds were recruited into the study. Chronic wounds were defined by the duration of wounds for more than 4 weeks of various aetiologies including wounds caused by pressure injuries, venous disease, arterial insufficiency, surgery or trauma and diabetic neuropathy. Participants were evaluated for pain by responding to the Brief Pain Inventory-Short Form, the McGill Pain Questionnaire-Short Form and the Leeds Assessment of Neuropathic Symptoms and Signs scale. Stress was measured by the Perceived Stress Scale (PSS). All wounds were assessed with the Pressure Ulcer Scale for Healing tool. The levels of matrix metalloproteinases were analysis by obtaining wound fluid from all participants. RESULTS: A total of 32 individuals with chronic wounds participated in the study. Correlation analysis indicated pain severity was positively and significantly related to pain interference, McGill Pain Questionnaire scores, neuropathic pain and matrix metalloproteinase levels. Logistic regression was used to determine the predictors for high or low perceived stress. The only significant variable that contributed to the stress levels was BPI-I. Results suggested that participants who experienced higher levels of pain interference also had an increased odds to report high level of stress by 1.6 times controlling for all other factor in the model. CONCLUSION: Pain is a complex biopsychosocial phenomenon affecting quality of life in people with chronic wounds. Results of this study identified a significant relationship between pain, stress and wound healing.

[Markers of inflammation with decreased functionality in the cognitive and psychological domains of individual vitality in middle-aged and elderly patients with metabolic syndrome.]

Metabolic syndrome is a group of disorders that are closely related to both the risk of developing type 2 diabetes mellitus and cardiovascular diseases, and generally leading to the phenomenon of premature aging of the body. Excessive accumulation of adipose tissue contributes to the development of chronic immune inflammation and oxidative stress, which are both precursors to various disorders, such as insulin resistance, arterial hypertension and dyslipidemia, but also trigger inflammatory processes in patients. An increasing number of studies support the importance of chronic immune inflammation in the pathogenesis of metabolic syndrome, as pro-inflammatory markers such as TNF-α, IL-1ß, IL-6, monocyte chemotactic protein-1 and growth of vascular endothelium. Among a wide range of cytokines, monocyte chemotactic protein-1 is considered one of the most important chemokines, which activates monocytes and other immune cells actively involved in inflammation. Another important point of chronic immune inflammation is its impact on the mental health of patients with metabolic syndrome. Increased levels of anxiety and depression are associated with levels of pro-inflammatory cytokines produced by adipose tissue, which ultimately has an adverse effect on the cognitive status of patients.

A tale of two marital stressors: Comparing proinflammatory responses to partner distress and marital conflict.

Marital quality shares ties to inflammatory conditions like cardiovascular disease and diabetes. For decades, research has focused on marital conflict as a primary mechanism given its potential to trigger inflammatory responses. However, longitudinal evidence suggests that marital conflict declines over time, and little attention has been paid to the inflammatory aftermath of other types of marital exchanges. A spouse's emotional distress is an important but overlooked marital context, as partners are exposed to each other's upsetting emotions throughout adulthood. To directly compare reactivity in proinflammatory gene expression to these two marital stressors and to examine differences by age and marital satisfaction, 203 community adults ages 25-90 (N = 102 couples) provided blood samples and rated their negative mood before and after they 1) watched their partner relive an upsetting personal memory and, in a separate visit 1-2 weeks later, 2) discussed a conflictual topic in their relationship. Controlling for age, sex, race/ethnicity, BMI, alcohol use, smoking, and comorbidities, increases in proinflammatory gene expression were significantly larger after the partner's upsetting disclosure than after marital conflict (B = 0.073, SE = 0.031, p = .018). This pattern paralleled emotional reactivity to the tasks, wherein negative mood rose more in response to the partner's disclosure than to marital conflict (B = 4.305, SE = 1.468, p = .004). In sum, proinflammatory and mood reactivity to spousal distress exceeded reactivity to marital conflict, a well-established marital stressor. Findings reveal spousal distress as a novel mechanism that may link marriage to inflammation-related diseases, and even pose risks for both happy and unhappy couples across adulthood.

The loneliness factor in eating disorders: Implications for psychopathology and biological signatures.

OBJECTIVES: Eating disorders (ED) are severe psychiatric conditions. While the biological consequences of EDs are well established, including an increase in inflammatory biomarkers, the influence of psychological factors, such as loneliness, has only recently gained attention in research. Loneliness has been associated with more severe psychopathology in ED patients, while its association with inflammatory biomarkers has only been explored in the general population. For these reasons, we aimed to investigate any possible associations between psychological features, trauma, and inflammatory biomarkers with loneliness in people with ED. METHODS: This study examined the interaction between loneliness, eating psychopathology, and biological markers in people with EDs. A group of 97 female patients with various diagnoses of ED was assessed for loneliness, general and eating psychopathology, traumatic history during childhood, and clinical biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and urinary-free cortisol (UFC). RESULTS: The results indicated that individuals with ED who reported moderate to severe loneliness also displayed greater general psychopathology (p = 0.001), weight concerns (p = 0.007), and physical neglect during childhood (p = 0.006). Furthermore, people with higher levels of loneliness also had higher inflammatory indexes (ESR p = 0.001, CRP p = 0.027) and were positively correlated with markers of stress reaction such as UFC (p < 0.05). CONCLUSION: The findings underscore the importance of considering loneliness in the assessment of individuals with an ED. We observed notable associations between loneliness and increased psychopathology (both general and specific to eating), as well as higher levels of inflammation and childhood physical neglect. Addressing loneliness may contribute to improving overall well-being and potentially support recovery. This consideration encompasses both psychological and physical factors that interplay in the clinical presentation of individuals.

The role of mild stressors in children's cognition and inflammation: positive and negative impacts depend on timing of exposure.

Although the impact of stressful life events (SLEs) on mental health is well-established, the research on the impact of such stressors on cognitive outcomes has produced mixed results. Arguably, the timing and severity of exposure may play a key role. In this study, we shed light on the relationship between timing of exposure to relatively minor SLEs and cognitive ability in children, while taking into account the role of a plausible biological mediator: inflammation. Using data from the Avon Longitudinal Study of Parents and Children, a general population birth cohort, we explored the role of relatively minor SLEs, experienced during two crucial developmental stages: up to transition to school (1-4.5 years) and up to transition to puberty (5.5-8.5 years). We then tested if they may impact differently on inflammatory markers (serum C-reactive protein [CRP] and interleukin 6 [IL-6]) at age 9 and general intelligence, measured with the Wechsler Abbreviated Scale of Intelligence at age 15. Data (n = 4,525) were analyzed using path analysis while controlling for covariates. We found that when relatively minor stressful events were experienced up to transition to school they were significantly associated with higher IQ at age 15, whereas when experienced up to transition to puberty they were significantly associated with higher levels of IL-6 at age 9. Results were robust to adjustment for relevant covariates, including IQ at age 8. Mild stressors in childhood may result in positive (i.e., improved cognition) or negative (i.e., inflammation) outcomes depending on the timing of exposure.

Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase.

INTRODUCTION: Experimental endotoxemia is a translational model of systemic inflammation that has contributed significantly to our current understanding of sickness behavior and inflammation-associated depression. Previous studies using this model revealed a strong association between cytokine levels, endocrine changes, and psychological sickness symptoms during the acute phase of inflammation. The objective of this randomized, double-blind, placebo-controlled crossover study was to gain insight into potential post-acute physiological and psychological consequences of endotoxin administration that may either persist or newly emerge between 24 and 72 h after injection. The main focus was on associations between serum levels of C-reactive protein (CRP) and affective symptoms as well as alterations in diurnal cortisol profile, the two key features of inflammation-associated depression. METHODS: Healthy male volunteers (N = 18) received an injection of either endotoxin (0.8 ng/kg) or placebo on two separate but otherwise identical study days, 7 days apart. Blood and saliva samples were collected during acute and post-acute phases after injection to measure blood inflammatory markers (interleukin [IL]-6, IL-1 receptor antagonist [ra], CRP) and salivary cortisol levels. In addition, participants completed a comprehensive battery of questionnaires to assess physical and psychological sickness symptoms. RESULTS: Endotoxin treatment induced a short-time rise in plasma IL-6 and a longer increase in IL-1ra. The increase in serum CRP was delayed compared to cytokines, peaking at 24 h and gradually decreasing until 72 h after injection. The inflammatory response was accompanied by bodily and psychological sickness symptoms which occurred only in the acute phase, whereas none of the symptoms persisted or recurred in the post-acute phase. Salivary cortisol levels were significantly increased during the acute phase and exhibited pronounced circadian changes. However, no significant differences in diurnal cortisol profiles were observed between placebo and endotoxin conditions on the days after treatment. CONCLUSION: Our findings suggest that CRP, which is elevated in patients with inflammation-associated depression, does not appear to be responsible for depressive symptomatology. Moreover, a single inflammatory episode is not sufficient to alter diurnal cortisol profiles, as observed in inflammation-associated depression. In addition, the absence of persistent lipopolysaccharide-induced psychological and physiological changes beyond the acute phase further supports the safety of endotoxin administration in humans.

Patterns of adolescent perceived social support and inflammation in adulthood within major racial groups: Findings from a longitudinal, nationally representative sample.

Inflammation, the body's protective response to injury and infection, plays a critical role in physical and mental health outcomes. Elevated chronic inflammation is implicated as a predictor of disease and all-cause mortality and is linked with several psychological disorders. Given that social support is associated with lower rates of mortality and psychopathology, the links between inflammation and social support are well-studied. However, there are many significant gaps related to both the specificity and generalizability of extant findings. There is a paucity of research on the association between social support and inflammation within different racial groups. Additionally, more research is warranted to understand whether social support from different sources uniquely contributes to inflammation, above and beyond other sources of support. Thus, the current study examined whether perceived emotional social support during adolescence predicted inflammation during adulthood within several racial groups. Participants (n = 3,390) were drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health), identified as either Asian, Black, Latinx, White, or Multiracial, and had complete data on study variables. Consistent with our hypotheses and previous research, greater perceived support during adolescence was associated with lower inflammation during adulthood, but only for White participants. Contrastingly, greater perceived support during adolescence was associated with higher inflammation during adulthood for individuals who identified as Asian, Latinx, Black, or Multiracial. Furthermore, patterns of social support and inflammation within each racial group varied by relationship type. These results highlight the importance of studying relationship processes and health outcomes within racial groups to understand their unique, lived experiences.

Mediators of inflammation at the maternal-fetal interface are altered by SARS-CoV-2 infection and pandemic stress.

PROBLEM: It is now recognized that SARS-CoV-2 infection and pandemic-related stress impacts maternal health. However, their effects at the maternal-fetal interface are still debated. METHOD OF STUDY: We recruited 199 women between March 2020 and July 2021, 79 SARS-CoV-2+ and 120 negative (the latter exposed to pandemic stress only). We also included 40 historic controls (i.e. pre-pandemic uncomplicated pregnancies recruited before March 2020). Placental samples were collected for protein and histological analysis. RESULTS: The majority of SARS-CoV-2+ women were multiethnic, had higher pre-pregnancy BMI and elevated preterm birth rate (17%) vs SARS-CoV-2- or historic control. Placental inflammatory profile revealed increased IL-1Ra and CRP, independently of SARS-CoV-2 status, whilst MCP-1, IL-6 and IFNγ were elevated in the negative, but pandemic stress-exposed, group. These changes were predominant in placentas with inflammatory lesions on histopathological analysis. Furthermore, we observed elevated immune cells (CD45+) in placentas from SARS-CoV-2+ and negative pregnancies vs historic controls, even when individuals with pregnancy complications were excluded. CONCLUSIONS: Placental inflammatory profiles differed between SARS-CoV-2 statuses, namely exposed to pandemic stress +/- SARS-CoV-2 infection. This highlights the need to understand the differences between the effects of pandemic-related stress and the added burden of SARS-CoV-2 infection on placental health.

Evolutionary Aspects of Diverse Microbial Exposures and Mental Health: Focus on "Old Friends" and Stress Resilience.

The prevalence of inflammatory disease conditions, including allergies, asthma, and autoimmune disorders, increased during the latter half of the twentieth century, as societies transitioned from rural to urban lifestyles. A number of hypotheses have been put forward to explain the increasing prevalence of inflammatory disease in modern urban societies, including the hygiene hypothesis and the "Old Friends" hypothesis. In 2008, Rook and Lowry proposed, based on the evidence that increased inflammation was a risk factor for stress-related psychiatric disorders, that the hygiene hypothesis or "Old Friends" hypothesis may be relevant to psychiatric disorders. Since then, it has become more clear that chronic low-grade inflammation is a risk factor for stress-related psychiatric disorders, including anxiety disorders, mood disorders, and trauma- and stressor-related disorders, such as posttraumatic stress disorder (PTSD). Evidence now indicates that persons raised in modern urban environments without daily contact with pets, relative to persons raised in rural environments in proximity to farm animals, respond with greater systemic inflammation to psychosocial stress. Here we consider the possibility that increased inflammation in persons living in modern urban environments is due to a failure of immunoregulation, i.e., a balanced expression of regulatory and effector T cells, which is known to be dependent on microbial signals. We highlight evidence that microbial signals that can drive immunoregulation arise from phylogenetically diverse taxa but are strain specific. Finally, we highlight Mycobacterium vaccae NCTC 11659, a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, as a case study of how single strains of bacteria might be used in a psychoneuroimmunologic approach for prevention and treatment of stress-related psychiatric disorders.

Specific Associations Between Type of Childhood Abuse and Elevated C-Reactive Protein in Young Adult Psychiatric Rehabilitation Participants.

BACKGROUND: Early-life adversity such as childhood emotional, physical, and sexual trauma is associated with later-life psychiatric and chronic medical conditions, including elevated inflammatory markers. Although previous research suggests a role for chronic inflammatory dysfunctions in several disease etiologies, specific associations between childhood trauma types and later-life inflammation and health status are poorly understood. METHODS: We studied patients (n = 280) admitted to a psychiatric rehabilitation center. Self-reported histories of childhood emotional, physical, and sexual trauma were collected with a standard instrument. At the time of admission, we also assessed individuals' body mass index and collected blood samples used to examine inflammatory marker C-reactive protein (CRP) levels. RESULTS: The prevalence of all 3 types of abuse was relatively high at 21% or more. Fifty percent of the sample had elevations in CRP, with clinically significant elevations in 26%. We found that compared with a history of emotional or physical abuse, a history of childhood sexual trauma was more specifically associated with elevated CRP. This result held up when using linear regressions to examine the contribution of body mass index. LIMITATION: Our sample was relatively young, with an average age of 27.2 years and minimal representation of ethnic and racial minority participants. CONCLUSION: Relative to childhood emotional and physical trauma, childhood sexual trauma may lead to elevated inflammatory responses, as confirmed in our finding of an association between CRP and sexual abuse. Future studies need to assess the causal link between childhood sexual trauma and poorer health outcomes later in life.

Longitudinal associations between salivary cortisol to C-reactive protein ratios and psychological well-being in Chinese adults.

BACKGROUND: Salivary C-reactive protein (CRP) could be a viable biomarker of inflammation and has been associated with stress outcomes. The hypothalamic-pituitary-adrenal axis can modulate stress-related inflammation. This study aimed to evaluate the interaction effects of immune-endocrine markers on psychological outcomes. METHODS: The study participants were 52 healthy Chinese adults who collected 10 saliva samples over 2 consecutive days at baseline. The participants completed validated measures on anxiety, depression, positive affect, and sleep disturbance at baseline and 1 month later. The stability and diurnal patterns of salivary cortisol and CRP were investigated via paired t-tests and repeated-measures analyses of variance. Regression analysis was used to examine the longitudinal associations between immune-endocrine markers and their interactions (cortisol [Cort]: morning CRP [CRPmorn] and Cort:CRPeven) and psychological measures. RESULTS: Salivary cortisol and CRP displayed satisfactory stability over 2 consecutive days and diurnal patterns of abrupt and gradual decline during the day, respectively. Controlling for baseline psychological measures and confounding variables, Cortmorn and diurnal cortisol slope was significantly and negatively associated with anxiety symptoms and positive affect 1 month later, respectively. Cort:CRPeven and Cort:CRPmorn was significantly and positively associated with depressive symptoms and sleep disturbance 1 month later, respectively. CONCLUSION: These findings offer initial support for the prognostic utility of salivary cortisol and CRP and their balance as determinants of psychological health in healthy adults.

Association of depression and obesity with C-reactive protein in Germany: A large nationally representative study.

INTRODUCTION: Depression and obesity often occur comorbidly, and once both are present, they further increase the risk of developing other medical comorbidities, likely due to the underlying chronic low-grade inflammation. We investigated to what extent depression and obesity are associated with levels of high-sensitivity C-reactive protein (hsCRP) in a nationally representative sample of the German adult population. METHODS: We analyzed data from the German Health Interview and Examination Survey for Adults (DEGS1, N = 7115), and its mental health module (DEGS1-MH; N = 4483). Two different depression measures were used: current depressive symptoms assessed by the self-administered German version of the Patient Health Questionnaire-9 and major depressive disorder (MDD) in the last 12 months assessed by a modified German version of the Composite International Diagnostic Interview. Obesity was defined by body mass index calculated from measured data. Associations with log(x + 1)-transformed hsCRP levels were analyzed using multivariable linear regression models. RESULTS: Obese participants with depressive symptoms had significantly higher hsCRP compared to non-obese participants with depressive symptoms adjusted for sociodemographic and behavioral variables and medication use. In non-obese individuals, depressive symptoms were inversely associated with hsCRP, whereas MDD was not associated with hsCRP after adjustment for covariates. Additional analyses suggested symptom-specific associations of hsCRP as higher levels were linked to fatigue (ß = 0.10, p <.001) while lower levels were linked to cognitive problems (ß = -0.09, p <.001). Low SES, current smoking, lower levels of physical exercise, and the use of anti-inflammatory/anti-rheumatic medication and antidepressants were additional determinants of hsCRP in the fully adjusted models. CONCLUSIONS: Our data suggest that obesity status is more strongly associated with increased inflammation than depressive symptoms or MDD. The relationship between depression and hsCRP in our population-based sample is substantially influenced by obesity status as well as other medical factors, lifestyle, and socioeconomic status. Furthermore, our findings suggest that the association between hsCRP and depression is symptom-specific rather than generalized.

Youth depression and inflammation: Cross-sectional network analyses of C-Reactive protein, interleukin-6 and symptoms in a population-based sample.

BACKGROUND: Inflammation-related proteins constitute a promising avenue in studying biological correlates of major depressive disorder (MDD). However, MDD is a heterogeneous condition - a crucial aspect to be considered in association studies. We examined whether inflammatory proteins are associated with categorical diagnosis, a dimensional total sum-score, and specific depressive symptoms among youths. METHODS: We analyzed data from the 1993 Pelotas Birth Cohort, a population-based study in Brazil that followed individuals up to age 22 years. Categorical psychiatric diagnoses were derived using adapted modules of the Mini International Neuropsychiatric Interview (MINI). Dimensional symptomatology was assessed using the Brazilian Portuguese version of the Center for Epidemiological Studies-Depression Scale-Revised (CESD-R). We estimated network structures that included individual depressive symptoms as measured by CESD-R items, peripheral inflammatory markers (C-Reactive Protein [CRP] and Interleukin-6 [IL-6]), as well as relevant covariates. RESULTS: We evaluated 2586 participants (mean age = 22.5[SD = 0.33]) There were no associations between concentrations of inflammatory proteins and categorical diagnosis of MDD or with CESD-R total sum-scores. In symptom-specific analysis, CRP and IL-6 were positively connected to somatic and cognitive items. DISCUSSION: We found cross-sectional connections of two commonly studied inflammatory proteins and specific depressive symptoms. Conducting symptom-specific analyses in relation to biological markers might advance our understanding of the heterogeneity of MDD.

A short Mindfulness retreat can improve biological markers of stress and inflammation.

OBJECTIVE: Mindfulness practice, a form of meditation, has shown benefit for psychological and physical health. In this study, we investigated the effect of an intensive period of Mindfulness practice on some biological mediators of stress and inflammation during a 3-day residential retreat. METHODS: A total of 95 healthy individuals (aged 18-67) were recruited and randomized to a Mindfulness retreat arm or an active control arm. Before (t0) and after (t1) the intervention, all the participants were assessed for salivary cortisol levels and for a panel of pro- and anti-inflammatory cytokines measured in saliva. Psychometric measures on stress, anxiety and awareness were carried out using PSS, STAI-Y and MAAS questionnaires, respectively. RESULTS: As to the within-group differences, we observed a statistically significant decrease in perceived stress (ß = -8.85, p < 0.0001), and anxiety scores (ß = -12.39, p < 0.0001), while awareness increased (ß = 15.26, p < 0.0001) between t0 to t1 in retreat participants. In the mindfulness intervention group, we also observed a statistically significant reduction in the levels of pro-inflammatory cytokines IL-6 (ß = -0.94 p = 0.001) and IL-8 (ß = -176.40, p < 0.0001), and an increase in anti-inflammatory IL-10 (ß = 0.89 p < 0.0001) levels at the end of the retreat. At t1 we observed a highly significant correlation between cortisol levels and both anxiety (r = 0.56, p < 0.0001) and perceived stress (r = 0.92, p < 0.0001) scores. CONCLUSIONS: Mindfulness retreat participants showed a significant reduction in perceived stress and anxiety levels, as well as an improved balance of some key mediators of inflammatory states. Our data provide evidence that a mindfulness retreat may be effective in improving physical and mental health. Future studies with larger numbers of subjects and follow-up periods may examine mindfulness practice as a non-pharmacological alternative to promote stress reduction and overall health and wellbeing.

Nrf2 Alleviates Cognitive Dysfunction and Brain Inflammatory Injury via Mediating Wfs1 in Rats with Depression-Like Behaviors.

Depression is a major threat to global mental health and demands targeted therapeutic regimens. The current study set out to evaluate the regulatory mechanism of nuclear factor erythroid-2 related factor 2 (Nrf2) in depression-induced cognitive dysfunction and inflammatory injury. First, depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests. Rats were further stereotactically injected with Nrf2 overexpression vector, with expression patterns of Nrf2, miR-17-5p, and wolfram syndrome 1 (Wfs1) detected using qRT-PCR and Western blot assay. In addition, pathological changes of murine hippocampus were analyzed using hematoxylin-eosin staining. In vitro cell models were additionally established using lipopolysaccharide. Cell viability was detected via the CCK-8 method. Moreover, levels of TNF-α, IL-1ß, and IL-10 were detected via ELISA. Furthermore, the binding relationships between Nrf2 and the miR-17-5p promoter, miR-17-5p, and Wfs1 were verified. It was found that Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury. Meanwhile, Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit Wfs1 transcription. miR-17-5p overexpression or Wfs1 downregulation partly reversed the role of Nrf2 in reliving inflammatory injury of murine hippocampal neurons. Overall, our findings indicated that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors.

Gut-derived systemic inflammation as a driver of depression in chronic liver disease.

Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.

Association between serum uric acid and depressive symptoms stratified by low-grade inflammation status.

Despite increasing evidence for an association between circulating uric acid (UA) and depression, the directionality of this association remains unclear and is potentially moderated by low-grade inflammation. Thus, the present study aimed to investigate the cross-sectional association between serum UA concentration and depressive symptoms in Korean individuals with and without low-grade inflammation, as measured using serum high-specific C-reactive protein (hs-CRP) levels. The final study sample comprised 4188 participants, aged 19-79 years, from the Korea National Health and Nutrition Examination Study 2016. Data on serum uric acid (UA) concentrations, serum hs-CRP levels, Patient Health Questionnaire-9 (PHQ-9) scores, and relative covariates were retrieved. Negative binomial regression with adjustment for the complex sample design was used to analyze the associations. After adjusting for covariates, log-transformed serum UA concentrations and total PHQ-9 scores were positively associated (incidence rate ratio [IRR] = 1.34 [95% confidence interval [CI] = 1.09-1.66]) for participants without low-grade inflammation and inversely associated (IRR = 0.64 [95% CI = 0.45-0.92]) for participants with low-grade inflammation. In conclusion, the direction of the association between serum UA and depressive symptoms was the opposite in participants with and without low-grade inflammation. The study has the limitation of potential uncontrolled confounders.

Association Between Systemic Inflammation and Individual Symptoms of Depression: A Pooled Analysis of 15 Population-Based Cohort Studies.

OBJECTIVE: Evidence from anti-inflammatory drug trials for the treatment of depression has been inconsistent. This may be ascribed to the differing symptom-specific effects of inflammation. Accordingly, the authors explored the associations between systemic inflammation and an array of individual symptoms of depression across multiple studies. METHODS: This random-effects pooled analysis included 15 population-based cohorts and 56,351 individuals age 18 years and older. Serum or plasma concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured at baseline. Using validated self-report measures, 24 depressive symptoms were ascertained in 15 cross-sectional studies, and, in seven cohorts, were also assessed at follow-up (mean follow-up period, 3.2 years). RESULTS: The prevalence of depressive symptoms ranged from 1.1% (suicidal ideation) to 21.5% (sleep problems). In cross-sectional analyses, higher concentrations of CRP were robustly associated with an increased risk of experiencing four physical symptoms (changes in appetite, felt everything was an effort, loss of energy, sleep problems) and one cognitive symptom (little interest in doing things). These associations remained after adjustment for sociodemographic variables, behavioral factors, and chronic conditions; in sex- and age-stratified analyses; in longitudinal analyses; when using IL-6 as the inflammatory marker of interest; in depressed individuals; and after excluding chronically ill individuals. For four exclusively emotional symptoms (bothered by things, hopelessness about the future, felt fearful, life had been a failure), the overall evidence was strongly against an association with inflammation. CONCLUSIONS: These findings suggest symptom-specific rather than generalized effects of systemic inflammation on depression. Future trials exploring anti-inflammatory treatment regimens for depression may benefit from targeting individuals presenting with symptom profiles characterized by distinct inflammation-related physical and cognitive symptoms.

Anxiolytic effect of GABAergic neurons in the anterior cingulate cortex in a rat model of chronic inflammatory pain.

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABAAR agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABAAR antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.

Social Support Is Inversely Associated With Sleep Disturbance, Inflammation, and Pain Severity in Chronic Low Back Pain.

BACKGROUND: Chronic low back pain (CLBP) is a significant cause of disability, lost wages, and healthcare costs. Inflammatory mediators, such as interleukin-6 (IL-6), have been associated with LBP severity. Patients with CLBP commonly experience sleep disturbance, and poor sleep has been shown to increase pain severity and inflammation. In contrast, social support may benefit patients with CLBP by reducing pain intensity and inflammation. OBJECTIVES: The purpose of this study was to examine the influence of social support on the relationships among sleep disturbance, inflammation, and pain severity in patients with CLBP. METHODS: In a cross-sectional study, men and women with CLBP were enrolled from an outpatient pain clinic. Participants completed psychometric instruments for social support, sleep quality, and pain severity. Blood samples were obtained for measurement of the pro-inflammatory cytokine IL-6 by enzyme-linked immunoassay. RESULTS: Linear regression revealed greater sleep disturbance predicted greater pain severity. In contrast, participants who reported higher social support had lower sleep disturbance and lower pain severity. Mediation analysis revealed sleep disturbance to mediate the relationship between social support and pain, such that sleep disturbance reduced the benefit of social support on pain severity. Furthermore, greater sleep disturbance and lower social support predicted increased IL-6. However, IL-6 did not mediate the relationship between social support and pain. DISCUSSION: The findings suggest that increased social support is associated with lower sleep disturbance, lower inflammation, and lower pain severity in patients with CLBP. Assessing the extent of social support and fostering social support as part of a comprehensive pain management program may benefit patients with CLBP. Interventions to strengthen social support systems and cultivate support from family and/or informal social networks may reduce symptom burden and improve quality of life.