Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19.

BACKGROUND: We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021. RESULTS: Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients ≤74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030). CONCLUSIONS: The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms.

Prenatal maternal Inflammation, childhood cognition and adolescent depressive symptoms.

BACKGROUND: Accumulating evidence indicates that higher prenatal maternal inflammation is associated with increased depression risk in adolescent and adult-aged offspring. Prenatal maternal inflammation (PNMI) may increase the likelihood for offspring to have lower cognitive performance, which, in turn, may heighten risk for depression onset. Therefore, this study explored the potential mediating role of childhood cognitive performance in the relationship between PNMI and adolescent depressive symptoms in offspring. METHODS: Participants included 696 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Biomarkers of maternal inflammation [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptor-II (sTNF-RII)] were assayed from first (T1) and second trimester (T2) sera. Childhood (ages 9-11) cognitive performance was assessed via standardized Peabody Picture Vocabulary Test (PPVT), a measure of receptive vocabulary correlated with general intelligence. Adolescent (ages 15-17) depressive symptoms were assessed via self-report. RESULTS: There were no significant associations between T1 biomarkers and childhood PPVT or adolescent depressive symptoms. Higher T2 IL1-RA was directly associated with lower childhood PPVT (b = -0.21, SE = 0.08, t = -2.55, p = 0.01), but not with adolescent depressive symptoms. T2 IL-6 was not directly associated with childhood PPVT, but higher T2 IL-6 was directly associated at borderline significance with greater depressive symptoms in adolescence (b = 0.05, SE = 0.03, t = 1.96, p = 0.05). Lower childhood PPVT predicted significantly higher adolescent depressive symptoms (b = -0.07, SE = 0.02, t = -2.99, p < 0.01). There was a significant indirect effect of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT (b = 0.03, 95 % CI = 0.002-0.03) indicating a partially mediated effect. No significant associations were found with T2 sTNF-RII nor IL-8. CONCLUSIONS: Lower childhood cognitive performance, such as that indicated by a lower PPVT score, represents a potential mechanism through which prenatal maternal inflammation contributes to adolescent depression risk in offspring.

Rapid decrease in IL-1Ra and IP-10 plasma levels following tuberculosis treatment initiation.

OBJECTIVES: Monitoring tools that could provide quick predictions of tuberculosis (TB) treatment outcomes are urgently needed. Here, we assessed whether the evolution of selected biomarkers of innate immunity may help monitoring TB treatment response within 2 weeks of treatment initiation. METHODS: ANRS12394-LILAC-TB was a proof-of-concept prospective study: adults with a rifampicin-susceptible TB who are HIV-negative and HIV-infected documented by a positive Xpert MTB/RIF test were enrolled in Cambodia and Côte d'Ivoire. Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interferon-γ-induced protein-10 and clusters of differentiation (CD) (scavenging CD163) were measured by commercial enzyme-linked immunosorbent assay kits. A Wilcoxon test for paired data was used for longitudinal comparisons. RESULTS: A total of 55 patients were enrolled (women: 31%, median age: 37 years; median CD4 count in the 10 of 13 participants with HIV: 53 cells/mm3). Overall, 83% were considered in TB treatment success. Compared with baseline, the IL-1Ra plasma levels significantly decreased as soon as week (W) 1, independent of HIV status (-71% in HIV-positive vs -33% in HIV-negative; P <0.001). The IP-10 plasma levels significantly decreased at W1 and W2 compared with baseline (P <0.0001); however, that decrease was less marked in participants with HIV. CONCLUSIONS: Our findings suggest that measuring IL-1Ra plasma levels with a standard enzyme-linked immunosorbent assay technique at baseline and then 1 week after TB treatment onset could help clinicians to quickly assess TB treatment response.

Serum Levels of Interleukins in Endometriosis Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: The aims of this systematic review and meta-analysis were to produce a comprehensive survey of the serum levels of interleukins (ILs) in untreated people with endometriosis compared with people without endometriosis. DATA SOURCES: A systematic literature search of English language studies within Cinahl, Medline Complete, PubMed, and Scopus from inception to May 2023 was performed. METHODS OF STUDY SELECTION: We included studies that compared IL serum levels in people with endometriosis to those without endometriosis. Meta-analysis was performed on IL-1RA, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-37. TABULATION, INTEGRATION, AND RESULTS: The systematic search retrieved 651 studies, of which 77 underwent a full-text review. A total of 30 studies met inclusion criteria for the meta-analysis. IL-1Ra, IL-6, and IL-37 serum levels were 2.56 (95% CI 2.20-2.92, p <.001), 1.38 (95% CI 0.58-2.17, p <.001), and 1.77 (95% CI 1.33-2.20, p <.001) standard deviations higher in the patients with endometriosis compared with patients without endometriosis while IL-23 serum levels 0.40 (95% CI -0.73 to -0.07, p = .02) standard deviations lower, respectively. CONCLUSION: There is mounting evidence that ILs, especially IL-6, may be good candidates for unique noninvasive diagnostic tools and/or treatment pathways for endometriosis.

Elevated IL-1ß and Comparable IL-1 Receptor Antagonist Levels Are Characteristic Features of L-PRP in Female College Athletes Compared to Male Professional Soccer Players.

Autologous platelet-rich plasma (PRP) therapy has been becoming popular for the treatment of musculotendinous injuries among athletes. However, for individual and practical variations, clinical success is hardly predictable. To overcome this difficulty, we have been exploring possible criterion candidates for monitoring its clinical effectiveness. In this study, we focused on sex-based differences in young elite athletes and compared the biochemical compositions of their PRP. Leukocyte-rich PRP (L-PRP) was manually prepared from blood samples collected from male professional soccer players (mPSPs) (n = 25) and female college athletes (fCAs) (n = 36). Platelet-derived growth factor-BB (PDGF-BB), transforming-growth factor-ß1 (TGFß1), platelet factor-4 (PF4), interleukin-1ß (IL-1ß), and IL-1 receptor antagonist (IL-1RA) were quantified using an enzyme-linked immunosorbent assay. The levels of PDGF-BB, TGFß1, and PF4 in L-PRP were significantly higher in mPSPs than in fCAs. Conversely, IL-1ß and IL-1RA were detected at significantly and slightly higher levels, respectively, in fCAs than in mPSPs. Our findings suggest that, even though L-PRP from fCAs may have lower potential to induce cell growth and differentiation than that of mPSPs, due to the latter's higher capacity to control inflammation, it does not necessarily imply that PRP treatment in fCAs is less effective. Thus, these cytokine levels should be checked before PRP therapy.

Blood levels of adiponectin and IL-1Ra distinguish type 3c from type 2 diabetes: Implications for earlier pancreatic cancer detection in new-onset diabetes.

BACKGROUND: Screening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM. METHODS: Using mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation. FINDINGS: Of 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM. INTERPRETATION: Adiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM. FUNDING: North West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK.

Interleukin-1Ra (Il-1Ra) and serum cortisol level relationship in horse as dynamic adaptive response during physical exercise.

The monitoring of endocrine and immunologic markers during exercise is of paramount importance to assess and/or maintain the physical well-being of athletes as well as to optimize the athletic performance. This study aimed to investigate the linkage between acute stress response and immune status in Thoroughbred horses competing in an official 1300-m race. From 10 horses blood was collected 1 week before the day of the race (1W-BEFORE), before (REST) and immediately after the race to assess the cortisol, Interleukin-1 receptor antagonist (IL-1Ra), total proteins, white blood cells (WBC), red blood cells (RBC), haemoglobin (Hb) and haematocrit (Hct) concentration. Higher levels of cortisol, Il-1Ra, WBC and erythrocytes indices after exercise was found than 1W-BEFORE and REST (P < 0.0001). Cortisol concentration was positively correlated with Il-1Ra, WBC, RBC, Hb and Hct. Overall, the findings suggest that submaximal exercise induces an acute stress response and an immune system reaction in athletic horse. Also, the correlation found between cortisol levels and Il-1Ra, WBC and erythrocytes indices open new scenario on the positive role of this hormone on the complex and dynamic physiological adaptation to exercise implemented by the organism to re-establish the homeostatic equilibrium, and, interestingly, to maintain an adequate anti-inflammatory environment after exercise.

Evaluation of Serum Interleukin-38 Levels in Different Radiographic Grades of Idiopathic Knee Osteoarthritis.

The aim of this study was to assess interleukin-1ß (IL-1ß), IL-1Ra, IL-36, and IL-38 levels together with hs-CRP levels in patients with different radiographic grades of knee osteoarthritis (OA) in comparison to healthy individuals. Consecutive patients aged over 50 years who were admitted to our Orthopaedics and Traumatology department between November 2018 and March 2019 and diagnosed as knee OA according to the American College of Rheumatology criteria were included in this prospective case-control study. Patients with knee OA were staged according to radiographic Kellgren-Lawrence (K-L) classification and 20 patients were assigned to each group. An age and gender matched control group consisted healthy volunteers with no clinical and radiographic sign of arthritis were conducted as the control group. Venous blood samples were collected and assessed for hs-CRP, IL-1ß, IL-1Ra, IL-36, and IL-38 levels using the double-antibody sandwich ELISA method. The hs-CRP, IL-1ß, IL-36 and IL-38 levels did not significantly differ among controls and independent radiographic stage groups except IL-1Ra levels which was significantly higher in K-L grade 4 knee OA groups compared to healthy controls (P = 0.045). When we compared all patients with knee OA and healthy controls, we detected that IL-1 and IL-1Ra were significantly lower and IL-38 levels were significantly higher in healthy control group compared to patients with knee OA (P = <0.001, <0.001, and 0.019, respectively). According to results obtained from our study, IL-1ß, IL-1Ra, and IL-38 levels significantly differed between healthy individuals and patients with knee OA. However, we did not observe a significant difference and correlation between radiographic grade of knee OA and interleukin levels.

Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN ß-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5-4-fold in response to sc IFN ß-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN ß-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN ß-1a treatment efficacy over 5 years.

Investigating the release of inflammatory cytokines in a human model of incontinence-associated dermatitis.

Incontinence-associated dermatitis (IAD) is a painful complication in elderly patients, leading to reduced quality of life. Despite recent attention, its underlying inflammatory mechanisms remain poorly understood. This study was designed to quantify the release of inflammatory cytokines in a human model of IAD. The left volar forearm of ten healthy volunteers was exposed to synthetic urine and synthetic faeces for 2 h, simulating the effects of urinary and faecal incontinence, respectively, and the subsequent cytokine response compared to that of an untreated control site. Inflammatory cytokines were collected using both the Sebutape® absorption method and dermal microdialysis and quantified using immunoassays. Results from the former demonstrated an upregulation in IL-1α, IL-1RA and TNF-α. Synthetic urine caused a higher median increase in IL-1α from baseline compared to synthetic faeces, whereas synthetic faeces were associated with significantly higher median TNF-α levels compared to synthetic urine (p = 0.01). An increase in IL-1α/IL-1RA ratio was also observed with significant differences evident following exposure to synthetic urine (p = 0.047). Additionally, microdialysis revealed a time-dependent increase in IL-1ß and IL-8 following exposure of up to 120 min to synthetic urine and synthetic faeces, respectively. This study demonstrated the suitability of both sampling approaches to recover quantifiable cytokine levels in biofluids for the assessment of skin status following exposure to synthetic fluids associated with incontinence. Findings suggest some differences in the inflammatory mechanisms of IAD, depending on moisture source, and the potential of the cytokines, IL-1α and TNF-α, as responsive markers of early skin damage caused by incontinence.

Persistent level of mental distress in PTSD patients is not reflected in cytokine levels 1 year after the treatment.

OBJECTIVE: Cross-sectional data show that post-traumatic stress disorder (PTSD) patients often have increased levels of circulating inflammatory markers. There is, however, still a paucity of longitudinal studies with long follow-up times on levels of cytokines in such patients. The current study assesses patients with and without PTSD diagnosis 1 year after discharge from inpatient treatment. METHODS: Patients in treatment for serious non-psychotic mental disorders were recruited at the beginning of their treatment stay at a psychiatric centre in Norway. Ninety patients submitted serum samples and filled out the Hopkins Symptom Checklist-90 Revised Global Severity Index (HSCL-90R GSI) questionnaire during their mainstay and at a follow-up stay 1 year after discharge. Of these patients, 33 were diagnosed with PTSD, 48 with anxiety, depression, or eating disorder, while 9 patients had missing data. The patients were diagnosed using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: At the follow-up stay (T3), PTSD patients had higher levels of GSI scores than non-PTSD patients (p = 0.048). These levels were unchanged from the year before (T2) in both groups. The levels of circulating cytokines/chemokine did not differ between the PTSD and non-PTSD patients at T3. At T2, however, the PTSD and non-PTSD groups exhibited different levels of interleukin 1ß (IL-1ß) (p = 0.053), IL-1RA (p = 0.042), and TNF-α (p = 0.037), with the PTSD patients having the higher levels. CONCLUSION: Despite exhibiting different mental distress scores, the PTSD and non-PTSD patients did not differ regarding levels of circulating inflammatory markers at 1-year follow-up.

Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B.

BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS: In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION: Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.

Integrated traditional Chinese medicine alleviates sciatica while regulating gene expression in peripheral blood.

BACKGROUND: Although integrated traditional Chinese medicine (TCM) has long been indicated to be effective in the treatment of sciatica and is widely used in the management of this condition, the mechanism by which integrated TCM alleviates sciatica has not yet been fully defined, and the effect of integrated TCM on gene expression in the peripheral blood of patients with sciatica is still unknown. We performed this study to investigate the effect of integrated TCM on peripheral blood gene expression in patients with sciatica and to explore new clues for studying the mechanism of integrated TCM in alleviating sciatica. METHODS: We used a microarray to identify differentially expressed genes (DEGs) in the peripheral blood of patients with sciatica and healthy controls (DEGs-baseline), bioinformatic analysis to reveal the characteristics of DEGs-baseline, and the key genes that contribute to the gene dysregulation. A microarray was also used to identify DEGs in the peripheral blood of patients with sciatica after integrated TCM treatment compared with those at baseline, and the expression levels of DEGs were validated by qRT-PCR. RESULTS: We identified 153 DEGs-baseline, which included 131 upregulated genes and 22 downregulated genes. Bioinformatic analysis revealed that most of the DEGs-baseline were related to immunity and the inflammatory response and that TLR4, MMP9, MPO, CAMP, RETN, TLR5, and IL1RN were key genes involved in the dysregulation of genes in the peripheral blood of patients with sciatica. The expression levels of TLR5, IL1RN, SLC8A1, RBM20, GPER1, IL27, SOCS1, and GRTP1-AS1 were decreased in the peripheral blood of patients after integrated TCM treatment compared with that at baseline, which was accompanied by relief of pain. CONCLUSION: Integrated TCM treatment relieved pain while regulating the gene expression of TLR5, IL1RN, SLC8A1, RBM20, GPER1, IL27, SOCS1, and GRTP1-AS1 in the peripheral blood of patients with sciatica. Our study provides new clues for studying the mechanism of TCM in treating sciatica.

Cytokine ranking via mutual information algorithm correlates cytokine profiles with presenting disease severity in patients infected with SARS-CoV-2.

Although the range of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is variable, cytokine storm is observed in a subset of symptomatic individuals. To further understand the disease pathogenesis and, consequently, to develop an additional tool for clinicians to evaluate patients for presumptive intervention, we sought to compare plasma cytokine levels between a range of donor and patient samples grouped by a COVID-19 Severity Score (CSS) based on the need for hospitalization and oxygen requirement. Here we utilize a mutual information algorithm that classifies the information gain for CSS prediction provided by cytokine expression levels and clinical variables. Using this methodology, we found that a small number of clinical and cytokine expression variables are predictive of presenting COVID-19 disease severity, raising questions about the mechanism by which COVID-19 creates severe illness. The variables that were the most predictive of CSS included clinical variables such as age and abnormal chest x-ray as well as cytokines such as macrophage colony-stimulating factor, interferon-inducible protein 10, and interleukin-1 receptor antagonist. Our results suggest that SARS-CoV-2 infection causes a plethora of changes in cytokine profiles and that particularly in severely ill patients, these changes are consistent with the presence of macrophage activation syndrome and could furthermore be used as a biomarker to predict disease severity.

The effects of local versus systemic passive heating on the acute inflammatory, vascular and glycaemic response.

The aim of this study was to compare the acute cardiometabolic and perceptual responses between local and whole-body passive heating. Using a water-perfused suit, 10 recreationally active males underwent three 90 min conditions: heating of the legs with upper-body cooling (LBH), whole-body heating (WBH) and exposure to a thermoneutral temperature (CON). Blood samples were collected before and up to 3 h post-session to assess inflammatory markers, while a 2 h oral glucose tolerance test was initiated 1 h post-session. Femoral artery blood flow and perceptual responses were recorded at regular intervals. The interleukin (IL)-6 incremental area under the curve (iAUC) was higher for LBH (1096 ± 851 pg/mL × 270 min) and WBH (833 ± 476 pg/mL × 270 min) compared with CON (565 ± 325 pg/mL × 270 min; p < 0.047). Glucose concentrations were higher after WBH compared with LBH and CON (p < 0.046). Femoral artery blood flow was higher at the end of WBH (1713 ± 409 mL/min) compared with LBH (943 ± 349 mL/min; p < 0.001), and higher in LBH than CON (661 ± 222 mL/min; p = 0.002). Affect and thermal comfort were more negative during WBH compared with LBH and CON (p < 0.010). In conclusion, local passive heating elevated blood flow and the IL-6 iAUC. However, while resulting in more positive perceptual responses, the majority of the included cardiometabolic markers were attenuated compared with WBH. Novelty: The increase in the IL-6 iAUC in response to passive heating is not reduced by upper-body cooling. Upper-body cooling attenuates the plasma nitrite, IL-1ra and femoral artery blood flow response to passive heating. Upper-body cooling leads to more positive perceptual responses to passive heating.

Systemic inflammation and symptomatology in patients with prostate cancer treated with androgen deprivation therapy: Preliminary findings.

BACKGROUND: Increases in fatigue, depressive symptomatology, and cognitive impairment are common after the initiation of androgen deprivation therapy (ADT) for prostate cancer. To date, no studies have examined the potential role of inflammation in the development of these symptoms in ADT recipients. The goal of the current study was to examine circulating markers of inflammation as potential mediators of change in fatigue, depressive symptomatology, and cognitive impairment related to the receipt of ADT. METHODS: Patients treated with ADT for prostate cancer (ADT+; n = 47) were assessed around the time of the initiation of ADT and 6 and 12 months later. An age- and education-matched group of men without a history of cancer (CA-; n = 82) was assessed at comparable time points. Fatigue, depressive symptomatology, and cognitive impairment were assessed with the Fatigue Symptom Inventory, the Center for Epidemiological Studies Depression Scale, and a battery of neuropsychological tests, respectively. Circulating markers of inflammation included interleukin 1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), soluble tumor necrosis factor receptor II (sTNF-RII), and C-reactive protein (CRP). RESULTS: Fatigue, depressive symptomatology, and serum IL-6 increased significantly over time in the ADT+ group versus the CA- group; rates of cognitive impairment also changed significantly between the groups. No significant changes in IL-1RA, sTNF-RII, or CRP over time were detected. Treatment-related increases in IL-6 were associated with worsening fatigue but not depressive symptomatology or cognitive impairment. CONCLUSIONS: Results of this preliminary study suggest that increases in circulating IL-6, perhaps due to testosterone inhibition, may play a role in fatigue secondary to receipt of ADT. Additional research is needed to determine whether interventions to reduce circulating inflammation improve fatigue in this population.

Cardiovascular-related proteins and the abdominal visceral to subcutaneous adipose tissue ratio.

BACKGROUND AND AIMS: An increased amount of visceral adipose tissues has been related to atherosclerosis and future cardiovascular events. The present study aims to investigate how the abdominal fat distribution links to plasma levels of cardiovascular-related proteins. METHOD AND RESULTS: In the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 326, all aged 50 years), abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue volumes were quantified by MRI. Eighty-six cardiovascular-related proteins were measured by the proximity extension assay (PEA). Similar investigations were carried out in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 400, all aged 75 years). In the discovery dataset (POEM), 10 proteins were related to the VAT/SAT-ratio using false discovery rate <.05. Of those, Cathepsin D (CTSD), Interleukin-1 receptor antagonist protein (IL-1RA) and Growth hormone (GH) (inversely) were related to the VAT/SAT-ratio in the validation in PIVUS following adjustment for sex, BMI, smoking, education level and exercise habits (p < 0.05). In a secondary analysis, a meta-analysis of the two samples suggested that 15 proteins could be linked to the VAT/SAT-ratio following adjustment as above and Bonferroni-correction of the p-value. CONCLUSION: Three cardiovascular-related proteins, cathepsin D, IL-1RA and growth hormone, were being associated with the distribution of abdominal adipose tissue using a discovery/validation approach. A meta-analysis of the two samples suggested that also a number of other cardiovascular-related proteins could be associated with an unfavorable abdominal fat distribution.

Evaluation of alpha defensin, IL-1 receptor antagonist, and IL-18 levels in COVID-19 patients with macrophage activation syndrome and acute respiratory distress syndrome.

BACKGROUND: Many laboratory parameters have been associated with morbidity and mortality in SARS-CoV-2 (COVID-19), which emerged in an animal market in Wuhan, China in December 2019 and has infected over 20 million people. This study investigated the relationship between serum interleukin (IL)-18, IL-1 receptor antagonist (IL-1Ra), and alpha defensin levels and the clinical course and prognosis of COVID-19. MATERIALS AND METHODS: This study included 100 patients who were admitted to the chest diseases department and intensive care unit of our hospital and diagnosed with COVID-19 by real-time polymerase chain reaction (PCR) of nasopharyngeal swab samples between March 24 and May 31, 2020. The control group consisted of 50 nonsymptomatic health workers with negative real-time PCR results in routine COVID-19 screening in our hospital. RESULTS: Serum alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in patients who developed macrophage activation syndrome (MAS) and acute respiratory distress syndrome (ARDS) compared to patients who did not (p < .001 for all). Alpha defensin, IL-1Ra, and IL-18 levels were significantly higher in COVID-19 patients with and without MAS or ARDS when compared to the control group (p < .001 for all). When the 9 patients who died were compared with the 91 surviving patients, IL-1Ra and IL-18 levels were found to be significantly higher in the nonsurvivors (p < .001). CONCLUSION: Our findings of correlations between alpha defensin and levels of IL-1Ra and IL-18, which were previously shown to be useful in COVID-19 treatment and follow-up, indicates that it may also be promising in treatment.

Anti-inflammatory cytokines IL-27, IL-10, IL-1Ra and TGF-ß in subjects with increasing grades of glucose intolerence (DM-LTB-2).

Anti-inflammatory cytokines act as double edged swords- they can dampen inflammation but can also suppress immunity. The role played by these cytokines in latent TB infected (LTBI) subjects, with various grades of glucose intolerance was studied. Both serum levels and recall-secretion of IL-27, IL-10, IL-1Ra and TGF-ß in Normal Glucose Tolerance (NGT), Pre-Diabetes (PDM), Newly diagnosed Diabetes (NDM) and Known Diabetes (KDM) subjects, both with and without LTBI (n = 382), were quantified by ELISA. All the subjects were screened for LTBI by QuantiFERON-TB Gold test. Serum levels of IL-27, IL-10 and IL-1Ra were significantly elevated in the LTB-PDM, compared to LTB-NGT group. Increased IL-27 and IL-10 levels and decreased levels of TGF-ß were seen in the LTB-NDM, compared to LTB-NGT group. Decreased serum levels of IL-27 and increased levels of IL-1Ra and TGF-ß were seen in the LTB-KDM, compared to LTB-NGT group. TB antigens induced the secretion of IL-1Ra in LTB+ subjects in the NGT, PDM and NDM groups, but not in the KDM group. Co-morbidity with LTBI brought about (diabetic) stage-specific modulation, in these cytokine levels. Major defects in the circulating levels and recall secretion of anti-inflammatory cytokines, as seen in LTB+KDM subjects, could fuel DM-TB synergy.

Systematic review and meta-analysis of the associations of vegan and vegetarian diets with inflammatory biomarkers.

Plant-based diets like vegetarian or vegan diets might influence circulating levels of inflammatory biomarkers, thereby reducing the risk of chronic diseases. This systematic review and meta-analysis aimed to investigate the associations of veganism and vegetarianism with circulating inflammatory biomarkers in comparison to omnivores. Literature search was conducted in Pubmed and EMBASE until April 2020 and mean differences of biomarkers were assessed for: C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1 receptor antagonist (IL-1 RA), tumor necrosis factor-alpha (TNF-ɑ), E-selectin, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), adiponectin, omentin-1 and resistin. Of initially identified 1073 publications, 21 cross-sectional studies met the inclusion criteria and were included in the systematic review and meta-analysis. Vegan diet was associated with lower levels of CRP compared to omnivores [mean difference - 0.54 mg/l, 95%-CI: - 0.79 to - 0.28, p < 0.0001]. This association was less pronounced in vegetarians [mean difference - 0.25 mg/l, 95%-CI: - 0.49 to 0.00, p = 0.05]. In patients with impaired kidney function, the association between vegetarian nutrition and CRP was much stronger with - 3.91 mg/l (95%-CI: - 5.23 to - 2.60; p < 0.0001). No substantial effects were observed for all other inflammatory biomarkers. Despite strong associations between CRP and a vegan or vegetarian diet were seen, further research is needed, as most inflammatory biomarkers were investigated only in single studies so far.