Serum Levels of the Steroid Hormone Dehydroepiandrosterone Are Associated with Psychological Trauma and Lymphocyte Telomere Integrity in Women Suffering from Depression.

INTRODUCTION: Emerging studies highlight the telomere system as an aging mechanism underlying the association between exposure to psychological trauma and the development of a wide range of physical and mental disorders, including major depressive disorder (MDD). Here, we investigated associations of circulating levels of the steroid hormone dehydroepiandrosterone (DHEA) with immune cell telomere length (TL) in the context of lifetime trauma exposure and MDD. METHODS: Lifetime traumatic events (trauma load) were assessed using the Essener Trauma Inventory in n = 22 postmenopausal female inpatients with MDD and n = 22 non-depressed controls. All women completed the Beck's Depression Inventory II to assess the severity of current depressive symptoms. DHEA concentration in serum was measured by immunoassay, and TL was quantified in kilobase units using quantitative fluorescent in situ hybridization in total peripheral blood mononuclear cells (PBMC) and in selected T-cell subpopulations isolated by FACS separation. RESULTS: Higher trauma load was significantly associated with lower DHEA concentration, which in turn was linked to more depression-related fatigue. Furthermore, DHEA concentration was positively and significantly associated with TL in memory CD4+ T cells as well as in naïve and memory CD8+ T cells, but not in naïve CD4+ T cells and total PBMC. Mediational analysis suggested that DHEA concentration is a mediator in the relationship between trauma load and memory CD8+ T-cell TL. CONCLUSION: The current findings suggest a potential role of DHEA as a biological resilience factor that may exert beneficial effects on telomere integrity, especially in conditions related to distress.

Investigating mitochondrial bioenergetics in peripheral blood mononuclear cells of women with childhood maltreatment from post-parturition period to one-year follow-up.

BACKGROUND: Childhood maltreatment (CM) exerts various long-lasting psychological and biological changes in affected individuals, with inflammation being an interconnecting element. Besides chronic low-grade inflammation, CM might also affect the energy production of cells by altering the function and density of mitochondria, i.e. the body's main energy suppliers. Here, we compared mitochondrial respiration and density in intact peripheral blood mononuclear cells (PBMC), from women with and without CM between two time points, i.e. at the highly inflammatory phase within 1 week after parturition (t0) and again after 1 year (t2). METHODS: CM exposure was assessed with the Childhood Trauma Questionnaire. Whole blood was collected from n = 52 healthy women within the study 'My Childhood - Your Childhood' at both time points to isolate and cryopreserve PBMC. Thawed PBMC were used to measure mitochondrial respiration and density by high-resolution respirometry followed by spectrophotometric analyses of citrate-synthase activity. RESULTS: Over time, quantitative respiratory parameters increased, while qualitative flux control ratios decreased, independently of CM. Women with CM showed higher mitochondrial respiration and density at t0, but not at t2. We found significant CM group × time interaction effects for ATP-turnover-related respiration and mitochondrial density. CONCLUSIONS: This is the first study to longitudinally investigate mitochondrial bioenergetics in postpartum women with and without CM. Our results indicate that CM-related mitochondrial alterations reflect allostatic load, probably due to higher inflammatory states during parturition, which normalize later. However, later inflammatory states might moderate the vulnerability for a second-hit on the level of mitochondrial bioenergetics, at least in immune cells.

Childhood maltreatment is associated with changes in mitochondrial bioenergetics in maternal, but not in neonatal immune cells.

Childhood maltreatment (CM) comprises experiences of abuse and neglect during childhood. CM causes psychological as well as biological alterations in affected individuals. In humans, it is hardly explored whether these CM consequences can be transmitted directly on a biological level to the next generation. Here, we investigated the associations between maternal CM and mitochondrial bioenergetics (mitochondrial respiration and intracellular mitochondrial density) in immune cells of mothers and compared them with those of their newborns. In n = 102 healthy mother-newborn dyads, maternal peripheral blood mononuclear cells and neonatal umbilical cord blood mononuclear cells were collected and cryopreserved shortly after parturition to measure mitochondrial respiration and intracellular mitochondrial density with high-resolution respirometry and spectrophotometric analyses, respectively. Maternal CM was assessed with the Childhood Trauma Questionnaire Maternal and neonatal mitochondrial bioenergetics were quantitatively comparable and positively correlated. Female newborns showed higher mitochondrial respiration compared to male newborns. Maternal CM load was significantly and positively associated with mitochondrial respiration and density in mothers, but not with mitochondrial respiration in newborns. Although maternal and neonatal mitochondrial bioenergetics were positively correlated, maternal CM only had a small effect on mitochondrial density in newborns, which was not significant in this study after adjustment for multiple comparisons. The biological relevance of our finding and its consequences for child development need further investigation in future larger studies. This study reports data on mitochondrial bioenergetics of healthy mother-newborn dyads with varying degrees of CM.

Characterization of the effects of age and childhood maltreatment on ELOVL2 DNA methylation.

DNA methylation of the elongation of very long chain fatty acids protein 2 (ELOVL2) was suggested as a biomarker of biological aging, while childhood maltreatment (CM) has been associated with accelerated biological aging. We investigated the association of age and CM experiences with ELOVL2 methylation in peripheral blood mononuclear cells (PBMC). Furthermore, we investigated ELOVL2 methylation in the umbilical cord blood mononuclear cells (UBMC) of newborns of mothers with and without CM. PBMC and UBMC were isolated from 113 mother-newborn dyads and genomic DNA was extracted. Mothers with and without CM experiences were recruited directly postpartum. Mass array spectrometry and pyrosequencing were used for methylation analyses of ELOVL2 intron 1, and exon 1 and 5' end, respectively. ELOVL2 5' end and intron 1 methylation increased with higher age but were not associated with CM experiences. On the contrary, overall ELOVL2 exon 1 methylation increased with higher CM, but these changes were minimal and did not increase with age. Maternal CM experiences and neonatal methylation of ELOVL2 intron 1 or exon 1 were not significantly correlated. Our study suggests region-specific effects of chronological age and experienced CM on ELOVL2 methylation and shows that the epigenetic biomarker for age within the ELOVL2 gene does not show accelerated biological aging years after CM exposure.

History of child maltreatment and telomere length in immune cell subsets: Associations with stress- and attachment-related hormones.

Experiencing maltreatment during childhood can have long-lasting consequences for both mental and physical health. Immune cell telomere length (TL) shortening might be one link between child maltreatment (CM) experiences and adverse health outcomes later in life. While the stress hormone cortisol has been associated with TL attrition, the attachment-related hormone oxytocin may promote resilience. In 15 mothers with and 15 age- and body mass index-matched mothers without CM, we assessed TL in peripheral blood mononuclear cells and selected immune cell subsets (monocytes, naive, and memory cytotoxic T cells) by quantitative fluorescence in situ hybridization, as well as peripheral cortisol and oxytocin levels. Memory cytotoxic T cells showed significantly shorter TL in association with CM, whereas TL in monocytes and naive cytotoxic T cells did not significantly differ between the two groups. Across both groups, cortisol was negatively associated with TL, while oxytocin was positively associated with TL in memory cytotoxic T cells. These results indicate that long-lived memory cytotoxic T cells are most affected by the increased biological stress state associated with CM. Keeping in mind the correlational and preliminary nature of the results, the data suggest that cortisol may have a damaging and oxytocin a protective function on TL.

Telomere shortening in leukocyte subpopulations in depression.

BACKGROUND: Telomere shortening is a normal age-related process. However, premature shortening of telomeres in leukocytes--as has been reported in depression--may increase the risk for age-related diseases. While previous studies investigated telomere length in peripheral blood mononuclear cells (PBMCs) as a whole, this study investigated specific changes in the clonal composition of white blood cells of the adaptive immune system (CD4+ helper and CD8+ cytotoxic T lymphocytes, and CD20+ B lymphocytes). METHODS: Forty-four females with a history of unipolar depression were investigated and compared to fifty age-matched female controls. Telomere lengths were compared between three groups: 1) individuals with a history of depression but currently no clinically relevant depressive symptoms, 2) individuals with a history of depression with relevant symptoms of depression, and 3) healthy age-matched controls. Telomere length was assessed using quantitative fluorescence in situ hybridization (qFISH). RESULTS: Both groups with a history of unipolar depression (with and without current depressive symptoms) showed significantly shorter telomeres in all three lymphocyte subpopulations. The effect was stronger in CD8+ and CD20+ cells than in CD4+ cells. Individuals with a history of depression and with (without) current symptoms exhibited a CD8+ telomere length shortening corresponding to an age differential of 27.9 (25.3) years. CONCLUSIONS: A history of depression is associated with shortened telomeres in the main effector populations of the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression independently of the severity of depressive symptoms. CD8+ cytotoxic T cells and CD20+ B cells seem to be particularly affected in depression. The total number of depressive episodes did not influence telomere length in the investigated adaptive immune cell populations.

The paradigm change from reactive medical services to 3PM in ischemic stroke: a holistic approach utilising tear fluid multi-omics, mitochondria as a vital biosensor and AI-based multi-professional data interpretation.

Worldwide stroke is the second leading cause of death and the third leading cause of death and disability combined. The estimated global economic burden by stroke is over US$891 billion per year. Within three decades (1990-2019), the incidence increased by 70%, deaths by 43%, prevalence by 102%, and DALYs by 143%. Of over 100 million people affected by stroke, about 76% are ischemic stroke (IS) patients recorded worldwide. Contextually, ischemic stroke moves into particular focus of multi-professional groups including researchers, healthcare industry, economists, and policy-makers. Risk factors of ischemic stroke demonstrate sufficient space for cost-effective prevention interventions in primary (suboptimal health) and secondary (clinically manifested collateral disorders contributing to stroke risks) care. These risks are interrelated. For example, sedentary lifestyle and toxic environment both cause mitochondrial stress, systemic low-grade inflammation and accelerated ageing; inflammageing is a low-grade inflammation associated with accelerated ageing and poor stroke outcomes. Stress overload, decreased mitochondrial bioenergetics and hypomagnesaemia are associated with systemic vasospasm and ischemic lesions in heart and brain of all age groups including teenagers. Imbalanced dietary patterns poor in folate but rich in red and processed meat, refined grains, and sugary beverages are associated with hyperhomocysteinaemia, systemic inflammation, small vessel disease, and increased IS risks. Ongoing 3PM research towards vulnerable groups in the population promoted by the European Association for Predictive, Preventive and Personalised Medicine (EPMA) demonstrates promising results for the holistic patient-friendly non-invasive approach utilising tear fluid-based health risk assessment, mitochondria as a vital biosensor and AI-based multi-professional data interpretation as reported here by the EPMA expert group. Collected data demonstrate that IS-relevant risks and corresponding molecular pathways are interrelated. For examples, there is an evident overlap between molecular patterns involved in IS and diabetic retinopathy as an early indicator of IS risk in diabetic patients. Just to exemplify some of them such as the 5-aminolevulinic acid/pathway, which are also characteristic for an altered mitophagy patterns, insomnia, stress regulation and modulation of microbiota-gut-brain crosstalk. Further, ceramides are considered mediators of oxidative stress and inflammation in cardiometabolic disease, negatively affecting mitochondrial respiratory chain function and fission/fusion activity, altered sleep-wake behaviour, vascular stiffness and remodelling. Xanthine/pathway regulation is involved in mitochondrial homeostasis and stress-driven anxiety-like behaviour as well as molecular mechanisms of arterial stiffness. In order to assess individual health risks, an application of machine learning (AI tool) is essential for an accurate data interpretation performed by the multiparametric analysis. Aspects presented in the paper include the needs of young populations and elderly, personalised risk assessment in primary and secondary care, cost-efficacy, application of innovative technologies and screening programmes, advanced education measures for professionals and general population-all are essential pillars for the paradigm change from reactive medical services to 3PM in the overall IS management promoted by the EPMA.

Relationship Dysfunction in Couples When One Partner Is Diagnosed with Borderline Personality Disorder: Findings from a Pilot Study.

Relationship dysfunction-marked by frequent conflicts-is one of the hallmark features of borderline personality disorder (BPD). However, the BPD couple as a dyad and partner-related features have rarely been taken into account. The aim of the present study was to investigate hormonal, personality, and relationship relevant factors, such as relationship satisfaction, attachment, and trauma in both partners within a dyad where one partner is diagnosed with BPD. The total sample consisted of 26 heterosexual couples. All studies were conducted at 2 p.m. Primary outcomes: Neo-Five-Factor-Inventory, Childhood Trauma Questionnaire, Experiences in Close Relationships Scale. Secondary outcomes: Problem List, Partnership Questionnaire, Questionnaire for Assessing Dyadic Coping. Upon questionnaire completion, one saliva sample was taken via passive drool to assess baseline cortisol and testosterone levels. Results showed that females with BPD have higher scores on childhood maltreatment, dysfunctional attachment styles, and neuroticism than mentally healthy females. Furthermore, they have more relationship-related problems and are less satisfied in their romantic relationship. Male partners of women with BPD showed lower testosterone levels, higher levels of childhood maltreatment, dysfunctional attachment styles, neuroticism, and openness compared with the healthy control partners. Furthermore, childhood trauma, neuroticism as well as dysfunctional attachment styles displayed a significant positive correlation with relationship-related problems. Traumatic childhood experiences, insecure attachment styles as well as neurotic personality characteristics contribute to increased relationship disruptions in couples. Relevant hormonal and psychosocial parameters in BPD partners should be taken into account when treating females with BPD.

Effects of serotonergic psychedelics on mitochondria: Transdiagnostic implications for mitochondria-related pathologies.

The use of serotonergic psychedelics has gained increasing attention in research, clinical practice and society. Growing evidence suggests fast-acting, transdiagnostic health benefits of these 5-hydroxytryptamine 2A receptor agonists. Here, we provide a brief overview of their benefits for psychological, cardiovascular, metabolic, neurodegenerative, and immunological pathologies. We then review their effect on mitochondria including mitochondrial biogenesis, functioning and transport. Mitochondrial dysregulation is a transdiagnostic mechanism that contributes to the aforementioned pathologies. Hence, we postulate that psychedelic-induced effects on mitochondria partially underlie their transdiagnostic benefits. Based on this assumption, we propose new treatment indications for psychedelics and that the health benefits induced by psychedelics depend on patient-specific mitochondrial dysregulation.

Randomized controlled trial investigating potential effects of relaxation on mitochondrial function in immune cells: A pilot experiment.

This study aimed to investigate the effect of a relaxation response induced by hypnosis on the mitochondrial energy production of immune cells compared to an everyday relaxing situation. Chronically stressed individuals (88% women) with at least moderate suggestibility were randomized to a hypnosis (20 min relaxation hypnosis; n = 20) or a control condition (20 min documentary; n = 22). Before and after intervention, peripheral blood was collected. The primary outcomes were mitochondrial respiration and density in immune cells measured by high-resolution respirometry and citrate synthase activity assays. As secondary outcome, perceived stress, anxiety, and depressive mood were assessed. The intervention led to no significant Group × Time effects on mitochondrial bioenergetic parameters but a significant Time effect (ηp2 = .09 -.10). Thus, there were no differences in the experimental conditions concerning the measured parameters of mitochondrial bioenergetics. Exploratory subanalyses indicated that stress, anxiety, and depressive mood were linked to lower mitochondrial respiration. Individuals with higher anxiety had less decrease in routine respiration over time than those with lower anxiety (ηp2 = .09). This study explores the effects of relaxation in the form of hypnosis compared to watching a video on the energy metabolism of immune cells. Relaxation, whether in targeted (hypnosis) or untargeted (documentary) form, affected mitochondrial respiration. Further research should focus on the long-term effects of relaxation on bioenergetics. The trial was retrospectively registered on 07/12/2021, DRKS00027356, https://drks.de/search/de/trial/DRKS00027356.

Biochemical clusters predict mortality and reported inability to work 10 ​years later.

BACKGROUND: Chronic systemic inflammation has been linked to premature mortality and limited somatic as well as mental health with consequences for capability to work and everyday functioning. We recently identified three biochemical clusters of endocrine and immune parameters (C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, cortisol and creatinine) in participants, age 35-81 years, of the open access Midlife in the United States Study (MIDUS) dataset. These clusters have been validated in an independent cohort of Japanese mid-life adults. Among these clusters, the one characterized by high inflammation coupled with low cortisol and creatinine concentrations was associated with the highest disease burden, referred to as high-risk cluster in the following. The current study aims to further examine the nature of this cluster and specifically whether it predicts mortality and the reported inability to work the last 30 days 10 years after the biomarker assessment. METHODS AND FINDINGS: Longitudinally assessed health data from N â€‹= â€‹1234 individuals were analyzed in the current study. Logistic regression analyses were performed to predict mortality within one decade after first assessment (T0 â€‹= â€‹first assessment; T1 â€‹= â€‹second assessment). General linear models were used to predict the number of days study participants were unable to work due to health issues in the last 30 days (assessed at T1, analyses restricted to individuals <70 years of age). Biological sex, disease burden, and age at T0 were used as covariates in all analyses. Individuals in the previously identified high-risk cluster had a higher risk for mortality (22% of individuals deceased between T0 and T1 versus 10% respectively 9% in the two other clusters). Logistic regression models predicting mortality resulted in a significant difference between individuals from the high-risk cluster compared to those from an identified reference cluster (indicator method, p â€‹= â€‹.012), independently of age and disease burden. Furthermore, individuals in the high-risk cluster reported a higher number of disability days during the past 30 days (3.4 days in the high-risk cluster versus 1.5 respectively 1.0 days in the reference clusters) assessed at T1. All pairwise comparisons involving the high-risk cluster were significant (all ps â€‹< â€‹.001). CONCLUSIONS: Immune-endocrine profiles are predictive of mortality within the following decade over and above age and disease burden. The findings thus highlight the importance of biomarker-based risk profiling that may provide new targets for interventions in the context of preventive medicine in the transition from health to disease and disease-related mortality.

Secure Attachment Representation in Adolescence Buffers Heart-Rate Reactivity in Response to Attachment-Related Stressors.

To date, we know very little about the effects of the differences in attachment classifications on the physiological correlates of stress regulation in adolescent age groups. The present study examined for the first time heart rate (HR) and heart rate variability (HRV) during an attachment interview in adolescents. HR and HRV data were collected during a baseline assessment as well as during the administration of the Adult Attachment Projective Picture System (AAP) in a community-based sample of 56 adolescents (26 females and 30 males, mean age = 16.05 years [SD = 1.10]). We additionally used the Adult Attachment Interview (AAI) in 50% of our sample to test the convergent validity. Adolescents with a secure attachment representation showed a higher HRV from baseline to the AAP interview compared to those with an insecure-dismissing (Ds) and the unresolved group. A comparison between the two insecure attachment groups showed no significant difference related to HR and HRV. Cohen's Kappa (κ = 0.81) revealed an almost perfect agreement between the AAP and the AAI for the four-group classification. Our results indicate that adolescents with a secure attachment representation are more capable of dealing with attachment-related distress which is represented in higher HRV during an attachment interview.

Identifying Risk and Resilience Factors in the Intergenerational Cycle of Maltreatment: Results From the TRANS-GEN Study Investigating the Effects of Maternal Attachment and Social Support on Child Attachment and Cardiovascular Stress Physiology.

Introduction: Childhood maltreatment (CM) is a developmental risk factor and can negatively influence later psychological functioning, health, and development in the next generation. A comprehensive understanding of the biopsychosocial underpinnings of CM transmission would allow to identify protective factors that could disrupt the intergenerational CM risk cycle. This study examined the consequences of maternal CM and the effects of psychosocial and biological resilience factors on child attachment and stress-regulatory development using a prospective trans-disciplinary approach. Methods: Mother-child dyads (N = 158) participated shortly after parturition (t 0), after 3 months (t 1), and 12 months later (t 2). Mothers' CM experiences were assessed at t 0, attachment representation at t 1 and psychosocial risk and social support were assessed at t 1 and t 2. At t 2, dyads participated in the Strange Situation Procedure (SSP). Children's attachmen status were classified as organized vs. disorganized, including their level of disorganized behavior, and heart rate (HR) and respiratory sinus arrhythmia (RSA) were recorded as stress response measures of the autonomic nervous system. Maternal caregiving during SSP was assessed using the AMBIANCE scale. Child's single nucleotide polymorphisms rs2254298 within the oxytocin receptor (OXTR) and rs2740210 of the oxytocin gene (OXT) were genotyped using DNA isolated from cord blood. Results: Maternal CM experiences (CM+) were significantly associated with an unresolved attachment status, higher perceived stress and more psychological symptoms. These negative effects of CM were attenuated by social support. As expected, maternal unresolved attachment and child disorganized attachment were significantly associated. Maternal caregiving did not mediate the relationship between maternal and child attachment but influenced children's HR and RSA response and disorganized behavior. Moreover, the rs2254298 genotype of the OXTR gene moderated the stress response of children from mothers with CM. Children carrying the rs2740210 risk allele of the OXT gene showed more disorganized behavior independent from maternal CM experiences. Conclusion: We replicated and extended existing CM and attachment models by co-examining maternal attachment, social support, and child genetic susceptibility on child attachment and cardiovascular stress regulation. The findings contribute to an extended understanding of risk and resilience factors and enable professionals to target adequate services to parents and children at risk.

Hair cortisol level might be indicative for a 3PM approach towards suicide risk assessment in depression: comparative analysis of mentally stable and depressed individuals versus individuals after completing suicide.

Depression and suicidal behavior are interrelated, stress-associated mental health conditions, each lacking biological verifiability. Concepts of predictive, preventive, and personalized medicine (3PM) are almost completely missing for both conditions but are of utmost importance. Prior research reported altered levels of the stress hormone cortisol in the scalp hair of depressed individuals, however, data on hair cortisol levels (HCL) for suicide completers (SC) are missing. Here, we aimed to identify differences in HCL between subject with depression (n = 20), SC (n = 45) and mentally stable control subjects (n = 12) to establish the usage of HCL as a new target for 3PM. HCL was measured in extracts of pulverized hair (1-cm and 3-cm hair segments) using ELISA. In 3-cm hair segments, an average increase in HCL for depressed patients (1.66 times higher; p = .011) and SC (5.46 times higher; p = 1.65 × 10-5) compared to that for controls was observed. Furthermore, the average HCL in SC was significantly increased compared to that in the depressed group (3.28 times higher; p = 1.4 × 10-5). A significant correlation between HCL in the 1-cm and the 3-cm hair segments, as well as a significant association between the severity of depressive symptoms and HCL (3-cm segment) was found. To conclude, findings of increased HCL in subjects with depression compared to that in controls were replicated and an additional increase in HCL was seen in SC in comparison to patients with depression. The usage of HCL for creating effective patient stratification and predictive approach followed by the targeted prevention and personalization of medical services needs to be validated in follow-up studies.

A history of childhood maltreatment is associated with altered DNA methylation levels of DNA methyltransferase 1 in maternal but not neonatal mononuclear immune cells.

Childhood maltreatment (CM) is associated with alterations in DNA methylation (DNAm) especially in stress response genes. Due to the higher risk of overall health complications of individuals with a parental history of CM, intergenerational transmission of CM-associated DNAm changes has been investigated but remains unclear. In this study, we investigated if different severities of CM have any influence on the DNAm of DNA methyltransferase 1 (DNMT1), an important enzyme of the DNAm machinery, in immune and buccal cells of mother-newborn dyads. DNAm was assessed by mass spectrometry using immune cell DNA from mothers (N = 117) and their newborns (N = 113), and buccal cell DNA of mother-newborn dyads (N = 68 each). Mothers with a history of CM had lower mean methylation of DNMT1 in immune cells compared to the mothers without a CM history. CM status only influenced maternal DNMT1 gene expression when at least moderate CM was reported. Buccal cell DNAm was not associated with CM status. Maternal history of CM was not linked to any alterations in DNMT1 mean DNAm in any of the cell types studied in newborns. We conclude that the CM-associated alterations in DNMT1 DNAm might point to allostatic load and can be physiologically relevant, especially in individuals with more severe CM experiences, resulting in an activated DNA methylation machinery that might influence stress response genes. Our lack of significant findings in buccal cells shows the tissue-specific effects of CM on DNAm. In our sample with low to moderate maternal CM history, there was no intergenerational transmission of DNMT1 DNAm in newborns.

Ischemic stroke of unclear aetiology: a case-by-case analysis and call for a multi-professional predictive, preventive and personalised approach.

Due to the reactive medical approach applied to disease management, stroke has reached an epidemic scale worldwide. In 2019, the global stroke prevalence was 101.5 million people, wherefrom 77.2 million (about 76%) suffered from ischemic stroke; 20.7 and 8.4 million suffered from intracerebral and subarachnoid haemorrhage, respectively. Globally in the year 2019 - 3.3, 2.9 and 0.4 million individuals died of ischemic stroke, intracerebral and subarachnoid haemorrhage, respectively. During the last three decades, the absolute number of cases increased substantially. The current prevalence of stroke is 110 million patients worldwide with more than 60% below the age of 70 years. Prognoses by the World Stroke Organisation are pessimistic: globally, it is predicted that 1 in 4 adults over the age of 25 will suffer stroke in their lifetime. Although age is the best known contributing factor, over 16% of all strokes occur in teenagers and young adults aged 15-49 years and the incidence trend in this population is increasing. The corresponding socio-economic burden of stroke, which is the leading cause of disability, is enormous. Global costs of stroke are estimated at 721 billion US dollars, which is 0.66% of the global GDP. Clinically manifested strokes are only the "tip of the iceberg": it is estimated that the total number of stroke patients is about 14 times greater than the currently applied reactive medical approach is capable to identify and manage. Specifically, lacunar stroke (LS), which is characteristic for silent brain infarction, represents up to 30% of all ischemic strokes. Silent LS, which is diagnosed mainly by routine health check-up and autopsy in individuals without stroke history, has a reported prevalence of silent brain infarction up to 55% in the investigated populations. To this end, silent brain infarction is an independent predictor of ischemic stroke. Further, small vessel disease and silent lacunar brain infarction are considered strong contributors to cognitive impairments, dementia, depression and suicide, amongst others in the general population. In sub-populations such as diabetes mellitus type 2, proliferative diabetic retinopathy is an independent predictor of ischemic stroke. According to various statistical sources, cryptogenic strokes account for 15 to 40% of the entire stroke incidence. The question to consider here is, whether a cryptogenic stroke is fully referable to unidentifiable aetiology or rather to underestimated risks. Considering the latter, translational research might be of great clinical utility to realise innovative predictive and preventive approaches, potentially benefiting high risk individuals and society at large. In this position paper, the consortium has combined multi-professional expertise to provide clear statements towards the paradigm change from reactive to predictive, preventive and personalised medicine in stroke management, the crucial elements of which are:Consolidation of multi-disciplinary expertise including family medicine, predictive and in-depth diagnostics followed by the targeted primary and secondary (e.g. treated cancer) prevention of silent brain infarctionApplication of the health risk assessment focused on sub-optimal health conditions to effectively prevent health-to-disease transitionApplication of AI in medicine, machine learning and treatment algorithms tailored to robust biomarker patternsApplication of innovative screening programmes which adequately consider the needs of young populations.

Atypical maternal interaction is associated with elevated levels of hair cortisol in children.

The quality of maternal caregiving is an important factor in the healthy development of a child. One consequence of prolonged insensitive and atypical maternal interaction behavior (e.g., withdrawing from interactions with the child and role-reversal, i.e., the takeover of the parental role or parts of it by the child) in mother-child-dyads can cause alteration of the child's stress response system. Higher salivary cortisol concentrations were reported in infants and toddlers directly after negative interactions with their parents. However, no study to date has examined the association between atypical maternal interaction behavior and hair cortisol concentrations (HCC) in infants. Here, we studied the association of maternal interaction behavior with HCC of the child. Mother-child dyads (N = 112) participated in the longitudinal study My Childhood-Your Childhood. The AMBIANCE scale and its subscales were used to assess atypical maternal interaction behavior during the Strange Situation Procedure. Chronic stress levels in the child were assessed by HCC of 3 cm hair strands at the age of 12 months. Maternal educational level (operationalized in highest education level) served as a control variable. Robust multiple linear regression analyses revealed that role/boundary confusion was associated with HCC, i.e., the higher atypical interaction behavior of the mother the higher the HCC in the children. By measuring hair cortisol in this study, it is possible to determine the average long-term activity of the child's stress response system.Thus, atypical maternal interaction behavior could be a risk factor for persistent stress in children, contributing to a higher risk for negative health outcomes in later life. The results of this study highlight the importance of early intervention programs that focus on the relationship between mother and child.

Reactivity of the Oxytocinergic and Neuroendocrine System Following the Adult Attachment Projective Picture System in Men of Recent Fatherhood: Results from an Exploratory Pilot Study with a Cross-Sectional Design.

The attachment representation (AR) of individuals affects emotional and cognitive information processes and is considered an important modulating factor of neuroendocrine stress responses. The neuropeptide oxytocin is studied as one biomolecular component underpinning this modulation. A validated procedure used in attachment-related research is the Adult Attachment Projective Picture System (AAP). To date, only a limited number of studies investigated oxytocin and neuroendocrine reactivity in the context of an attachment-related stimulus similar to the APP. In this pilot study, N = 26 men of recent fatherhood were exposed to the AAP to classify AR and to investigate salivary changes in oxytocin, cortisol and dehydroepiandrosterone (DHEA) after AAP stimulation. We observed increased oxytocin levels in response to AAP exposure, and this increase was more pronounced in fathers with unresolved/disorganized AR. No significant changes in cortisol and DHEA concentrations were observed in response to AAP administration. Interestingly, differences in basal cortisol levels (before the AAP) also depended on AR classification. Here, the group of men with unresolved/disorganized AR showed higher levels of cortisol compared to fathers with organized AR. To conclude, the finding of increased salivary oxytocin levels in response to the AAP further indicates its validity as an instrument to stimulate the attachment system.

How biomarker patterns can be utilized to identify individuals with a high disease burden: a bioinformatics approach towards predictive, preventive, and personalized (3P) medicine.

Prevalences of non-communicable diseases such as depression and a range of somatic diseases are continuously increasing requiring simple and inexpensive ways to identify high-risk individuals to target with predictive and preventive approaches. Using k-mean cluster analytics, in study 1, we identified biochemical clusters (based on C-reactive protein, interleukin-6, fibrinogen, cortisol, and creatinine) and examined their link to diseases. Analyses were conducted in a US American sample (from the Midlife in the US study, N = 1234) and validated in a Japanese sample (from the Midlife in Japan study, N = 378). In study 2, we investigated the link of the biochemical clusters from study 1 to childhood maltreatment (CM). The three identified biochemical clusters included one cluster (with high inflammatory signaling and low cortisol and creatinine concentrations) indicating the highest disease burden. This high-risk cluster also reported the highest CM exposure. The current study demonstrates how biomarkers can be utilized to identify individuals with a high disease burden and thus, may help to target these high-risk individuals with tailored prevention/intervention, towards personalized medicine. Furthermore, our findings raise the question whether the found biochemical clusters have predictive character, as a tool to identify high-risk individuals enabling targeted prevention. The finding that CM was mostly prevalent in the high-risk cluster provides first hints that the clusters could indeed have predictive character and highlight CM as a central disease susceptibility factor and possibly as a leverage point for disease prevention/intervention. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00255-0.

Salivary beta-endorphin in nonsuicidal self-injury: an ambulatory assessment study.

Nonsuicidal self-injury (NSSI) is a prevalent and impairing behavior, affecting individuals with and without additional psychopathology. To shed further light on biological processes that precede and result from NSSI acts, we built on previous cross-sectional evidence suggesting that the endogenous opioid system, and especially ß-endorphin, is involved in the psychopathology of NSSI. This is the first study assessing salivary ß-endorphin in daily life in the context of NSSI acts. Fifty-one female adults with repetitive NSSI participated over a period of 15 days in an ambulatory assessment study. Salivary ß-endorphin was assessed before and after engagement in NSSI, during high urge for NSSI, and on a non-NSSI day. Furthermore, NSSI specific variables such as pain ratings, as well as method, severity, and function of NSSI were assessed. We found that ß-endorphin levels immediately before an NSSI act were significantly lower than directly after NSSI. However, there was no difference between ß-endorphin during high urge for NSSI and post NSSI measures. We found a positive association between severity of the self-inflicted injury and ß-endorphin levels, but no significant association between ß-endorphin levels and subjectively experienced pain. The results of the present study indicate that it is possible to assess salivary ß-endorphin in daily life in the context of NSSI. Furthermore, our results provide a first indication that NSSI acts could be associated with a momentary increase of ß-endorphin, and this might reinforce NSSI engagement. More research is needed to replicate and extend our findings on peripheral ß-endorphin in daily life.