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Objectives: To explore the incidence of adverse childhood experiences (ACEs) in breast cancer survivors and potential associations with long-term treatment-related sequelae., Sample & Setting: English-speaking breast cancer survivors three or more years from diagnosis with complete treatment response (N = 120) were recruited prior to scheduled survivorship clinic visits., Methods & Variables: Participants in this cross-sectional observational feasibility study rated anxiety, depression, fatigue, sleep disturbance, cognitive issues, resilience, and ACEs (experienced prior to age 18 years). Blood samples were analyzed for inflammatory and epigenetic biomarkers., Results: ACEs assessment was feasible. Higher ACE scores correlated with greater fatigue, anxiety, and depression, and with lower cognitive function (p < 0.05). Resilience was positively associated with cognitive function and negatively associated with fatigue, anxiety, and depression., Implications for Nursing: There is evidence for the impact of ACEs on long-term treatment-related sequelae in women with breast cancer. Oncology nurses should consider incorporating ACEs assessment into the workflow for women receiving survivorship care.

Introduction: In military populations, the potential for under-reporting of Post-traumatic Stress Disorder (PTSD) symptoms and challenges in recognising early changes can make it difficult to detect an emerging disorder. However, early identification of PTSD symptoms would improve opportunities for intervention, and potentially reduce the likelihood of chronic mental health problems., Method: This study explored if changes in levels of inflammation, measured by C reactive protein (CRP) and interleukin 6 (IL-6), were associated with the onset of psychological symptoms associated with PTSD. It also examined if changes in inflammation over time contributed to psychological risk and resilience, which was defined by psychological reactivity to deployment-related combat exposures. Participants were special forces personnel who completed psychological self-report questionnaires and had measures of CRP and IL-6 taken pre and post deployment. Regression analysis was used to examine how psychological symptoms predicted change in inflammation, and Analysis of Variance (ANOVA) were used to examine differences between identified subgroups., Results: Results identify this population as having high levels of combat and trauma exposures, with low-level psychological symptoms. The results also identified a decrease in CRP and an increase in IL-6 over time. A significant difference in inflammation was identified between subgroups (p<0.05). An association between inflammatory markers and subthreshold symptoms related to anger (p<0.01) and sleep (p<0.05) was also identified., Conclusion: These preliminary findings suggest inflammatory markers may help to identify adaptive responses post deployment. In addition, low-level increases in inflammatory markers may be associated with subthreshold PTSD symptoms. These findings offer potential insights for prevention, early identification and treatment in military and veteran populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Research suggests that systemic inflammation may link loneliness to adverse health outcomes, yet there is a gap in comprehensively reviewing recent evidence on the relationship between loneliness and biological measures of inflammation in adults. This scoping review synthesizes current research to address the question: Is there a definitive link between loneliness and biological markers of inflammation in adults?, Methods: Following the methods outlined by Arksey and O'Malley, we developed a protocol, defined our research question, and systematically searched PubMed, CINAHL, Embase, and Scopus for English-language studies conducted from 2018 to 2023 exploring the relationship between loneliness and biomarkers of inflammation in adults., Results: Twelve studies meeting the inclusion criteria displayed heterogeneity in terms of sample characteristics, loneliness scales, and inflammatory biomarkers. The UCLA Loneliness Scale, in various forms, emerged as the predominant tool for measuring loneliness, while C-reactive protein and interleukin-6 were the most frequently evaluated inflammatory biomarkers. Notably, all 12 studies reported an association between loneliness and at least 1 biological marker of inflammation., Conclusion: Research consistently associates loneliness with poor health outcomes in aging adults, but the underlying mechanisms remain unclear. This scoping review suggests that inflammation may serve as a pathway linking loneliness to adverse health outcomes. However, the variability across studies highlights the need for standardized measurement methods and a consideration of both the duration and extent of loneliness. Enhancing our understanding of how loneliness affects systemic inflammation may help clarify why loneliness is associated with negative health outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Author(s). International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest There were no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The mechanisms through which acculturation influences the onset of cognitive impairment and dementia are not well understood, especially among older Hispanics., Objective: To investigate whether inflammation and psycho-behavioral factors mediate the relationship between acculturation and incident dementia among older Mexican Americans., Methods: We analyzed the Sacramento Area Latino Study on Aging (1998-2007, SALSA), a longitudinal study (N = 1,194) with 10 years of follow-up, and used g-computation for mediation analysis with pooled logistic regression to evaluate whether acculturation (assessed by the Revised Acculturation Rating Scale for Mexican Americans [ARSMA-II]) affected dementia or cognitive impairment but not dementia (CIND) through inflammation (i.e., interleukin 6 [IL-6], tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein [hs-CRP]), smoking, alcohol consumption, and depressive symptoms. The potential mediators were assessed at baseline., Results: The 10-year average adjusted risk ratio (aRR) for the effect of high U.S. acculturation and dementia/CIND was 0.66, 95% CI (0.36, 1.30). The indirect effects were: IL-6 (aRR = 0.98, 95% CI (0.88, 1.05)); TNF-α (aRR:0.99, 95% CI (0.93, 1.05)); hs-CRP: (aRR = 1.21, 95% CI (0.84, 1.95)); current smoking: aRR = 0.97, 95% CI (0.84, 1.16); daily/weekly alcohol consumption (aRR = 1.00, 95% CI (0.96, 1.05)); and depressive symptom score (aRR = 1.03, 95% CI (0.95, 1.26)). Hs-CRP yielded a proportion mediated of -26%, suggesting that hs-CRP could suppress the potential effect of high U.S. acculturation. The other factors explored resulted in little to no mediation., Conclusions: The effect of acculturation on time to incident dementia/CIND varied over time. Our study suggests that inflammation could suppress the effect between high U.S. acculturation and dementia risk.

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-1β, 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.

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

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., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (Published by Oxford University Press on behalf of CINP 2022.)

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 [CRP morn ] and Cort:CRP even ) 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, Cort morn and diurnal cortisol slope was significantly and negatively associated with anxiety symptoms and positive affect 1 month later, respectively. Cort:CRP even and Cort:CRP morn 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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 (β = 0.10, p <.001) while lower levels were linked to cognitive problems (β = -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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (Copyright © 2022. Published by Elsevier Ltd.)

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., Competing Interests: Conflict of interest CP is funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. CP has received research funding from Johnson & Johnson as part of a research programme on depression and inflammation, and from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & Johnson, GSK and Lundbeck; however, the present paper is independent from this funding. DLS has participated in advisory boards for Norgine Pharmaceuticals Ltd, EnteroBiotix, Kaleido Biosciences, Mallinckrodt and Shionogi and has delivered paid lectures for Norgine Pharmaceuticals Ltd, Falk Pharma and Alfa Sigma. THT and DLS have also received funding for an investigator-initiated study (EMITTIC Study) from Norgine Pharmaceuticals Ltd. THT has also received funding from the Medical Research Council (MRC). VTK has no COI to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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-1β, 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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 (β = -8.85, p < 0.0001), and anxiety scores (β = -12.39, p < 0.0001), while awareness increased (β = 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 (β = -0.94 p = 0.001) and IL-8 (β = -176.40, p < 0.0001), and an increase in anti-inflammatory IL-10 (β = 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

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., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2021. The Author(s).)

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 GABA A R agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABA A R 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., (© 2021. The Author(s).)

Neuropsychiatric sequalae to coronavirus disease 2019 (COVID-19) infection are beginning to emerge, like previous Spanish influenza and severe acute respiratory syndrome episodes. Streptococcal infection in paediatric patients causing obsessive compulsive disorder (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, widespread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long-term-specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favourable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease-modifying therapies are increasingly being applied to neuropsychiatric diseases characterised by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.

Introduction: Discrimination is associated with negative health outcomes among Latinos. Research on the link between discrimination and inflammation in adults has focused on pro-inflammatory markers rather than characterizing the more informative balance of pro- and anti-inflammatory markers. The purpose of this cross-sectional study was to examine the associations of everyday discrimination with inflammation ratio (defined as the ratio of pro- to anti-inflammatory cytokines) in a sample of middle-aged and older Latinas., Methods: Latinas were recruited from an existing study in New York City. Participants reported frequency and count of everyday discrimination. Peripheral blood was used to analyze pro- (IL-1 B and IL-6) and anti-inflammatory (IL-4 and IL-10) cytokines. The inflammation ratio was calculated by dividing the sum of pro-inflammatory cytokines by the sum of anti-inflammatory cytokines. We used linear regression to assess the link between everyday discrimination and inflammation ratio., Results: The final sample included 40 Latinas (mean age = 63.2 years). Approximately 68% had household incomes less than $15,000. More than half (53%) reported experiencing some form of everyday discrimination. Regression models showed everyday discrimination was not associated with individual pro- and anti-inflammatory cytokines. In adjusted regression models, the frequency of everyday discrimination was not associated with inflammation ratios ( B [ SE ] = 0.57[0.30], p = .07). However, a higher count of everyday discrimination was associated with inflammation ratios ( B [ SE ] = 1.15[0.55], p = .04)., Conclusions: The count of everyday discrimination was positively associated with inflammation in Latina women. Future studies should replicate these findings using longitudinal assessment of discrimination and inflammatory markers.

Background: Sleep disturbances and insufficient sleep are highly prevalent. Both clinical sleep disorders and multiple forms of experimental sleep loss predict heightened inflammation. As such, it is necessary to investigate potential protective factors. Given that trait positive affect (PA) is associated with reduced inflammation, and buffers the proinflammatory effects of stress, it is possible that high trait positive affect might protect individuals from an inflammatory response to sleep disruption. The present study tested this hypothesis in an experimental sleep disruption paradigm with assessment of cellular inflammation., Methods: Data were drawn from good sleeping adults (n = 79) who participated in a randomized, within-subjects crossover experiment comparing the effects of two nights of sleep disruption versus two nights of uninterrupted sleep. Stimulated monocytic production of intracellular proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) were assayed using flow cytometric methods and indexed as the percentage of monocytes expressing TNF, IL-6, or co-expressing both. Hypotheses were evaluated using linear mixed effects models., Results: Controlling for negative affect, body mass index, age, and sex, PA significantly moderated the associations between sleep condition and stimulated monocyte production of IL-6 (b = -1.03, t = -2.02, p = .048) and its co-expression with TNF (b = -0.93, t = -2.00, p = .049), such that inflammatory responses were blunted among those high in PA with increases principally among those low in PA. The effect on TNF was similar in terms of effect size, but marginally significant., Conclusions: Activation of cellular inflammation in response to sleep disruption is buffered by PA independent of negative affect. Interventions that promote PA might protect persons from the inflammatory activation following sleep loss, with the potential to mitigate the adverse health consequences of sleep disturbance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Depression and vitamin D deficiency are major public health problems. The existing literature indicates the complex relationship between depression and vitamin D. The purpose of this study was to examine whether this relationship is moderated or mediated by inflammation. A community sample ( n = 7162) from the LIFE-Adult-Study was investigated, for whom depressive symptoms were assessed via the German version of CES-D scale and serum 25-hydroxyvitamin D (25(OH)D) levels and inflammatory markers (IL-6 and CRP levels, WBC count) were quantified. Mediation analyses were performed using Hayes' PROCESS macro and regression analyses were conducted to test moderation effects. There was a significant negative correlation between CES-D and 25(OH)D, and positive associations between inflammatory markers and CES-D scores. Only WBC partially mediated the association between 25(OH)D levels and depressive symptoms both in a simple mediation model (ab: -0.0042) and a model including covariates (ab: -0.0011). None of the inflammatory markers showed a moderation effect on the association between 25(OH)D levels and depressive symptoms. This present work highlighted the complex relationship between vitamin D, depressive symptoms and inflammation. Future studies are needed to examine the effect of vitamin D supplementation on inflammation and depressive symptomatology for causality assessment.

The role of platelets in hemostasis and thrombosis has long been recognized, recently their contribution to immunological and inflammatory processes is emerging. Platelets could be the missing link between cardiovascular disease, chronic stress and depressive symptoms. Both physical and mental stressors cause platelet activation reflected by changes in platelet bioactivity and aggregation. Here we evaluate the proinflammatory platelet response to acute and chronic mental stress. In a prospective study design an acute mental stress test was administered to 55 healthy male participants once without and once in the presence of chronic mental stress. Blood was collected prior to and at three time points following an acute mental stress test (0, 30, 60 min). Platelet proinflammatory activation markers, were assessed using FACS analysis and aggregability was measured in response to ADP or epinephrine using PFA-100. A linear mixed model was used for analysis. Chronic mental stress lead to a significant increase in state anxiety (p < 0.001), depressive symptoms (p = 0.045) and perceived stress (p = 0.001). The factor "chronic mental stress" was significantly associated with increased numbers of CD63+ platelets (p = 0.009). The factor "acute mental stress" was associated with alterations in CD62P+ platelets (p < 0.001), CD63+ platelets (p = 0.011), PAC-1+ platelets (p < 0.001) as well as platelet leucocyte aggregates (p = 0.019). The recovery of CD62P function following the acute mental stress exposure was significantly impaired by chronic stress (p = 0.023). Aggregation was affected by chronic and acute mental stress. In conclusion, mental stress is linked to an increased and prolonged proinflammatory platelet bioactivity. This proinflammatory and immunomodulatory stimuli could help to explain the link between mental and somatic disorders. Graphical Abstract.

Inflammation plays an important role in depression pathology, making it a promising target for ameliorating depression-like behaviors. The peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional coactivator being able to constrain inflammatory events through NF-κB signaling. However, the role of PGC-1α in depression is not yet clear. This study was designed to investigate the role of PGC-1α in depression and explore the underlying mechanisms. Mice modeled with chronic unpredictable mild stimulation (CUMS) were explored for the relationship between depression-like behaviors and PGC-1α. Baicalin was used to evaluate the effect regulating PGC-1α. Furthermore, the anti-neuroinflammatory effect of baicalin was investigated both in BV2-SH-SY5Y co-culture system and in mice by LPS challenge. The role of PGC-1α in neuroinflammation was explored in cell co-culture systems under gene silencing conditions targeting NF-κB signaling. We found that the expression of PGC-1α was inhibited in the hippocampus of mice exposed to CUMS or LPS, while baicalin could increase the expression of PGC-1α and alleviate the depression-like behaviors. Furthermore, baicalin attenuated neuroinflammation in the hippocampus of mice and BV2-SH-SY5Y co-culture system by LPS challenge via regulating NF-κB signaling; however, knockdown of the PGC-1α could reverse the effect of baicalin on neuroinflammation and NF-κB signaling. Our results revealed a vital role for PGC-1α in attenuating neuroinflammation in depression, indicating that PGC-1α might be a therapeutic target for depression.

Major depressive disorder (MDD) is an important contributor to the total disease burden because of its high comorbidity with chronic illnesses. Many people with high levels of depressive symptoms exhibit elevated systemic inflammation, but inflammation is not a necessary determinant of depression onset. Among those who recently experienced the death of a spouse, we investigated whether (a) inflammation assessed early in bereavement predicted future depressive symptoms and whether (b) inflammation predicted change in depressive symptoms from baseline to follow-up. Ninety-nine spousally bereaved individuals (M=68.61, SD=10.70) from a larger study were evaluated at baseline (3 months post-death) and follow-up (6 months post-death). Subjects received a venous blood draw and completed the Center for Epidemiologic Studies Depression Scale (CES-D). Stimulated T-cell derived cytokines (IL-6, TNF-α, and IFN-γ) were assessed individually and as a pro-inflammatory composite index. After controlling for confounding factors (i.e., age, sex, body mass index, race, ethnicity, anti-inflammatory medication, days since spousal death, smoking status, comorbidities), individuals with higher levels of IL-6, TNF-α, and IFN-γ at baseline exhibited more depressive symptoms (composite index, p = .05) and an increased probability of experiencing clinical levels of depression (CES-D score ≥16) (composite index, p = .04). Inflammatory levels were not predictive of change in depressive symptoms or in clinical depression status from baseline to follow-up. Among individuals who did not experience clinical levels of depression at baseline, baseline inflammatory levels predicted clinical levels of depression 3 months later (p = .03). This study provides support for an inflammatory mechanism underlying depression following bereavement. It suggests that one's inflammatory profile following a significant social stressor in older adulthood can be prognostic of depression risk months later. These findings add to our understanding of the physiological and mental health risks experienced by the bereaved population and provide insight into identifying vulnerable widow(er)s at risk for maladaptive grief coping., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Epilepsy, one of the most common neurological disorders worldwide, is characterized by recurrent seizures and subsequent brain damage. Despite strong evidence supporting a deleterious impact on seizure occurrence and outcome severity, stress is an overlooked component in people with epilepsy. With regard to stressor duration and timing, acute stress can be protective in epileptogenesis, while chronic stress often promotes seizure occurrence in epilepsy patients. Preclinical research suggests that chronic stress promotes neuroinflammation and leads to a depressive state. Depression is the most common psychiatric comorbidity in people with epilepsy, resulting in a poor quality of life. Here, we summarize studies investigating acute and chronic stress as a seizure trigger and an important factor that worsens epilepsy outcomes and psychiatric comorbidities. Mechanistic insight into the impact of stress on epilepsy may create a window of opportunity for future interventions targeting neuroinflammation-related disorders.

Introduction: Child maltreatment (CM) is associated with mental and physical health disorders in adulthood. Some studies have identified elevated markers of systemic inflammation in adult survivors of CM, and inflammation may mediate the association between CM and later health problems. However, there are methodological inconsistencies in studies of the association between CM and systemic inflammation and findings are conflicting. We performed a systematic review to examine the association of CM with systemic inflammation in adults., Methods: A pre-registered systematic review was performed following PRISMA guidelines. Medline, Embase, Scopus and PsychInfo were searched for studies of the association of CM with blood markers of inflammation in adults. Quality was assessed using the Crowe Critical Appraisal Tool. We had intended to perform a meta-analysis, but this was not possible due to variation in study design and reporting., Results: Forty-four articles met criteria for inclusion in the review. The most widely reported biomarkers were C-Reactive Protein (CRP) (n = 27), interleukin-6 (IL-6) (n = 24) and Tumour Necrosis Factor-alpha (TNF-a) (n = 17). Three studies were prospective (all relating to CRP) and the remainder were retrospective. 86% of studies were based in high income countries. In the prospective studies, CM was associated with elevated CRP in adulthood. Results of retrospective studies were conflicting. Methodological issues relating to the construct of CM, methods of analysis, and accounting for confounding or mediating variables (particularly Body Mass Index) may contribute to the uncertainty in the field., Conclusions: There is some robust evidence from prospective studies that CM is associated with elevated CRP in adulthood. We have identified significant methodological inconsistencies in the literature and have proposed measures that future researchers could employ to improve consistency across studies. Further prospective, longitudinal, research using robust and comparable measures of CM with careful consideration of confounding and mediating variables is required to bring clarity to this field., Competing Interests: The authors have declared that no competing interests exist.

Background: Increasing evidence suggests a causal link between periodontitis and cognitive disorders. Systemic inflammation initiated by periodontitis may mediate the development of cognitive impairment. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of signal transducers and activators of transcription 3 (STAT3) in this process., Materials and Methods: Ligature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography analysis and histopathological evaluation. Locomotor activity and cognitive function were evaluated by the open field test and the Morris water maze test, respectively. The activation of microglia and astrocytes in the hippocampus and cortex was assessed by immunohistochemistry (IHC). The expression of interleukins (IL-1β, IL-6, IL-8, IL-21) in both the periphery and cortex was evaluated by RT-PCR and ELISA. The expression of TLR/NF-κB and ROS cascades was evaluated by RT-PCR. The expression of pSTAT3 and the activation of the STAT3 signaling pathway (JAK2, STAT3, and pSTAT3) in the periodontal tissue and cortex were assessed by IHC and Western blot. The expression of amyloid precursor protein (APP) and its key secretases was evaluated by RT-PCR. The level of amyloid β-protein (Aβ) and the ratio of Aβ1-40/1-42 were measured via ELISA in the plasma and cortex while IHC was used to detect the level of Aβ1-42 in the brain., Results: In periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-21) were detected in peripherial blood and brain. Additionally, spatial learning and memory ability was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus, presenting as enlarged cell bodies and irregular protrusions. Levels of TLR/NF-kB, PPAR and ROS were altered. The STAT3 signaling pathway was activated in both the periodontal tissue and cortex, and the processing of APP by β- and γ-secretases was promoted. The changes mentioned above could be relieved by the pSTAT3 inhibitor CTS., Conclusions: Ligature-induced periodontitis in rats resulted in systemic inflammation and further abnormal APP processing, leading to cognitive impairments. In this progress, the activation of the STAT3 signaling pathway may play an important role by increasing inflammatory load and promoting neuroinflammation.

Clinical studies have shown that diabetes can present with underlying depression, and a combination of the two can lead to emotional, memory and cognitive disorders, closely associated with hippocampal neuroinflammation. However, the mechanism underlying the development of hippocampal neuroinflammation under the above condition remains elusive. The aims of this study were to explore the pathogenesis of diabetes combined with depression, and the effect of dexamethasone (Dex), a glucocorticoid receptor (GR) agonist, on hippocampal neuroinflammation in diabetic rats with chronic unpredictable mild stress (CUMS). Therefore, rats were intragastrically fed on a high-fat diet (10% cholesterol 10 ml/kg) for 14 days and thereafter injected with 38 mg/kg of streptozotocin on the 15th day to induce diabetes. Dex treatment of the diabetic and CUMS rats ameliorated the depression-associated behavior in the respective rats. Apart from enhanced depressive behavior, diabetes-depressed condition also up-regulated the expression of hippocampus microglia chemokine Ⅰ receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - α (TNF-α). Hematoxylin-eosin staining revealed inflammatory damages in the hippocampus. Western blot analysis further revealed repression of GR proteins converse to the nuclear factor kappa-B (NF-κB) proteins, which were up-regulated. Intriguingly, Dex reversed the above events by inhibiting inflammatory reactions in the hippocampus. Consequently, played an antidepressant effect in diabetic and CUMS model rats. Overall, findings of this research suggest that the physiopathology of diabetes with stress cormobity are mediated by inflammatory reactions in the hippocampus. In particular, the responses are associated with regulation of GR/NF-κB signaling pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A previously healthy 68-year-old man rapidly developed a severe melancholic depression following influenza infection. There is an evolving understanding of the complex and possibly bidirectional relationship between depression and inflammation. We review the literature concerning this relationship in the context of viral infection and discuss possible implications for treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Reduced motivation is one of the main symptomatic features of inflammation-induced depression. However, the exact nature of inflammation-induced alterations in motivation remains to be fully defined. As inflammation has been shown to increase sensitivity to negative stimuli, the present series of experiments was initiated to determine whether systemic inflammation induced by infra-septic doses of lipopolysaccharide (LPS) in mice influences consummatory and instrumental responding to successive negative contrast., Methods: Successive negative contrast was operationally defined by a shift to a lower value reward than the one mice were trained with. Mice were trained to drink a high sucrose concentration solution and exposed to an acute shift to a lower concentration of sucrose. In another series of experiments, mice were trained to nose poke for chocolate pellets according to a fixed reinforcement schedule 10 (10 nose pokes for the food reinforcement) and exposed to a shift to a lower reward value (decreased number of chocolate pellets or replacement of chocolate pellets by less preferred grain pellets). Lipopolysaccharide (LPS) was administered at the dose of 0.33 1 mg/kg 24 h before the shift., Results: Mice trained to drink a high sucrose concentration responded to the shift in reward value by a reduction in the volume of sucrose consumed and a decrease in lick numbers and bout durations. Mice trained to nose poke for chocolate pellets responded to the shift by alterations in their total number of nose pokes. In both conditions, LPS had no consistent effect on the response to the shift in reward value., Conclusions: These findings indicate a high variability in the effects of LPS on successive negative contrast and fail to provide evidence in favor of the hypothesis that LPS increases sensitivity to decreases in expected rewards.

Disgust is hypothesized to be an evolved emotion that functions to regulate the avoidance of pathogen-related stimuli and behaviors. Individuals with higher pathogen disgust sensitivity (PDS) are predicted to be exposed to and thus infected by fewer pathogens, though no studies have tested this directly. Furthermore, PDS is hypothesized to be locally calibrated to the types of pathogens normally encountered and the fitness-related costs and benefits of infection and avoidance. Market integration (the degree of production for and consumption from market-based economies) influences the relative costs/benefits of pathogen exposure and avoidance through sanitation, hygiene, and lifestyle changes, and is thus predicted to affect PDS. Here, we examine the function of PDS in disease avoidance, its environmental calibration, and its socioecological variation by examining associations among PDS, market-related lifestyle factors, and measures of bacterial, viral, and macroparasitic infection at the individual, household, and community levels. Data were collected among 75 participants (ages 5 to 59 y) from 28 households in three Ecuadorian Shuar communities characterized by subsistence-based lifestyles and high pathogen burden, but experiencing rapid market integration. As predicted, we found strong negative associations between PDS and biomarkers of immune response to viral/bacterial infection, and weaker associations between PDS and measures of macroparasite infection, apparently mediated by market integration-related differences. We provide support for the previously untested hypothesis that PDS is negatively associated with infection, and document variation in PDS indicative of calibration to local socioeconomic conditions. More broadly, findings highlight the importance of evolved psychological mechanisms in human health outcomes., Competing Interests: The authors declare no competing interest.

Objectives: Growing research on the impact of physical touch on health has revealed links to lower blood pressure, higher oxytocin levels, and better sleep, but links to inflammation have not been fully explored. Physical touch may also buffer stress, underscoring its importance during the stressful time of living in the COVID-19 global pandemic-a time that has substantially limited social interactions and during which physical touch has been specifically advised against., Method: We analyze nationally representative longitudinal data on older adults (N = 1,124) from the National Social Life, Health, and Aging Project using cross-lagged path models., Results: More frequent physical touch is significantly related to a lower likelihood of subsequent elevated inflammation., Discussion: These findings highlight the importance of finding safe ways to incorporate physical touch, even in the aftermath of the COVID-19 pandemic., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1-21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

Treatment of depression is hampered by the failure to identify distinct symptom profiles with distinct pathophysiologies that differentially respond to distinct treatments. We posit that inflammatory depression is a meaningful depression subtype associated with specific symptoms and biological abnormalities. We review several upstream, potentially causative, mechanisms driving low-grade inflammation in this subtype of depression. We also discuss downstream mechanisms mediating the link between inflammation and symptoms of depression, including alterations in dopaminergic neurotransmission and tryptophan metabolism. Finally, we review evidence for several non-pharmacological interventions for inflammatory depression, including probiotics, omega-3 fatty acids, and physical exercise interventions. While some evidence suggests that these interventions may be efficacious in inflammatory depression, future clinical trials should consider enriching patient populations for inflammatory markers, or stratify patients by inflammatory status, to confirm or refute this hypothesis.

Background: Studies investigating the link between depressive symptoms and inflammation have yielded inconsistent results, which may be due to two factors. First, studies differed regarding the specific inflammatory markers studied and covariates accounted for. Second, specific depressive symptoms may be differentially related to inflammation. We address both challenges using network psychometrics., Methods: We estimated seven regularized Mixed Graphical Models in the Netherlands Study of Depression and Anxiety (NESDA) data (N = 2321) to explore shared variances among (1) depression severity, modeled via depression sum-score, nine DSM-5 symptoms, or 28 individual depressive symptoms; (2) inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α); (3) before and after adjusting for sex, age, body mass index (BMI), exercise, smoking, alcohol, and chronic diseases., Results: The depression sum-score was related to both IL-6 and CRP before, and only to IL-6 after covariate adjustment. When modeling the DSM-5 symptoms and CRP in a conceptual replication of Jokela et al., CRP was associated with 'sleep problems', 'energy level', and 'weight/appetite changes'; only the first two links survived covariate adjustment. In a conservative model with all 38 variables, symptoms and markers were unrelated. Following recent psychometric work, we re-estimated the full model without regularization: the depressive symptoms 'insomnia', 'hypersomnia', and 'aches and pain' showed unique positive relations to all inflammatory markers., Conclusions: We found evidence for differential relations between markers, depressive symptoms, and covariates. Associations between symptoms and markers were attenuated after covariate adjustment; BMI and sex consistently showed strong relations with inflammatory markers.

Objective: To investigate the role of IL-33 in gouty arthritis., Material: 174 Balb/c (wild-type) and 54 ST2 -/- mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels., Methods: Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM., Results: Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1β and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1β and TNF-α, and BMDMs from ST2 -/- showed reduced levels of these cytokines after stimulus with MSU crystals., Conclusion: IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.

Background: Preclinical and human studies suggest an association between chronic inflammation and the development of depressive behaviors. This is proposed to occur through downstream effects of inflammatory cytokines on neuroplasticity, neurogenesis and neurotransmitter function, although the neural correlates remain poorly understood in humans., Methods: In Study 1, structural magnetic resonance imaging and serum inflammatory cytokine data were analyzed from 53 psychiatrically healthy female participants. Correlational analyses were conducted between interleukin-6 (IL-6) and volume in a priori regions implicated in the pathophysiology of major depressive disorder (MDD). In Study 2, medical data [including serum inflammatory acute phase reactants (C-reactive protein)] were analyzed for 12 589 participants. Participants were classified as having (n = 2541) v. not having (n = 10 048) probable lifetime MDD using phenotypes derived using machine-learning approaches. Non-parametric analyses compared inflammation between groups, whereas regression analyses probed whether inflammation predicted probable MDD classification while accounting for other variables., Results: In Study 1, significant negative correlations emerged between IL-6 and hippocampal, caudate, putamen and amygdalar volume. In Study 2, the MDD group showed a higher probability of elevated inflammation than the non-MDD group. Moreover, elevated inflammation was a significant predictor of probable MDD classification., Conclusions: Findings indicate that inflammation is cross-sectionally related to reduced volume in brain regions implicated in MDD phenotypes among a sample of psychiatrically healthy women, and is associated with the presence of probable MDD in a large clinical dataset. Future investigations may identify specific inflammatory markers predicting first MDD onset.

Objective: The underlying mechanisms of depression remain unclear; however, current literature suggests a relationship between inflammation and depression. The association between the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) and depression has been previously investigated, but the relationship between GlycA, a novel spectroscopic inflammatory biomarker, and depression does not appear to have been examined., Methods: Data were obtained from The Dallas Heart Study (DHS, conducted between 2000 and 2002), which consisted of a large community-based sample of Dallas County residents (N = 3,033). Depressive symptom severity was assessed with the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). It was hypothesized that the serum GlycA level would be a statistically significant predictor of QIDS-SR scores after control for demographic covariates. Multiple linear regression was used to assess the relationship between GlycA level and QIDS-SR scores. The role of hs-CRP in predicting QIDS-SR scores was also explored., Results: GlycA level was a statistically significant positive predictor of QIDS-SR score (β = .053, P = .038) with control for sex, age, antidepressant use, ethnicity, smoking status, drinking status, body mass index, and years of education. In a subset of adults with moderate-to-severe depression, GlycA level was not associated with QIDS-SR scores. Additionally, hs-CRP level was not a statistically significant predictor of QIDS-SR scores., Conclusions: This study found a positive association between the inflammatory biomarker GlycA, but not hs-CRP, and depressive symptom severity in a large multiethnic and multiracial community-based sample. Thus, these results provide the first indication that GlycA may be a potentially useful novel biomarker of depression., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Trauma exposure is associated with increased inflammatory biomarkers (e.g. C-reactive protein [CRP] and cytokines), and inflammation has been shown to impact corticostriatal reward circuitry and increase anhedonia-related symptoms. We examined resting-state functional MRI in a high-trauma inner-city population of African-American women (n = 56), who reported on average five different types of trauma exposures, to investigate whether inflammation correlated with functional connectivity (FC) in corticostriatal reward circuitry in association with symptoms of anhedonia and PTSD. Plasma CRP negatively correlated with bilateral ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) FC (P < 0.01). In participants where plasma was available to also measure cytokines and their soluble receptors, left (L)VS-vmPFC FC negatively correlated with an inflammatory composite score (previously shown to be increased in plasma and cerebrospinal fluid of depressed patients with high CRP) only in women with significant PTSD symptoms (n = 14; r = -0.582, P = 0.029) and those who experienced moderate-severe childhood trauma (r = -0.595, P = 0.009). Exploratory analyses indicated that LVS-vmPFC FC correlated with anhedonia-related subscales from the Beck Depression Inventory (r = -0.691, P = 0.004) and PTSD Symptom Scale (avoidance/numbness; r = -0.514, P = 0.042) in participants with an inflammatory score over the median (n = 16). Results suggest that inflammation contributes to compromised reward circuitry and symptoms of anhedonia and PTSD in trauma-exposed women., (© The Author(s) 2019. Published by Oxford University Press.)

Psychological stress induces different alterations in the organism in order to maintain homeostasis, including changes in hematopoiesis and hemostasis. In particular, stress-induced hyper activation of the autonomic nervous system and hypothalamic-pituitary-adrenal axis can trigger cellular and molecular alterations in platelets, coagulation factors, endothelial function, redox balance, and sterile inflammatory response. For this reason, mental stress is reported to enhance the risk of cardiovascular disease (CVD). However, contrasting results are often found in the literature considering differences in the response to acute or chronic stress and the health condition of the population analyzed. Since thrombosis is the most common underlying pathology of CVDs, the comprehension of the mechanisms at the basis of the association between stress and this pathology is highly valuable. The aim of this work is to give a comprehensive review of the studies focused on the role of acute and chronic stress in both healthy individuals and CVD patients, focusing on the cellular and molecular mechanisms underlying the relationship between stress and thrombosis.

Tanshinone IIA (Tan IIA) is reported to have neuroprotective effects to suppress cell apoptosis of cortical neurons induced by Aβ 25-35 through inhibiting oxidative stress. Nevertheless, few studies have investigated the effects of Tan IIA on depressive disorder. Here, we aimed to measure the effects of Tan IIA on chronic unpredictable mild stress (CUMS) induced mouse model and its underlying mechanism. For 28 days, mice were subjected to CUMS while Tan IIA was administered once daily at doses of 0, 1, 2.5, 5, or 10 mg/kg. CUMS exposure increased depressive-like behaviors, as indicated by increased immobility time in the forced swim and tail suspension tests, decreased sucrose preference in the sucrose preference test, and reduced exploratory behavior in the open field test. All of these behaviors were reversed dose-dependently by Tan IIA treatment. Oxidative stress was determined by measuring malondialdehyde, glutathione peroxidase, and superoxide dismutase activity and total antioxidant capacity. Levels of pro-inflammatory factors IL-1β and IL-18, cAMP response element binding protein and brain derived neurotrophic factor were detected by ELISA and western blot assay, respectively. The results showed that CUMS increased oxidative stress and pro-inflammatory factors and decreased levels of cAMP response element binding protein and brain-derived neurotrophic factor. Tan IIA treatment again reversed these effects. Importantly, RasGRF1 expression increased in CUMS-exposed mice but decreased after Tan IIA administration. Using RasGRF1 -/- mice to determine the role of RasGRF1 in mice exposed to CUMS, we found that knockdown of RasGRF1 reversed the effects of CUMS on mice, just like Tan IIA. These results indicate that Tan IIA may reverse depressive-like behaviors in CUMS-exposed mice by regulating RasGRF1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To explore whether anxiety and depression are associated with clinical measures of disease for adolescent patients with juvenile idiopathic arthritis (JIA) and whether anxiety and depression are associated with increased peripheral proinflammatory cytokine levels in adolescent patients with JIA and in healthy adolescent controls., Methods: A total of 136 patients with JIA and 88 healthy controls ages 13-18 years completed questionnaires on anxiety and depressive symptoms. For patients with JIA, pain, disability, physician global assessment (using a visual analog scale [VAS]), and number of joints with active inflammation (active joint count) were recorded. In a subsample, we assessed lipopolysaccharide-stimulated interleukin 6 (IL-6) production from peripheral blood mononuclear cells, serum IL-6, cortisol, and C-reactive protein levels. Data were analyzed by linear regression analysis., Results: Levels of anxiety and depressive symptoms in patients with JIA were not significantly different than those in healthy controls. For patients with JIA, anxiety was significantly associated with disability (β = 0.009, P = 0.002), pain (β = 0.029, P = 0.011), and physician global assessment VAS (β = 0.019, P = 0.012), but not with active joint count (β = 0.014, P = 0.120). Anxiety was not associated with any laboratory measures of inflammation for JIA patients. These relationships were also true for depressive symptoms. For healthy controls, there was a trend toward an association of anxiety (but not depressive symptoms) with stimulated IL-6 (β = 0.004, P = 0.052)., Conclusion: Adolescent patients with JIA experience equivalent levels of anxiety and depressive symptoms as healthy adolescents. For adolescent patients with JIA, anxiety and depressive symptoms are associated with pain, disability, and physician global assessment VAS, but not with inflammation., (© 2019 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)