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Results for “Bidirectional mediation”

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At least 19 recordsLinked to original sources

PubMed1992

Bidirectional control by glycyrrhizin of the growth response of lymphocytes stimulated through a receptor-bypassed pathway.

This study demonstrates a unique action of glycyrrhizin (GL) in bidirectionally controlling the growth response of lymphocytes stimulated through a receptor-bypassed pathway by calcium ionophore A23187 and phorbol 12-myristate 13-acetate (PMA). GL up-regulated the response of lymphocytes in vitro to lower concentrations of A23187 and PMA, and down-regulated the response to higher concentrations. We also provide evidence that GL controls the response of lymphocytes of different cell types or maturation stages in different ways, probably because these lymphocytes require different levels of signals as optimum. Finally, the GL-mediated bidirectional controls of the lymphocyte growth response were shown to be adherent cell-independent. The bidirectional controls demonstrated may be significant in normalizing the lymphocyte responses to very weak or very high stimuli.

Animals↗

PubMed1992

Cytokines and neuropathology.

Inflammatory processes in the brain require the cooperation of immunocompetent cells and glial cells, which communicate by secreting bidirectional mediators. Resident cells within the nervous system can synthesize and secrete inflammatory cytokines, as well as neuropeptides, contributing to the response within the CNS to injury or immunological challenge. Although the mechanisms of cell activation and immune interaction are poorly understood, accumulating evidence implicates these pathways in neuropathogenesis, as described here by Sharon Wahl and colleagues. For example, in the acquired immune deficiency syndrome (AIDS), HIV-1-induced nervous system dysfunction and dementia are associated with the presence of infiltrating leukocytes and the release of inflammatory cytokines. Defining the pathways of cytokine dysregulation and neurotoxicity invoked by the infiltrating leukocytes, as well as the contribution of the neural cells themselves, may help to identify mechanisms of intervention in this and other debilitating CNS diseases.

Acquired Immunodeficiency Syndrome↗

PubMed2026

To unveil the causal relationship between immunophenotypes and colorectal cancer using two-sample bidirectional Mendelian randomization and mediation analyses.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The mechanisms underlying this trend are not yet fully understood. This study aimed to examine the potential role of genetically predicted immunophenotypes in the development of CRC. A two-sample bidirectional Mendelian randomization study was conducted to explore the relationship between 731 genetically predicted immune cells and CRC. Furthermore, a two-step Mendelian randomization approach was employed to assess the possible mediating effect of immune cells on CRC. The inverse-variance weighted method identified 5 immunophenotypes as significantly inversely associated with CRC risk: the odds ratios for CRC risk associated with activated CD4 regulatory T cells (%CD4 regulatory T cells), CD25++ CD45RA- CD4 nonregulatory T cells (%CD4 + T cells), CD25++ CD45RA- CD4 nonregulatory T cells (%T cells), CD25++ CD8 + T cells (%T cells), and CD64 + CD16 + monocytes were 0.925 (95% CI = 0.874-0.978, P = 6.516 × 10-3), 0.935 (95% CI = 0.878-0.995, P = .035), 0.936 (95% CI = 0.889-0.985, P = .011), 0.863 (95% CI = 0.786-0.948, P = 2.142 × 10-3), and 0.636 (95% CI = 0.519-0.778, P = 1.18 × 10-5), respectively. The mediation analysis indicated that the absolute count of CD25++ CD8 + T cells led to a 33.9% decrease in the risk associated with the percentage of activated CD4 regulatory T cells within CD4 regulatory T cells and CRC. Our analysis revealed that 5 immunophenotypes may be risk factors for CRC. Since other complementary methods have yielded inconsistent results, however, further investigation is necessary.

Colorectal Neoplasms↗

PubMed2026

Gender-specific pathways linking body dissatisfaction, self-disgust, and social anxiety in Chinese adolescents: A three-wave longitudinal study.

Adolescence is a critical period for physical and psychological development. Body dissatisfaction is a significant concern during this stage, contributing to psychological issues such as social anxiety. However, the longitudinal relationships among body dissatisfaction, self-disgust, and social anxiety, as well as the potential role of gender differences in these dynamics, remain unclear. A total of 1109 junior high school students in China completed the baseline survey, with data collected at three time points (Mage = 12.67 years, SD = 0.68; 51.9% girls). Data were collected using the Body Areas Satisfaction Scale (BASS), the Self-Disgust Scale (SDS), and the Social Anxiety Scale for Children (SASC). Structural equation modeling (SEM) was employed to examine the longitudinal mediating effects among body dissatisfaction, self-disgust, and social anxiety, as well as to explore gender differences in these relationships. After controlling for autoregressive effects of self-disgust and social anxiety across waves, body dissatisfaction at T1 was found to indirectly predict social anxiety at T3 through self-disgust at T2, while indirectly predicting self-disgust at T3 through social anxiety at T2. Multi-group analyses revealed significant gender differences: for females, only the mediating pathway with self-disgust as the mediator was significant; for males, only the pathway with social anxiety as the mediator was significant. These findings contribute to a more nuanced understanding of the emotional mechanisms linking body dissatisfaction to social anxiety and highlight the importance of considering gender-specific pathways in prevention and intervention efforts.

Adolescent↗

PubMed2026

A Mendelian Randomization Study of Immune Cell Traits and Plasma Metabolites in Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) is an autoimmune disorder of the thyroid. While immune cells are implicated in its pathogenesis, their specific roles have yet to be fully clarified. A two-sample Mendelian randomization (MR) analysis was conducted integrating genome-wide association study (GWAS) summary statistics from large public datasets for immune cell traits (ebi-a-GCST90001391 to ebi-a-GCST90002121), plasma metabolites (GCST90199621-9020102), and HT (ebi-a-GCST90018855). Causal effects were estimated using inverse-variance weighted (IVW) methods, with MR-Egger, weighted median, and leave-one-out analyses to assess pleiotropy and robustness. Bidirectional and mediation MR analyses were further applied to test directionality and identify potential metabolite-mediated pathways. CD3⁺CD4⁺CD25⁺CD39⁺Treg cells were quantified in peripheral blood samples using flow cytometry. Isovalerylcarnitine (C5) was measured by liquid chromatography tandem mass spectrometry. IVW analysis identified 32 immune cell phenotypes significantly associated with HT risk (P < 0.05 after FDR correction). Reverse MR analysis demonstrated that HT was positively causally linked with 2 immune characteristics, while 4 immune characteristics (all P < 0.05) were inversely associated with HT. Sensitivity analyses revealed no horizontal pleiotropy or heterogeneity. Additionally, the IVW method preliminarily identified 9 plasma metabolites as causally related to HT, including risk-enhancing C5 (OR = 1.120, 95% CI: 1.032-1.215, P = 0.006) and protective ergothioneine (OR = 0.958, 95% CI: 0.927-0.990, P = 0.010). Two-step MR mediation identified C5 as a candidate mediator connecting CD3⁺ CD39⁺ Treg to HT (mediation proportion 8.89%, 95% CI: 2.34%-15.4%, P = 0.008). Flow cytometry elevated CD39⁺Treg levels and plasma C5 in HT patients, with C5 positively correlated with CD39⁺Treg cells proportion. This study establishes novel causal links between immune cell phenotypes and HT, and highlights plasma metabolites, particularly C5, as potential mediators in HT pathogenesis. These findings deepen mechanistic understanding of autoimmune thyroid disease and may guide future biomarker and therapeutic target discovery.

Humans↗

PubMed2024

Effect of inflammatory cytokines and plasma metabolome on OSA: a bidirectional two- sample Mendelian randomization study and mediation analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder. Inflammatory factors and plasma metabolites are important in assessing its progression. However, the causal relationship between them and OSA remains unclear, hampering early clinical diagnosis and treatment decisions. METHODS: We conducted a large-scale study using data from the FinnGen database, with 43,901 cases and 366,484 controls for our discovery MR analysis. We employed 91 plasma proteins from 11 cohorts (totaling 14,824 participants of European descent) as instrumental variables (IVs). Additionally, we conducted a GWAS involving 13,818 cases and 463,035 controls to replicate the MR analysis. We primarily used the IVW method, supplemented by MR Egger, weighted median, simple mode, and weighted mode methods. Meta-analysis was used to synthesize MR findings, followed by tests for heterogeneity, pleiotropy, and sensitivity analysis (LOO). Reverse MR analysis was also performed to explore causal relationships. RESULTS: The meta-analysis showed a correlation between elevated Eotaxin levels and an increased risk of OSA (OR=1.050, 95% CI: 1.008-1.096; p < 0.05). Furthermore, we found that the increased risk of OSA could be attributed to reduced levels of X-11849 and X-24978 (decreases of 7.1% and 8.4%, respectively). Sensitivity analysis results supported the reliability of these findings. CONCLUSIONS: In this study, we uncovered a novel biomarker and identified two previously unknown metabolites strongly linked to OSA. These findings underscore the potential significance of inflammatory factors and metabolites in the genetic underpinnings of OSA development and prognosis.

Female↗

PubMed1976

Evidence for carrier-mediated uptake and efflux of sugars at the serosal side of the rat intestinal mucosa in vitro.

A modification of the everted sac technique is described which allows several sacs to be prepared rapidly and simultaneously from the same segment of rat intestine. 2. A method has been developed for comparing the transport of two sugars by measuring changes in the ratios of their concentrations as they pass across the intestinal wall. 3. With this method significant differences were observed between the D-[3H]galactose and L-[14C]glucose ratios in the mucosal epithelium, the serosal tissue and the serosal compartment. These results indicate that both the efflux of galactose from the serosal side of the mucosal epithelium and the uptake of the sugar into the mucosa are carrier-mediated processes. 4. The mediated efflux of galactose at the serosal side of the epithelial layer is inhibited by the presence of phlorizin on the mucosal side and to some extent by any reduction in the mucosal Na+ concentration. Both of these treatments inhibited galactose uptake at the brush border. Serosal efflux of the sugar appeared to be saturated at high concentrations of D-galactose. 5. Pre-treatment of the sacs with mercuric chloride considerably reduced D-galactose uptake from the luminal side, but did not affect its efflux relative to L-glucose at the serosal side of the mucosal epithelium. 6. Carrier-mediated sugar uptake into the mucosal epithelium from the serosal side was also examined. The role of the bidirectional, carrier-mediated sugar transport processes at the serosal pole of the mucosal epithelial cell in transintestinal transport is discussed.

Animals↗

PubMed1992

Prostate and bone fibroblasts induce human prostate cancer growth in vivo: implications for bidirectional tumor-stromal cell interaction in prostate carcinoma growth and metastasis.

Prostate cancer selectively metastasizes to the axial skeleton to produce osteoblastic lesions, which suggests that bidirectional paracrine interactions exist between prostate cancer and bone cells. To evaluate the role of tumor-stromal cell interaction and stromal-specific growth factors in prostate cancer growth and dissemination, we coinoculated nontumorigenic human prostate cancer cells (LNCaP) and various tissue-specific fibroblasts subcutaneously in athymic mice. LNCaP tumors were induced most consistently by human bone fibroblasts (62%), followed by two prostate fibroblast cell lines (31% and 17%), but not by lung, kidney, or embryonic 3T3 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. Immunohistochemical and biochemical techniques confirmed the human prostate component of these tumors and were paralleled by elevations in serum prostate specific antigen. In vitro mitogenic assays revealed a two-to three-fold bidirectional stimulation between LNCaP and bone or prostate fibroblast conditioned media, but not lung, kidney, or 3T3 fibroblast conditioned media. A novel method developed to deliver concentrated bone or prostate fibroblast conditioned media in vivo using a slowly absorbed matrix (gelfoam) also induced tumor formation, emphasizing the importance of fibroblast growth factors in LNCaP tumor formation. Northern analysis identified the stromal compartment as the primary source of extracellular matrix (collagen, fibronectin), while only LNCaP cells expressed transforming growth factor alpha. Although LNCaP and stromal cells express basic fibroblast growth factor (bFGF), the bidirectional paracrine-mediated mitogenic activity between these cells is not inhibited by anti-bFGF antibodies, suggesting that other undefined growth factors may be involved in stimulating LNCaP growth. These observations illustrate the importance of stromal-epithelial interaction in prostate tumor growth and suggest that extracellular matrix and paracrine-mediated growth factors play a role in prostate cancer growth and metastasis.

Androgens↗

PubMed2026

Genetically Predicted Muscle Mass and Function in Relation to Deep Vein Thrombosis: A Two-step Mendelian Randomization Study Highlighting the Mediating Role of BMI.

BackgroundSarcopenia is observationally linked to venous thromboembolism, but the causal architecture and underlying biological pathways remain largely unclear. This study investigated the causal effects of sarcopenia-related traits on lower extremity deep vein thrombosis (DVT) and quantified potential mediating mechanisms.MethodsWe performed two-sample bidirectional Mendelian randomization (MR) and two-step mediation MR using large-scale GWAS data from UK Biobank, EMBL-EBI, and FinnGen. Exposures included appendicular lean mass (ALM), leg fat-free mass (LFM), hand grip strength, and walking pace. Eighteen candidate mediators were screened for indirect pathways.ResultsGenetically predicted higher ALM was significantly associated with increased DVT risk (FinnGen: OR = 1.288, 95% CI: 1.215-1.365, P < 0.001). Similar positive associations were observed for LFM (OR = 1.920-1.954, P < 0.001). By contrast, muscle functional traits - grip strength and walking pace - demonstrated no consistent causal effects. Reverse MR confirmed a unidirectional relationship. Body mass index (BMI) emerged as a pivotal mediator, accounting for 7.58% - 10.50% of the ALM-DVT effect and 52.74% - 62.73% of the LFM-DVT effect. Notably, the independent effect of ALM was largely attenuated after adjusting for metabolic confounders in multivariable MR.ConclusionGenetic predisposition to high muscle mass, rather than functional strength, increases DVT risk. This relationship appears to be significantly driven by metabolic adiposity, suggesting that the "muscle-vascular-coagulation" interaction is partly explained by body-size-related metabolic burden. Risk stratification should integrate muscle mass evaluation with comprehensive metabolic health assessments.

Humans↗

PubMed2025

Immunosuppressant use may be a potential mediator in the progression of systemic lupus erythematosus to osteomyelitis: A bidirectional Mendelian randomization study.

The prevalence of osteomyelitis (OM) is elevated in patients with systemic lupus erythematosus (SLE), but the causal direction and proportion of immunosuppressant (IS) use in this relationship is unclear. Therefore, this study used a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between SLE and OM and to quantify the role of IS use as a potential mediator. Genome-wide association study summary-level data were used to obtain genetic instrumental variables for SLE (5201 cases and 9066 controls), OM (1881 cases and 391,037 controls), and IS (3954 cases and 268,648 controls) genetic instrumental variables with no overlap between their participant populations. Causal and total effects of SLE and OM were analyzed using bidirectional MR. Subsequent "2-step" MR was used to assess the direct effect between the 2 and the indirect effect of IS. Inverse variance weighting was used as the primary method of MR, while a series of sensitivity analyses were performed to assess the reliability of the results. Forward MR of inverse variance weighting results demonstrated a positive causal association between SLE and OM (P = .003, odds ratio [OR] = 1.062, 95% confidence interval [Cl]-OR: 1.019-1.107). The reverse MR results indicated no causal effect of OM on SLE was found (P = .503, OR = 0.914, 95% Cl-OR: 0.703-1.188). The direct effect of SLE acting on OM in our study was found to be 19.36% by 2-step analysis, and the indirect effect of OM through IS was found to be 68.11% (proportion mediated: 68.11%; 95% CI = 0.2277331-1.134507). There was no heterogeneity in all MR analyses of causality, except for the MR analysis of SLE causally related to IS. Sensitivity analysis found no evidence of horizontal pleiotropy. The present study found an increased relative risk of OM in SLE. Mediation analysis suggested a potential substantial mediating role for IS; however, this estimate was highly imprecise and requires further validation. In clinical practice, clinicians should remain aware of the potential for IS therapy to influence infection risk, including OM, in SLE patients.

Humans↗

PubMed1992

BCL2 oncogene translocation is mediated by a chi-like consensus.

Examination of 64 translocations involving the major breakpoint region (mbr) of the BCL2 oncogene and the immunoglobulin heavy chain locus identified three short (14, 16, and 18 bp) segments within the mbr at which translocations occurred with very high frequency. Each of these clusters was associated with a 15-bp region of sequence homology, the principal one containing an octamer related to chi, the procaryotic activator of recombination. The presence of short deletions and N nucleotide additions at the breakpoints, as well as involvement of JH and DH coding regions, suggested that these sequences served as signals capable of interacting with the VDJ recombinase complex, even though no homology with the traditional heptamer/spacer/nonamer (IgRSS) existed. Furthermore, the BCL2 signal sequences were employed in a bidirectional fashion and could mediate recombination of one mbr region with another. Segments homologous to the BCL2 signal sequences flanked individual members of the XP family of diversity gene segments, which were themselves highly overrepresented in the reciprocal products (18q-) of BCL2 translocation. We propose that the chi-like signal sequences of BCL2 represent a distinct class of recognition sites for the recombinase complex, responsible for initiating interactions between regions of DNA separated by great distances, and that BCL2 translocation begins by a recombination event between mbr and DXP chi signals. Since recombinant joints containing chi, not IgRSS, occur in brain cells expressing RAG-1 (Matsuoka, M., F. Nagawa, K. Okazaki, L. Kingsbury, K. Yoshida, U. Muller, D. T. Larue, J. A. Winer, and H. Sakano. 1991. Science [Wash. DC]. 254:81; reference 1), we further suggest that the product of this gene could mediate both BCL2 translocation and the first step of normal DJ assembly through the creation of chi joints, rather than signal or coding joints.

Base Sequence↗

PubMed2026

The role of ferroptosis in juvenile idiopathic arthritis: Causal inference and mediation by immune phenotypes.

This study employed a bidirectional 2-step, two-sample Mendelian randomization approach to investigate the causal relationships between ferroptosis-related genes and juvenile idiopathic arthritis (JIA) and to explore the mediating role of immune cells. Ferroptosis genes were identified from the deCODE database and matched with protein quantitative trait locus data as exposures to evaluate their causal effects on JIA, while immune cell traits were similarly assessed. For genes showing positive Mendelian randomization results, further analyses were conducted to determine whether immune cells mediated the effects on JIA, with mediation analysis performed only in the presence of causal associations. Data were sourced from the GWAS, FerrDb, and other public repositories. Nine ferroptosis-related genes were found to have causal links with JIA: HSPB1, DECR1, LIFR, and CTSB increased JIA risk, whereas PIEZO1, DPP4, BID, and others were protective. Forty immune cell traits were also causally associated with JIA. Mediation analysis revealed that several immune cells, including CD127- CD8+ T cells, partially mediated the genetic effects, with mediation proportions reaching up to 18.6%. Collectively, these results point to a ferroptosis-immune-JIA axis, suggesting that ferroptosis-related genes contribute to JIA pathogenesis through immune cell mediation and offering new mechanistic insights and potential therapeutic targets.

Arthritis, Juvenile↗

PubMed1992

Extracellular matrix synthesis and turnover by type II pulmonary epithelial cells.

Both type I and type II pulmonary epithelial cells contact the extracellular matrix (ECM). Type II cell-ECM interactions are bidirectional; they involve matrix-mediated modulation of type II cell differentiation, as well as cellular synthesis and deposition of ECM components. The present experiments examine the kinetics of accumulation of newly synthesized proteins in cell and matrix fractions from primary cultures of type II pneumocytes. Cycloheximide-sensitive incorporation of [3H]leucine into total protein of both the cell and ECM fractions was linear for 24-30 h, when steady-state labeling was reached and maintained to at least day 8. Over this interval, the cells enlarged but did not divide. Newly synthesized proteins recovered in the matrix fraction averaged 1-2% of those in the cells. Relative rates of radiolabeling of matrix proteins peaked at culture day 2 and increased in the absence of serum. In short-pulse studies, initial rates of protein synthesis were equal on culture days 1 and 3; this suggested that the steady-state labeling kinetics above reflected protein turnover. This was supported by rapid loss of radioactivity from the ECM after fresh type II cells were seeded on a prelabeled, cell-free matrix surface. Fresh or conditioned Dulbecco's modified Eagle's medium containing 10% fetal calf serum had little effect on matrix stability. These results demonstrate regulated deposition and turnover of a complex ECM by type II cells and provide a basis for further investigations of factors that control these processes.

Animals↗

PubMed2025

Causal relationships between antibody-mediated immune responses and acute pancreatitis: Evidence from a genetic study.

Certain specific antibody-mediated immune responses may be associated with acute pancreatitis (AP), but their causal relationship remains uncertain. Therefore, we used bidirectional two-sample Mendelian randomization (MR) to investigate their causal link and potential mediation by inflammatory cytokines. Data for this study were sourced from a large-scale Genome Wide Association Study (GWAS) communal data pool. To explore the causality between antibody-mediated immune responses and AP, we performed two-sample bidirectional MR analyses using 5 approaches: inverse-variance weighted (IVW), MR-Egger, weighted mode, weighted median, and simple mode. We also studied the potential mediating effect of 91 circulating inflammatory cytokines using a two-step MR method. Additionally, sensitivity analyses were conducted using MR-Egger intercept test and Cochran Q test to ensure the robustness of the outcomes. The results of forward MR analysis showed that anti-Epstein-Barr virus (anti-EBV) IgG seropositivity [OR = 0.941; 95% CI, 0.893-0.992; P = .023] and human herpes virus (HHV) 6 IE1A antibody levels [OR = 0.894; 95% CI, 0.816-0.981; P = .017] significantly reduced the risk of AP. The results of the reverse MR analysis revealed a negative correlation between AP and anti-EBV IgG seropositivity [OR = 0.775; 95% CI, 0.605-0.992; P = .043]. Furthermore, none of the 91 circulating inflammatory cytokines could mediate the causal relationship between HHV-6 IE1A antibody levels and the risk of AP. The results of sensitivity analysis confirmed the robustness of these causalities. The current study suggests that HHV-6 IE1A antibody levels are a protective factor against AP, and there is a bidirectional causality between AP and anti-EBV IgG seropositivity. In addition, the mediation analysis results showed that the 91 circulating inflammatory cytokines could not serve as mediators between the 46 antibody-mediated immune responses and AP.

Humans↗

PubMed1992

Mediators of communication and adaptation in the neuroendocrine and immune systems.

Bidirectional interactions between the immune and neuroendocrine systems influence specifically physiological activities as diverse as tissue localization of lymphocytes, antibody responses, hypothalamic-pituitary hormone secretion, and neural signal transmission. Our understanding of intersystem communications has been increased by the delineation of the innervation of immune organs, effects of neuromediators on immune cells, and neuroendocrine responses to individual immune cytokines. Two patterns of responses to neuroimmune mediators have been defined to distinguish between direct alterations in cellular function and the more complex states of differentiation and adaptation that condition the threshold and nature of reactions to subsequent stimuli. Recent identification of the molecular mechanisms of action of neuroimmune mediators is exemplified by elucidation of the requirement for prolactin in T lymphocyte proliferation and of the effects of vasoactive intestinal peptide on B lymphocyte expression of adherence proteins. Further knowledge of the advantages of multisystem integration of functions in host defense may reveal other novel mechanisms of cellular communication and biological adaptation.

Cell Communication↗

PubMed2025

Clonal Hematopoiesis and Risk of New-Onset Myocarditis and Pericarditis.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways. OBJECTIVE: To test whether CHIP is associated with the development of myocarditis and pericarditis. DESIGN, SETTING, AND PARTICIPANTS: This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025. EXPOSURES: Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases. RESULTS: Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation. CONCLUSIONS AND RELEVANCE: In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

Adult↗

PubMed1992

Bidirectional transbilayer movement of phospholipid analogs in human red blood cells. Evidence for an ATP-dependent and protein-mediated process.

The transbilayer movement of fluorescent and isotopically labeled analogs of phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) from the outer to the inner leaflet (flip) and from the inner to the outer leaflet (flop) of human red blood cells (RBC) was examined. The inward movement of 1-oleoyl-2-(N-4-nitrobenzo-2-oxa-1,3-diazole-aminocaproyl)- (C6-NBD-), 1-oleoyl-2-(N-(3-(3-[125I]iodo-4-hydroxyphenyl)propionyl)aminocaproyl)- (C6-125I-), or 1-oleoyl-2-(N-(3-3-[125I]iodo-4-azido-phenyl)propionyl)aminocaproyl- (C6-125I-N3-) analogs of PC and PE were relatively slow. In contrast, all analogs of PS and PE analogs containing aminododecanoic acid (C12 lipids) were rapidly transported to the cell's inner leaflet. Analysis of 125I-N3 lipids cross-linked to membrane proteins revealed labeling of 32-kDa Rh polypeptides that was dependent on the lipid's capacity to be transported to the inner leaflet but was independent of lipid species. To investigate whether lipids could also be transported from the inner to the outer leaflet, lipid probes residing exclusively in the inner leaflet were monitored for their appearance in the outer leaflet. Lipid movement could not be detected at 0 degrees C. At 37 degrees C, however, approximately 70% of the PC, 40% of the PE, and 15% of the PS redistributed to the cells outer leaflet, thereby attaining their normal asymmetric distribution. Continuous incubation in the presence of bovine serum albumin depleted the cells of the analogs (t1/2 approximately 1.5 h) in a manner that was independent of lipid species. Similar to the inward movement of aminophospholipids, the outward movement of PC, PE, and PS was ATP-dependent and could be blocked by oxidation of membrane sulfhydryls and by the histidine reagent bromophenacyl bromide. Evidence is presented which suggests that the outward movement of lipids is an intrinsic property of the cells unrelated to compensatory mechanisms due to an imbalance in lipid distribution.

Amines↗

PubMed1992

[Stress related immune regulation].

The immune system ist capable of producing factors, which apart from playing a crucial role during the immune response, serve to integrate immune-neuroendocrine circuits with immunoregulatory and metabolic consequences for the organism. Hormones and neuropeptides on the other hand exert direct effects on immune cells via specific surface receptors on such cells. Therefore, there is strong evidence for a bidirectional communication between the immune, endocrine, and central nervous systems mediated by peptide hormones and receptors common to these systems. One element of the immune system's response to stress factors may involve the activation of the hypothalamo-pituitary-adrenal axis and other neuroendocrine circuits. A complex network of neuroendocrine immune systems is able to sustain biologic adaptation and homeostasis in response to stresses and needs to be taken into account in every clinical context of stress responses.

Adaptation, Psychological↗