G × E interactions as a basis for toxicological uncertainty.

To transfer toxicological findings from model systems, e.g. animals, to humans, standardized safety factors are applied to account for intra-species and inter-species variabilities. An alternative approach would be to measure and model the actual compound-specific uncertainties. This biological concept assumes that all observed toxicities depend not only on the exposure situation (environment = E), but also on the genetic (G) background of the model (G × E). As a quantitative discipline, toxicology needs to move beyond merely qualitative G × E concepts. Research programs are required that determine the major biological variabilities affecting toxicity and categorize their relative weights and contributions. In a complementary approach, detailed case studies need to explore the role of genetic backgrounds in the adverse effects of defined chemicals. In addition, current understanding of the selection and propagation of adverse outcome pathways (AOP) in different biological environments is very limited. To improve understanding, a particular focus is required on modulatory and counter-regulatory steps. For quantitative approaches to address uncertainties, the concept of "genetic" influence needs a more precise definition. What is usually meant by this term in the context of G × E are the protein functions encoded by the genes. Besides the gene sequence, the regulation of the gene expression and function should also be accounted for. The widened concept of past and present "gene expression" influences is summarized here as Ge. Also, the concept of "environment" needs some re-consideration in situations where exposure timing (Et) is pivotal: prolonged or repeated exposure to the insult (chemical, physical, life style) affects Ge. This implies that it changes the model system. The interaction of Ge with Et might be denoted as Ge × Et. We provide here general explanations and specific examples for this concept and show how it could be applied in the context of New Approach Methodologies (NAM).

Determinants and Mechanisms of the Renin-Aldosterone Stress Response.

OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) plays a relevant role in regulating blood pressure and thus maintaining cardiovascular homeostasis. Although it was recently shown that RAAS parameters are responsive to acute psychosocial stress, the psychobiological determinants of the acute stress-induced RAAS activation have not yet been investigated. In a randomized placebo-controlled design, we investigated potential psychological and physiological determinants of the RAAS response and underlying mechanisms. METHODS: Fifty-seven young healthy male participants underwent either an acute standardized psychosocial stress test or a nonstress placebo task. We measured aldosterone in plasma and saliva, as well as renin, and the stress-reactive endocrine measures adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine in plasma at rest, immediately after the task and several times up to 3 hours thereafter. Moreover, we assessed stress-reactive psychological (anticipatory cognitive stress appraisal, mood, physical discomfort) and basal demographic-physiological measures (age, body mass index, blood pressure). RESULTS: Acute psychosocial stress elicited changes in all assessed endocrine (p values ≤ .028, ηp2 values ≥ 0.07) and stress-reactive psychological measures (p values ≤ .003, ηp2 values ≥ 0.15). The basal parameter body mass index, the stress-reactive endocrine parameters ACTH and norepinephrine, and the psychological parameter anticipatory stress appraisal were identified as determinants of higher RAAS parameter reactivity to acute psychosocial stress. The association between anticipatory cognitive stress appraisal and plasma RAAS measures was fully mediated by ACTH increases (p values ≤ .044, ηp2 values ≥ 0.05). CONCLUSIONS: Cognitive stress appraisal processes seem to modulate RAAS stress reactivity. This points to potential clinical implications for psychoeducative therapeutical interventions targeting stress appraisal processes to reduce endocrine stress reactivity.

Do Hypertensive Men Spy With an Angry Little Eye? Anger Recognition in Men With Essential Hypertension - Cross-sectional and Prospective Findings.

BACKGROUND: Higher trait anger has inconsistently been associated with hypertension and hypertension development, but social context in terms of recognition of other persons' anger has been neglected in this context. PURPOSE: Here, we investigated anger recognition of facial affect and trait anger in essential hypertensive and normotensive men in addition to prospective associations with blood pressure (BP) increases. METHODS: Baseline assessment comprised a total of 145 participants including 57 essential hypertensive and 65 normotensive men who were otherwise healthy and medication-free. Seventy-two eligible participants additionally completed follow-up assessment 3.1 (±0.08 SEM) years later to analyze BP changes over time. We assessed emotion recognition of facial affect with a paradigm displaying mixed facial affect of two morphed basic emotions including anger, fear, sadness, and happiness. Trait anger was assessed with the Spielberger trait anger scale. RESULTS: Cross-sectionally, we found that with increasing BP, hypertensive men overrated anger displayed in facial expressions of mixed emotions as compared to normotensive men (ps ≤ .019) while there were no differences in trait anger (p = .16). Prospectively, the interaction between mean anger recognition and trait anger independently predicted BP increases from baseline to follow-up (ps ≤ .043), in that overrating displayed anger predicted future BP increases only if trait anger was high. CONCLUSIONS: Our findings indicate an anger recognition bias in men with essential hypertension and that overrating displayed anger in combination with higher trait anger seems to predict future BP increases. This might be of clinical relevance for the development and progression of hypertension and cardiovascular disease.

Aldosterone hyperreactivity to acute psychosocial stress induction in men with essential hypertension.

Essential hypertension is a pivotal risk factor for the development of cardiovascular disease (CVD). Hypertensives exhibit greater stress-induced responses in various physiological systems considered to contribute to CVD progression. Whether this stress hyperreactivity extends to the adrenal hormone aldosterone has not yet been investigated in essential hypertension. Here, we investigated reactivity of plasma aldosterone to acute psychosocial stress induction in hypertensive and normotensive men. 21 hypertensive men and 25 normotensive controls underwent the standardized Trier-Social-Stress-Test (TSST). We repeatedly assessed plasma aldosterone before and up to 1 h after TSST cessation. Acute psychosocial stress induced significantly greater increases in hypertensives as compared to normotensives (F(3.60, 158.50) = 3.75; p = .008, f = 0.29). Our findings suggest stress-induced hyperreactivity of aldosterone in essential hypertension. Potential implications for stress-related cardiovascular risk remain to be elucidated.

The Role of Norepinephrine and α-Adrenergic Receptors in Acute Stress-Induced Changes in Granulocytes and Monocytes.

OBJECTIVE: Acute stress induces redistribution of circulating leucocytes in humans. Although effects on lymphocytes as adaptive immune cells are well understood, the mechanisms underlying stress effects on granulocytes and monocytes as innate immune blood cells are still elusive. We investigated whether the stress hormone norepinephrine (NE) and α-adrenergic receptors (α-ADRs) may play a mediating role. METHODS: In a stress study, we cross-sectionally tested 44 healthy men for associations between stress-induced NE increases and simultaneous granulocyte and monocyte cell count increases, as measured immediately before and several times after the Trier Social Stress Test. In a subsequent infusion study, 21 healthy men participated in three different experimental trials with sequential infusions of 1- and 15-minute duration with varying substances (saline as placebo, the nonspecific α-ADR blocker phentolamine [2.5 mg/min], and NE [5 µg/min]): trial 1 = saline+saline, trial 2 = saline+NE, trial 3 = phentolamine+NE. Granulocyte and monocyte cell numbers were assessed before, immediately after, 10 minutes, and 30 minutes after infusion procedures. RESULTS: In the stress study, higher NE related to higher neutrophil stress changes (ß = .31, p = .045, R change = .09), but not epinephrine stress changes. In the infusion study, saline+NE induced significant increases in neutrophil (F(3/60) = 43.50, p < .001, η = .69) and monocyte (F(3/60) = 18.56, p < .001, η = .48) numbers compared with saline+saline. With phentolamine+NE, neutrophil (F(3/60) = 14.41, p < .001, η = .42) and monocyte counts (F(2.23/44.6) = 4.32, p = .016, η = .18) remained increased compared with saline+saline but were lower compared with saline+NE (neutrophils: F(3/60) = 19.55, p < .001, η = .494, monocytes: F(3/60) = 2.54, p = .065, η = .11) indicating partial mediation by α-ADRs. Trials did not differ in eosinophil and basophil count reactivity. CONCLUSIONS: Our findings suggest that NE-induced immediate increases in neutrophil and monocyte numbers resemble psychosocial stress effects and can be reduced by blockade of α-ADRs.

Psychological Stress, Inflammation, and Coronary Heart Disease.

PURPOSE OF REVIEW: In this review, we summarize evidence on the risk factor psychological stress in the context of coronary heart disease (CHD) in humans and explore the role of inflammation as a potential underlying mechanism. RECENT FINDINGS: While chronic stress increases the risk of incident CHD and poor cardiovascular prognosis, acute emotional stress can trigger acute CHD events in vulnerable patients. Evidence supporting a potential role for inflammation as a promising biological mechanism comes from population-based studies showing associations between chronic stress and increased inflammation. Similarly, experimental studies demonstrate acute stress-induced increases in inflammatory markers and suggest modulatory potential for pharmacological and biobehavioral interventions. So far, studies investigating patients with cardiovascular disease are few and the full sequence of events from stress to inflammation to CHD remains to be established. Psychological stress is an independent CHD risk factor associated with increased inflammation. Although promising, causality needs to be further explored.

Macrophage Superoxide Anion Production in Essential Hypertension: Associations With Biological and Psychological Cardiovascular Risk Factors.

OBJECTIVE: Essential hypertension is an important risk factor for coronary artery disease and its underlying process atherosclerosis, but involved mechanisms are not fully understood. Both macrophages and superoxide anions have been proposed to play a major role in the pathogenesis of atherosclerosis. In the present study, we investigated whether macrophages of individuals with hypertension show higher nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide anion production compared with normotensive individuals. Furthermore, we examined associations between macrophage superoxide anion production and the psychological factors depression and chronic stress independent from hypertension status. METHODS: We studied 30 hypertensive (mean [standard deviation] = 48.7 [2.4] years) and 30 age-matched normotensive men (mean [standard deviation] = 48.6 [2.4] years). We assessed macrophage superoxide anion production using the WST-1 assay. The assay is based on the chemical reduction of the cell-impermeative tetrazolium salt WST-1 by superoxide anions that are produced by activated human ex vivo isolated monocyte-derived macrophages. We further evaluated whether chronic stress or depressive symptom severity was associated with macrophage superoxide anion production. All analyses were adjusted for potential confounders. RESULTS: Individuals with hypertension showed higher superoxide anion production compared with normotensive individuals (F(1,58) = 11.56, p = .001). Complementary analyses using mean arterial blood pressure as a continuous measure revealed that higher mean arterial pressure correlated significantly with higher WST-1 reduction (ß = .38, p = .003, ΔR = .145). These results remained significant when controlling for potential confounding influences. Chronic stress was related to higher WST-1 reduction scores, but this association was not statistically significant (ß = .24, p = .067, ΔR = .053); depression levels were not significantly associated with WST-1 reduction scores (p = .24). CONCLUSIONS: Our results indicate higher macrophage superoxide anion production in individuals with hypertension compared with normotensive individuals. This may suggest a mechanism underlying cardiovascular risk with hypertension.

Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: A randomized controlled trial.

Flavanol-rich dark chocolate consumption relates to lower risk of cardiovascular mortality, but underlying mechanisms are elusive. We investigated the effect of acute dark chocolate consumption on inflammatory measures before and after stress. Healthy men, aged 20-50years, were randomly assigned to a single intake of either 50g of flavanol-rich dark chocolate (n=31) or 50g of optically identical flavanol-free placebo-chocolate (n=34). Two hours after chocolate intake, both groups underwent the 15-min Trier Social Stress Test. We measured DNA-binding-activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, as well as plasma and whole blood mRNA levels of the pro-inflammatory cytokines IL-1ß and IL-6, and the anti-inflammatory cytokine IL-10, prior to chocolate intake as well as before and several times after stress. We also repeatedly measured the flavanol epicatechin and the stress hormones epinephrine and cortisol in plasma and saliva, respectively. Compared to the placebo-chocolate-group, the dark-chocolate-group revealed a marginal increase in IL-10 mRNA prior to stress (p=0.065), and a significantly blunted stress reactivity of NF-κB-BA, IL-1ß mRNA, and IL-6 mRNA (p's⩽0.036) with higher epicatechin levels relating to lower pro-inflammatory stress reactivity (p's⩽0.033). Stress hormone changes to stress were controlled. None of the other measures showed a significant chocolate effect (p's⩾0.19). Our findings indicate that acute flavanol-rich dark chocolate exerts anti-inflammatory effects both by increasing mRNA expression of the anti-inflammatory cytokine IL-10 and by attenuating the intracellular pro-inflammatory stress response. This mechanism may add to beneficial effects of dark chocolate on cardiovascular health.

Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men.

Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-κB-BA and delayed increases in plasma IL-6 and mRNA of IL-1ß, IL-6, and IκBα (p's<.045). In the stress group, significant increases over time were also observed for NF-κB mRNA and plasma IL-1ß and IL-10 (p's<.055). NF-κB-BA correlated significantly with mRNA of IL-1ß (r=.52, p=.002), NF-κB (r=.48, p=.004), and IκBα (r=.42, p=.013), and marginally with IL-6 mRNA (r=.31, p=.11). Plasma cytokines did not relate to NF-κB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF-κB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress-induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells.

Eating After Acute Psychosocial Stress in Healthy Men and Women: Sex Differences and Endocrine Mechanisms.

CONTEXT: Overweight and obesity have become a major health burden with a higher prevalence of obesity in women than in men. Mental stress has been discussed to play a role in this context. OBJECTIVE: We investigated endocrine mechanisms underlying eating after acute psychosocial stress and potential sex differences therein. METHODS: A total of 32 male and 31 female healthy participants underwent the Trier Social Stress Test before they tasted ice cream in a bogus taste test 15 minutes after stress. We repeatedly assessed the stress hormone cortisol and the satiety hormone cholecystokinin (CCK) in saliva as well as perceived hunger before and up to 1 hour after stress. RESULTS: Lower immediate total cortisol stress reactivity predicted higher hunger (Ps ≤ .004), but was not associated with food intake (Ps ≥ .90) or total CCK release (Ps ≥ .84). As compared to men, women ate less after stress (Ps < .001) and had consistently lower levels of hunger (Ps ≤ .024) and cortisol (Ps ≤ .008) as well as a lower immediate total cortisol stress reactivity (Ps = .002). Further, they differed in the kinetics of CCK over the total experimental procedure (Ps ≤ .011), in immediate reaction to stress (Ps ≤ .038), and after eating (Ps ≤ .072), with women's CCK levels continuously decreasing while men's CCK levels were reactive. CONCLUSION: We found evidence for lower immediate total cortisol stress reactivity relating to higher perceived hunger, with lower cortisol levels in women. Unlike in men, CCK levels in women were not reactive to acute stress and eating and decreased continuously. Our results may suggest a higher risk for stress-induced eating in women.

Is your stress my stress? A standardized, randomized-controlled paradigm to study physiological stress contagion based on direct stress observation.

BACKGROUND & OBJECTIVES: Existing research indicates that not only own stress leads to physiological stress reactions, but also observing stress in others. So far, a standardized paradigm to reliably induce physiological stress contagion based on direct face-to-face stress observation compared to an active placebo-stress observing control condition is lacking. Here, we tested a standardized randomized placebo-controlled experimental paradigm to investigate physiological reactivity to direct stress observation and characterized the stress contagion response of the major endocrine stress systems, including full reactivity kinetics. METHODS: Healthy young male participants were randomly assigned to (1) undergo an adapted version of the Trier Social Stress Test ("TSST participants", n = 20), (2) observe it ("stress observers", n = 36), or (3) observe a corresponding placebo-stress control condition ("placebo-stress observers", n = 30). We repeatedly assessed heart rate, salivary alpha-amylase, salivary cortisol, and salivary aldosterone. RESULTS: Stress observers exhibited greater physiological reactivity to stress observation as compared to placebo-stress observers to placebo-stress observation in heart rate, salivary alpha-amylase, and cortisol (p's ≤ .027), but not in aldosterone. We observed similar reactivity kinetics in TSST participants and stress observers but less pronounced in stress observers. DISCUSSION: Extending previous literature, our findings indicate that independent of secondary effects of the observation setting, direct observation of stress in other individuals induces activation of the hypothalamus-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis. Moreover, the physiological stress contagion response resembles the physiological reactivity to first-hand stress but is less pronounced. Potential implications of physiological stress contagion regarding health, cognition, or behavior, as well as modulating factors need to be further elucidated.

Stress in the collective: Psychophysiological reactivity to an orchestra concert as a collective naturalistic, real-life stressor of psychosocial nature.

BACKGROUND & OBJECTIVES: The investigation of collective stress experiences, including collective stressors and the psychophysiological reactivity of a collective to these stressors, has been widely neglected so far. Here, we examined public non-professional orchestra concerts as collective naturalistic, real-life stressors of psychosocial nature and the resulting psychophysiological reactivity in a collective of non-professional orchestra musicians. METHODS: The members of two non-professional music orchestras (N = 54) were accompanied during a public concert (stress condition) and a rehearsal (control condition). We repeatedly assessed heart rate, salivary cortisol, and excitement levels before, during, and after the concert/rehearsal in addition to the anticipatory cognitive stress appraisal. RESULTS: We observed greater physiological reactivity to the concert compared to the rehearsal (p's ≤.017), with higher increases in heart rate levels in anticipation of and in reaction to the concert and in cortisol levels in reaction to the concert compared to the rehearsal. Moreover, orchestra members reported greater psychological reactivity to the concert than to the rehearsal (p's ≤.024) in terms of higher cognitive stress appraisal in anticipation and increased excitement levels before and during the concert compared to the rehearsal. DISCUSSION: Our findings indicate that orchestra concerts by non-professional musicians constitute collective naturalistic, real-life stressors of psychosocial nature, resulting in significant psychophysiological stress responses with reactivity kinetics differing between the sympathetic-adrenal-medullary axis, the hypothalamic-pituitary-adrenal axis, and the psychological response. Potential implications and modulating factors need to be elucidated in future studies.

Increased daytime and awakening salivary free aldosterone in essential hypertensive men.

Background: While aldosterone plays an important role in blood pressure regulation, its role in essential hypertension (EHT) remains unclear. Here, we systematically investigated the secretion of biologically-active free aldosterone in saliva in response to awakening (AldAR) and during the day (AldDay) in EHT compared to normotensive controls (NT). Methods: In 30 men with EHT and 30 age-matched NT, AldAR saliva samples were collected immediately after awakening and 15, 30, 45, and 60 min thereafter and AldDay samples were collected from 08:30-22:00 h on two consecutive days. Results: Over the course of the day, men with EHT had higher repeated AldDay levels compared to NT (p = .002) with higher concentrations in the morning hours (p's ≤ .047), a steeper decline over the course of the day (p's ≤ .018), and similar concentrations in the evening (p's ≥ .21). Regarding AldAR, we observed higher concentrations in EHT at awakening (p = .017) and borderline higher concentrations at 15 min (p = .086). No differences were found 30-60 min after awakening (p's ≥ .34). Analyses with repeated and aggregated AldAR levels resulted in borderline significantly higher free aldosterone in EHT (p's ≤ .077). Complementary analyses confirmed linear associations between higher blood pressure and higher AldAR and AldDay levels. Conclusions: Our data point to elevated salivary free aldosterone secretion in EHT over the course of the day, particularly in the morning hours. As the free aldosterone fraction is considered biologically active, our data may point to a biological mechanism underlying EHT.

Taking appreciation to heart: appreciation at work and cardiovascular risk in male employees.

Introduction: While perceived appreciation at work has been associated with self-reported health and wellbeing, studies considering biological health markers are lacking. In this study, we investigated whether appreciation at work would relate to coronary heart disease (CHD) risk as well as the specificity of this proposed association. Methods: Our study comprised a total of 103 male participants, including apparently healthy, medication-free, non-smoking men in the normotensive to hypertensive range (n = 70) as well as medicated hypertensive and CHD patients (n = 33). CHD risk was assessed by blood pressure [mean arterial pressure (MAP)], the diabetes marker glycated hemoglobin A1c (HbA1c), blood lipids [total cholesterol (TC)/high-density lipoprotein-cholesterol (HDL-C) ratio], coagulation activity (D-dimer and fibrinogen), and inflammation [interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP)]. Perceived appreciation at work, as well as potentially confounding psychological factors (social support, self-esteem, and work strain due to a lack of appreciation), were measured by self-report questionnaires. Results: We found higher appreciation at work to relate to lower overall composite CHD risk (p's ≤ 0.011) and, in particular, to lower MAP (p's ≤ 0.007) and lower blood lipids (p's ≤ 0.031) in medication-free participants as well as all participants. This overall association was independent of confounding factors, including related psychological factors (p's ≤ 0.049). Discussion: Our findings indicate that appreciation at work might be an independent health-promoting resource in terms of CHD risk. Implications include that encouraging appreciation at work may help reduce the development and progression of CHD.

An in vitro method to investigate the microbicidal potential of human macrophages for use in psychosomatic research.

OBJECTIVE: Psychological states relate to changes in circulating immune cells, but associations with immune cells in peripheral tissues such as macrophages have hardly been investigated. Here, we aimed to implement and validate a method for measuring the microbicidal potential of ex vivo isolated human monocyte-derived macrophages (HMDMs) as an indicator of macrophage activation. METHODS: The method was implemented and validated for two blood sampling procedures (short-term cannula insertion versus long-term catheter insertion) in 79 participants (34 women, 45 men) aged between 18 and 75 years. The method principle is based on the reduction of 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-dis-ulfophenyl)-2H-tetrazolium, monosodium salt (WST-1) by superoxide anions, the first in a series of pathogen-killing reactive oxygen species produced by phorbol myristate acetate-activated HMDM. Cytochrome c reduction and current generation were measured as reference methods for validation purposes. We further evaluated whether depressive symptom severity (Beck Depression Inventory) and chronic stress (Chronic Stress Screening Scale) were associated with macrophage microbicidal potential. RESULTS: The assay induced superoxide anion responses by HMDM in all participants. Assay results depended on blood sampling procedure (cannula versus catheter insertion). Interassay variability as a measure for assay reliability was 10.92% or less. WST-1 reduction scores correlated strongly with results obtained by reference methods (cytochrome c: r = 0.57, p = .026; current generation: r values ≥ 0.47, p values <.033) and with psychological factors (depressive symptom severity: r = 0.35 [cannula insertion] versus r = -0.54 [catheter insertion]; chronic stress: r = 0.36 [cannula insertion]; p values ≤ .047). CONCLUSIONS: Our findings suggest that the implemented in vitro method investigates microbicidal potential of HMDM in a manner that is valid and sensitive to psychological measures.

Physiological reactivity to acute mental stress in essential hypertension-a systematic review.

Objective: Exaggerated physiological reactions to acute mental stress (AMS) are associated with hypertension (development) and have been proposed to play an important role in mediating the cardiovascular disease risk with hypertension. A variety of studies compared physiological reactivity to AMS between essential hypertensive (HT) and normotensive (NT) individuals. However, a systematic review of studies across stress-reactive physiological systems including intermediate biological risk factors for cardiovascular diseases is lacking. Methods: We conducted a systematic literature search (PubMed) for original articles and short reports, published in English language in peer-reviewed journals in November and December 2022. We targeted studies comparing the reactivity between essential HT and NT to AMS in terms of cognitive tasks, public speaking tasks, or the combination of both, in at least one of the predefined stress-reactive physiological systems. Results: We included a total of 58 publications. The majority of studies investigated physiological reactivity to mental stressors of mild or moderate intensity. Whereas HT seem to exhibit increased reactivity in response to mild or moderate AMS only under certain conditions (i.e., in response to mild mental stressors with specific characteristics, in an early hyperkinetic stage of HT, or with respect to certain stress systems), increased physiological reactivity in HT as compared to NT to AMS of strong intensity was observed across all investigated stress-reactive physiological systems. Conclusion: Overall, this systematic review supports the proposed and expected generalized physiological hyperreactivity to AMS with essential hypertension, in particular to strong mental stress. Moreover, we discuss potential underlying mechanisms and highlight open questions for future research of importance for the comprehensive understanding of the observed hyperreactivity to AMS in essential hypertension.

Lower diurnal HPA-axis activity in male hypertensive and coronary heart disease patients predicts future CHD risk.

Background: Coronary heart disease (CHD) and its major risk factor hypertension have both been associated with altered activity of the hypothalamus-pituitary-adrenal (HPA)-axis but the biological mechanisms underlying prospective associations with adverse disease outcomes are unclear. We investigated diurnal HPA-axis activity in CHD-patients, hypertensive (HT) and healthy normotensive men (NT) and tested for prospective associations with biological CHD risk factors. Methods: Eighty-three male CHD-patients, 54 HT and 54 NT men repeatedly measured salivary cortisol over two consecutive days. Prospective CHD risk was assessed by changes between baseline and follow-up in the prothrombotic factors D-dimer and fibrinogen, the pro-inflammatory measures interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and acute phase protein C-reactive protein (CRP), as well as blood lipids in terms of total cholesterol (tChol)/high-density-lipoprotein cholesterol (HDL)-ratio. We aggregated coagulation and inflammatory measures to respective indices. Results: The groups differed in repeated daytime cortisol (dayCort) secretion (p=.005,η2 p=.03,f=0.18) and cortisol awakening response (CAR) (p=.006,η2 p=.03,f=0.18), with similarly lower overall dayCort and CAR in CHD-patients and HT, as compared to NT. The groups differed further in cortisol at awakening (p=.015,η2 p=.04,f=0.20) with highest levels in HT (p´s≤.050), and in diurnal slope between waking and evening cortisol (p=.033,η2 p=.04,f=0.20) with steepest slopes in HT (p´s≤.039), although in part not independent of confounders. Lower aggregated dayCort and CAR in terms of area-under-the-curve (AUC) independently predicted increases in future overall CHD risk (AUCdayCort: p=.021,η2 p=.10,f=0.33;AUCCAR: p=.028,η2 p=.09,f=0.31) 3.00 ± 0.06(SEM) years later, with risk prediction most pronounced in fibrinogen (AUCdayCort: p=.017,ΔR 2= 0.12;AUCCAR: p=.082). Conclusion: We found evidence for an HPA-axis hypoactivity in CHD and HT with lower diurnal HPA-axis activity predicting increases in cardiovascular risk as evidenced by increases in circulating levels of biomarkers of atherothrombotic risk. Down-regulation of basal HPA-axis activity may contribute to the pathogenesis of atherosclerosis and thrombosis in CHD via effects on coagulation.

Acceptance criteria for new approach methods in toxicology and human health-relevant life science research - part I.

Every test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects, and mistakes introduced by operators, laboratory equipment, or materials used. Adherence to an SOP and comprehensive validation of the test method cannot guarantee that each test run produces data within the acceptable range of variability and with the precision and accuracy determined during the method validation. We illustrate here (part I) why controlling the validity of each test run is an important element of experimental design. The definition and application of acceptance criteria (AC) for the validity of test runs is important for the setup and use of test methods, particularly for the use of new approach methods (NAM) in toxicity testing. AC can be used for decision rules on how to handle data, e.g., to accept the data for further use (AC fulfilled) or to reject the data (AC not fulfilled). The adherence to AC has important requirements and consequences that may seem surprising at first sight: (i) AC depend on a test method's objectives, e.g., on the types/concentrations of chemicals tested, the regulatory context, the desired throughput; (ii) AC are applied and documented at each test run, while validation of a method (including the definition of AC) is only performed once; (iii) if AC are altered, then the set of data produced by a method can change. AC, if missing, are the blind spot of quality assurance: Test results may not be reliable and comparable. The establishment and uses of AC will be further detailed in part II of this series.

Stress-induced alterations in coagulation: assessment of a new hemoconcentration correction technique.

OBJECTIVE: For the examination of psychological stress effects on coagulation, the Dill and Costill correction (DCC) for hemoconcentration effects has been used to adjust for stress-induced plasma volume changes. Although the correction is appropriate for adjusting concentrations of various large blood constituents, it may be inappropriate for time-dependent or functional coagulation assays. Two new plasma reconstitution techniques for correcting hemoconcentration effects on stress-induced changes in coagulation were compared with the DCC. METHODS: Blood was collected from 31 men during baseline, the Trier Social Stress Test (TSST), and after 20-minute recovery. For the reconstitution techniques, TSST plasma samples were reconstituted with either baseline plasma or physiological saline equal to the amount of plasma lost during stress. RESULTS: Uncorrected activated partial thromboplastin time (APTT) decreased, whereas fibrinogen, factor VIII clotting activity (FVIII:C), D-dimer and prothrombin time (PT%) increased significantly during the TSST. The DCC produced a significantly greater decrease in APTT during stress compared to uncorrected APTT, a significant decrease in PT% compared to uncorrected PT%, and stress D-dimer and fibrinogen and FVIII:C being no different than baseline. APTT, fibrinogen, D-dimer and PT% after saline reconstitution were not different from baseline, whereas FVIII:C after saline reconstitution remained elevated. APTT, PT%, fibrinogen and D-dimer after plasma reconstitution were no different from uncorrected values, whereas FVIII:C remained significantly elevated. CONCLUSIONS: The observed changes in coagulation are likely in part a consequence of stress and hemoconcentration, but the DCC seems to be an inappropriate hemoconcentration correction technique of time-dependent assays. The saline reconstitution technique may be more biologically relevant when examining stress-hemoconcentration effects on coagulation.

Getting started with taiji: investigating students expectations and teachers appraisals of taiji beginners courses.

In recent years, Taiji has been frequently investigated and considered as a stress management intervention. Although health care providers' appraisals and consumers' expectations are regarded as essential for treatment outcome, little attention has been drawn to this issue in Taiji research. In our study we have conducted two surveys to explore beginners' (n = 74) expectations and teachers' (n = 136) appraisals of their Taiji courses in general as well as more particularly related to stress management. Qualitative data analysis revealed that beginners mainly expected to learn a new method that is applicable in their daily life to foster peace of mind and to enhance their stress management. Congruently moderate-to-high improvements in stress management have also been found in quantitative analysis, whereby a lower educational level predicted higher expectations (P = 0.016). Taiji-teachers stated body- and mind-related benefits most frequently and appraised moderate-to-high improvements in stress management. Higher appraisals were predicted by a shorter teaching experience (P = 0.024). Our results inform about beginners' expectations and teachers' appraisals related to a Taiji-beginners course and highlight the role of educational background and teaching experience in shaping stress-management-related beginners' expectations and teachers' appraisals.