Involvement of G-CSF, IL-6, and cortisol in transient neutrophilia after marathon races.

OBJECTIVES: The aim of this study was to clarify the mechanisms of the transient increase in neutrophils after running standard marathon races by measurement of cytokines involved in the production and survival of neutrophils, and cortisol. METHODS: Fourteen male runners who participated in the Hokkaido Marathon, which is the sole marathon race held in summer in Japan, and finished the standard marathon were analyzed sequentially from the start until a maximum of 8 days after the finish. RESULTS: Neutrophilia was observed in all runners just after they reached the goal (mean neutrophils: 13 226/µL). IL-6, G-CSF, and cortisol, but not GM-CSF, increased at the same time. Time-course studies with complete blood counts, biochemical markers, cytokines, and cortisol showed transient increases in neutrophils, monocytes, myoglobin, high-sensitivity C-reactive protein (hsCRP), G-CSF, IL-6, and cortisol. The increase in hsCRP was delayed 6 hours from the first increase in neutrophils. Correlations were observed between the neutrophil count and G-CSF, IL-6, and cortisol (G-CSF; r = .667, IL-6; r = .667, cortisol; r = .623). CONCLUSION: These results suggest that G-CSF is directly involved, and IL-6 is involved via cortisol in the transient neutrophilia that occurs after marathon races.

Mediators of the effects of rice intake on health in individuals consuming a traditional Japanese diet centered on rice.

Although the Japanese diet is believed to be balanced and healthy, its benefits have been poorly investigated, especially in terms of effects on mental health. We investigated dietary patterns and physical and mental health in the Japanese population using an epidemiological survey to determine the health benefits of the traditional Japanese diet. Questionnaires to assess dietary habits, quality of life, sleep quality, impulsivity, and depression severity were distributed to 550 randomly selected middle-aged and elderly individuals. Participants with any physical or mental disease were excluded. Two-hundred and seventy-eight participants were selected for the final statistical analysis. We determined rice to be one of the most traditional foods in Japanese cuisine. Scores for each questionnaire were computed, and the correlations between rice intake and health indices were assessed. When analyzing the direct correlations between rice intake and health indices, we found only two correlations, namely those with quality of life (vitality) and sleep quality. Path analysis using structural equation modeling was performed to investigate the association between rice intake and health, with indirect effects included in the model. Additional associations between rice intake and health were explained using this model when compared to those using direct correlation analysis. Path analysis was used to identify mediators of the rice-health association. These mediators were miso (soybean paste) soup, green tea, and natto (fermented soybean) intake. Interestingly, these mediators have been major components of the Japanese diet since 1975, which has been considered one of the healthiest diets since the 1960s. Our results indicate that the combination of rice with other healthy foods, which is representative of the traditional Japanese diet, may contribute to improvements in physical and mental health.

Contrasting associations of body mass index and measles with asthma and rhinitis in young adults.

Asthma and allergic rhinitis often coexist and are increasing worldwide, particularly among the younger generation. Although the prevalences of adult asthma and allergic rhinitis and their risk factors have been reported, there have been few studies focusing on young adults. The aim of this study was to evaluate the prevalences of asthma and allergic rhinitis and their associated factors in Japanese young adults. A questionnaire survey of new students at Hokkaido University about the presence of current wheeze and rhinitis and a history of several viral infections during childhood was conducted in 2008 and 2010. The prevalences of wheeze and rhinitis and their associated factors were evaluated. Of 4076 nonsmoking subjects aged 18-25 years, 261 (6.4%) had current wheeze and 1373 (33.7%) had allergic rhinitis. On multivariate analyses, current wheeze was associated with high body mass index (BMI), atopic dermatitis, allergic rhinitis, food allergy, and a history of measles infection. In contrast, allergic rhinitis was associated with low BMI, current wheeze, atopic dermatitis, food allergy, and no history of measles. When subjects were classified into four groups by the presence or absence of wheeze and rhinitis, both high BMI and a history of measles were positively associated with wheeze without rhinitis but negatively associated with rhinitis without wheeze. High BMI and past measles infection showed contrasting associations with asthma and allergic rhinitis in nonsmoking young adults. It is important to not only recognize the common pathophysiological characteristics of asthma and allergic rhinitis but also to understand their differences.

[Sensitization to laboratory animal allergens among students and researchers exposed to laboratory rodents in Hokkaido university].

BACKGROUND: Based on a case who developed anaphylaxis after mouse bite which occurred at Hokkaido University, we studied on allergic sensitization prevalence for laboratory animals among students and researchers who are exposed to laboratory rodents and rabbit, for the purpose of allergy prevention, particularly anaphylaxis. METHODS: We carried out the health check-up on laboratory animal allergy (LAA) by questionnaires and specific-IgE antibody test for 555 rodents and/or rabbit handlers from whom informed consent was obtained. RESULT: Prevalence of positive IgE antibody higher than class 1 to mice, rats, hamsters, guinea pigs, and/or rabbits in the examinees was 14.1% (62/441) , 17.9% (50/279) , 18.8% (6/32) , 17.4% (4/23) , and 11.3% (12/106) , respectively. Moreover, among users of mouse, those who had allergic symptoms during contact with animals resulted in significantly higher positive rate for anti-mouse IgE antibody test than the other (38.1% vs 8.8%, p<0.01) . CONCLUSION: Health check-up including measurement of specific-IgE antibody against laboratory animals is useful for understanding allergic sensitization.

Serum DJ-1 level is positively associated with improvements in some aspects of metabolic syndrome in Japanese women through lifestyle intervention.

DJ-1 is a protein that is associated with Parkinson disease and cancer, and the reduction of DJ-1 function and expression is also thought to be a cause of diabetes and hypertension. However, little is known about the association between the plasma concentration of DJ-1 and risk of metabolic syndrome. We hypothesized that a lifestyle intervention would increase serum DJ-1 and that up-regulated DJ-1 functions will result in the prevention of metabolic syndrome. The objective of our study is to examine whether the level of serum DJ-1 is associated with the risk of metabolic syndrome. Therefore, to reveal the association between DJ-1 and metabolic syndrome, this study investigated lifestyle intervention in a control group (n = 37) and intervention group (n = 45). The results showed that body mass index, body fat ratio, waist-hip ratio, waist circumference, blood pressure, and plasma glucose level were improved in the intervention group, as compared with those in the control group. Furthermore, serum levels of DJ-1 were increased in the intervention group, when compared with those in the control group. These results suggest that serum DJ-1 is increased by lifestyle intervention and that increased serum DJ-1 prevents metabolic syndrome. Thus, the level of serum DJ-1 will become one of the indexes for the risk of metabolic syndrome.

Non-superiority of Kakkonto, a Japanese herbal medicine, to a representative multiple cold medicine with respect to anti-aggravation effects on the common cold: a randomized controlled trial.

OBJECTIVE: Kakkonto, a Japanese herbal medicine, is frequently used to treat the common cold not only with a physician's prescription, but also in self-medication situations. This study aimed to examine whether Kakkonto prevents the aggravation of cold symptoms if taken at an early stage of illness compared with a well-selected Western-style multiple cold medicine. METHODS: This study was a multicenter, active drug-controlled, randomized trial. Adults 18 to 65 years of age who felt a touch of cold symptoms and visited 15 outpatient healthcare facilities within 48 hours of symptoms onset were enrolled. The participants were randomly assigned to two groups: one treated with Kakkonto (Kakkonto Extract-A, 6 g/day) (n=209) and one treated with a Western-style multiple cold medicine (Pabron Gold-A, 3.6 g/day) (n=198) for at most four days. The primary outcome of this study was the aggravation of cold, nasal, throat or bronchial symptoms, scored as moderate or severe and lasting for at least two days within five days after entry into the study. RESULTS: Among the 410 enrollees, 340 (168 in the Kakkonto group and 172 in the Pabron group) were included in the analyses. The proportion of participants whose colds were aggravated was 22.6% in the Kakkonto group and 25.0% in the Pabron group (p=0.66). The overall severity of the cold symptoms was not significantly different between the groups. No harmful adverse events occurred in either group. CONCLUSION: Kakkonto did not significantly prevent the progression of cold symptoms, even when prescribed at an early stage of the disease.

[Intestinal bleeding in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors].

Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of chronic myelogenous leukemia (CML), but there have been a few adverse event reports describing gastrointestinal bleeding. We clinically analyzed two patients who developed intestinal bleeding during the administration of TKIs for CML. Platelet counts of both patients were normal. The patients showed endoscopic findings characterized by mildly hemorrhagic mucosa. The imatinib patient was diagnosed by capsule endoscopy of the small intestine, and required frequent blood transfusions. The dasatinib patient showed occult bleeding due to CD8-positive colitis. We should adequately recognize that gastrointestinal bleeding may occur during the administration of TKIs.

Biphenotypic Acute Leukemia with t(15;17) Lacking Promyelocytic-retinoid Acid Receptor α Rearrangement.

Biphenotypic acute leukemias (BAL) account for less than 4% of all cases of acute leukemia. Philadelphia chromosome and 11q23 rearrangement are the most frequently found cytogenetic abnormalities. Since t(15;17) is almost always associated with acute promyelocytic leukemia, t(15;17) in BAL cases is extremely uncommon. We report here a rare and instructive case of BAL with t(15;17) and the successful treatment approach adopted. A 55-year old woman was referred to our hospital for an examination of elevated white blood cell (WBC) counts with blasts (WBC 13.4×10(9)/L; 76% blasts). The blasts with acute lymphoblastic leukemia (ALL-L2, FAB) morphology co-expressed B-lymphoid and myeloid lineages, and a cytogenetic study revealed 4q21 abnormalities and t(15;17). However, promyelocytic-retinoid acid receptor α rearrangement was not detected by fluorescence in situ hybridization on interphase nuclei. Our patient was treated with chemotherapy for ALL and gemtuzumab ozogamicin without all-trans-retinoic acid, and has remained in hematologic first complete remission for more than 3.7 years.

Reliability and validity of Kano Test for Social Nicotine Dependence (KTSND), and development of its revised scale assessing the psychosocial acceptability of smoking among university students.

PURPOSE: To examine reliability and validity of Kano Test for Social Nicotine Dependence (KTSND), a scale assessing the psychosocial acceptability of smoking, and to develop a new version when validity or reliability of KTSND was not acceptable. METHODS: We carried out a self-administered cross-sectional survey on undergraduate university students. The participants completed the KTSND, and supplemented three questions on the attitudes toward tobacco control policies and smoking states. Using daily smokers, we examined the relationship between the KTSND and Fagerström Test for Nicotine Dependence (FTND). In each study, we examined test-retest reliability and construct validity, discriminant and convergent validity, and factor validity. RESULTS: Although the KTSND had high internal consistency (Cronbach's a 0.82) and high test-retest reliability (r=0.72), the results of factor analysis were unacceptable; we expected three factors to be extracted, however, only two factors of "Overestimate of smoking usefulness" and "Allege smoking as a taste and/or culture" were extracted. Using the Kano's Test for Assessing Acceptability of Smoking (KTAAS), the new version of KTSND in which a question was replaced with another one, the third factor of "Neglect of harm of tobacco smoking" was extracted adding to the above-mentioned two. KTAAS had also both high internal consistency (Cronbach's alpha 0.82) and test-retest reliability (r=0.66). Overall, the KTSND and the KTAAS score differed according to smoking states, and the nonsmokers' scores were the lowest. CONCLUSION: The KTSND was a popular questionnaire in Japan, however, its validity assessed using factor analysis was not acceptable, while KTAAS had sufficient reliability and validity, and might assess the cognition and attitude affirming or accepting tobacco smoking among university students.

p53 transactivation is involved in the antiproliferative activity of the putative tumor suppressor RBM5.

RBM5 (RNA-binding motif protein 5) is a nuclear RNA binding protein containing 2 RNA recognition motifs. The RBM5 gene is located at the tumor suppressor locus 3p21.3. Deletion of this locus is the most frequent genetic alteration in lung cancer, but is also found in other human cancers. RBM5 is known to induce apoptosis and cell cycle arrest but the molecular mechanisms of RBM5 function are poorly understood. Here, we show that RBM5 is important for the activity of the tumor suppressor protein p53. Overexpression of RBM5 enhanced p53-mediated inhibition of cell growth and colony formation. Expression of RBM5 augmented p53 transcriptional activity in reporter gene assays and resulted in increased mRNA and protein levels for endogenous p53 target genes. In contrast, shRNA-mediated knockdown of endogenous RBM5 led to decreased p53 transcriptional activity and reduced levels of mRNA and protein for endogenous p53 target genes. RBM5 affected protein, but not mRNA, levels of endogenous p53 after DNA damage suggest that RBM5 contributes to p53 activity through post-transcriptional mechanisms. Our results show that RBM5 contributes to p53 transcriptional activity after DNA damage and that growth suppression and apoptosis mediated by RBM5 are linked to activity of the tumor suppressor protein p53.

Risks of chest X-ray examination for students.

Chest X-ray (CXR) examination is considered essential for health checkups of students;thus, it is important to objectively assess the CXR for a better understanding of the appropriate X-ray exposure dose, and the risks such an examination entails. Accordingly, we performed a multi-institutional study regarding students' CXR exposure, during a 6year-period from 2002 (partially including 2001) to 2007, with the collaboration of national, municipal, and private universities and colleges in Japan. A glass badge was worn by the students at the time of CXR screening examination. These glass badges were collected, and their X-ray exposure doses were measured. The results indicated a tendency of decreasing exposure dose over the 6 years, though the difference was not significant. In a comparison of the chest X-ray systems within institutions (own X-ray equipmentinside systems) with those outside the institution (mobile X-ray equipmentoutside systems), the average exposure dose with the outside systems exceeded that of the inside systems. Both inside and outside systems included a few X-ray machines with which the exposure was more than 1mSv. Based on these facts, individuals in charge of student health checkups should be aware of the exposure dose of each chest fluorographic system at their institution.

Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse.

Infection with cagA-positive Helicobacter pylori is associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma of B cell origin. The cagA-encoded CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system and, upon tyrosine phosphorylation by Src family kinases, specifically binds to and aberrantly activates SHP-2 tyrosine phosphatase, a bona fide oncoprotein in human malignancies. CagA also elicits junctional and polarity defects in epithelial cells by interacting with and inhibiting partitioning-defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) independently of CagA tyrosine phosphorylation. Despite these CagA activities that contribute to neoplastic transformation, a causal link between CagA and in vivo oncogenesis remains unknown. Here, we generated transgenic mice expressing wild-type or phosphorylation-resistant CagA throughout the body or predominantly in the stomach. Wild-type CagA transgenic mice showed gastric epithelial hyperplasia and some of the mice developed gastric polyps and adenocarcinomas of the stomach and small intestine. Systemic expression of wild-type CagA further induced leukocytosis with IL-3/GM-CSF hypersensitivity and some mice developed myeloid leukemias and B cell lymphomas, the hematological malignancies also caused by gain-of-function SHP-2 mutations. Such pathological abnormalities were not observed in transgenic mice expressing phosphorylation-resistant CagA. These results provide first direct evidence for the role of CagA as a bacterium-derived oncoprotein (bacterial oncoprotein) that acts in mammals and further indicate the importance of CagA tyrosine phosphorylation, which enables CagA to deregulate SHP-2, in the development of H. pylori-associated neoplasms.

Effect of imatinib mesylate combined with granulocyte colony-stimulating factor on leukaemic blast cells derived from advanced-stage chronic myelogenous leukaemia patients.

Neutropenia is a severe adverse effect that can occur when treating patients with imatinib mesylate for advanced-stage chronic myelogenous leukaemia (CML). Therefore, we evaluated in vitro the combined effect of imatinib and granulocyte colony-stimulating factor (G-CSF) on proliferation and apoptosis of Bcr-Abl-expressing leukaemic cells to infer the safety of G-CSF administration. In KU812 and K562 cell lines, G-CSF neither stimulated their proliferation nor abolished the suppressive effect of imatinib. However, it stimulated the proliferation of blast cells in 2 out of the 5 cases with advanced-stage CML. These in vitro studies appear to provide data for the decision of G-CSF administration in combination with imatinib in the treatment of neutropenic patients with advanced-stage CML.

[Current status of treatment for patients with idiopathic thrombocytopenic purpura in the Hokkaido area (evaluation of Helicobacter pylori eradication)].

Treatment guidelines for patients with idiopathic thrombocytopenic purpura (ITP) have been changed recently due to the clinical application of Helicobacter pylori (H. pylori) eradication but there has been no detailed multi-center analysis of the hematological effects of H. pylori eradication. The Clinical Hematology Forum consists of 11 large hematological departments and divisions in the Hokkaido area. We sent questionnaires to these 11 hematological departments and divisions in March 2003 to obtain information on current treatment strategies for patients with ITP and hematological results after the eradication of H. pylori. Questionnaires were returned by 9 (81.8%) of the 11 departments. Doctors in all hospitals had experience in diagnosis and treatment of H. pylori infection. Diagnostic examinations for H. pylori infection were performed in 54.3% of the registered cases. H. pylori infection was detected in 68.1% of the examined cases, and eradication treatment was performed in 87.7% of H. pylori-positive patients. H. pylori was eradicated in 52 (83.9%) of the 62 patients in whom the results of treatment could be evaluated. Among the patients whose platelet counts were less than 10.0 x 10(4)/microl, platelet recovery was observed in 48.8% of cases with successful eradication, a percentage similar to previously reported percentages in Japan. There was no prognostic factor to predict good responders before eradication treatment. Since the side effects of eradication treatment, including gastrointestinal symptoms and skin eruptions, were not serious, this method might become a front-line treatment for patients with ITP. Patient selection for eradication as an up-front treatment, analysis of the pathophysiology of platelet recovery after eradication and long-term effects should be investigated to make new treatment guidelines for newly diagnosed patients with ITP.

[A survey on smoking behavior in Hokkaido University School of Medicine, 2003].

OBJECTIVE: A survey was carried out to assess smoking among students, and administration and teaching staff in Hokkaido University School of Medicine in 2003. METHODS: We conducted a questionnaire survey on smoking of undergraduates, graduate students, administration personnel and teaching staff in Hokkaido University School of Medicine in February 2003. The majority of question items were targeted for all subjects while some items were addressed separately to smokers, ex-smokers and non-smokers. RESULTS AND DISCUSSION: The survey showed that 1) the smoking rate of the study subjects is lower than that of physicians, in general; 2) dependence on cigarettes among smokers is relatively low; and 3) 80% of the ex-smokers are in the maintenance stage, while 20% are in the action stage. Furthermore, 1) there was a tendency for smokers and non-smokers to be concerned with the health effects of passive smoking than that of active smoking; 2) smokers tended to ignore the unpleasant smell of cigarettes as compared with ex-smokers and non-smokers; 3) although the three groups acknowledged the health affects of smoking, they are not proactive in the promotion of anti-smoking; and 4) everyone is generally concerned with the smell of cigarettes but tended to accept it in the school of medicine. CONCLUSIONS: It is an important issue how smokers in the interested stage can move to the anti-smoking stage, and how those in the action stage shift to the maintenance stage. We have carried out anti-smoking events and campaigns on the campus based on the results of the survey and further plan to formulate a strategy for anti-smoking on the campus. The specific activities will be undertaken and the results evaluated in future.

Successful micafungin (FK463) treatment of invasive pulmonary aspergillosis in a patient with acute lymphoblastic leukemia in a phase II study.

We treated a 52-year-old woman with acute lymphoblastic leukemia (ALL) who developed invasive pulmonary aspergillosis (IPA) as a result of neutropenia following remission-induction chemotherapy. Although serological test results, such as those for platelia and pastrex, were all negative and the serum level of beta-D-glucan was low, Aspergillus DNA was detected in blood by the polymerase chain reaction method. A clinically documented diagnosis of IPA was made on the basis of chest x-rays, computed tomography scan findings, and the detection of Aspergillus DNA. Micafungin (FK463), a candin class antifungal agent, was administered at a dose of 75 to 150 mg/day, because other antifungal agents were not effective. The increase in serum concentration of micafungin was dose-dependent and was accompanied by improvement of symptoms and objective findings. Micafungin was effective for the treatment of IPA in this patient with ALL.