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Sex Differences in Physiological Stress Induced by a Long-Lasting Adventure Race: A Prospective Observational Analytical Study.
Silva, RPM, Vilaça, A, Guerra, FD, Mundim, AV, de Agostini, GG, de Abreu, LC, Zhiguo, Z, Sorpreso, IC, Valenti, VE, Penha-Silva, N
Sportverletzung Sportschaden : Organ der Gesellschaft fur Orthopadisch-Traumatologische Sportmedizin. 2020;(2):84-95
Abstract
BACKGROUND In order to provide additional information on the behaviour of biochemical parameters related to stress responses to a specific long-term competition, we aimed to compare the stressful effects of a long-lasting competition on physiological variables in men and women. METHODS This is a prospective observational analytical study. Twenty-five professional athletes, 15 men and 10 women, travelled 460 km for 4 days in an international edition of the Ecomotion/Pro AR World. RESULTS After the competition, we detected an increase in α-amylase and cortisol levels and a decrease in salivary immunoglobulin A (lgA) levels. The relative percentage changes in α-amylase, IgA and cortisol levels were significantly higher in women than in men, whereas women had lower relative percentage changes in glucose and lactate levels compared with men. There was a decrease in lymphocyte, eosinophil and monocyte counts, with relative percentage decreases in lymphocytes and monocytes being significantly higher in female athletes than in males. There were increases in the serum activities of total creatine kinase (CK), the creatine kinase myocardial isoform (CKMB), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) at the end of the test, with significantly higher elevations of total CK, CKMB and LDH in men and ALT in women. CONCLUSION Long-lasting competition induced stress, muscle damage, anaemia and changes in the immune system. Women had more intense responses of cortisol and leukocytes.
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Immune recovery markers in a double blind clinical trial comparing dolutegravir and raltegravir based regimens as initial therapy (SPRING-2).
Blanco, JR, Alejos, B, Moreno, S
PloS one. 2020;(1):e0226724
Abstract
BACKGROUND Multiple T-cell marker recovery (MTMR: CD4+ T-cells >500 cel/mm3 plus CD4+% >29% plus CD4+/CD8+ ratio >1) has been proposed as the most complete level of immune reconstitution. In this study we quantified differences in the CD4+/CD8+ ratio, CD4+% recovery and MTMR after starting HIV-1 treatment with dolutegravir (DTG) vs. raltegravir (RAL) plus a NRTI backbone. METHODS Exploratory post-hoc analysis of the SPRING-2 study, a randomized double-blind clinical trial comparing DTG and RAL as third agents in naive HIV-infected patients at 100 sites in Canada, USA, Australia, and Europe. Percentage differences and corresponding precision based on 95% confidence intervals (CI) and p-values were calculated for i) CD4+/CD8+ ratio normalization, ii) CD4+% normalization, and iii) the achievement of MTMR. RESULTS A total of 822 participants were analyzed (411 in each group). No statistically significant differences in the proportion of patients who reached a CD4+/CD8+ ratio ≥0.5 & ≥1 at w48 & w96 were observed. At w96, the proportion of patients with a CD4+/CD8+ ratio ≥1 was similar (30.43% DTG vs. 29.57% RAL). No differences were observed in the mean increase in CD4+/CD8+ ratio from baseline at both w48 & w96. Similarly, no significant differences in the CD4+/CD8+>29% were observed at w96 (72.95% DTG vs 69.28% RAL). The proportion of patients attaining MTMR criteria was also similar in the DTG group and the RAL group at w48 (20.33% vs. 18.26%; difference 2.07 (95%CI (-3.67;7.81) P = 0.481 and w96 (28.70% vs. 27.13; difference 1.56 (95%CI -5.22;8.34) P = 0.652). CONCLUSION After comparing DTG and RAL, no differences on immune recovery markers were observed.
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Differential Plasma Protein Regulation and Statin Effects in Human Immunodeficiency Virus (HIV)-Infected and Non-HIV-Infected Patients Utilizing a Proteomics Approach.
deFilippi, C, Toribio, M, Wong, LP, Sadreyev, R, Grundberg, I, Fitch, KV, Zanni, MV, Lo, J, Sponseller, CA, Sprecher, E, et al
The Journal of infectious diseases. 2020;(6):929-939
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Abstract
BACKGROUND People with human immunodeficiency virus (PWH) demonstrate increased atherosclerotic cardiovascular disease (ASCVD). Statins are being studied to prevent ASCVD in human immunodeficiency virus (HIV), but little is known regarding the effects of statins on a broad range of inflammatory and cardiovascular proteins in this population. METHODS We used a highly specific discovery proteomic approach (Protein Extension Assay), to determine statin effects on over 350 plasma proteins in relevant ASCVD pathways among HIV and non-HIV groups. Responses to pitavastatin calcium were assessed in 89 PWH in the INTREPID trial and 46 non-HIV participants with features of central adiposity and insulin resistance. History of cardiovascular disease was exclusionary for both studies. RESULTS Among participants with HIV, PCOLCE (enzymatic cleavage of type I procollagen) significantly increased after pitavastatin therapy and PLA2G7 (systemic marker of arterial inflammation) decreased. Among participants without HIV, integrin subunit alpha M (integrin adhesive function) and defensin alpha-1 (neutrophil function) increased after pitavastatin therapy and PLA2G7 decreased. At baseline, comparing participants with and without HIV, differentially expressed proteins included proteins involved in platelet and endothelial function and immune activation. CONCLUSIONS Pitavastatin affected proteins important to platelet and endothelial function and immune activation, and effects differed to a degree within PWH and participants without HIV.
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Using Serum Metabolomics to Predict Development of Anti-drug Antibodies in Multiple Sclerosis Patients Treated With IFNβ.
Waddington, KE, Papadaki, A, Coelewij, L, Adriani, M, Nytrova, P, Kubala Havrdova, E, Fogdell-Hahn, A, Farrell, R, Dönnes, P, Pineda-Torra, I, et al
Frontiers in immunology. 2020;:1527
Abstract
Background: Neutralizing anti-drug antibodies (ADA) can greatly reduce the efficacy of biopharmaceuticals used to treat patients with multiple sclerosis (MS). However, the biological factors pre-disposing an individual to develop ADA are poorly characterized. Thus, there is an unmet clinical need for biomarkers to predict the development of immunogenicity, and subsequent treatment failure. Up to 35% of MS patients treated with beta interferons (IFNβ) develop ADA. Here we use machine learning to predict immunogenicity against IFNβ utilizing serum metabolomics data. Methods: Serum samples were collected from 89 MS patients as part of the ABIRISK consortium-a multi-center prospective study of ADA development. Metabolites and ADA were quantified prior to and after IFNβ treatment. Thirty patients became ADA positive during the first year of treatment (ADA+). We tested the efficacy of six binary classification models using 10-fold cross validation; k-nearest neighbors, decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions. Results: We were able to predict future immunogenicity from baseline metabolomics data. Lasso logistic regression with/without interactions and support vector machines were the most successful at identifying ADA+ or ADA- cases, respectively. Furthermore, patients who become ADA+ had a distinct metabolic response to IFNβ in the first 3 months, with 29 differentially regulated metabolites. Machine learning algorithms could also predict ADA status based on metabolite concentrations at 3 months. Lasso logistic regressions had the greatest proportion of correct classifications [F1 score (accuracy measure) = 0.808, specificity = 0.913]. Finally, we hypothesized that serum lipids could contribute to ADA development by altering immune-cell lipid rafts. This was supported by experimental evidence demonstrating that, prior to IFNβ exposure, lipid raft-associated lipids were differentially expressed between MS patients who became ADA+ or remained ADA-. Conclusion: Serum metabolites are a promising biomarker for prediction of ADA development in MS patients treated with IFNβ, and could provide novel insight into mechanisms of immunogenicity.
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Elucidating potential molecular signatures through host-microbe interactions for reactive arthritis and inflammatory bowel disease using combinatorial approach.
Verma, A, Sharda, S, Rathi, B, Somvanshi, P, Pandey, BD
Scientific reports. 2020;(1):15131
Abstract
Reactive Arthritis (ReA), a rare seronegative inflammatory arthritis, lacks exquisite classification under rheumatic autoimmunity. ReA is solely established using differential clinical diagnosis of the patient cohorts, where pathogenic triggers linked to enteric and urogenital microorganisms e.g. Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia have been reported. Inflammatory Bowel Disease (IBD), an idiopathic enteric disorder co-evolved and attuned to present gut microbiome dysbiosis, can be correlated to the genesis of enteropathic arthropathies like ReA. Gut microbes symbolically modulate immune system homeostasis and are elementary for varied disease patterns in autoimmune disorders. The gut-microbiota axis structured on the core host-microbe interactions execute an imperative role in discerning the etiopathogenesis of ReA and IBD. This study predicts the molecular signatures for ReA with co-evolved IBD through the enveloped host-microbe interactions and microbe-microbe 'interspecies communication', using synonymous gene expression data for selective microbes. We have utilized a combinatorial approach that have concomitant in-silico work-pipeline and experimental validation to corroborate the findings. In-silico analysis involving text mining, metabolic network reconstruction, simulation, filtering, host-microbe interaction, docking and molecular mimicry studies results in robust drug target/s and biomarker/s for co-evolved IBD and ReA. Cross validation of the target/s or biomarker/s was done by targeted gene expression analysis following a non-probabilistic convenience sampling. Studies were performed to substantiate the host-microbe disease network consisting of protein-marker-symptom/disease-pathway-drug associations resulting in possible identification of vital drug targets, biomarkers, pathways and inhibitors for IBD and ReA.Our study identified Na(+)/H(+) anti-porter (NHAA) and Kynureninase (KYNU) to be robust early and essential host-microbe interacting targets for IBD co-evolved ReA. Other vital host-microbe interacting genes, proteins, pathways and drugs include Adenosine Deaminase (ADA), Superoxide Dismutase 2 (SOD2), Catalase (CAT), Angiotensin I Converting Enzyme (ACE), carbon metabolism (folate biosynthesis) and methotrexate. These can serve as potential prognostic/theranostic biomarkers and signatures that can be extrapolated to stratify ReA and related autoimmunity patient cohorts for further pilot studies.
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Biological Processes and Biomarkers Related to Frailty in Older Adults: A State-of-the-Science Literature Review.
Wang, J, Maxwell, CA, Yu, F
Biological research for nursing. 2019;(1):80-106
Abstract
The objectives of this literature review were to (1) synthesize biological processes linked to frailty and their corresponding biomarkers and (2) identify potential associations among these processes and biomarkers. In September 2016, PubMed, Cumulative Index to Nursing and Allied Health, Cochrane Library, and Embase were searched. Studies examining biological processes related to frailty in older adults (≥60 years) were included. Studies were excluded if they did not employ specific measures of frailty, did not report the association between biomarkers and frailty, or focused on nonelderly samples (average age < 60). Review articles, commentaries, editorials, and non-English articles were also excluded. Fifty-two articles were reviewed, reporting six biological processes related to frailty and multiple associated biomarkers. The processes (biomarkers) include brain changes (neurotrophic factor, gray matter volume), endocrine dysregulation (growth hormones [insulin-like growth factor-1 and binding proteins], hormones related to glucose and insulin, the vitamin D axis, thyroid function, reproductive axis, and hypothalamic-pituitary-adrenal axis), enhanced inflammation (C-reactive protein, interleukin-6), immune dysfunction (neutrophils, monocytes, neopterin, CD8+CD28-T cells, albumin), metabolic imbalance (micronutrients, metabolites, enzyme-activity indices, metabolic end products), and oxidative stress (antioxidants, telomere length, glutathione/oxidized glutathione ratio). Bidirectional interrelationships exist within and between these processes. Biomarkers were associated with frailty in varied strengths, and the causality remains unclear. In conclusion, frailty is related to multisystem physiological changes. Future research should examine the dynamic interactions among these processes to inform causality of frailty. Given the multifactorial nature of frailty, a composite index of multisystem biomarkers would likely be more informative than single biomarkers in early detection of frailty.
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Novel autoantibodies in Sjögren's syndrome: A comprehensive review.
Martín-Nares, E, Hernández-Molina, G
Autoimmunity reviews. 2019;(2):192-198
Abstract
Sjögren's syndrome is a systemic autoimmune disease characterized by immune- mediated injury of exocrine glands, as well as a diverse array of extraglandular manifestations. B cell over-activation is a key feature of the disease, attested by the wide spectrum of autoantibodies detected in these patients. Up to date, anti- Ro/SSA and anti-La/SSB antibodies are traditional biomarkers for disease classification and diagnosis. On the other hand, the detection of novel autoantibodies in SS has increased in the last years, opening a window of opportunity to denote particular stages of the disease, to establish clinical phenotypes, and to predict long-term complications such as lymphoma. For instance, anti-SP-1, anti-CA6 and anti-PSP antibodies occur in an earlier stage than anti-Ro/La antibodies, and may identify a subset of primary Sjögren's syndrome patients with mild or incomplete disease, whereas anti-cofilin-1, anti- alpha-enolase and anti-RGI2 antibodies are potential biomarkers of MALT lymphoma. Antibody detection is also important to elucidate new aspects of SS pathophysiology, and in the future to permit a phenotype-specific patient approach. Herein we review the literature regarding new autoantibodies in SS and attempt to dissect their usefulness as diagnostic tools, pathogenic role, identification of clinical phenotypes and as predictors of an overlap syndrome.
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Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections.
Sühs, KW, Novoselova, N, Kuhn, M, Seegers, L, Kaever, V, Müller-Vahl, K, Trebst, C, Skripuletz, T, Stangel, M, Pessler, F
The Journal of infectious diseases. 2019;(1):127-138
Abstract
BACKGROUND The tryptophan-kynurenine-nicotinamide adenine dinucleotide (oxidized; NAD+) pathway is closely associated with regulation of immune cells toward less inflammatory phenotypes and may exert neuroprotective effects. Investigating its regulation in central nervous system (CNS) infections would improve our understanding of pathophysiology and end-organ damage, and, furthermore, open doors to its evaluation as a source of diagnostic and/or prognostic biomarkers. METHODS We measured concentrations of kynurenine (Kyn) and tryptophan (Trp) in 221 cerebrospinal fluid samples from patients with bacterial and viral (due to herpes simplex, varicella zoster, and enteroviruses) meningitis/encephalitis, neuroborreliosis, autoimmune neuroinflammation (due to anti-N-methyl-D-aspartate receptor [NMDA] encephalitis and multiple sclerosis), and noninflamed controls (ie, individuals with Bell palsy, normal pressure hydrocephalus, or Tourette syndrome). RESULTS Kyn concentrations correlated strongly with CSF markers of neuroinflammation (ie, leukocyte count, lactate concentration, and blood-CSF-barrier dysfunction), were highly increased in bacterial and viral CNS infections, but were low or undetectable in NMDA encephalitis, multiple sclerosis, and controls. Trp concentrations were decreased mostly in viral CNS infections and neuroborreliosis. Multiple logistic regression analysis revealed that combinations of Kyn concentration, Trp concentration, and Kyn/Trp concentration ratio with leukocyte count or lactate concentration were accurate classifiers for the clinically important differentiation between neuroborreliosis, viral CNS infections, and autoimmune neuroinflammation. CONCLUSIONS The Trp-Kyn-NAD+ pathway is activated in CNS infections and provides highly accurate CSF biomarkers, particularly when combined with standard CSF indices of neuroinflammation.
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, LCK, Wilson, SJ, et al
The Journal of allergy and clinical immunology. 2019;(2):577-590
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Abstract
BACKGROUND Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. CONCLUSIONS Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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Relationship between natural killer cell activity and glucose control in patients with type 2 diabetes and prediabetes.
Kim, JH, Park, K, Lee, SB, Kang, S, Park, JS, Ahn, CW, Nam, JS
Journal of diabetes investigation. 2019;(5):1223-1228
Abstract
AIMS/INTRODUCTION Natural killer (NK) cells are cytotoxic lymphocytes critical to human immunity. Previous studies showed correlations between NK cell function and blood glucose concentrations. The purpose of the present study was to assess the NK cell activity and various metabolic parameters in people with type 2 diabetes, prediabetes and normal glucose tolerance. MATERIALS AND METHODS A total of 49 participants were enrolled in the study. Anthropometric and biochemical parameters including age, sex, body mass index, smoking status, blood pressure, fasting plasma glucose, C-peptide, insulin, glycated hemoglobin, total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were assessed. The 75 g oral glucose tolerance test was carried out for 2-h postload glucose level. Homeostatic model assessment was calculated for insulin resistance and β-cell function. NK cell activity was measured by detecting the circulating interferon-gamma level secreted from NK cells. RESULTS NK cell activity was lower in patients with type 2 diabetes (768.01 ± 650.35) compared with those with prediabetes (2,396.08 ± 653.76, P < 0.001) and normal glucose tolerance (2,435.31 ± 633.22, P < 0.001). In patients with type 2 diabetes, there was a significant inverse linear relationship between NK cell activity and fasting plasma glucose, glycated hemoglobin, and 2-h postload glucose level (all P < 0.001). Multiple regression analysis showed glycated hemoglobin to be an independent predictor of NK cell activity in patients with type 2 diabetes. CONCLUSIONS Compared with individuals with normal glucose tolerance or prediabetes, type 2 diabetes patients have a reduced NK cell activity, and it is significantly related to glucose control.