Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
kazufumi Yoshihara Last modified date:2020.01.17

Lecturer / Department of Psychosomatic Medicine / Department of Clinical Medicine / Faculty of Medical Sciences

1. Tomokazu Hata, Noriyuki Miyata, Shu Takakura, Kazufumi Yoshihara, Yasunari Asano, Tae Kimura-Todani, Makoto Yamashita, Xue Ting Zhang, Natsuru Watanabe, Katsunaka Mikami, Yasuhiro Koga, Nobuyuki Sudo, The Gut Microbiome Derived from Anorexia Nervosa Patients Impairs Weight Gain and Behavioral Performance in Female Mice, Endocrinology, 10.1210/en.2019-00408, 160, 10, 2441-2452, 2019.08, Anorexia nervosa (AN) results in gut dysbiosis, but whether the dysbiosis contributes to AN-specific pathologies such as poor weight gain and neuropsychiatric abnormalities remains unclear. To address this, germ-free mice were reconstituted with the microbiota of four patients with restricting-type AN (gAN mice) and four healthy control individuals (gHC mice). The effects of gut microbes on weight gain and behavioral characteristics were examined. Fecal microbial profiles in recipient gnotobiotic mice were clustered with those of the human donors. Compared with gHC mice, gAN mice showed a decrease in body weight gain, concomitant with reduced food intake. Food efficiency ratio (body weight gain/food intake) was also significantly lower in gAN mice than in gHC mice, suggesting that decreased appetite as well as the capacity to convert ingested food to unit of body substance may contribute to poor weight gain. Both anxiety-related behavior measured by open-field tests and compulsive behavior measured by a marble-burying test were increased only in gAN mice but not in gHC mice. Serotonin levels in the brain stem of gAN mice were lower than those in the brain stem of gHC mice. Moreover, the genus Bacteroides showed the highest correlation with the number of buried marbles among all genera identified. Administration of Bacteroides vulgatus reversed compulsive behavior but failed to exert any substantial effect on body weight. Collectively, these results indicate that AN-specific dysbiosis may contribute to both poor weight gain and mental disorders in patients with AN..
2. Tomokazu Furukawa, Hiroshi Nakano, Kazufumi Yoshihara, Nobuyuki Sudo, Predictors of objectively measured snoring in a working population, Sleep and Biological Rhythms, 10.1007/s41105-019-00220-5, 17, 3, 349-354, 2019.07, Although there have been many epidemiological studies of snoring, most did not assess snoring objectively. The aim of this study was to identify predictive factors for snoring measured objectively in a working population in Japan. We used IC recorders for the overnight tracheal sound monitoring of 191 employees of two facilities for two nights. Snoring was characterized by two variables: snoring time (%ST) as a percentage of recording time, and the mean tracheal sound energy during recording time (Leq, the equivalent sound pressure level). After excluding those with insufficient data, 172 subjects were included in the final analysis [124 men; age, 44.3 ± 9.9 years; body mass index (BMI), 22.9 ± 3.7 kg/m2]. Relationships between the two snoring variables and age, sex, BMI, drinking, smoking, and night nasal congestion were evaluated, and the predictors of snoring were identified using multiple regression analysis with %ST and Leq as the dependent variables. The mean values of %ST and Leq were 7.4 ± 7.4% and 102.1 ± 5.2 dB, respectively. Multiple regression analysis revealed that BMI (p < 0.001), night nasal congestion (p = 0.007), habitual drinking (p = 0.014) were significant predictors of %ST and that being male (p < 0.001) and BMI (p = 0.007) were significant predictors of Leq. These results suggested that being male, obesity, habitual alcohol consumption, and night nasal congestion are predictors of objectively measured snoring in a working population..
3. Tetsuya Hiramoto, Kazufumi Yoshihara, Yasunari Asano, Nobuyuki Sudo, Protective Role of the Hepatic Vagus Nerve against Liver Metastasis in Mice, NeuroImmunoModulation, 10.1159/000487483, 24, 6, 341-347, 2018.04.
4. Tomokazu Hata, Yasunari Asano, Kazufumi Yoshihara, Tae Kimura-Todani,Noriyuki Miyata, Xue-Ting Zhang, Shu Takakura, Yuji Aiba, Yasuhiro Koga,Nobuyuki Sudo, Regulation of gut luminal serotonin by commensal microbiota in mice., PLOS ONE, 10.1371/journal.pone.0180745, 6, 12(7), 2017.07.
5. Michelle G. Rooks, Patrick Veiga, Analise Z. Reeve, Sydney Lavoie, Koji Yasuda, Yasunari Asano, Kazufumi Yoshihara, Monia Michaud, Leslie Wardwell-Scott, Carey Ann Gallini, Jonathan N. Glickman, Nobuyuki Sudo, Curtis Huttenhower, Cammie F. Lesser, Wendy S. Garretta, QseC inhibition as an antivirulence approach for colitis-associated bacteria, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.1612836114, 114, 1, 142-147, 2017.01, Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/- Rag2-/- IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management..
6. Tomokazu Furukawa, Hiroshi Nakano, Kazufumi Yoshihara, Nobuyuki SUDO, The Relationship between Snoring Sound Intensity and Morning Blood Pressure in Workers., J Clin Sleep Med., 10.5664/jcsm.6340, 12, (12), 1601-1606, 2016.12.
7. Naoki Hirabayashi, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Masaharu Nagata, Mao Shibata, Seiji Gotoh, Yoshihiko Furuta, Fumio Yamashita, Kazufumi Yoshihara, Takanari Kitazono, Nobuyuki Sudo, Yutaka Kiyohara, Toshiharu Ninomiya, Association between diabetes and hippocampal atrophy in Elderly Japanese
The Hisayama study, Diabetes care, 10.2337/dc15-2800, 39, 9, 1543-1549, 2016.09, OBJECTIVE To investigate the association between diabetes and brain or hippocampal atrophy in an elderly population. RESEARCH DESIGN AND METHODS A total of 1,238 community-dwelling Japanese subjects aged ≥65 years underwent brain MRI scans and a comprehensive health examination in 2012. Total brain volume (TBV), intracranial volume (ICV), and hippocampal volume (HV) were measured using MRI scans for each subject. We examined the associations between diabetes-related parameters and the ratios of TBV to ICV (an indicator of global brain atrophy), HV to ICV (an indicator of hippocampal atrophy), and HV to TBV (an indicator of hippocampal atrophy beyond global brain atrophy) after adjustment for other potential confounders. RESULTS Themultivariable-adjustedmean values of the TBV-to-ICV,HV-to-ICV, and HV-to-TBV ratios were significantly lower in the subjects with diabetes compared with those without diabetes (77.6%vs. 78.2%for the TBV-to-ICV ratio, 0.513%vs. 0.529%for the HV-to-ICV ratio, and 0.660% vs. 0.676% for the HV-to-TBV ratio; all P < 0.01). These three ratios decreased significantlywith elevated 2-h postload glucose (PG) levels (all P for trend <0.05) but not fasting plasma glucose levels. Longer duration of diabetes was significantly associated with lower TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios. The subjectswith diabetes diagnosed in midlife had significantly lower HV-to-ICV and HV-to-TBV ratios than those without and those diagnosed in late life. CONCLUSIONS Our data suggest that a longer duration of diabetes and elevated 2-h PG levels, a marker of postprandial hyperglycemia, are risk factors for brain atrophy, particularly hippocampal atrophy..
8. Matsunaga Masahiro, Kawamichi Hiroaki, Koike Takahiko, Yoshihara Kazufumi, Yoshida Yumiko, Takahashi Haruka K., Nakagawa Eri, Sadato Norihiro, Structural and functional associations of the rostral anterior cingulate cortex with subjective happiness, NEUROIMAGE, 10.1016/j.neuroimage.2016.04.020, 134, 132-141, 2016.07.
9. Yoshihara Kazufumi, Tanabe Hiroki C., Kawamichi Hiroaki, Koike Takahiko, Yamazaki Mika, Sudo Nobuyuki, Sadato Norihiro, Neural correlates of fear-induced sympathetic response associated with the peripheral temperature change rate, NEUROIMAGE, 10.1016/j.neuroimage.2016.04.040, 134, 522-531, 2016.07, 恐怖による交感神経活動に関する脳活動および脳内ネットワークを明らかにした.
10. Kawamichi Hiroaki, Yoshihara Kazufumi, Sugawara Sho K., Matsunaga Masahiro, Makita Kai, Hamano Yuki H., Tanabe Hiroki C., Sadato Norihiro, Helping behavior induced by empathic concern attenuates anterior cingulate activation in response to others' distress, SOCIAL NEUROSCIENCE, 10.1080/17470919.2015.1049709, 11, 2, 109-122, 2016.03.
11. Koike Takahiko, Tanabe Hiroki C., Okazaki Shuntaro, Nakagawa Eri, Sasaki Akihiro T., Shimada Koji, Sugawara Sho K., Takahashi Haruka K., Yoshihara Kazufumi, Bosch-Bayard Jorge, Sadatoa Norihiro, Neural substrates of shared attention as social memory: A hyperscanning functional magnetic resonance imaging study, NEUROIMAGE, 10.1016/j.neuroimage.2015.09.076, 125, 401-412, 2016.01.
12. Morita Chihiro, Tsuji Hirokazu, Hata Tomokazu, Gondo Motoharu, Takakura Shu, Kawai Keisuke, Yoshihara Kazufumi, Ogata Kiyohito, Nomoto Koji, Miyazaki Kouji, Sudo Nobuyuki, Gut Dysbiosis in Patients with Anorexia Nervosa, PLOS ONE, 10.1371/journal.pone.0145274, 10, 12, 2015.12.
13. Takeharu Chijiwa, Takakazu Oka, Battuvshin Lkhagvasuren, Kazufumi Yoshihara, Nobuyuki Sudo, Prior chronic stress induces persistent polyI
C-induced allodynia and depressive-like behavior in rats: Possible involvement of glucocorticoids and microglia, Physiology and Behavior, 10.1016/j.physbeh.2015.04.050, 147, 264-273, 2015.08, When animals suffer from viral infections, they develop a set of symptoms known as the "sickness response." Recent studies suggest that psychological stress can modulate the sickness response. However, it remains uncertain whether acute and chronic psychosocial stresses have the same effect on viral infection-induced sickness responses. To address this question, we compared changes in polyI:C-induced sickness responses, such as fever, change of body weight and food intake, mechanical allodynia, and depressive-like behavior, in rats that had been pre-exposed to single and repeated social defeat stresses. Intraperitoneal injection of polyI:C induced a maximal fever of 38.0. °C 3. h after injection. Rats exposed to prior social defeat stress exhibited blunted febrile responses, which were more pronounced in the repeated stress group. Furthermore, only the repeated stress group showed late-onset and prolonged mechanical allodynia lasting until 8. days after injection in the von Frey test and prolonged immobility time in the forced swim test 9. days post-injection. To assess the role of glucocorticoids and microglia in the delayed and persistent development of these sickness responses in rats exposed to repeated stress, we investigated the effect of pretreatment with RU486, a glucocorticoid receptor antagonist, and minocycline, an inhibitor of microglial activation, on polyI:C-induced allodynia and depressive-like behavior. Pretreatment with either drug inhibited both the delayed allodynia and depressive-like behavior. The present study demonstrates that repeated, but not single, social defeat stress followed by systemic polyI:C administration induced prolonged allodynia and depressive-like behavior in rats. Our results show that even though a single-event psychosocial stress does not have any effect by itself, animals may develop persistent allodynia and depressive-like behavior when they suffer from an infectious disease if they are pre-exposed to repeated or chronic psychosocial stress. Furthermore, this study suggests that stress-induced corticosterone and microglial activation play a pivotal role in this phenomenon..
14. Kawamichi Hiroaki, Kitada Ryo, Yoshihara Kazufumi, Takahashi Haruka, Sadato Norihiro, Interpersonal touch suppresses visual processing of aversive stimuli, FRONTIERS IN HUMAN NEUROSCIENCE, 10.3389/fnhum.2015.00164, 9, 2015.04.
15. Kazufumi Yoshihara, Psychosomatic treatment for allergic diseases, BioPsychoSocial Medicine, 10.1186/s13030-015-0036-2, 9, 1, 2015.03, Summary: Many reports have been published concerning how psychosocial stress influences the occurrence and progression of allergic diseases such as bronchial asthma and atopic dermatitis. As for asthma, a typical allergic disease often accompanied by psychosomatic related problems, the Global Initiative for Asthma (GINA), international medical guidelines for asthma, describes psychosocial problems as causative factors of poor asthma control and as risk factors for asthma exacerbation, even if symptoms are well controlled. However, because there is little high quality evidence for effective treatments for asthma patients with psychosocial problems, concrete assessments and treatments for such problems is scarcely described in GINA. Therefore, psychosomatic intervention for asthma patients is not effectively conducted on a worldwide scale. In contrast, the "Japanese Guidelines for the Diagnosis and Treatment of Psychosomatic Diseases" describe the assessment and treatment of psychosomatic disorders in detail. In the guidelines, psychosocial factors are classified into five categories; 1) Relation between stress and asthma occurrence or progression, 2) Relation between emotion and asthma symptoms, 3) Problems related to a patient's character and behaviors, 4) Problems of daily life and Quality of Life (QOL), and 5) Problems related to family relationships and life history. The employment of a self-administered questionnaire, the "Psychosomatic Questionnaire related to Asthmatic Occurrence and Progression", is useful for clarifying psychosocial factors and for setting up treatment strategies according to the problems identified. The Japanese guidelines have been proven to be useful, but empirical evidence for their effectiveness is still relatively limited. It will be necessary in the future to accumulate high-quality evidence and to revise the psychosomatic approaches in the guidelines that are universally valid..
16. Kawamichi Hiroaki, Kazufumi Yoshihara, Sasaki Akihiro T., Sugawara Sho K., Tanabe Hiroki C., Shinohara Ryoji, Sugisawa Yuka, Tokutake Kentaro, Mochizuki Yukiko, Anme Tokie, Sadato Norihiro, Perceiving active listening activates the reward system and improves the impression of relevant experiences, SOCIAL NEUROSCIENCE, 10.1080/17470919.2014.954732, 10, 1, 16-26, 2015.01.
17. Kitada Ryo, Kazufumi Yoshihara, Sasaki Akihiro T., Hashiguchi Maho, Kochiyama Takanori, Sadato Norihiro, The Brain Network Underlying the Recognition of Hand Gestures in the Blind: The Supramodal Role of the Extrastriate Body Area, JOURNAL OF NEUROSCIENCE, 10.1523/JNEUROSCI.0500-14.2014, 34, 30, 10096-10108, 2014.07.
18. Kazufumi Yoshihara, Tetsuya Hiramoto, Takakazu Oka, Chiharu Kubo, Nobuyuki Sudo, Effect of 12 weeks of yoga training on the somatization, psychological symptoms, and stress-related biomarkers of healthy women, BioPsychoSocial Medicine, 10.1186/1751-0759-8-1, 8, 1, 2014.01, Background: Previous studies have shown that the practice of yoga reduces perceived stress and negative feelings and that it improves psychological symptoms. Our previous study also suggested that long-term yoga training improves stress-related psychological symptoms such as anxiety and anger. However, little is known about the beneficial effects of yoga practice on somatization, the most common stress-related physical symptoms, and stress-related biomarkers. We performed a prospective, single arm study to examine the beneficial effects of 12 weeks of yoga training on somatization, psychological symptoms, and stress-related biomarkers.Methods: We recruited healthy women who had no experience with yoga. The data of 24 participants who were followed during 12 weeks of yoga training were analyzed. Somatization and psychological symptoms were assessed before and after 12 weeks of yoga training using the Profile of Mood State (POMS) and the Symptom Checklist-90-Revised (SCL-90-R) questionnaires. Urinary 8-hydroxydeoxyguanosine (8-OHdG), biopyrrin, and cortisol levels were measured as stress-related biomarkers. The Wilcoxon signed-rank test was used to compare the stress-related biomarkers and the scores of questionnaires before and after 12 weeks of yoga training.Results: After 12 weeks of yoga training, all negative subscale scores (tension-anxiety, depression, anger-hostility, fatigue, and confusion) from the POMS and somatization, anxiety, depression, and hostility from the SCL-90-R were significantly decreased compared with those before starting yoga training. Contrary to our expectation, the urinary 8-OHdG concentration after 12 weeks of yoga training showed a significant increase compared with that before starting yoga training. No significant changes were observed in the levels of urinary biopyrrin and cortisol after the 12 weeks of yoga training.Conclusions: Yoga training has the potential to reduce the somatization score and the scores related to mental health indicators, such as anxiety, depression, anger, and fatigue. The present findings suggest that yoga can improve somatization and mental health status and has implications for the prevention of psychosomatic symptoms in healthy women.Trial registration: University Hospital Medical Information Network (UMIN CTR) UMIN000007868..
19. Hiroaki Kawamichi, Akihiro T. Sasaki, Masahiro Matsunaga, Kazufumi Yoshihara, Haruka K. Takahashi, Hiroki C. Tanabe, Norihiro Sadato, Medial Prefrontal Cortex Activation Is Commonly Invoked by Reputation of Self and Romantic Partners, PloS one, 10.1371/journal.pone.0074958, 8, 9, 2013.09, The reputation of others influences partner selection in human cooperative behaviors through verbal reputation representation. Although the way in which humans represent the verbal reputations of others is a pivotal issue for social neuroscience, the neural correlates underlying the representation of verbal reputations of others are unclear. Humans primarily depend on self-evaluation when assessing reputation of self. Likewise, humans might primarily depend on self-evaluation of others when representing their reputation. As interaction promotes the formation of more nuanced, individualized impressions of an interaction partner, humans tend to form self-evaluations of persons with whom they are intimate in their daily life. Thus, we hypothesized that the representation of reputation of others is modulated by intimacy due to one's own evaluation formation of that person. To test this hypothesis, we conducted a functional magnetic resonance imaging experiment with 11 pairs of romantic partners while they viewed an evaluation of a target person (self, partner [intimate other], or stranger [non-intimate other]), made by other evaluators. When compared with strangers, viewing evaluations of self and partner activated overlapping regions in the medial prefrontal cortex. Verbal reputation of self-specific activation was found in the precuneus, which represents self-related processing. The data suggest that midline structures represent reputation of self. In addition, intimacy-modulated activation in the medial prefrontal cortex suggests that the verbal reputation of intimate others is represented similarly to reputation of self. These results suggest that the reputation representation in the medial prefrontal cortex is engaged by verbal reputation of self and intimate others stemming from both own and other evaluators' judgments..
20. Yasunari Asano, Tetsuya Hiramoto, Ryo Nishino, Yuji Aiba, Tae Kimura, Kazufumi Yoshihara, Yasuhiro Koga, Nobuyuki Sudo, Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice, American Journal of Physiology - Gastrointestinal and Liver Physiology, 10.1152/ajpgi.00341.2012, 303, 11, G1288-G1295, 2012.12, There is increasing interest in the bidirectional communication between the mammalian host and prokaryotic cells. Catecholamines (CA), candidate molecules for such communication, are presumed to play an important role in the gut lumen; however, available evidence is limited because of the lack of actual data about luminal CA. This study evaluated luminal CA levels in the gastrointestinal tract and elucidated the involvement of gut microbiota in the generation of luminal CA by comparing the findings among specific pathogen-free mice (SPF-M), germ-free mice (GF-M), and gnotobiotic mice. Substantial levels of free dopamine and norepinephrine were identified in the gut lumen of SPF-M. The free CA levels in the gut lumen were lower in GF-M than in SPF-M. The majority of CA was a biologically active, free form in SPF-M, whereas it was a biologically inactive, conjugated form in GF-M. The association of GF-M with either Clostridium species or SPF fecal flora, both of which have abundant β-glucuronidase activity, resulted in the drastic elevation of free CA. The inoculation of E. coli strain into GF-M induced a substantial amount of free CA, but the inoculation of its mutant strain deficient in the β-glucuronidase gene did not. The intraluminal administration of DA increased colonic water absorption in an in vivo ligated loop model of SPF-M, thus suggesting that luminal DA plays a role as a proabsorptive modulator of water transport in the colon. These results indicate that gut microbiota play a critical role in the generation of free CA in the gut lumen..
21. Kazufumi Yoshihara, Tetsuya Hiramoto, Nobuyuki Sudo, Chiharu Kubo, Profile of mood states and stress-related biochemical indices in long-term yoga practitioners, BioPsychoSocial Medicine, 10.1186/1751-0759-5-6, 5, 2011.06, Background: Previous studies have shown the short-term or intermediate-term practice of yoga to be useful for ameliorating several mental disorders and psychosomatic disorders. However, little is known about the long-term influences of yoga on the mental state or stress-related biochemical indices. If yoga training has a stress-reduction effect and also improves an individual's mental states for a long time, long-term yoga practitioners may have a better mental state and lower stress-related biochemical indices in comparison to non-experienced participants. This study simultaneously examined the differences in mental states and urinary stress-related biochemical indices between long-term yoga practitioners and non-experienced participants.Methods: The participants were 38 healthy females with more than 2 years of experience with yoga (long-term yoga group) and 37 age-matched healthy females who had not participated in yoga (control group). Their mental states were assessed using the Profile of Mood States (POMS) questionnaire. The level of cortisol, 8-hydroxydeoxyguanosine (8-OHdG) and biopyrrin in urine were used as stress-related biochemical indices.Results: The average self-rated mental disturbance, tension-anxiety, anger-hostility, and fatigue scores of the long-term yoga group were lower than those of the control group. There was a trend toward a higher vigor score in the long-term yoga group than that in the control group. There were no significant differences in the scores for depression and confusion in the POMS between the two groups. The urine 8-OHdG concentration showed a trend toward to being lower in the long-term yoga group in comparison to the control group. There were no significant differences in the levels of urine biopyrrin or cortisol.Conclusions: The present findings suggest that long-term yoga training can reduce the scores related to mental health indicators such as self-rated anxiety, anger, and fatigue..
22. Tomokazu Furukawa, Hiroshi Nakano, Kenji Hirayama, Tokusei Tanahashi, Kazufumi Yoshihara, Nobuyuki Sudo, Chiharu Kubo, Sankei Nishima, Relationship between snoring sound intensity and daytime blood pressure, Sleep and Biological Rhythms, 10.1111/j.1479-8425.2010.00455.x, 8, 4, 245-253, 2010.10, We hypothesized that snoring sound intensity may be associated with daytime blood pressure independent of sleep apnea. We aimed to test this hypothesis in a cross-sectional study. The study subjects comprised 515 patients who underwent polysomnography (PSG) for suspected obstructive sleep apnea (OSA) syndrome. Blood pressure was measured in the seated position at rest during the first hospital visit. Snoring sound intensity was assessed by the highest one percentile ambient sound pressure level (L1) while the patient slept during PSG. Of these, 378 patients who had no antihypertensive medication with sufficient data were included in our analysis. We classified the subjects into a non-to-mild OSA group (n= 200; apnea-hypopnea index: AHI < 15) and a moderate-to-severe OSA group (n= 178; AHI ≥ 15). L1 was correlated with both systolic and diastolic blood pressure (r = 0.30 [P < 0.0001] and r = 0.40 [P < 0.0001], respectively) in all of the subjects. A multivariate regression analysis showed L1 to be significantly associated with both the systolic and diastolic blood pressure after adjusting for AHI and other confounding factors (P= 0.017 and P= 0.012, respectively) only in the non-to-mild OSA group. Snoring sound intensity may be independently associated with daytime blood pressure in patients with either primary snoring or mild OSA..
23. Tetsuya Hiramoto, Takakazu Oka, Kazufumi Yoshihara, Chiharu Kubo, Pyrogenic cytokines did not mediate a stress interview-induced hyperthermic response in a patient with psychogenic fever, Psychosomatic Medicine, 10.1097/PSY.0b013e3181bfb02b, 71, 9, 932-936, 2009.01, 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°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°C and it began to increase immediately after commencement of the interview, reaching a maximum of 37.42°C 20 minutes after the end of the interview. The plasma level of prostaglandin E2 and the serum interleukin-6 level were increased 90 minutes after the interview. Serum levels of interleukin-1α, interleukin-1β, and macrophage inflammatory protein-1α 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°C) and cold (20°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..
24. Kazufumi Yoshihara, Chiharu Kubo, [Psychosomatic disorder and functional somatic syndrome]., Nippon rinsho. Japanese journal of clinical medicine, 67, 9, 1652-1658, 2009.01, 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..
25. Tetsuya Hiramoto, Yoichi Chida, Junko Sonoda, Kazufumi Yoshihara, Nobuyuki Sudo, Chiharu Kubo, The Hepatic Vagus Nerve Attenuates Fas-Induced Apoptosis in the Mouse Liver via α7 Nicotinic Acetylcholine Receptor, Gastroenterology, 10.1053/j.gastro.2008.03.005, 134, 7, 2122-2131, 2008.06, 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 α7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl2MDP), 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-Cl2MDP. 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 α7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species..
26. Sun X, Somada S, Shibata K, Muta H, Yamada H, Yoshihara K, Honda K, Nakamura K, Takayanagi R, Tani K, Podack ER, Yoshikai Y., A critical role of CD30 ligand/CD30 in controlling inflammatory bowel diseases in mice., Gastroenterology., 134:447-58, 2008.02.
27. Kazufumi Yoshihara, Hisakata Yamada, Akiko Hori, Toshiki Yajima, Chiharu Kubo, Yasunobu Yoshikai, IL-15 exacerbates collagen-induced arthritis with an enhanced CD4+ T cell response to produce IL-17, European Journal of Immunology, 10.1002/eji.200737229, 37, 10, 2744-2752, 2007.10, IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4+ T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4+ Tcells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4+ T cells. in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4+ T cells..
28. Xun Sun, Hisakata Yamada, Kazufumi Yoshihara, Akira Awaya, Yasunobu Yoshikai, In vivo treatment with a nonapeptide thymic hormone, facteur thymique serique (FTS), ameliorates chronic colitis induced by dextran sulphate sodium in mice, International Immunopharmacology, 10.1016/j.intimp.2007.02.014, 7, 7, 928-936, 2007.07, Facteur thymique serique (FTS), a thymic hormone with nonapeptide is involved in T cell differentiation in intestine. Here we investigated the effect of FTS on dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were subcutaneously treated with 1 μg/mouse/day of FTS daily. FTS did not affect the course of acute colitis induced by DSS as assessed by survival rate, clinical activity of diseases, extent of tissue damage of colons. On the other hand, FTS significantly ameliorated chronic colitis induced by multiple cycles of DSS as reflected by lower lethality, weight loss, clinical scores and histological scores. The levels of interferon (IFN)-γ, interleukin 1(IL-1)-β, and IL-12p40 in the culture supernatants of lamina propria (LP) cells of colon without any stimulation and IFN-γ by T cells in the LP T cells under T cell receptor (TCR) triggering were reduced in FTS-treated mice, whereas the levels of IL-10 by LP cells and LPT cells were higher in FTS-treated mice. Thus, FTS may serve to suppress inflammation in DSS-induced chronic colitis accompanied by increased IL-10 production..
29. Kazufumi Yoshihara, Chiharu Kubo, Overview of medical treatment and management of chronic fatigue syndrome, Nippon rinsho. Japanese journal of clinical medicine, 65, 6, 1077-1081, 2007.06, A tailor-made management plan that includes various combinations of non-pharmacologic and pharmacologic therapy for patients with chronic fatigue syndrome (CFS) is important. We present an overview of four aspects of our medical treatment and management for CFS: introduction of our medical management system, summary of our management strategy, non-pharmacologic therapy, and pharmacologic therapy; according to foreign guidelines and the latest studies. The main non-pharmacologic therapies for CFS are rehabilitation and lifestyle guidance. Using a graded exercise therapy, we have constructed a broad management strategy for CFS. Herein we introduce our graded exercise therapy. If the symptoms continue despite careful management of the program by the physician, consultation with a psychiatrist or psychosomatic medicine specialist is necessary..
30. K. Yoshihara, Toshiki Yajima, C. Kubo, Y. Yoshikai, Role of interleukin 15 in colitis induced by dextran sulphate sodium in mice, Gut, 10.1136/gut.2005.076000, 55, 3, 334-341, 2006.03, Background and aims: Interleukin (IL)-15 is a member of the IL-2 family, stimulating dendritic cells, natural killer (NK) cells, NK T cells and memory CD8+ T cells. IL-15 levels were elevated in the intestinal mucosa of inflammatory bowel diseases. Here we investigated the involvement of IL-15 in the pathogenesis of acute and chronic dextran sulphate sodium (DSS) induced colitis. Methods: IL-15 knockout (KO) mice and control C57BL/6 mice were used to induce colitis with DSS in their drinking water. Survival rate, clinical activity of diseases, extent of tissue damage, leucocyte population, and cytokine production of lamina propria (LP) cells of the large intestines were assessed. Results: IL-15 KO mice exhibited resistance to DSS induced acute colitis, as reflected by lower lethality, weight loss, clinical scores, and histological scores compared with those in control mice (p<0.05). The proportions of CD44high CD8+ T cells and NK cells in LP cells and levels of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, and IL-12p40 in culture supernatants of LP cells were reduced in IL-15 KO mice (p<0.05). In vivo depletion of CD8+ T cells and NK cells decreased levels of IFN-γ, TNF-α, and IL-12p40 in culture supernatants of LP cells in C57BL/6 mice (p<0.01). In chronic colitis, weight loss and clinical scores were improved and levels of IFN-γ, TNF-α, and IL-12p40 in culture supernatants of LP cells were also reduced in IL-15 KO mice (p<0.05). Conclusions: IL-15 plays an important role in the pathogenesis of both acute and chronic colitis induced by DSS in mice..
31. Toshiki Yajima, Kazufumi Yoshihara, Kenji Nakazato, Shino Kumabe, Shigeo Koyasu, Subash Sad, Hao Shen, Hiroyuki Kuwano, Yasunobu Yoshikai, IL-15 regulates CD8+ T cell contraction during primary infection, Journal of Immunology, 10.4049/jimmunol.176.1.507, 176, 1, 507-515, 2006.01, During the course of acute infection with an intracellular pathogen, Ag-specific T cells proliferate in the expansion phase, and then most of the T cells die by apoptosis in the following contraction phase, but the few that survive become memory cells and persist for a long period of time. Although IL-15 is known to play an important role in long-term maintenance of memory CD8+ T cells, the potential roles of IL-15 in CD8+ T cell contraction are not known. Using an adoptive transfer system of OT-I cells expressing OVA257-264/Kb-specific TCR into control, IL-15 knockout (KO) and IL-15 transgenic (Tg) mice followed by challenge with recombinant Listeria monocytogenes expressing OVA, we found that the survival of CD44+CD62L-CD127- effector OT-I cells during the contraction phase is critically dependent on IL-15. In correlation with the expression level of Bcl-2 in OT-I cells, the number of OT-I cells was markedly reduced in IL-15 KO mice but remained at a high level in IL-15 Tg mice during the contraction phase, compared with control mice. In vivo administration of rIL-15 during the contraction phase in IL-15 KO mice inhibited the contraction of effector OT-I cells accompanied by up-regulation of Bcl-2 expression. Furthermore, enforced expression of Bcl-2 protected the majority of effector OT-I cells from death in IL-15 KO mice after infection. These results suggest that IL-15 plays a critical role in protecting effector CD8+ T cells from apoptosis during the contraction phase following a microbial infection via inducing antiapoptotic molecules..