Higher Levels Of Systemic Inflammation Research Articles

Characterization of obesity-related diseases and inflammation using single cell immunophenotyping in two different diet-induced obesity models.

Obesity is a growing problem worldwide and a major risk factor for many chronic diseases. The accumulation of adipose tissue leads to the release of significant amounts of pro-inflammatory cytokines and adipokines, resulting in a low-grade systemic inflammation. However, the mechanisms behind the development of obesity-related diseases are not fully understood. Therefore, our study aimed to investigate the pathological changes and inflammatory processes at systemic level and in individual organs in two different diet-induced mouse obesity models. Male C57BL6/J mice were fed by high-fat diet (HFD), high-fat/high-fructose diet (HFD + FR) or normal chow for 21 weeks starting at 3 months of age (n = 15 animals/group). Insulin resistance was tested by oral glucose tolerance test. Pathological changes were investigated on hematoxylin-eosin-stained liver and brown adipose tissue sections. The gene expression levels of adipokines and cytokines were analyzed by qPCR in adipose tissues, whereas serum protein concentrations were determined by multiplex immunoassays. Immunophenotyping of isolated blood, bone marrow and spleen cells was performed by single-cell mass cytometry. Weight gain, glucose intolerance and hepatic steatosis were more severe in the HFD + FR group than in the control and HFD groups. This was accompanied by a higher level of systemic inflammation, as indicated by increased expression of pro-inflammatory genes in visceral white adipose tissue and by a higher serum TNFα level. In addition, immunophenotyping revealed the increase of the surface expressions of CD44 and CD69 on various cell types, such as CD8+ and CD4 + T-cells, B-cells and macrophages, in animals with obesity. The combination of HFD with fructose supplementation promotes more properly the symptoms of metabolic syndrome. Therefore, the combined high-fat/high-fructose nutrition can be a more suitable model of the Western diet. However, despite these differences, both models showed immunophenotypic changes that may be associated with increased risk of obesity-related cancer.

Myocardial infarction & C-reactive protein levels among Mexican adults with arthritis: Findings from the Mexican Health and Aging Study

BackgroundStudies of adult populations in high-income countries have found an association between arthritis and myocardial infarction (MI) due to high levels of systemic inflammation. Our objectives were to examine the association between arthritis and MI among Mexican adults and to assess the mediating effect of C-reactive protein (CRP) on this association. MethodsData came from the 2012, 2015, and 2018 observation waves of the Mexican Health and Aging Study. Our sample included 11,707 participants aged 50 and older with no prior MI before 2012. We used self-reported information for arthritis, joint pain, medication use, and limitations to daily activities in 2012. Logistic regression was used to model the association between arthritis and self-reported MI in 2015 or 2018. We used a sub-sample of 1602 participants to assess the mediating effect of CRP. ResultsIn the full sample, participants with arthritis that limited their daily activities had higher odds of MI than participants with no arthritis (OR = 1.40; 95 % CI = 1.04–1.88). In the sub-sample, arthritis that limited daily activities was associated with higher mean CRP (5.2 mg/dL; 95 % CI = 4.10–6.21) than arthritis with no limitations (3.5 mg/dL; 95 % CI = 2.93–4.01). However, CRP levels had a small mediating effect, and the relationship between arthritis with physical limitations and MI remained statistically significant. ConclusionMexican adults with arthritis that limits their daily activities are at an increased risk for MI. Continued research is needed to identify factors that contribute to this increased risk.

Links between systemic inflammation and the chemoreflex control of breathing following COVID-19

The emergence of SARS-CoV-2 resulted in millions of hospitalizations and 6.9 million deaths to-date. Many individuals who recover from COVID-19 report prolonged dyspnea, with this symptom persisting for months following recovery. Furthermore, data suggests COVID-19 has been linked to systemic and neuronal inflammation which may have downstream impacts on the neural control of breathing. As such, we hypothesized that individuals recovered from COVID-19 may exhibit changes in their ventilatory chemosensitivity to CO2 and/or O2 and that these changes may be linked to higher levels of systemic inflammation. To test this hypothesis, we measured baseline ventilatory patterns and chemoreflex sensitivity using a modified rebreathing technique in individuals recovered from COVID-19 (n = 77), as well as an age and sex-matched control group (n = 41). Peripheral blood samples were also collected for inflammatory profiling. Recovered participants demonstrated lower ventilatory responses to hypercapnia, particularly under a combined hypoxic stimulus (p = 0.032). Furthermore, higher levels of plasma IL-1β and IL-6 were associated with lower hypoxic ventilatory responses (R2 = -0.53, p = 0.025; R2 = -0.49, p = 0.04), highlighting a potential link between systemic inflammation and ventilatory chemoreflex sensitivity. When separated by time-post-recovery, we observed a decreased ventilatory recruitment threshold (VRT) beginning at 4 months post-recovery (p = 0.019) that returned to baseline after one-year post-recovery. A decrease in sensitivity to CO2 was also noted immediately after recovery with no return to baseline observed within the two-year tested time frame (p = 0.023). Overall, this data indicates that (1) COVID-19 may have impacts on the neural control of breathing, and (2) systemic inflammation may play a role in modulating ventilatory chemoreflex sensitivity. These findings may have implications for the pathology of long-COVID symptoms, including sleep disturbance and prolonged dyspnea. This work was funded by the Health Disparities Research Center and the OASIS center at University of California, Riverside. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Role of Neighborhood Disadvantage, Systemic Inflammation, and Acute Chest Syndrome in Children with Sickle Cell Disease

Introduction: Acute chest syndrome (ACS) is a frequent pulmonary complication of sickle cell disease (SCD) and is a leading cause of morbidity and mortality in both children and adults with SCD. In addition to biological factors, there is increasing recognition that social and environmental factors, such as low socioeconomic status and air pollution, respectively, play a role in disease processes. Current evidence suggests that neighborhood disadvantage influences cardiopulmonary outcomes in non-SCD populations. The disproportionate presence of polluting industries and major roadways near disadvantaged neighborhoods could impact lung health in children with SCD, and exposure to toxic metals has also been linked to worsening systemic inflammation. Yet, the impact of neighborhood disadvantage on inflammation in ACS has not been assessed. The goal of this study is to investigate the effects of neighborhood disadvantage on inflammatory markers in children presenting with ACS. Methods: We enrolled children in our institution with SCD (all genotypes) aged 2-21 years of age with and without a history of ACS. We abstracted clinical information including sex, age, number of ACS episodes up to enrollment, and residential address. In addition, blood samples were collected during routine hematology appointments and hospitalizations for ACS. Plasma cytokine levels were measured using multiplex assays on a subset of participants. Using census tract-level data on poverty, education, housing and employment from the US Census, we computed the area deprivation index (ADI) for census tracts across the greater Houston area and assigned an ADI score to each study subject based on their geocoded address at the time of visit. We dichotomized ADI at the median value (99.0; minimum 42.4, maximum of 156.5) across the study area into “high” and “low” deprivation categories. Results: Forty-four participants met inclusion criteria with complete ADI, clinical and cytokine data. Mean age was 11.6 years (SD 5.1), 52% were male, and 66% lived in a high ADI tract. In children over 10 years of age (n=24), there were higher levels of IL-4, IL-6, IL-8, and IL-13 in those from high ADI areas compared to those from low ADI areas [median concentrations (pg/mL): 139.2 vs 75.7, p=0.53; 17.18 vs 11.92, p=0.67; 15.85 vs 5.38, p=0.20; 19.28 vs 8.30, p=0.38, respectively]. Similarly, IL-4, IL-6, and IL-13 levels were higher in children 10 years and younger from high ADI areas, though not statistically significant. There were no differences between median ADI for patients without a history of ACS and those with recurrent ACS (107.7 vs 108.1, p=0.9). Conclusion: In Houston children with SCD, especially 10 years and older, there were overall higher levels of systemic inflammation in those from high ADI areas compared to those from low ADI areas. However, these findings did not reach statistical significance. There was also no significant difference in ADI scores based on frequency of admissions for ACS. Future studies are needed to analyze cytokines from a larger cohort of patients with SCD and compare ACS outcomes to other regions for a more powered, comprehensive investigation.

Cross-sectional analysis of depressive symptom profiles and serum C-reactive protein levels: data from the Northern Finland 1966 birth cohort

Purpose Individuals with depression exhibit significantly higher levels of systemic inflammation than those without depression, particularly among those with atypical depression. However, this association has been less convincing at the population level among individuals without a formal depression diagnosis but with suggestive symptoms. Our aim was to clarify this association. Materials and methods In a large birth cohort sample of the Finnish general population, we examined the cross-sectional association between high-sensitivity C-reactive protein (hsCRP) levels in venous blood samples and atypical/non-atypical depressive symptoms using the Beck Depression Inventory-II to screen 5443 middle-aged participants. Results As expected, depressive symptoms associated to elevated hsCRP-levels compared to non-depressed. Participants with the atypical subtype of depressive symptoms (n = 84) had an odds ratio (OR) of 2.59 (95% CI 1.40–4.81) for elevated hsCRP levels compared to the non-depressed group. Similarly, our findings indicate that participants with non-atypical symptoms (n = 440) also showed an OR of 1.42 (95% CI 1.05–1.92) when compared to the non-depressed group (n = 4919). Conclusions These results provide additional support for previous research linking depression and inflammation and add to the field with a unique and sizeable study population. Furthermore, the current results support the notion that different types of depressive symptoms may be associated with inflammatory markers in slightly different ways.

Pneumococcal pneumonia and endotoxemia: An experimental and clinical reappraisal.

Circulating endotoxins could result from bacterial digestive translocation during sepsis, thus contributing to uncontrolled systemic inflammation, leading in turn to organ dysfunction. We addressed this issue in the setting of severe pneumococcal pneumonia. Endotoxemia was measured in a clinically relevant rabbit model of ventilated pneumococcal pneumonia and in 110 patients with bacteraemic pneumonia, using a patented mass spectrometry (LC-MS/MS) method for detection of 3-OH fatty acids (C10, C12, C14, C16 and C18), which are molecules bound to the lipid A motif of LPS. Whereas higher levels of systemic inflammation and organ dysfunctions were found, there was no significant difference in lipopolysaccharide concentrations when infected rabbits were compared to non-infected ones, or when patients were compared to healthy volunteers. Seemingly, endotoxins do not drive the overwhelming inflammation associated with severe forms of pneumococcal pneumonia.

Midlife Systemic Inflammatory Markers Are Associated With Late-Life Brain Volume

Background and Objectives To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late-life using a large biracial prospective cohort study. Methods Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and factor VIII) were assessed at baseline in 1,617 participants (mean age 52 [8] years, 61% female, 26% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3 T MRI, 24 years later. Results Each SD increase in midlife inflammation composite score was associated with 42 mm3 smaller hippocampal (p = 0.08), 204 mm3 smaller occipital (p = 0.07), and 197 mm3 smaller Alzheimer disease (AD) signature region (p = 0.010) volumes 24 years later. Compared with participants with no elevated (fourth quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had significantly smaller AD signature region (−751 mm3; p = 0.038) and hippocampal (−148 mm3; p = 0.038) volumes and reduced episodic memory (p = 0.049). The association between midlife inflammation and late-life brain volume was modified by age, whereby younger participants with higher levels of systemic inflammation during midlife demonstrated significantly reduced late-life brain volumes subsequently. Discussion Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.

ФАКТОРЫ РИСКА КОРОНАРНОГО РЕСТЕНОЗА

Introduction. Cardiovascular disease has been the leading cause of death and disability worldwide for many years. The widespread use of percutaneous coronary intervention has significantly improved clinical outcomes in patients with cardiovascular diseases. However, inflammatory reactions that occur in response to mechanical stretch, endothelial exposure and subintimal hemorrhage play a key role, triggering a cascade of proliferative processes leading to neointimal hyperplasia and restenosis. Aim. Aim of this review was to study the known mechanisms of coronary restenosis and to search possible new risk factors for in-stent restenosis. Material and methods. A review of current medical publications in PubMed, MedLine, Google Scholar, ScienceDirect was carried out. Search coverage included articles published from 1993 to 2021. Results and discussion. Risk factors for restenosis have been shown, such as genetic, mechanical (under exploitation, fracture, excessive dilatation, polymer damage), high level of systemic inflammation. In addition, it has been shown that vitamin D deficiency can also be a risk factor for atherosclerosis and immune inflammation. Conclusion. The in-stent restenosis is an actual problem. Incidence of in-stent restenosis has been reported in up to 10% after percutaneous coronary intervention. Multiple mechanical, genetic and inflammatory factors might contribute to in-stent restenosis. In recent years, serum levels of NT-proBNP, pentraxin-3, vitamin D have been studied as restenosis risk factors. Further research of this subject may allowed to develop methods for preventing this complication.

In HIV-infected patients, intestinal bacteria-derived products interfere with CD4<sup>+</sup>T cell regeneration

Despite successful suppression of viral replication by antiretroviral drugs there is no significant increase in the number of peripheral CD4+T lymphocytes in some HIV-infected patients (immune nonresponse to therapy). One of the crucial factors for immunodeficiency aggravation is immune activation developing in response to the bacterial products entry into the bloodstream through the damaged intestinal barrier. Additionally, the intestinal microflora produces various solutes that accumulate in the blood and exhibit toxic properties. This work aimed to evaluate the effect of intestinal microbial products (para-cresol sulfate and indoxyl sulfate) on the number of CD4+T lymphocytes in HIV-infected patients receiving antiretroviral therapy. The object of the study was the peripheral blood of HIV-infected subjects with different immune system restoration efficiency during the therapy. Uninfected donors were enrolled as healthy controls. Plasma concentrations of IL-6 (p = 0.012), IP-10 (p = 0.0004), and sCD14 (p = 0.003) in HIV-infected immune nonresponders were increased compared with those in individuals with effective restoration of CD4+Tcells (immune responders). Although both groups of HIV-positive subjects did not differ in plasma lipopolysaccharide and I-FABP levels, para-cresol sulfate (p = 0.001) and indoxyl sulfate (p = 0.042) concentrations were increased in immune non-responders. In vitro experiments showed a negative dose-dependent effect of para-cresol sulfate and indoxyl sulfate on the viability and mitotic activity of CD4+T lymphocytes. Thus, in HIV-infected patients with impaired regeneration of CD4+T lymphocytes during antiretroviral therapy, a higher level of systemic inflammation is noted than in subjects responding to treatment with an increase in the number of CD4+T cells. The severity of the intestinal barrier damage and the load of bacterial components released into the bloodstream are approximately the same in HIV-infected individuals with different efficiency of immune recovery in response to treatment. Simultaneously, the blood plasma of immune non-responders is significantly enriched with microbial products of intestinal origin: para-cresol sulfate and indoxyl sulfate. The significant decrease in the proliferative capacity of CD4+T cells stimulated in vitro and the induction of their death in the presence of these toxins may be a reason for the ineffective restoration of the number of CD4+T lymphocytes in HIV-infected individuals receiving antiretroviral therapy.

The relationship between sleep and salivary and serum inflammatory biomarkers in adolescents.

Poor sleep behavior can trigger an inflammatory response and contribute to the development of inflammatory diseases. Cytokines can act as indicators of inflammation and may precede the onset of inflammatory diseases. This study aimed to determine the association between sleep timing parameters (bedtime, sleep duration, sleep debt, and social jetlag) and the levels of nine serum and salivary inflammatory and metabolic biomarkers. Data were collected from 352 adolescents aged 16-19 years enrolled in Kuwait's public high schools. The levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), adiponectin, leptin, and insulin were measured from saliva and serum samples. We conducted mixed-effect multiple linear regression modeling to account for the school variable as a random effect to assess the relationship between the sleep variables and salivary and serum biomarkers. Mediation analysis was conducted to check if BMI was a mediator between bedtime and the biomarkers. There was a statistically significant elevation in serum IL-6 level associated with later bedtime (0.05 pg./mL, p = 0.01). Adolescents with severe sleep debt of ≥2 h had an increase in salivary IL-6 biomarker levels (0.38 pg./mL, p = 0.01) compared to those who had sleep debt of <1 h. Adolescents with sleep debt of ≥2 h had significantly higher levels of serum CRP (0.61 μg/mL, p = 0.02) than those without sleep debt. Additionally, we found that the inflammatory biomarkers (CRP, IL-6, IL-8, IL-10, VEGF, and MCP-1) and metabolic biomarkers (adiponectin, leptin, and insulin) had more statistically significant associations with the bedtime variables than with sleep duration variables. CRP, IL-6, and IL-8 were associated with sleep debt, and IL-6, VEGF, adiponectin, and leptin levels were associated with social jetlag. BMIz was a full mediator in the relationship between late bedtime and increased serum levels of CRP, IL-6, and insulin. Adolescents who go to bed at or later than midnight had dysregulated levels of salivary and serum inflammatory biomarkers, suggesting that disrupted circadian rhythm can trigger higher levels of systemic inflammation and potentially exacerbate chronic inflammation and the risk of metabolic diseases.

The pro-inflammatory response to influenza A virus infection is fueled by endothelial cells.

Morbidity and mortality from influenza are associated with high levels of systemic inflammation. Endothelial cells play a key role in systemic inflammatory responses during severe influenza A virus (IAV) infections, despite being rarely infected in humans. How endothelial cells contribute to systemic inflammatory responses is unclear. Here, we developed a transwell system in which airway organoid-derived differentiated human lung epithelial cells were co-cultured with primary human lung microvascular endothelial cells (LMECs). We compared the susceptibility of LMECs to pandemic H1N1 virus and recent seasonal H1N1 and H3N2 viruses and assessed the associated pro-inflammatory responses. Despite the detection of IAV nucleoprotein in LMEC mono-cultures, there was no evidence for productive infection. In epithelial-endothelial co-cultures, abundant IAV infection of epithelial cells resulted in the breakdown of the epithelial barrier, but infection of LMECs was rarely detected. We observed a significantly higher secretion of pro-inflammatory cytokines in LMECs when co-cultured with IAV-infected epithelial cells than LMEC mono-cultures exposed to IAV. Taken together, our data show that LMECs are abortively infected by IAV but can fuel the inflammatory response.

Effect of sphincter of Oddi dysfunction on the abundance of biliary microbiota (biliary microecology) in patients with common bile duct stones.

Biliary calculi, a common benign disease of the gastrointestinal tract, are affected by multiple factors, including diet, lifestyle, living environment, and personal and genetic background. Its occurrence is believed to be related to a change in biliary microbiota. Approximately 10%-20% of symptomatic patients with cholecystolithiasis have choledocholithiasis, resulting in infection, abdominal pain, jaundice, and biliary pancreatitis. This study aimed to determine whether a dysfunction in the sphincter of Oddi, which controls the outflow of bile and separates the bile duct from the intestine, leads to a change in biliary microbiota and the occurrence of biliary calculi. Forty patients with cholecystolithiasis and choledocholithiasis were prospectively recruited. Bile specimens were obtained, and biliary pressure was measured during and after surgery. The collected specimens were analyzed with 16S rRNA gene to characterize the biliary microbiota. The risk factors of common bile duct calculi were analyzed numerically combined with the pressure in the sphincter of Oddi. Different biliary microbiota were found in all cases. Patients with sphincter of Oddi dysfunction had significantly increased biliary microbiota as well as significantly higher level of systemic inflammation than patients with normal sphincter of Oddi. The systemic inflammatory response of patients with sphincter of Oddi dysfunction is more severe, and their microbial community significantly differs from that of patients with normal sphincter of Oddi, which makes biliary tract infection more likely; furthermore, the biliary tract of patients with sphincter of Oddi dysfunction has more gallstone-related bacterial communities.

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4–45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6–3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

Associations of particulate matter exposures with brain cortical thickness and white matter hyperintensities: effect modification by c-reactive protein

Background and aim: Numerous studies have shown the effect of particulate matter exposure on brain imaging markers. However, little evidence exists about whether the effect differs by the level of systemic inflammation, a mechanism of neurotoxicity of particulate matter. We investigated whether the level of c-reactive protein (CRP; a marker of systemic inflammation) modifies the associations of particulate matter exposures with brain cortical thickness and white matter hyperintensities (WMH). Methods: Adults with no dementia or stroke were recruited. Concentrations of particulate matter &amp;#x2264;10 µm in diameter (PM10) and &amp;#x2264;2.5 µm (PM2.5) at each participant’s home address were estimated. Mean cortical thickness (n=874) and WMH volumes (n=397) were estimated from brain magnetic resonance images. We built generalized linear and logistic regression models for mean cortical thickness and WMH volumes (higher versus lower than median), respectively. Significance of the CRP group (higher versus lower than median) difference in the association was expressed as p for interaction. Results: Particulate matter exposures were significantly associated with a reduced mean cortical thickness only in the higher CRP group among men (p for interaction=0.012 for PM10 and 0.006 for PM2.5). A 10 &amp;#x3bc;g/m3 increase in PM10 was associated with having higher volumes of total WMH (odds ratio, 1.67; 95% confidence interval, 1.01–2.76) and periventricular WMH (1.81; 1.10–2.98). A 1 &amp;#x3bc;g/m3 increase in PM2.5 was associated with having a higher volume of periventricular WMH (odds ratio, 1.53; 95% confidence interval, 1.01–2.33). These associations did not significantly differ by the level of CRP. Conclusions: Particulate matter exposures were associated with a reduced mean cortical thickness in men with a high level of systemic inflammation. Particulate matter exposures were associated with having a high volume of WMH, with no evidence of effect modification by the level of systemic inflammation. Keywords: air pollution; neuroimaging; inflammation

C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder

Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated with gray matter volume in depression. This study examined whether the inflammatory mediator, C-reactive protein (CRP) and the putative neuroprotective index, KynA/QA, were associated with white matter integrity in MDD, and secondly, whether any such associations were independent of each other or whether the effect of CRP was mediated by KynA/QA. One hundred and sixty-six participants in the Tulsa 1000 study with a DSM-V diagnosis of MDD completed diffusion tensor imaging and provided a serum sample for the quantification of CRP, KynA, and QA. Correlational tractography was performed using DSI Studio to map the specific white matter pathways that correlated with CRP and KynA/QA. CRP was negatively related to KynA/QA (standardized beta coefficient, SBC = -0.35 with standard error, Std.E = 0.13, p < 0.01) after controlling for nine possible confounders, i.e., age, sex, body mass index (BMI), medication status, lifetime alcohol use, severity of depression, severity of anxiety, length of illness, and smoking status. Higher concentrations of CRP were associated with decreased white matter integrity (fractional anisotropy, FA) of the bilateral cingulum and fornix after controlling for the nine potential confounders (SBC = -0.43, Std.E = 0.13, p = 0.002). Greater serum KynA/QA was associated with increased white matter integrity of the bilateral fornix, bilateral superior thalamic radiations, corpus callosum, and bilateral cingulum bundles after controlling for the same possible confounders (SBC = 0.26, Std.E = 0.09, p = 0.005). The relationship between CRP and FA was not mediated by KynA/QA. Exploratory analyses also showed that KynA/QA but not CRP was associated with self-reported positive affect, attentiveness, and fatigue measured with the PANASX (SBCs = 0.17–0.23). Taken together, these results are consistent with the hypothesis that within a subgroup of MDD patients, a higher level of systemic inflammation alters the balance of KP metabolism but also raise the possibility that CRP and neuroactive KP metabolites represent independent molecular mechanisms underlying white matter alterations in MDD.

Stress-Related Mental Health Disorders and Inflammation in Pregnancy: The Current Landscape and the Need for Further Investigation.

Many studies have focused on psychoimmunological mechanisms of risk for stress-related mental health disorders. However, significantly fewer studies have focused on understanding mechanisms of risk for stress-related disorders during pregnancy, a period characterized by dramatic changes in both the innate and adaptive immune systems. The current review summarizes and synthesizes the extant literature on the immune system during pregnancy, as well as the sparse existing evidence highlighting the associations between inflammation and mood, anxiety, and fear-related disorders in pregnancy. In general, pregnant persons demonstrate lower baseline levels of systemic inflammation, but respond strongly when presented with an immune challenge. Stress and trauma exposure may therefore result in strong inflammatory responses in pregnant persons that increases risk for adverse behavioral health outcomes. Overall, the existing literature suggests that stress, trauma exposure, and stress-related psychopathology are associated with higher levels of systemic inflammation in pregnant persons, but highlight the need for further investigation as the existing data are equivocal and vary based on which specific immune markers are impacted. Better understanding of the psychoimmunology of pregnancy is necessary to reduce burden of prenatal mental illness, increase the likelihood of a successful pregnancy, and reduce the intergenerational impacts of prenatal stress-related mental health disorders.

P143 Frailty is associated with inflammation, impaired glucose metabolism and reduced bone mineral density after adjustment for fat mass index: a UK biobank study

Abstract Background/Aims Frailty, a common syndrome associated with aging, represents a huge public health burden. An improved understanding of the mechanisms underlying frailty are essential, especially in younger populations in whom frailty could be prevented. Fundamental aging processes such as chronic inflammation are associated with frailty, but the independence of these relationships from age, sex, lifestyle and adiposity is unclear. Using UK Biobank, we investigated associations between frailty, blood biomarkers and bone health, independent of these characteristics. Methods 502,640 participants aged 40-69 years were recruited to UK Biobank 2006-10. Venous blood samples were obtained and fat mass was measured by bioelectrical impedance. From 2014 onwards, a subset attended an imaging follow-up, including whole-body DXA (GE Lunar iDXA), grip strength (Jamar dynamometer), and a questionnaire. Frailty was defined using a modification of Fried’s classification (at least 3 of weight loss, mental exhaustion, low physical activity, slow gait speed and low grip strength). The presence of 1-2 criteria designated pre-frailty. Linear regression was used to discern associations between frailty status, biochemical markers (CRP, 25(OH)-vitamin D, IGF-1, Calcium, Phosphate, ALP, Creatinine, Urate, glucose and HbA1c) and bone outcomes, adjusting for age, sex, fat mass, smoking, alcohol and educational level. Non-frail was the reference category and blood biomarkers were standardised (β representing the mean difference in SD). Results 22,332 participants (11,484 women and 10,848 men) with frailty assessment and either DXA bone measures or blood biochemistry were included in the analysis; of these 547 (2.4%) were frail and 9359 (41.9%) pre-frail. Frail participants were more likely to be female [59.6% vs. 50.9%], with higher BMI [mean (SD) 30.7 (6.4) vs. 25.9 (4.0) kg/m2] and of older age [mean (SD) 63.2 (7.9) vs. 62.6 (7.3) years]. After full adjustment, frail participants had lower 25(OH)-vitamin D levels [-0.36 SD (-0.45,-0.27)], higher CRP [+0.29 SD (95% CI 0.21, 0.37)], and higher HbA1c [+0.32 SD (0.23, 0.40)], all p &amp;lt; 0.001. Frail participants had lower femoral neck [-0.18 SD (-0.26, -0.10)] and lumbar spine bone mineral density (BMD) [-0.13 SD (-0.21, -0.06)], both p &amp;lt; 0.001. BMD associations were only apparent after fat mass adjustment, prior to fat mass adjustment the direction of association was positive. Similar associations were observed for pre-frail vs. non-frail participants. Conclusion In the UK Biobank cohort of middle-older aged people, frailty is associated with high levels of systemic inflammation, low 25(OH)-vitamin D, poorer glucose handling and lower BMD, independent of age, sex and lifestyle. The inversion of BMD associations after adjustment for fat mass is intriguing and suggests substantial phenotypic complexity in the associations. Our findings support further investigation of frailty phenotypes at younger ages and elucidation of possible contributions from conditions such as metabolic syndrome and obesity-related chronic inflammation. Disclosure E.M. Curtis: None. S. D'Angelo: None. S. Woolford: None. R. Durdin: None. Z. Raisi-Estabragh: None. K.A. Ward: None. C. Cooper: None. N.C. Harvey: None.

First-generation College Students Have Greater Systemic Inflammation than Continuing-Generation College Students Following the Initial College Transition: A Brief Report.

First-generation college students ("first-gens") are often at a disadvantage socially and academically; whether they are at risk physiologically is unknown despite the well-established link between greater education and better long-term health. To examine whether first-gens have higher levels of cardiovascular disease (CVD) risk markers relative to continuing-generation college students ("continuing-gens"). A panel of CVD risk markers was assessed among 87 emerging adults (41 first-gens) twice over their first year of college. Compared to continuing-gens, first-gens had greater systemic inflammation (composite of averaged z-scores for C-reactive protein and interleukin-6; B = 0.515, SE = 0.171, p = .003) during the fall but not spring semester (p > .05). Associations were independent of family home ownership and childhood adversity, even though first-gens were more likely to live in rental homes and reported riskier home environments. Lower childhood subjective social status (SSS) accounted for greater systemic inflammation among first-gens as evidenced by an indirect effect of college generation status on systemic inflammation through childhood SSS (a1b1 = 0.261, bootstrapped SE = 0.103, 95% boot CI [0.078, 0.482]). There were no differences in metabolic risk and latent virus regulation by college generation status in either semester (p > .10). This is the first study to find that first-gens have higher levels of systemic inflammation than continuing-gens following the college transition and that childhood SSS may be one explanatory pathway. First-gens may benefit from university resources that address social class differences, which should be provided early on so that first-gens can reap the health-relevant benefits of higher education, at least in the short term.

HCV co-infection is related to acute ischemic severity and outcome

Background and aimHCV infection is associated with increased risk of ischemic cerebral stroke. HCV stroked patients are younger with a lower burden of classical risk factors and higher levels of systemic inflammation. The present study aimed to discover the association between HCV infection functional outcome of stroke.Patients and methodsThe present prospective study included 60 patients with acute ischemic stroke. All patients were subjected to careful history taking and through clinical and neurological examination. Stroke severity at presentation was assessed using National Institute of Health Stroke Scale (NIHSS). Quantitative HCV RNA test was used to diagnose HCV infection. The prognosis of the studied patients was 3 months after treatment using modified Rankin scale (mRS) for neurologic disability.ResultsThe present study was conducted on 60 patients with ischemic stroke. They comprised 13 patients (21.7%) with HCV and 47 patients without. Stroke patients with HCV had significantly higher frequency of carotid artery stenosis, higher NIHSS (17.9 ± 6.9 versus 9.9 ± 5.3, p < 0.001) and higher frequency of severe stroke (46.1% versus 4.3%, p = 0.001) when compared with patients without HCV. Logistic regression analysis identified patients’ sex, NIHSS and HCV as significant predictors of outcome in univariate analysis. However, in multivariate analysis, only NIHSS proved to be significant.ConclusionsThe present study suggests a significant link between chronic HCV infection and ischemic stroke severity and poor outcome. This is probably related to the pathogenic effects of the chronic inflammatory state induced by HCV infection on the cerebral microvasculature.

Arterial stiffness in rheumatoid arthritis: Current knowledge and future perspectivess

Rheumatoid arthritis (RA) is characterized by the excess cardiovascular risk that remains essentially unaltered despite current medical advances. The introduction of reliable markers towards early identification and subsequently effective management of high-risk patients with RA are urgently needed. Arterial stiffness represents an early indicator of cardiovascular morbidity and mortality and has emerged as a surrogate marker of cardiovascular disease. From a pathophysiological perspective, it is significantly accelerated by the accumulation of cardiovascular risk factors and is considered an intermediate process towards the development and progression of atherosclerotic cardiovascular disease. The aim of this review is to critically upraise current knowledge on arterial stiffness in patients with RA. Although not all studies concur, increased Pulse Wave Velocity (PWV) has been repeatedly reported in patients with RA. However, results need to be interpreted with caution as most studies enrolled patients with multiple cardiovascular risk factors and/or established cardiovascular disease, or with uncontrolled RA with high levels of systemic inflammation. Whether and to which extent increased arterial stiffness among patients with RA is associated with the disease per se, or rather represents the composite effect of hypertension and other classical cardiovascular risk factors, warrants further investigation. The impact of antirheumatic drugs on arterial stiffness is also discussed. Considering the well-established predictive value of increased PWV both in the general population and patients at high cardiovascular risk, future studies need to focus on the clinical utility of this surrogate risk marker specifically in patients with RA.