Hisayoshi Okamura

Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans

Activation of the innate immune system is commonly accompanied by a set of behavioural, psychological and physiological changes known as ‘sickness behaviour’. In animals, infection-related sickness symptoms are significantly increased by exposure to psychosocial stress, suggesting that psychological and immune stressors may operate through similar pathways to induce sickness. We used a double-blind, randomised, placebo-controlled design to examine the effect of acute psychological stress on immune and subjective mood responses to typhoid vaccination in 59 men. Volunteers were assigned to one of four experimental conditions in which they were either injected with typhoid vaccine or saline placebo, and then either rested or completed two challenging behavioural tasks. Typhoid vaccine induced a significant rise in participants’ serum levels of interleukin-6 (IL-6) and this response was significantly larger in the stress versus rest conditions. Negative mood increased immediately post-tasks, an effect also more pronounced in the vaccine/stress condition. In the vaccine/stress group, participants with larger IL-6 responses had heightened systolic blood pressure responses to tasks and elevated post-stress salivary levels of the noradrenaline metabolite 3-methoxy-phenyl glycol (MHPG) and cortisol. Our findings suggest that, as seen in animals, psychological and immune stressors may act synergistically to promote inflammation and sickness behaviour in humans.

The effects of depressive symptoms on cardiovascular and catecholamine responses to the induction of depressive mood.

We examined the effects of depressive symptoms on cardiovascular and catecholamine responses to the induction of different mood states. Fifty-five healthy men and women (mean age 23.4 +/- 3 years) were recruited. Depressive symptoms were evaluated using the Center for Epidemiological Studies Depression Scale (CES-D) and participants were classified into high depressive (CES-D*16) or low depressive symptoms (CES-D < 16) groups. Following a baseline period, participants were required to complete two separate speech tasks where they were asked to recall life events that made them feel angry or depressed. The tasks were separated by a 30-min recovery period and the order was randomised between participants using a counterbalanced design. Cardiovascular function was monitored continuously using a Finometer device and saliva was collected for the assessment of 3-methoxy-phenylglycol (MHPG, the major metabolite of norephinephrine). Blood pressure (BP), heart rate, and total peripheral resistance (TPR) were significantly increased in response to both tasks (p = .001). Averaged over conditions, higher diastolic BP and higher MHPG levels were observed in high depressive symptoms participants. MHPG levels did not change in response to mood induction in the low depressive symptoms group. However, the high depression symptoms group showed significantly higher levels of MHPG during recovery from the depressed mood induction task and increased levels immediately after the anger induction task. These findings suggest depressive symptoms are associated with heightened central adrenergic activation during negative mood induction, but that the time course of responses is dependent on the type of emotion elicited.

Diurnal Cortisol Changes in Newborn Infants Suggesting Entrainment of Peripheral Circadian Clock in Utero and at Birth

BACKGROUND In the rodent and human fetus, a diurnal cortisol rhythm is observed that is entrained in antiphase to the maternal rhythm. However, after birth, the adrenal circadian rhythm becomes unsynchronized with the clock time, and an adult-type, 24-h rhythm is observed only after a few months. Little is known about when and how the fetal adrenal circadian rhythm is synchronized with the day-night cycle. METHODS To investigate the function of adrenal circadian clock in the newborn infant, eight serial saliva samples were collected every 3 h over 24 h (starting at 0900 h) in 27 newborn infants. RESULTS Cortisol levels were higher during the period 1500 to earlier than 2100 h than during 0900 to earlier than 1500 h and 0300 to earlier than 0900 h (both P < 0.05). Salivary cortisol levels collected during 0 to <6, 6 to <12, and 12 to <18 hours after the clock time at birth (birth time) were higher than those collected during 18 to <24 hours after the birth time (P < 0.005, 0.05, and 0.05, respectively). The acrophase of salivary cortisol was linearly correlated with the birth time within the first 5 d of life (P < 0.005) but not thereafter. CONCLUSION In the newborn infant, diurnal increase in cortisol was observed in the late afternoon and in correspondence with the birth time. The adrenal circadian rhythm acquired in utero may be reentrained by endocrinological events at birth. Such complex regulation of the adrenal circadian clock may inhibit a swift synchronization of the circadian clock to the day-night rhythm.

Self-perceived Work-related Stress and its Relation to Salivary IgA, Cortisol and 3-Methoxy-4-hydroxyphenyl Glycol Levels among Neonatal Intensive Care Nurses

This study investigated self-perceived work-related stress, along with salivary IgA (s-IgA), cortisol and 3-methoxy-4-hydroxyphenyl glycol (MHPG) in 38 neonatal intensive care unit (NICU) nurses and 26 general ward (GW) nurses. To adjust for sociodemographic characteristics, the two groups of nurses were strictly matched for age, gender (feminine), average work experience and marital status (unmarried). General fatigue and anxiety were significantly higher, and depressive mood tended to be higher, in NICU nurses compared to GW nurses, based on Cumulative Fatigue Symptoms Index scores (p < 0.05, p < 0.05, p = 0.079, respectively). s-IgA concentrations were also inversely correlated with self-perceived work-related stress and were significantly lower in NICU nurses than in GW nurses (p < 0.01). There tended to be a positive association between high cortisol concentrations and the CFSI subscale of depressive mood in both NICU and GW nurses (p = 0.053). Cortisol and MHPG levels were not different between NICU and GW nurses. These work-related stress markers, both self-perceived (CFSI) and biological (s-IgAand cortisol concentrations), highlight the importance of creating and sustaining healthy work environments for NICU and GW nurses.

Increased plasma type B natriuretic peptide in the acute phase of Kawasaki disease

Background:  The aim of this study was to identify possible factors associated with type‐B natriuretic peptide (BNP) production in the acute phase of Kawasaki disease (KD).

Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers

BackgroundL-ornithine is a non-essential, non-protein amino acid. Although L-ornithine is contained in various foods, the amount is usually small.Recently, studies have shown that orally administered L-ornithine reduced the stress response in animals.From these findings, we speculated that L-ornithine may play a role in the relieve of stress and improve sleep and fatigue symptoms in humans. Through a randomised, double-blind, placebo-controlled clinical study, we asked if L-ornithine could be beneficial to stress and sleep in healthy workers.MethodFifty-two apparently healthy Japanese adults who had previously felt slight stress as well as fatigue were recruited to be study participants and were randomly divided into either the L-ornithine (400 mg/day) or placebo group. They orally consumed the respective test substance every day for 8 weeks. Serum was collected for the assessment of cortisol and dehydroepiandrosterone-sulphate (DHEA-S). Perceived mood and quality of sleep were measured by the Profile of Mood States (POMS), Athens Insomnia Scale (AIS), and Ogri-Shirakawa-Azumi sleep inventory MA version (OSA-MA).ResultsSerum cortisol levels and the cortisol/DHEA-S ratio were significantly decreased in the L-ornithine group in comparison with the placebo group. Also, anger was reduced and perceived sleep quality was improved in the L-ornithine group.ConclusionL-ornithine supplementation has the potential to relieve stress and improve sleep quality related to fatigue, both objectively and subjectively.

Short sleeping time and psychobiological responses to acute stress

The aim of this study was to examine the association between self-reported sleeping time and psychobiological stress responses [3-Methoxy-4-hydroxyphenylglycol (MHPG) and Secretory immunoglobulin A (IgA), perceived stress responses]. Thirty seven healthy men and women were recruited, and participants were divided according to the habitual number of hours of sleep as follows: adequate sleepers (AS) (6-8h sleep per night regularly) (N=22) and short sleepers (SS) (less than 5h sleep per night regularly) (N=15). Salivary MHPG, s-IgA and perceived stress were measured at baseline, immediately after task and recovery period. An increase in free-MHPG during the task period was observed in AS although free-MHPG increased only after the task period in SS. The level of s-IgA in both groups significantly increased during the task period, and quickly returned to a basal level during the recovery period. The results show that less than 5h of sleep was associated with different responsiveness to the Stroop color word conflict task compared to sufficient sleep, especially in the NA system.

Noninvasive Surrogate Markers for Plasma Cortisol in Newborn Infants: Utility of Urine and Saliva Samples and Caution for Venipuncture Blood Samples

CONTEXT Hypothalamus-pituitary-adrenal function is associated with important physiological/pathological events in neonates. Plasma/serum cortisol levels have been used to assess hypothalamus-pituitary-adrenal function. Several noninvasive surrogate markers have been used without sufficient validation. OBJECTIVE The objectives of the study were to investigate whether plasma cortisol levels are correlated with those in saliva and urine and whether these correlations are affected by procedural pain at blood sampling. DESIGN, SETTING, AND PATIENTS Fifty neonates were recruited from a tertiary neonatal intensive care unit. Saliva and urine samples were collected shortly before routine clinical blood sampling. MAIN OUTCOME MEASURES Cortisol levels were compared between plasma and noninvasive samples using a linear regression analysis for the entire study population and groups, whose blood was obtained via indwelling arterial catheters (group A) or by venipuncture (group V). Predictive values of salivary/urinary cortisol for low plasma cortisol levels less than 2.0 μg/dL were evaluated by receiver-operating characteristic analysis. RESULTS Plasma cortisol showed linear correlations with salivary and urinary cortisol for the entire study population and patients in group A (all P < .0002) but not in group V. Areas under the curves of salivary and urinary cortisol to predict low plasma cortisol levels were 0.87 (95% confidence interval 0.78-0.97) and 0.84 (95% confidence interval 0.74-0.95), respectively. CONCLUSIONS Cortisol levels from saliva or urine samples were shown to be useful surrogate markers for plasma cortisol levels in neonates. Caution is required in interpreting the findings of plasma cortisol levels in young patients when blood samples are obtained by venipuncture because procedural pain may induce alteration of cortisol levels.

Salivary 3‐methoxy‐4‐hydroxyphenylglycol increases after awakening in healthy young adults

Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) may reflect central noradrenergic activity. In this study, we investigated salivary MHPG changes after awakening, and explored their relationships with cortisol and peripheral autonomic activity. The participants were 25 college students. Saliva samples were collected on awakening and 30 min after awakening to determine MHPG and cortisol. Ambulatory electrocardiograms were obtained to assess heart rate, cardiac sympathetic index (CSI), and cardiac vagal index (CVI) before and after awakening. MHPG levels increased significantly during the first 30 min after awakening. Similarly, cortisol, heart rate, and CSI increased during the 30 min after awakening, but changes in MHPG did not correlate with changes in cortisol, heart rate, CSI, and CVI during that period. This study demonstrated that salivary MHPG levels increase after awakening, in common with cortisol, heart rate, and cardiac sympathetic activity.

Paradoxical diurnal cortisol changes in neonates suggesting preservation of foetal adrenal rhythms

Studies suggested the presence of foetal adrenal rhythms of cortisol, which are entrained in antiphase to maternal rhythms. In contrast, neonates are thought to have no adrenal rhythm until 2–3 months after birth. To test the hypothesis that a foetal-type adrenal rhythm is preserved after birth, saliva samples were collected from 65 preterm/term infants during hospital stay (30–40 weeks corrected age) at 10:00 and 19:00 h. Cortisol levels were assessed for their diurnal difference and dependence on antenatal/postnatal clinical variables. Cortisol levels were lower during periods 15–28 days and >28 days than ≤5 days of life. Lower cortisol was associated with pregnancy-induced hypertension (PIH), gestational age <28 weeks, and mechanical ventilation after birth. Higher cortisol was associated with vaginal delivery and non-invasive ventilation support at saliva collection. PIH and non-invasive mechanical ventilation at saliva collection were associated with cortisol levels even after adjustment for postnatal age. Cortisol levels were higher in the evening than in the morning, which was unassociated with gestational and postnatal age. Higher cortisol levels in the evening suggest the preservation of a foetal-type diurnal rhythm. Cortisol levels are associated with intrinsic and extrinsic variables, such as PIH, delivery mode, gestational age, and respiratory conditions.