京都大学 / 新制・論文博士 / 博士(医学) / 乙第13439号 / 論医博第2238号 / 新制||医||1054(附属図書館) / (主査)教授 万代 昌紀, 教授 小杉 眞司, 教授 稲垣 暢也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Receiving a breast cancer (BC) diagnosis generates significant physical and psychological stress that may persist months, years, or even decades beyond treatment completion. Such chronic stress can severely alter the biological systems of BC survivors (BCS). Yet, little is known about the impact and associated variables of these long-term physiological sequelae. Considering that the number of BCS continues to grow each year, it is imperative to assess the extent to which a BC experience impacts human physiological mechanisms by examining the secretion patterns of associated stress- and immune-related biomarkers and by exploring the behavioural, physical, and psychological variables implicated in these dysregulations. Such research is of particular importance in order to guide cancer survivorship care and develop interventions promoting optimal health outcomes in BCS. This research program sought to address this through three inter-related studies. Study One was a quasi-experimental design study examining both the diurnal and reactive concentration patterns of secretory immunoglobulin A (SIgA) in a sample of women with (n = 22) and without a prior history of BC (n = 26). SIgA concentration patterns were contrasted to concentration patterns of cortisol and salivary alpha-amylase (sAA) in the same individuals (complementary to two previously published studies). Participants supplied saliva samples at five time points on two consecutive typical days (for diurnal data) and at seven time points before, during, and after an acute laboratory stressor (for reactive data). Results reveled no evidence of uncharacteristic SIgA diurnal or reactive concentration patterns, suggesting a normal and well-functioning immunological SIgA system in BCS on average 4.6 years post-diagnosis. Study One acted as a summary article allowing readers to grasp the "big picture" of long-term physiological dysregulations in BCS as a whole. Building on this, Study Two, which used the same dataset as Study One, aimed to determine whether physical activity (PA) could mitigate the adverse physiological effects of a BC experience in BCS (n = 25), as indexed by their cortisol concentration patterns. Participants self-reported their PA frequency and engaged in the same cortisol assay protocol reported in Study One. Results indicated no statistically significant differences in diurnal and reactive cortisol patterns between low- and high-PA groups. A trend that PA might not have the same effect on women with and without a history of BC was noted. Important limitations to Study Two included the small sample size and the lack of sensitivity and objectivity of the PA measure. To address Study Two’s limitations and to consider a wider range of modifiable variables that could contribute to the physiological dysregulations observed in BCS, Study Three aimed to assess the predictive value of six behavioural, physical, and psychological variables on the physiological effects of a BC experience, as indexed by cortisol (n = 192) and C-reactive protein (CRP; n = 168) levels over the first 1.5 year post-treatment. CRP, a biomarker that had not been considered so far in this research program, allowed to assess systemic inflammation in BCS post-treatment. Study Three also aimed to describe naturally occurring changes in cortisol and CRP levels and assess whether they changed in tandem. Data were drawn from 201 BCS who provided capillary blood and saliva samples at approximately 3.5 months post-treatment and again 3, 6, 9, and 12 months later. At each time point, participants also completed self-report questionnaires and wore an accelerometer for seven consecutive days. Multilevel modeling analyses revealed no significant change over time for cortisol levels post-treatment and a non-linear trajectory of change for CRP levels which was not predicted by cortisol levels. Associations between cortisol and sedentary time as well as associations between CRP and PA, body mass index, and health- and cancer-related stress were found. Collectively, these three inter-related studies uniquely add to the literature by describing long-term physiological trajectories of stress- and immune-related biomarkers in BCS. This research program attempts to gain a better understanding of the underlying mechanisms that tie behavioural, physical, and psychological variables and biomarker secretion to a BC experience. It also offers opportunities to identify women at greater risk of physiological dysregulations following a BC experience. This represents an important step towards the development of tailored interventions targeting specific BCS that most warrant them. With the number of BCS climbing each year, cancer survivorship needs to be a priority in research and efforts to better understand, monitor, and mitigate the physiological consequences of a BC experience are critical.

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Research has found that adverse childhood experiences (ACEs) are associated with changes in both parenting stress and cortisol. Resilience-building interventions may be able to help diminish the effects of ACEs, thus impacting parenting stress and cortisol reactivity. This study aims to examine how two resilience-building interventions (emotion-based and behavior-based) will impact parenting stress and cortisol reactivity in mothers with ACEs. This project is in the preliminary stages of data collection; as such, this honors thesis will review the relevant literature, describe current methodology and proposed analyses, and discuss possible implications and future directions. Participants (goal N=100) undergo a pre-assessment where parenting stress and cortisol reactivity are measured. Participants are then randomly assigned to receive an emotion-based curriculum (goal n= 50) or behavior-based curriculum (goal n=50) for 8 weeks. After completing their curriculum, participants’ parenting stress and cortisol reactivity will be reassessed. Participants from both resilience-building interventions are hypothesized to have a reduction in parenting stress and cortisol reactivity, but participants who received the emotion-based curriculum are predicted to have greater reductions. Additionally, it is hypothesized that changes in parenting stress will be correlated with changes in cortisol reactivity, so participants with greater reductions in parenting stress are anticipated to have greater reductions in cortisol reactivity.

Juvenile rainbow trout (Oncorhynchus mykiss) held in pairs form dominance hierarchies, with subordinate individuals experiencing chronic social stress, as evidenced by prolonged elevation of the stress hormone cortisol. Prior work revealed that the thermal tolerance (measured as critical thermal maximum, CTmax) of subordinate fish was reduced, but the cause of this impairment was unknown. Here we tested the hypothesis that reduced thermal tolerance in subordinate trout is caused by prolonged elevation of circulating cortisol levels, affecting cardiac structure and function. In support of this hypothesis, subordinate trout that were allowed to recover from social stress for 48 h, a period sufficient to return cortisol to normal baseline levels, no longer showed a reduced CTmax. Furthermore, treatment of subordinates with cortisol to maintain elevated cortisol levels during the period of recovery from social stress prevented thermal tolerance from recovering. The possibility that prolonged elevation of cortisol levels induces cardiac remodelling in subordinate trout was explored by assessing heart histology and cardiac remodelling markers, and monitoring heart rate (fH). Picrosirius red staining revealed lower collagen levels in the ventricles of subordinate relative to dominant trout, although this difference was not accompanied by changes in collagen type I transcript abundances or protein levels, or by changes in markers of collagen turnover. Transcript abundances of markers of cardiac remodelling and ventricle mass were not significantly altered by chronic social stress. Heart rate in subordinates during social interactions was comparable to that in dominant fish. However, differences in fH responses of subordinate versus dominant fish were detected during acute warming. Specifically, peak heart rates tended to be observed at lower temperatures in subordinate fish relative to dominant. Thus, high baseline cortisol levels in subordinate trout result in lowered thermal tolerance, and chronic social stress has only minor effects on cardiac structure and function.

No description available.

Depression and other mental disorders are the leading cause of disability worldwide and their burden has increased considerably over past decades. However, advances in psychopharmacology of psychiatric disorders are not in measure with this negativ trend. As a result, a large body of researchinpsychiatryandneurosciencestries to furtherourunderstanding of pathophysiologicalmechanismsunderlyingmooddisorders andothermentalillnesses in order to improve the efficacy of current treatments and to identify new therapeutic agents. According to current evidence, stress-related pathways and inflammation processes are directly involved in thedevelopment of depressive disorder andseveral other psychiatric conditions.Thestudy of the effects and consequences of stress exposure requires an interdisciplinary approach,taking into account specific aspects of the "inputs", such as chronic stress and traumatic experiences, and related psychological processes, with the crucial role of dissociation. Following these theoretical findings, the empirical research performed in two cohorts of inpatients with depressive disorder focused on immune and endocrine responses to stress and their relationship to psychopathological symptoms, specifically trauma-related symptoms, psychic and somatoform dissociation and depressive...

Low water pH is an ionoregulatory challenge to freshwater teleosts. Larval zebrafish (Danio rerio) exposed to pH 4 water experience increased loss of Na⁺ and respond with increases in ionocyte abundance and whole-body concentrations of cortisol. Because cortisol plays a role in regulating early development, particularly of the stress axis, the present study asked whether the increase in cortisol in embryos exposed to pH 4 water causes dysregulation of the stress axis in later life. Baseline whole-body cortisol levels measured at 4, 6, and 15 days post-fertilization (dpf) did not differ between pH 4-exposed and control fish. At 6 dpf, pH 4-exposed fish had higher concentrations of cortisol compared to control fish following a stressor, but no difference was detected at 15 dpf. In addition, transcript abundances for key genes of the stress axis did not differ between control and pH 4-exposed fish. Based on these results, exposure to pH 4 water in early life does not influence the stress axis or cortisol responses later in life. Increases in ionocyte abundance in response to low pH have the potential to alter gill morphology, thereby impairing gas transfer, a trade-off known as the osmorespiratory compromise. The present study tested the hypothesis that zebrafish reared in pH 4 water have reduced gas transfer capacity in accordance with the osmorespiratory compromise. Indicators of gas transfer and ionoregulation were measured at 6, 15, 30 and 90 dpf. Across all ages examined, fish reared in pH 4 water had significantly higher whole-body concentrations of Na⁺, higher ionocyte abundances and thicker gills than control fish. These differences were accompanied by higher ventilation frequencies and higher critical PO₂ (Pcrit) values. Additionally, adult fish raised in low pH had a significantly higher rate of oxygen consumption compared to control fish. These results support the hypothesis that development in water of low pH impairs gas transfer, as predicted by the osmorespiratory compromise.

This thesis focuses on women's competition in female basketball players and their hormonal responses to winning and losing. We tested saliva samples of 29 female players for testosterone and cortisol which were collected in three phases: baseline samples, pregame samples and after game samples. In every collection phase we also inquired about the emotional state of mind of the respondents. Players completed a survey examining their subjective evaluation of the match result. We also used statistical data from every match, which provided an objective evidence on the players' usefulness. All the aforementioned variables were examined in relation to the testosterone and cortisol levels. The results have revealed that the cortisol levels are responsive to the match results, whereas the losing players display a significant rise of the stress hormone level after the match. The winners display only a slight increase in the cortisol levels. Testosterone levels did not prove to react to the match results. However, it was discovered that the winners exhibited higher levels of testosterone in all collection phases than their competitors. Nevertheless, the difference between the winners and the losers was not significant in any of the cases. The winners felt more positive after the match than the losers. The correlation...

Past research indicates that social rejection predicts a wide range of psychological problems (e.g., depression), but laboratory studies examining self-reports of negative affect after social rejection have reported inconsistent results. Salivary cortisol was measured before and after a social rejection/acceptance manipulation for objective assessment of psychological distress subsequent to peer rejection. Rejected participants were predicted to show significantly greater salivary cortisol than accepted or control participants. The present research also examined several factors that may moderate the relationship between acute rejection and cortisol. As predicted, rejected participants exhibited significantly higher cortisol than accepted or control participants. Defensiveness moderated the relationship between rejection and cortisol; highly defensive rejected participants showed significantly lower cortisol than less defensive rejected participants after peer rejection. Results indicate that social rejection causes psychological distress, but highly defensive individuals appear to be less susceptible than less defensive individuals to increases in salivary cortisol after acute social rejection.