Multicentric Assessment of a Multimorbidity-Adjusted Disability Score to Stratify Depression-Related Risks Using Temporal Disease Maps: Instrument Validation Study.

BACKGROUND: Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for the assessment and prediction of disease progression. Our study proposes a novel methodology, the Multimorbidity-Adjusted Disability Score (MADS), which integrates disease trajectory methodologies with advanced techniques for assessing interdependencies among concurrent diseases. This approach is designed to better assess the clinical burden of clusters of interrelated diseases and enhance our ability to anticipate disease progression, thereby potentially informing targeted preventive care interventions. OBJECTIVE: This study aims to evaluate the effectiveness of the MADS in stratifying patients into clinically relevant risk groups based on their multimorbidity profiles, which accurately reflect their clinical complexity and the probabilities of developing new associated disease conditions. METHODS: In a retrospective multicentric cohort study, we developed the MADS by analyzing disease trajectories and applying Bayesian statistics to determine disease-disease probabilities combined with well-established disability weights. We used major depressive disorder (MDD) as a primary case study for this evaluation. We stratified patients into different risk levels corresponding to different percentiles of MADS distribution. We statistically assessed the association of MADS risk strata with mortality, health care resource use, and disease progression across 1 million individuals from Spain, the United Kingdom, and Finland. RESULTS: The results revealed significantly different distributions of the assessed outcomes across the MADS risk tiers, including mortality rates; primary care visits; specialized care outpatient consultations; visits in mental health specialized centers; emergency room visits; hospitalizations; pharmacological and nonpharmacological expenditures; and dispensation of antipsychotics, anxiolytics, sedatives, and antidepressants (P<.001 in all cases). Moreover, the results of the pairwise comparisons between adjacent risk tiers illustrate a substantial and gradual pattern of increased mortality rate, heightened health care use, increased health care expenditures, and a raised pharmacological burden as individuals progress from lower MADS risk tiers to higher-risk tiers. The analysis also revealed an augmented risk of multimorbidity progression within the high-risk groups, aligned with a higher incidence of new onsets of MDD-related diseases. CONCLUSIONS: The MADS seems to be a promising approach for predicting health risks associated with multimorbidity. It might complement current risk assessment state-of-the-art tools by providing valuable insights for tailored epidemiological impact analyses of clusters of interrelated diseases and by accurately assessing multimorbidity progression risks. This study paves the way for innovative digital developments to support advanced health risk assessment strategies. Further validation is required to generalize its use beyond the initial case study of MDD.

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

New Evidence for the Role of the Blood-Brain Barrier and Inflammation in Stress-Associated Depression: A Gene-Environment Analysis Covering 19,296 Genes in 109,360 Humans.

Mounting evidence supports the key role of the disrupted integrity of the blood-brain barrier (BBB) in stress- and inflammation-associated depression. We assumed that variations in genes regulating the expression and coding proteins constructing and maintaining this barrier, along with those involved in inflammation, have a predisposing or protecting role in the development of depressive symptoms after experiencing severe stress. To prove this, genome-by-environment (GxE) interaction analyses were conducted on 6.26 M SNPS covering 19,296 genes on PHQ9 depression in interaction with adult traumatic events scores in the UK Biobank (n = 109,360) in a hypothesis-free setup. Among the 63 genes that were significant in stress-connected depression, 17 were associated with BBB, 23 with inflammatory processes, and 4 with neuroticism. Compared to all genes, the enrichment of significant BBB-associated hits was 3.82, and those of inflammation-associated hits were 1.59. Besides some sex differences, CSMD1 and PTPRD, encoding proteins taking part in BBB integrity, were the most significant hits in both males and females. In conclusion, the identified risk genes and their encoded proteins could provide biomarkers or new drug targets to promote BBB integrity and thus prevent or decrease stress- and inflammation-associated depressive symptoms, and possibly infection, e.g., COVID-19-associated mental and neurological symptoms.

Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.

BACKGROUND: Evidence from rodents indicated that after recent stress, reduced expression of tight junction protein claudin-5 may weaken the blood-brain barrier and allow interleukin-6 to induce depressive symptoms. Our aims were to prove this pathomechanism in humans. METHODS: We used a large population genetic database (UK Biobank, n = 277 501) to test whether variation in the CLDN5 gene could modulate effects of the IL6 gene variant in stress-induced depression. Three-way interaction of functional polymorphisms, rs885985 of CLDN5, and rs1800795 of IL6 with recent stressful life events were tested on current depressive symptoms. Analyses were performed in male and female populations as well. RESULTS: The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms in the UK Biobank sample, which was more pronounced in men and could be replicated on trend level in an independent cohort (NewMood, n = 1638). None of any other associations or interactions, including, for example, childhood stressors and lifetime depression as an outcome, yielded significance. CONCLUSIONS: These findings provide genetic evidence in humans for the interaction among interleukin-6, claudin-5, and recent stress, suggesting that inflammation is involved in the development of depression and that stress-connected brain entry of inflammatory molecules is a key factor in this pathomechanism. These genetic polymorphisms may help to identify people at higher risk for recent stress-induced depression.

A sound mind in a sound body: a novel concept unravelling heterogeneity of depression.

Depression is a highly prevalent and debilitating condition, yet we still lack both in-depth knowledge concerning its etiopathology and sufficiently efficacious treatment options. With approximately one third of patients resistant to currently available antidepressants there is a pressing need for a better understanding of depression, identifying subgroups within the highly heterogeneous illness category and to understand the divergent underlying biology of such subtypes, to help develop and personalise treatments. The TRAJECTOME project aims to address such challenges by (1) identifying depression-related multimorbidity subgroups and shared molecular pathways based on temporal disease profiles from healthcare systems and biobank data using machine learning approaches, and by (2) characterising these subgroups from multiple aspects including genetic variants, metabolic processes, lifestyle and environmental factors. Following the identification of multimorbidity trajectories, a disease burden score related to depression and adjusted for multimorbidity was established summarising the current state of the patient to weigh the molecular mechanisms associated with depression. In addition, the role of genetic and environmental factors, and also their interactions were identified for all subgroups. The project also attempted to identify potential metabolomic markers for the early diagnostics of these multimorbidity conditions. Finally, we prioritized molecular drug candidates matching the multimorbidity pathways indicated for the individual subgroups which would potentially offer personalised treatment simultaneously for the observable multimorbid conditions yet minimising polypharmacy and related side effects. The present paper overviews the TRAJECTOME project including its aims, tasks, procedures and accomplishments. (Neuropsychopharmacol Hung 2023; 25(4): 183-193)

Investigation of circulating lncRNAs as potential biomarkers in chronic respiratory diseases.

BACKGROUND: In the present study the blood expression level of inflammatory response and autoimmunity associated long non-coding RNAs (lncRNAs) were compared in patients with different chronic respiratory diseases and investigated whether they could be used as biomarkers in these diseases. METHODS: In the discovery cohort, the gene expression level of 84 lncRNAs were measured in the blood of 24 adult patients including healthy controls and patients with asthma and COPD. In the replication cohort the expression of 6 selected lncRNAs were measured in 163 subjects including healthy controls and adults with allergic rhinitis, asthma, COPD and children with asthma. It was evaluated whether these lncRNAs can be used as diagnostic biomarkers for any studied disease. With systems biology analysis the biological functions of the selected lncRNAs were predicted. RESULTS: In the discovery cohort, the mean expression of 27 lncRNAs showed nominally significant differences in at least one comparison. OIP5-AS1, HNRNPU, RP11-325K4.3, JPX, RP11-282O18.3, MZF1-AS1 were selected for measurement in the replication cohort. Three lncRNAs (HNRNPU, RP11-325K4.3, JPX) expressed significantly higher in healthy children than in adult controls. All the mean expression level of the 6 lncRNAs differed significantly between adult allergic rhinitis patients and controls. RP11-325K4.3, HNRNPU and OIP5-AS1 expressed higher in allergic asthma than in non-allergic asthma. COPD and asthma differed in the expression of RP11-325K4.3 from each other. In examining of the lncRNAs as biomarkers the weighted accuracy (WA) values were especially high in the comparison of healthy controls and patients with allergic rhinitis. OIP5-AS1 and JPX achieved 0.98 and 0.9 WA values, respectively, and the combination of the selected lncRNAs also resulted in a high performance (WA = 0.98). Altogether, OIP5-AS1 had the highest discriminative power in case of three out of six comparisons. CONCLUSION: Differences were detected in the expression of circulating lncRNAs in chronic respiratory diseases. Some of these differences might be utilized as biomarkers and also suggest a possible role of these lncRNAs in the pathomechanism of these diseases. The lncRNAs and the associated pathways are potential therapeutic targets in these diseases, but naturally additional studies are needed for the confirmation of these results.

[Anxiety and depression - the role of blood-brain barrier integrity]. / Szorongás és depresszió ­ a vér-agy gát integritásának szerepe.

Among mental illnesses, anxiety disorders represent the second most frequent disorder. According to WHO Survey 2017, 264 million people suffer from their different types globally. The emergence of anxiety disorders can often increase the likelihood of developing other psychiatric illnesses such as depression, which is the most common mental illness with 300 million people affected worldwide. Although the two diseases mentioned above are widespread throughout the world, the exact physiological causes of their development and the way they are connected are not well understood. However, in order to be able to use right treatment it would be important to know the physiological background in their development. The use of anxiolytics and antidepressants is not always effective and safe, which may be due to the subtypes of these mental disorders with different etiologies. Identifying the right therapeutic strategies could be also challenging because of the phenotypic overlap between anxiety disorders and depression. Their comorbidity has been confirmed by many studies, but their exact physiological relationship is still unclear. Previous studies suggested that blood-brain barrier proteins play an important role in the development of depression and anxiety disorders and might partially explain their comorbidities. In our summary we review the current literature related to this topic.

Transcriptomic changes following chronic administration of selective serotonin reuptake inhibitors: a review of animal studies.

The review focuses on transcriptomic changes following treatment with serotonin reuptake inhibitor (SSRI) antidepressants. We aimed to overview results of the most established methods for the investigation of the gene expression alterations including northern blotting, in situ hybridization, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray and RNAseq in various brain regions and after chronic treatment protocols. In spite of some measurable changes in serotonin system mRNA expression, serotonin transporter levels remained mostly unaltered following various treatment protocols. In contrast, tryptophan hydroxylase 2 appeared to be downregulated in serotonergic nuclei, and upregulated in the midbrain regions. Alterations in serotonin receptors lack clear conclusions and changes probably reflect animal strain/substance related- and brain region dependent effects. Brain derived neurotrophic factor was upregulated following many, but not all chronic treatment regimens. GABA and glutamate genes also showed heterogeneous changes, with a surprising NMDA receptor downregulation in areas including the striatum and amygdala, known to be involved in depressive states and stress reactions. The review of the above studies suggests alterations in multiple processes, reflecting the heterogeneity of the action depending on brain area and type of SSRI, and raises the possibility of a novel grouping of antidepressant medications based on their chronic molecular profile rather than on their initial actions.

Olfactory genes affect major depression in highly educated, emotionally stable, lean women: a bridge between animal models and precision medicine.

Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.

Unique genetic and risk-factor profiles in clusters of major depressive disorder-related multimorbidity trajectories.

The heterogeneity and complexity of symptom presentation, comorbidities and genetic factors pose challenges to the identification of biological mechanisms underlying complex diseases. Current approaches used to identify biological subtypes of major depressive disorder (MDD) mainly focus on clinical characteristics that cannot be linked to specific biological models. Here, we examined multimorbidities to identify MDD subtypes with distinct genetic and non-genetic factors. We leveraged dynamic Bayesian network approaches to determine a minimal set of multimorbidities relevant to MDD and identified seven clusters of disease-burden trajectories throughout the lifespan among 1.2 million participants from cohorts in the UK, Finland, and Spain. The clusters had clear protective- and risk-factor profiles as well as age-specific clinical courses mainly driven by inflammatory processes, and a comprehensive map of heritability and genetic correlations among these clusters was revealed. Our results can guide the development of personalized treatments for MDD based on the unique genetic, clinical and non-genetic risk-factor profiles of patients.

Variation along P2RX7 interacts with early traumas on severity of anxiety suggesting a role for neuroinflammation.

Emotional stress is a leading risk factor in the development of neuropsychiatric disorders possibly via immune activation. P2X7 receptors promote neuroinflammation, and research suggests a relationship between chromosome region 12q2431, in which the P2X7R gene is located, and development of mood disorders, however, few studies concentrate on its association with anxiety. Our aim was to investigate the effects of P2RX7 variation in interaction with early childhood traumas and recent stressors on anxiety. 1752 participants completed questionnaires assessing childhood adversities and recent negative life events, provided data on anxiety using the Brief Symptom Inventory, and were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into linear regression models followed by a linkage disequilibrium-based clumping procedure to identify clumps of SNPs with a significant main or interaction effect. We identified a significant clump with top SNP rs67881993 and containing a set of 29SNPs that are in high LD, which significantly interacted with early childhood traumas but not with recent stress conveying a protective effect against increased anxiety in those exposed to early adversities. Our study demonstrated that P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms, supporting previous scarce results and demonstrating its role in moderating the effects of stress.

Every Night and Every Morn: Effect of Variation in CLOCK Gene on Depression Depends on Exposure to Early and Recent Stress.

The role of circadian dysregulation is increasingly acknowledged in the background of depressive symptoms, and is also a promising treatment target. Similarly, stress shows a complex relationship with the circadian system. The CLOCK gene, encoding a key element in circadian regulation has been implicated in previous candidate variant studies in depression with contradictory findings, and only a few such studies considered the interacting effects of stress. We investigated the effect of CLOCK variation with a linkage-disequilibrium-based clumping method, in interaction with childhood adversities and recent negative life events, on two phenotypes of depression, lifetime depression and current depressive symptoms in a general population sample. Methods: Participants in NewMood study completed questionnaires assessing childhood adversities and recent negative life events, the Brief Symptom Inventory to assess current depressive symptoms, provided data on lifetime depression, and were genotyped for 1054 SNPs in the CLOCK gene, 370 of which survived quality control and were entered into linear and logistic regression models with current depressive symptoms and lifetime depression as the outcome variable, and childhood adversities or recent life events as interaction variables followed by a linkage disequilibrium-based clumping process to identify clumps of SNPs with a significant main or interaction effect. Results: No significant clumps with a main effect were found. In interaction with recent life events a significant clump containing 94 SNPs with top SNP rs6825994 for dominant and rs6850524 for additive models on current depression was identified, while in interaction with childhood adversities on current depressive symptoms, two clumps, both containing 9 SNPs were found with top SNPs rs6828454 and rs711533. Conclusion: Our findings suggest that CLOCK contributes to depressive symptoms, but via mediating the effects of early adversities and recent stressors. Given the increasing burden on circadian rhythmicity in the modern lifestyle and our expanding insight into the contribution of circadian disruption in depression especially as a possible mediator of stress, our results may pave the way for identifying those who would be at an increased risk for depressogenic effects of circadian dysregulation in association with stress as well as new molecular targets for intervention in stress-related psychopathologies in mood disorders.

P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms.

The P2X purinoceptor 7 (P2RX7) mediates inflammatory microglial responses and is implicated in neuroimmune mechanisms of depression and neurodegenerative disorders. A number of studies suggest that psychosocial stress may precipitate depression through immune activation. Genetic association studies of P2RX7 variants with depression have been inconclusive. However, nearly all studies have focused on only one single-nucleotide polymorphism (SNP) and have not considered interaction with psychosocial stress. We investigated the effect of several variations in P2RX7 gene using a clumping method in interaction with early adversities and recent stress on depression severity. 1752 subjects provided information on childhood adversities, recent life events, and current depression severity. Participants were genotyped for 681 SNPs in the P2RX7 gene, 335 of them passed quality control and were entered into linear regression models followed by a clumping procedure for main effect and interactions. No significant main effect was observed. Rs74892325 emerged as a top SNP for interaction with childhood adversities and rs61953400 for interaction with recent life events. Our study is the first to investigate several variants in the P2RX7 gene and in interaction with two types of stress, extending our understanding of neuroinflammation in depression, and supporting that the majority of genes influence depression by enhancing sensitivity to stressors.

Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene.

Although recently a large-sample GWASs identified significant loci in the background of depression, the heterogeneity of the depressive phenotype and the lack of accurate phenotyping hinders applicability of findings. We carried out a pilot GWAS with in-depth phenotyping of affective temperaments, considered as subclinical manifestations and high-risk states for affective disorders, in a general population sample of European origin. Affective temperaments were measured by TEMPS-A. SNP-level association was assessed by linear regression models, assuming an additive genetic effect, using PLINK1.9. Gender, age, the first ten principal components (PCs) and the other four temperaments were included in the regression models as covariates. SNP-level relevances (p-values) were aggregated to gene level using the PEGASUS method1. In SNP-based tests, a Bonferroni-corrected significance threshold of p ≤ 5.0 × 10-8 and a suggestive significance threshold of p ≤ 1.0 × 10-5, whereas in gene-based tests a Bonferroni-corrected significance of 2.0 × 10-6 and a suggestive significance of p ≤ 4.0 × 10-4 was established. To explore known functional effects of the most significant SNPs, FUMA v1.3.5 was used. We identified 1 significant and 21 suggestively significant SNPs in ADGRB3, expressed in the brain, for anxious temperament. Several other brain-relevant SNPs and genes emerged at suggestive significance for the other temperaments. Functional analyses reflecting effect on gene expression and participation in chromatin interactions also pointed to several genes expressed in the brain with potentially relevant phenotypes regulated by our top SNPs. Our findings need to be tested in larger GWA studies and candidate gene analyses in well-phenotyped samples in relation to affective disorders and related phenotypes.

Inflamed Mind: Multiple Genetic Variants of IL6 Influence Suicide Risk Phenotypes in Interaction With Early and Recent Adversities in a Linkage Disequilibrium-Based Clumping Analysis.

Background: Understanding and predicting suicide remains a challenge, and a recent paradigm shift regarding the complex relationship between the immune system and the brain brought attention to the involvement of inflammation in neuropsychiatric conditions including suicide. Among cytokines, IL-6 has been most frequently implicated in suicide, yet only a few candidate gene studies and without considering the effect of stress investigated the role of IL6 in suicidal behaviour. Our study aimed to investigate the association of IL6 variation with a linkage disequilibrium-based clumping method in interaction with childhood adversities and recent stress on manifestations along the suicide spectrum. Methods: One thousand seven hundred and sixty-two participants provided information on previous suicide attempts, current suicidal ideation, thoughts of death, and hopelessness, and were genotyped for 186 variants in IL6. Early childhood adversities were recorded with an instrument adapted from the Childhood Trauma Questionnaire, recent life events were registered using the List of Threatening Life Events. Following a 3-step quality control, logistic and linear regression models were run to explore the effect of genotype and gene-environment interactions on suicide phenotypes. All regression models were followed by a clumping process based on empirical estimates of linkage disequilibrium between clumps of intercorrelated SNPs. Interaction effects of distinct types of recent life events were also analysed. Results: No clumps with significant main effects emerged, but we identified several clumps significantly interacting with childhood adversities on lifetime suicide attempts, current suicidal ideation, and current thoughts of death. We also identified clumps significantly interacting with recent negative life events on current suicidal ideation. We reported no clumps with significant effect on hopelessness either as a main effect or in interaction with childhood adversities or recent stress. Conclusion: We identified variant clumps in IL6 influencing suicidal behaviour, but only in interaction with childhood or recent adversities. Our results may bring us a step further in understanding the role of neuroinflammation and specifically of IL-6 in suicide, towards identifying novel biological markers of suicidal behaviour especially in those exposed to stressful experiences, and to fostering the adaptation of a new paradigm and identifying novel approaches and targets in the treatment of suicidal behaviour.

Prevalence and characterization of severe asthma in Hungary.

BACKGROUND: Severe asthma (SA) database was established in Hungary to estimate the prevalence of SA and to define and analyze clinical phenotypes of the patients. METHODS: SA questionnaires were sent out to 143 public pulmonary dispensaries specialized for diagnosing and caring pulmonary patients. Data of 520 SA patients were evaluated. RESULTS: The prevalence of SA within the asthmatic population in Hungary was 0.89%. The mean age of patients were 56.4 ± 13.4 years, SA were more frequent in females (64%), the prevalence of allergy was 56.6%, 72.1% of patients had persistent airflow limitation (FEV1 < 80%), 37.9% severe airway obstruction (FEV1 ≤ 60%), 33.6% required systemic corticosteroid maintenance therapy, 21.5% had salicylate intolerance and 43.2% rhinosinusitis. A Bayesian dependency network was calculated which revealed several interdependencies between the characteristics. E.g. there was a strong association between salicylate intolerance and rhinosinusitis, more patients received regular systemic corticosteroid treatment who had salicylate intolerance and the proportion of salicylate intolerance was significantly higher in females. CONCLUSION: The prevalence of SA was determined in Hungary which was lower than in other studies. Using a Bayesian-based network analysis several interdependencies were revealed between patient characteristics.

Corrigendum: Investigation of the Possible Role of Tie2 Pathway and TEK Gene in Asthma and Allergic Conjunctivitis.

[This corrects the article DOI: 10.3389/fgene.2020.00128.].

Author Correction: Plasma neutrophil extracellular trap level is modified by disease severity and inhaled corticosteroids in chronic inflammatory lung diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Plasma neutrophil extracellular trap level is modified by disease severity and inhaled corticosteroids in chronic inflammatory lung diseases.

A flow cytometry-based method was developed to quantify in vivo circulating neutrophil extracellular trap (NET) levels in plasma and compare them in patients with different chronic inflammatory lung diseases. Seventeen asthmatic and 11 control children, 12 adult controls, 46 asthmatic, 6 COPD and 6 adult patients with asthma-COPD overlap syndrome (ACOS) were recruited in the study. The presence of NETs in unstimulated cell-free plasma was confirmed and visualized by confocal laser-scanning microscopy. No significant differences were found in plasma NET levels between children and adults, children with or without asthma and adults with or without asthma, COPD or ACOS. When asthmatic patients were stratified according to their disease severity the average plasma NET level was significantly higher in asthmatic patients with more serious symptoms (adjusted p = 0.027). Patients with poorer pulmonary functions had higher plasma NET levels which negatively correlated with the FEV1 values (r = -0.39, p = 0.002). Patients who were medicated daily with inhaled corticosteroids (ICS) had significantly lower average plasma NET level than patients who did not or just occasionally used ICS (p = 0.027). If further studies confirm the NET-lowering effect of ICS in the circulation, it can be utilized in diseases where NETosis contributes to the pathogenesis.

"Out, out, brief candle! Life's but a walking shadow": 5-HTTLPR Is Associated With Current Suicidal Ideation but Not With Previous Suicide Attempts and Interacts With Recent Relationship Problems.

BACKGROUND: Suicide is an unresolved psychiatric and public health emergency, claiming 800,000 lives each year, however, its neurobiological etiology is still not understood. In spite of original reports concerning the involvement of 5-HTTLPR in interaction with recent stress in the appearance of suicidal ideation and attempts, replication studies have yielded contradictory results. In our study, we analyzed the association between 5-HTTLPR and lifetime suicide attempts, current suicidal ideation, hopelessness and thoughts of death as main effects, and in interaction with childhood adversities, recent stress, and different types of recent life events in a general population sample. METHODS: Two thousand and three hundred fifty-eight unrelated European volunteers were genotyped for 5-HTTLPR, provided phenotypic data on previous suicide attempts, and current suicidal ideation, hopelessness and thoughts about death, and information on childhood adversities and recent life events. Logistic and linear regression models were run with age, gender, and population as covariates to test for the effect of 5-HTTLPR as a main effect and in interaction with childhood adversities and recent life events on previous suicide attempts and current suicidal ideation. Benjamini-Hochberg FDR Q values were calculated to correct for multiple testing. RESULTS: 5-HTTLPR had no significant effect on lifetime suicide attempts either as a main effect on in interaction with childhood adversities. 5-HTTLPR had a significant main effect on current suicidal ideation in the dominant model (Q=0.0344). 5-HTTLPR did not interact with childhood adversities or total number of recent life events on any phenotypes related to current suicidal risk, however, a significant interaction effect between 5-HTTLPR and current relationship problems emerged in the case of current suicidal ideation in the dominant model (Q=0.0218) and in the case of thoughts about death and dying in the dominant (Q=0.0094) and additive models (Q=0.0281). CONCLUSION: While 5-HTTLPR did not influence previous suicide attempts or interacted with childhood adversities, it did influence current suicidal ideation with, in addition, an interaction with recent relationship problems supporting the involvement of 5-HTTLPR in suicide. Our findings that 5-HTTLPR impacts only certain types of suicide risk-related behaviors and that it interacts with only distinct types of recent stressors provides a possible explanation for previous conflicting findings.