Age-associated effect of kestose on Faecalibacterium prausnitzii and symptoms in the atopic dermatitis infants.

BACKGROUND: Although Faecalibacterium prausnitzii is a major bacterium in the intestine of adults, which is known to have anti-inflammatory effects, the development in infants or the response to prebiotics remains unclear. METHODS: The counts of F. prausnitzii in the feces were examined by real-time polymerase chain reaction (PCR). Fecal samples were obtained from 65 atopic dermatitis (AD) infants who participated in a randomized controlled clinical trial to investigate the therapeutic effect of kestose, the smallest fructooligosaccharide. RESULTS: Although the F. prausnitzii count was undetectable level in most 0- to 1-y-old infants, the count reached a level comparable to that in adults in 2- to 5-y-old infants. The bacterial number increased about 10-fold by oral administration of kestose every day for 12 wk in the younger infants, but not so much in the older infants. This bacterial increase was significantly correlated with an improvement in the AD symptoms in the older infants. CONCLUSION: The F. prausnitzii population in the intestine reaches a level comparable to that in adult at approximately 2 y of age. Kestose efficiently stimulates the growth of this bacterium in the intestine, which might lead to an improvement in AD symptoms in infants.

Perceived inadequate care and excessive overprotection during childhood are associated with greater risk of sleep disturbance in adulthood: the Hisayama Study.

BACKGROUND: Sleep disturbance and poor sleep quality are major health problems worldwide. One potential risk factor for the development and maintenance of sleep disturbance is the parenting style experienced during childhood. However, its role in sleep disturbance in adulthood has not yet been estimated. This Japanese population study was done to clarify the relation between the parenting styles "care" and "overprotection" during childhood and sleep disturbance in adulthood. METHODS: A total of 702 community-dwelling Japanese residents aged ≥ 40 years were assessed in 2011 for their perceptions of the parenting style of their parents by use of the Parental Bonding Instrument (PBI) and for sleep disturbance by use of the Pittsburgh Sleep Quality Index (PSQI). The odds ratio (OR) for sleep disturbance (a global PSQI score > 5) was calculated using a logistic regression model. RESULTS: The prevalence of sleep disturbance was 29 %. After adjusting for sociodemographic, lifestyle, and physical factors in a comparison with the optimal parenting styles (high care and low overprotection), the ORs for sleep disturbance by men were significantly higher for low paternal care, by 2.49 times (95 % confidence interval [CI]: 1.21-5.09), and for high overprotection, by 2.40 times (95 % CI: 1.19-4.85), while the ORs were not significant for low maternal care and high overprotection. For women the only significant factor was high maternal overprotection, by 1.62 times (95 % CI: 1.05-2.52), while the ORs were not significant for low maternal care, low paternal care and high paternal overprotection. The association remained significant for high paternal overprotection for men after additionally controlling for depression. CONCLUSIONS: This study suggests that parenting style, especially inadequate care and excessive overprotection during childhood, is related to sleep disturbance in adulthood and that the association is much more significant for parents of the same sex as the child.

Current viewpoints on DSM-5 in Japan.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD-10) to categorize disorders and determine treatment fees. However, since the publication of the DSM-III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM-5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM-5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive-Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance-Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.

Paternal and maternal bonding styles in childhood are associated with the prevalence of chronic pain in a general adult population: the Hisayama Study.

BACKGROUND: Previous research has suggested that extraordinary adverse experiences during childhood, such as abuse, are possible risk factors for the development of chronic pain. However, the relationship between the perceived parental bonding style during childhood and chronic pain has been much less studied. METHODS: In this cross-sectional study, 760 community-dwelling Japanese adults were asked if they had pain that had been present for six months or more. They completed the Parental Bonding Instrument (PBI), a self-administrated questionnaire designed to assess perceived parental bonding, and the Patient Health Questionnaire-9 to assess current depressive symptoms. The PBI consists of care and overprotection subscales that are analyzed by assigning the parental bonding style to one of four quadrants: Optimal bonding (high care/low overprotection), neglectful parenting (low care/low overprotection), affectionate constraint (high care/high overprotection), and affectionless control (low care/high overprotection). Logistic regression analysis was done to estimate the contribution of the parental bonding style to the risk of chronic pain, controlling for demographic variables. RESULTS: Compared to the optimal bonding group, the odds ratios (ORs) for having chronic pain were significantly higher in the affectionless control group for paternal bonding (OR: 2.21, 95% CI: 1.50-3.27) and for maternal bonding (OR: 1.60, 95% CI: 1.09-2.36). After adjusting for depression, significance remained only for paternal bonding. CONCLUSION: The results demonstrate that the parental bonding style during childhood is associated with the prevalence of chronic pain in adults in the general population and that the association is more robust for paternal bonding than for maternal bonding.

A nationwide questionnaire survey of physicians regarding the impact of the COVID-19 pandemic on patients and treatment system of psychosomatic medicine.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected the treatment system of medical institutions across the world. Studies of the populations and patients have reported mental health problems caused by the pandemic. However, there are few large-scale studies that have examined the effects of the COVID-19 on diseases from the perspective of psychosomatic medicine. The purpose of this study was to examine changes made to the psychosomatic treatment system of Japan during the COVID-19 pandemic and the impact of the pandemic on patients with diseases treated in psychosomatic medicine. METHODS: We conducted a nationwide questionnaire survey of members of the Japanese Society of Psychosomatic Medicine and the Japanese Society of Psychosomatic Internal Medicine from December 24, 2021 to January 31, 2022. RESULTS: Of the 325 respondents, 23% reported restrictions in initial outpatient admissions, 66% implemented telemedicine, 46% reported a decrease in outpatient admissions, and 31% working in facilities with inpatient units reported decreased inpatient admissions. To reduce in-person visits, 56% of the respondents decreased the frequency of patient visits and 66% introduced telemedicine. Seventy-eight percent of the respondents reported that the COVID-19 pandemic affected the onset or exacerbation of diseases treated in psychosomatic medicine, including psychosomatic disorders, anxiety disorders, mood disorders, adjustment disorders, and eating disorders. CONCLUSIONS: This study revealed that the COVID-19 pandemic might have affected the practice of psychosomatic treatment in Japan and that various alternative measures were taken to prevent infection. In addition, although the items in this study were not compared to pre-pandemic data, the COVID-19 pandemic, it could have significant psychosocial effects on Japanese patients requiring psychosomatic care. Furthermore, respondents believed that numerous psychosocial factors were behind the impact of the COVID-19 pandemic on patients with diseases treated in psychosomatic medicine.

Daily physical complaints and hippocampal function: an fMRI study of pain modulation by anxiety.

Pain is a popular physical complaint in human. It is known that experimental anxiety modulates pain processing through hippocampal amplification, whereas it is not known whether a similar experimental reaction is related to daily physical complaints known as 'somatization'. The purpose of this study is to investigate the neural correlates of pain modulation induced by anxiety, particularly in the hippocampus, and how individual differences in this neural reaction relate to somatization. We measured neural response to noxious electrical stimulations, as well as the response to the preceding visual anticipatory cues (which induced low anxiety or high anxiety), by functional magnetic resonance imaging (fMRI). Individual daily physical symptoms were assessed by using the somatization subscale of the Symptom Checklist 90 revised (SCL-90-R). Correlation coefficients between the neural activations and the somatization scores were calculated. We found that manifestation of daily physical symptoms was related to smaller differences in hippocampus activation between high and low anxiety states, suggesting that the ability of the hippocampus to distinguish anxiety states was weakened by the chronic condition that caused the daily physical symptoms. The proper inhibition of neural activation in low anxiety states in the hippocampus and the anterior insula was observed to occur in companionship with lower daily physical complaints. These findings indicate that anxiety's alteration of the network that includes the hippocampus and that is associated with pain modulation underlies the manifestation of somatization.

Pain questionnaire development focusing on cross-cultural equivalence to the original questionnaire: the Japanese version of the Short-Form McGill Pain Questionnaire.

OBJECTIVES: The present study aimed to develop a Japanese version of the Short-Form McGill Pain Questionnaire (SF-MPQ-J) that focuses on cross-culturally equivalence to the original English version and to test its reliability and validity. DESIGN: Cross-sectional design. METHOD: In study 1, SF-MPQ was translated and adapted into Japanese. It included construction of response scales equivalent to the original using a variation of the Thurstone method of equal-appearing intervals. A total of 147 undergraduate students and 44 pain patients participated in the development of the Japanese response scales. To measure the equivalence of pain descriptors, 62 pain patients in four diagnostic groups were asked to choose pain descriptors that described their pain. In study 2, chronic pain patients (N=126) completed the SF-MPQ-J, the Long-Form McGill Pain Questionnaire Japanese version (LF-MPQ-J), and the 11-point numerical rating scale of pain intensity. Correlation analysis examined the construct validity of the SF-MPQ-J. RESULTS: The results from study 1 were used to develop SF-MPQ-J, which is linguistically equivalent to the original questionnaire. Response scales from SF-MPQ-J represented the original scale values. All pain descriptors, except one, were used by >33% in at least one of the four diagnostic groups. Study 2 exhibited adequate internal consistency and test-retest reliability, with the construct validity of SF-MPQ-J comparable to the original. CONCLUSION: These findings suggested that SF-MPQ-J is reliable, valid, and cross-culturally equivalent to the original questionnaire. Researchers might consider using this scale in multicenter, multi-ethnical trials or cross-cultural studies that include Japanese-speaking patients.

Global catastrophizing vs catastrophizing subdomains: assessment and associations with patient functioning.

OBJECTIVE: The primary objectives of the current study were to 1) confirm the three-factor model of the Pain Catastrophizing Scale (PCS) items in a Japanese sample and 2) identify the catastrophizing subdomain(s) most closely associated with measures of pain and functioning in a sample of individuals with chronic pain. DESIGN: This was based on a cross-sectional observational study. SETTING: This study was conducted in a university-based clinic. PATIENTS: One hundred and sixty outpatients with chronic pain participated in this study. OUTCOME MEASURES: Patients completed the PCS, the Brief Pain Inventory, and the Hospital Anxiety and Depression Scale; 30 patients completed the PCS again between 1 and 4 weeks later. RESULTS: Confirmatory factor analysis supported a three-factor structure of the Japanese version of the PCS, and univariate and multivariate associations with validity criterion supported the validity of the measure. Catastrophic helplessness was shown to make a unique contribution to the prediction of pain intensity, pain interference and depression, and catastrophic magnification made a unique contribution to the prediction of anxiety. CONCLUSIONS: The findings support the cross-cultural generalizability of the three-factor structure of the PCS and indicate that the PCS-assessed catastrophizing subdomains provide greater explanatory power than the PCS total score for understanding pain-related functioning.

The relationship between the age of onset of type 1 diabetes and the subsequent development of a severe eating disorder by female patients.

OBJECTIVES: To determine the age of onset of type 1 diabetes that is most closely related to the subsequent development of a severe eating disorder such as anorexia nervosa (AN) or bulimia nervosa (BN). METHODS: Participants were 53 female type 1 diabetes patients with AN or BN referred to our outpatient clinic from the Diabetes Center of Tokyo Women's Medical University. Forty-nine female type 1 diabetes patients who regularly visited the Diabetes Center and had no eating disorder-related problems constituted the 'direct control' group, whereas 941 female patients who for the first time visited the Diabetes Center constituted the 'historical control' group. The kernel function method was used to generate a density estimation of the onset age of each group and the chi-square test was used to compare the distribution. RESULTS: The control groups had similar density shapes for the onset age of type 1 diabetes, but both differed from the 'eating disorder' group. For onset age 7-18 yr, the density of the 'eating disorder' group was higher than those of the control groups, but for the younger and older onset ages the densities were lower. The 'eating disorder' group developed type 1 diabetes significantly more frequently than the 'historical control' group between 7 and 18 yr of age (χ2 = 9.066, p < 0.011). CONCLUSION: The development of type 1 diabetes in preadolescence or adolescence seems to place girls at risk for the subsequent development of AN or BN. Careful attention should be paid to these high-risk patients.

The effectiveness of Pictorial Representation of Illness and Self Measure (PRISM) for the assessment of the suffering and quality of interpersonal relationships of patients with chronic pain.

BACKGROUND: Pictorial Representation of Illness and Self Measure (PRISM) is a tool that can be used to visualize and evaluate the burden of suffering caused by an illness. The aim of this study was to identify which aspects of the burden of chronic pain patients are associated with Self/illness separation (SIS), an indicator of the magnitude of suffering. We also examined the effectiveness of PRISM for evaluating changes in the relationships between patients and their medical care and significant others due to our inpatient treatment. METHODS: Seventy-two patients with chronic pain who were outpatients or admitted to the Department of Psychosomatic Medicine completed PRISM, depression and anxiety scales, and three types of pain-related self-assessment questionnaires (Brief Pain Inventory, Short-form McGill Pain Questionnaire, and Pain Catastrophizing Scale). Outpatients were queried at the time of outpatient visits and inpatients at the time of admission. In addition to PRISM disks related to illness, we asked each patient to place disks related to things important to them and their medical care. Of the inpatients, 31 did PRISM at the time of discharge. Among the reported important factors, which significant other was placed at the time of admission and discharge was evaluated. The distances of self/medical care separation (SMcS) and self/significant others separation (SSoS) were measured. RESULTS: Of the 21 scales measured, 10 showed a significant correlation with SIS. Factor analysis of these 10 scales extracted three factors, Life interferences, Negative affects, and Pain intensity. The SMcS and SSoS distances were shorter at discharge than at admission. CONCLUSIONS: PRISM for patients with chronic pain is an integrated evaluation method that reflects three aspects of pain. By adding medical care and significant others to the usual method of placing only illness on the sheet it became possible to assess changes in the quality of interpersonal relationships.

BMI, body composition, and the energy requirement for body weight gain in patients with anorexia nervosa.

OBJECTIVE: Theories abound about the energy requirements for body weight gain in anorexia nervosa (AN). We hypothesized that malnutrition status affects the energy requirements. METHOD: On admission, 97 AN patients were measured for body composition by dual-energy X-ray absorptiometry. The relationship between body mass index (BMI) and body composition was investigated. In addition, 21 patients who completed our treatment program were tested for energy intake and body weight. RESULTS: The relationship between BMI and both fat-free mass and fat mass (FM) on admission was curvilinear. The weight gain per excess energy was greater in the group of patients with FM < 4 kg or BMI < 14 kg/m(2) than in the group with FM > or = 4 kg or BMI > or = 14 kg/m(2) (p = .037, p = .055, respectively). DISCUSSION: The energy requirements for weight gain in AN patients are related to the initial FM and BMI.

Parenting style during childhood is associated with the development of chronic pain and a patient's need for psychosomatic treatment in adulthood: A case-control study.

The aim of this study is to investigate the relation between parenting style and chronic pain and the patients' need for psychosomatic treatment in adulthood.We compared 4 combinations of 2 parenting style subscales, high and low care and overprotection, among the following 4 age- and sex-matched groups: community-dwelling subjects without chronic pain (n = 100), community-dwelling subjects with chronic pain (n = 100), outpatients with chronic pain (n = 50), and inpatients with chronic pain (n = 50). Parenting style was assessed for both the mother and father by use of the Parental Bonding Instrument questionnaire. The parenting style associated with the worst outcome was defined as both low care and high overprotection, as reported in previous studies.The frequency of reported adverse parenting style was significantly higher among chronic pain patients than community-dwelling subjects without chronic pain (all P < .05). The odds ratios for an adverse parenting style significantly increased through the categories after adjusting for demographic factors and the pain visual analog scale (P for trend <.01).These findings suggest that parental low care and high overprotection during childhood contribute to the future risk of chronic pain and the patients' need for psychosomatic treatment in adulthood.

The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor.

BACKGROUND & AIMS: Although accumulating evidence has recently shown that the efferent vagus nerve attenuates systemic inflammation, it remains unclear whether or not the vagus nerve can affect Fas-induced liver apoptosis. We investigated the effect of the vagus nerve by using a selective hepatic vagotomy. METHODS: We assessed the mortality and apoptosis in Fas-induced fulminant hepatitis in sham-operated and vagotomized male C57BL/6 mice. To determine how the nerve influences hepatocyte apoptosis, hepatitis was preceded by pretreatment with nicotine; PNU-282987, an alpha7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl(2)MDP), a macrophage eliminator; and Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), an oxidative inhibitor. RESULTS: Mortality in the vagotomized mice was significantly higher than that in the sham-operated mice following intravenous administration with the anti-Fas antibody Jo-2. This result was also supported by the data from both terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling and caspase-3 assay, in which vagotomized livers showed a significant elevation in the number of apoptotic hepatocytes and increased caspase-3 activity following Jo-2 treatment compared with the sham-operated livers. Supplementation with nicotine and PNU-282987 dose dependently inhibited this detrimental effect of the vagotomy. Moreover, the vagotomy-triggered exacerbation of Fas-induced hepatitis was completely blocked by lipo-Cl(2)MDP. Similarly, pretreatment with MnTBAP also completely suppressed the vagotomy-triggered exacerbation. CONCLUSIONS: The hepatic vagus nerve appears to play an important role in attenuating Fas-induced hepatocyte apoptosis through alpha7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species.

Pyrogenic cytokines did not mediate a stress interview-induced hyperthermic response in a patient with psychogenic fever: a case report.

OBJECTIVE: To investigate if pyrogenic cytokines mediated psychological stress-induced hyperthermic response in a patient with psychogenic fever. Despite many case reports on psychogenic fever, the mechanism responsible for how psychological stress increases core body temperature (Tc) in humans is not yet known. CASE PRESENTATION: A 13-year-old girl with fever (>38 degrees C) of unknown causes was referred to our department because psychogenic fever was suspected. To determine if the fever was actually induced by psychological stress, we conducted a 60-minute stress interview. Her baseline oral temperature was 36.60 degrees C and it began to increase immediately after commencement of the interview, reaching a maximum of 37.42 degrees C 20 minutes after the end of the interview. The plasma level of prostaglandin E(2) and the serum interleukin-6 level were increased 90 minutes after the interview. Serum levels of interleukin-1alpha, interleukin-1beta, and macrophage inflammatory protein-1alpha were all less than their minimum detectable level throughout the observation period. We also measured the patient's thermal preference by immersing her hands in warm (40 degrees C) and cold (20 degrees C) water. Her preference changed from cold to warm only during the increasing phase of oral temperature. CONCLUSIONS: This case report shows that a stress interview actually increased Tc in a patient with psychogenic fever. This study suggests that, although pyrogenic cytokines are not involved, the stress interview-induced increase in Tc was an active hyperthermia under the control of the brain, as is infection-induced fever.

Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine-alprazolam interaction in patients with psychosomatic disease.

PURPOSE: Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). METHODS: Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6. RESULTS: The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. CONCLUSIONS: The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.

Relationship between the body position-specific apnea-hypopnea index and subjective sleepiness.

BACKGROUND: It is well known that the sleeping position influences the rate of apnea-hypopnea events; however, whether events in one position may have more influence on daytime sleepiness than events in another position has not been thoroughly investigated. OBJECTIVES: We retrospectively examined the relationship between the body position-specific apnea-hypopnea index (AHI) and daily sleepiness. METHODS: We assessed the sleeping body position, the body position-specific AHI and the Epworth Sleepiness Scale (ESS) in a total of 699 patients who were referred for suspected obstructive sleep apnea-hypopnea syndrome (OSAHS) and underwent diagnostic polysomnography. RESULTS: For all subjects, only the lateral position-specific AHI (L-AHI) showed a weak but significant correlation with the ESS (r = 0.102; p < 0.05). For mild-to-moderate OSAHS patients, there was no correlation between the ESS and the AHI at any position. For severe OSAHS patients, the ESS showed a closer correlation with the L-AHI (r = 0.266; p < 0.001) than with the supine position-specific AHI (S-AHI; r = 0.141; p < 0.05). In a subgroup analysis, divided into positional and non-positional severe OSAHS patients, the correlation coefficients also identified a link between the L-AHI and the ESS. Finally, a multiple linear regression analysis indicated that the ESS was better explained by the L-AHI than by the S-AHI in severe OSAHS patients. CONCLUSION: The L-AHI is considered to have a stronger influence on daytime sleepiness than the S-AHI in Japanese patients with severe OSAHS.

[Psychosomatic disorder and functional somatic syndrome].

Functional somatic syndrome (FSS) has received a great deal of attention in recent years, and most have been treated as psychosomatic disorders. A psychosomatic disorder is a physical disorder that is closely related to psychosocial factors that affect the onset or clinical course of the disease. For most patients with FSS, the mind-body relationship is related to psychosocial stress. It is important to consider the psychosocial background of the patient as it relates to their pathology. Our psychosocial model that includes four psychosocial factors and our five-step treatment program for patients with functional somatic syndromes are presented.

Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm.

Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, p.o.) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, p.o.) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated with ischemic ECG changes (coronary vasospasm) in only the cortisol group. All of these responses were abolished by hydroxyfasudil, a specific Rho-kinase inhibitor, in vivo. Organ chamber experiments demonstrated that serotonin concentration-dependently caused hypercontractions of coronary vascular smooth muscle associated with Rho-kinase activation (as evidenced by the enhanced phosphorylation of myosin binding subunit, a substrate of Rho-kinase) in only the cortisol group. All of these responses were again inhibited by hydroxyfasudil in vitro. These results indicate that sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses through Rho-kinase activation, suggesting the link between stress and coronary vasospasm.