Keiki Ogino

Oxidative stress biomarkers and lifestyles in Japanese healthy people

The urinary concentrations of 8-isoprostane and 8-hydroxy-2’-deoxyguanosine (8-OHdG), which are biomarkers of oxidative stress, were measured in 677 Japanese people without any diseases, and their correlations with lifestyle facotrs, lifestyle-related blood biochemical parameters, and dietary intake of antioxidative vitamins were investigated. The mean urinary concentration of 8-isoprostane and 8-OHdG was 0.58 ng/mg creatinine and 8.43 ng/mg creatinine, respectively. Mean urinary 8-isoprostane was significantly different in terms of age, gender, smoking and alcohol consumption but not different in terms of body mass index (BMI) and exercise. By multiple regression analysis, urinary 8-isoprostane was significantly influenced by smoking and age. On the other hand, mean urinary 8-OHdG showed differences only by age group. Multiple regression analysis revealed that urinary 8-OHdG was significantly influenced by age, smoking, body weight, levels of high-sensitivity C-reactive protein (Hs-CRP) and low density lipoprotein-cholesterol in females, although it was significantly influenced by body weight in males. The present study shows that urinary 8-isoprostane is associated with lipid peroxidation related-lifestyles such as smoking, and urinary 8-OHdG is associated with arteriosclerosis related-factors such as Hs-CRP. Our findings suggest that 8-isoprostane and 8-OHdG appear to be prospective biomarkers for early prediction of lifestyle related-disease risk at the population level.

Relationship between indoor chemical concentrations and subjective symptoms associated with sick building syndrome in newly built houses in Japan

ObjectivesThis study explored possible associations between chemical substances and sick building syndrome (SBS)-type symptoms of residents living in new houses in Japan.MethodsWe randomly sampled 5,709 newly built conventional homes. In the end, 1,479 residents in 425 households completed a questionnaire survey and agreed to environmental monitoring for indoor aldehydes and volatile organic compounds (VOCs) to be conducted in their homes. If the residents had complained about at least one SBS-related symptom, they were classified as suffering from SBS. Multiple logistic regression analysis was used to select predictive chemical factors of SBS symptoms.ResultsAbout 14% of the subjects suffered from SBS. Many aldehydes and VOCs were associated factors of optical, nasal, and gular symptoms in univariate analysis. After adjustment for other possible risk factors, formaldehyde dose-dependently showed to be a significant risk factor for SBS. Several chemicals had tendency to be associated with SBS symptoms.ConclusionsChemicals detected in Japanese newly built houses tend to increase the risk of subjective symptoms in residents suffering from SBS.

c-Kit-Targeting Immunotherapy for Hereditary Melanoma in a Mouse Model

The role of c-Kit in the development of melanoma was studied in line 304/B6 of RET-transgenic mice, in which melanoma spontaneously develops. In Wv/Wv-RET (304/B6)-transgenic mice, in which c-Kit function was severely impaired, development of melanoma was strongly suppressed. Although 31 of the 44 original RET-transgenic mice died of rapidly growing melanoma within 12 months after birth, only 8 of the 44 Wv/Wv-RET-transgenic mice developed slowly growing melanocytic tumors with a greatly prolonged mean tumor-free period, 2 of which died of melanoma at a late stage. Even Wv/+-RET-transgenic mice had a clearly prolonged tumor-free period and definitely reduced frequency (6 of 61) of tumor death within 12 months after birth. Melanin production in the skin of these mice was not strongly impaired, suggesting that c-Kit affects the development of melanomas in these mice with only minor effects in melanin production. c-Kit expression in skin soon after birth was promoted in RET-transgenic mice, and c-Kit was expressed at high levels at the benign but not malignant stage of the tumor. A single injection of anti-c-Kit antibody (ACK2) into RET-transgenic mice soon after birth caused a surprisingly long-lasting suppression of development of melanoma, greatly prolonging the tumor-free period, and none of the 28 ACK2-treated RET-transgenic mice died from tumors at 12 months of age. The c-Kit function needed for melanin production was also suppressed for an unusually long time in ACK2-treated, RET-transgenic mice. These results suggest that c-Kit can be a unique target molecule for melanoma treatment.

NATURAL KILLER (NK) CELL ACTIVITY AND NK CELL SUBSETS IN WORKERS WITH A TENDENCY OF BURNOUT

The involvement of cellular immunity in the burnout syndrome remains to be elucidated. We assessed three components of burnout of the Maslach Burnout Inventory: emotional exhaustion; depersonalization (DP); and personal accomplishment, as well as natural killer cell activity (NKCA) and NK cell subsets in 42 male workers. Workers with a higher DP score showed a lower NKCA and a lower proportionality of CD57+CD16+ to total lymphocytes. There were no differences in any of the health behaviors (e.g., smoking, alcohol, or obesity) between workers showing higher burnout and those showing lower burnout. A stepwise multiple regressions analysis demonstrated that NKCA was closely correlated with DP, independent of other variables, including a stress index. These results suggest that the relationship between reduced cellular immunity and DP is not due to traditional work stress or health behavioral problems. Further studies on DP as a psychosomatic disorder as well as an occupational health problem should be performed in the future.

Nonthermal effects of mobile-phone frequency microwaves on uteroplacental functions in pregnant rats

Exposure to high-density microwaves can cause detrimental effects on the testis, eye, and other tissues, and induce significant biologic changes through thermal actions. To examine nonthermal effect of continuous wave (CW) 915MHz microwaves used in cellular phones, we compared the effects of microwaves with those of heat. Thirty-six pregnant rats were assigned to six groups: rats exposed to microwaves at 0.6 or 3mW/cm(2) incident power density at 915MHz for 90min, rats immersed in water at 38 or 40 degrees C, which induces about the same increase in colonic temperature of 1.0 or 3.5 degrees C as 0.6 or 3mW/cm(2) microwaves, respectively; rats immersed in water at 34 degrees C, which is considered to be thermoneutral; and control rats. We identified significant differences in the uteroplacental circulation, and in placental endocrine and immune functions between pregnant rats immersed in water at 34 and 38 degrees C, but not between rats immersed at 38 degrees C and those exposed to microwaves at 0.6mW/cm(2). By contrast, we observed significant decreases in uteroplacental blood flow and estradiol in rats exposed to microwaves at 3mW/cm(2) as compared with those immersed in water at 40 degrees C. These results suggest microwaves at 0.6mW/cm(2) at 915MHz, equal to a specific absorption rate (SAR) of 0.4W/kg, which is the maximum permissible exposure level recommended by the American National Standards Institute (ANSI), do not exert nonthermal effects on blood estradiol and progesterone, on splenic natural killer cell activity, on the uteroplacental circulation.

A longitudinal study of environmental risk factors for subjective symptoms associated with sick building syndrome in new dwellings.

This study was performed to explore possible environmental risk factors, including indoor chemicals, mold, and dust mite allergens, which could cause sick building syndrome (SBS)-type symptoms in new houses. The study was conducted in 2004 and 2005 and the final study population consisted of 86 men and 84 women residing in Okayama, Japan. The indoor concentrations of indoor aldehydes, volatile organic compounds, airborne fungi, and dust mite allergens in their living rooms were measured and the longitudinal changes in two consecutive years were calculated. A standardized questionnaire was used concomitantly to gather information on frequency of SBS-type symptoms and lifestyle habits. About 10% of the subjects suffered from SBS in the both years. Crude analyses indicated tendencies for aldehyde levels to increase frequently and markedly in the newly diseased and ongoing SBS groups. Among the chemical factors and molds examined, increases in benzene and in Aspergillus contributed to the occurrence of SBS in the logistic regression model. Indoor chemicals were the main contributors to subjective symptoms associated with SBS. A preventive strategy designed to lower exposure to indoor chemicals may be able to counter the occurrence of SBS.

Family History‐related Risk of Gastric Cancer in Japan: A Hospital‐based Case‐Control Study

In Japan, there have been a few reports on the familiar factors of gastric cancer (GC)and on the GC risk related to family history (FH) at other cancer sites. We analyzed the association between GC occurrence and a positive FH of cancer of the stomach and of other sites in a hospital‐based case‐control study. The subjects included cases histologically confirmed as incident cancer of the stomach (n=136; 86 male and 50 female patients) and sex and age (± 1 year)‐matched controls. GC risk was high when a subject had a parental history of GC [Mantel‐Haenszel odds ratio adjusted for sex and age (OR) =2.3; 95% confidence interval (95%CI):1.1–5.0]. GC risk was almost unity for a cancer FH of any other cancer site, even among closer relatives, suggesting little or no contribution to GC occurrence. The familial occurrence of GC found in this study suggests the existence of a genetic susceptibility to cancer of the stomach. Further, females tended to show higher GC risks than males, when reporting an affected mother (OR=6.0; 95%CI:1.1–31.4 and OR=1.4; 95%CI:0.4–4.8, respectively), whereas males showed a slightly higher risk than females when reporting an affected father (OR=2.4; 95%CI:0.8–7.5 and OR=2.3; 95%CI:0.4–15.6, respectively). This suggests a possible gender difference in how environmental factors influence GC occurrence. The development of gastric tumors seems to be due to a complex and unknown interaction between environmental and genetic factors.

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model

The expression of arginase I has been a focus of research into the pathogenesis of experimental asthma, because arginase deprives nitric oxide synthase (NOS) of arginine and therefore participates in the attenuation of bronchodilators such as nitric oxide (NO). The present study used an intranasal mite-induced NC/Nga mouse model of asthma to investigate the contribution of arginase to the asthma pathogenesis, using an arginase inhibitor, N(omega)-hydroxy-nor-l-arginine (nor-NOHA). The treatment with nor-NOHA inhibited the increase in airway hyperresponsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid. NOx levels in the lung were elevated despite suppressed NOS2 mRNA expression. Accompanied by the attenuated activity of arginase, the expression of arginase I at both the mRNA and protein level was downregulated. The levels of mRNA for T helper 2 cytokines such as IL-4, IL-5, and IL-13, and for chemotactants such as eotaxin-1 and eotaxin-2, were reduced. Moreover, the accumulation of inflammatory cells and the ratio of goblet cells in the bronchiole were decreased. The study concluded that the depletion of NO caused by arginase contributes to AHR and inflammation, and direct administration of an arginase inhibitor to the airway may be beneficial and could be of use in treating asthma due to its anti-inflammatory and airway-relaxing effects, although it is not clear whether the anti-inflammatory effect is direct or indirect.

Effect of sports activity on bone mineral density in wheelchair athletes

The present study carried out a measurement of body composition and a nutrition survey, targeting 28 male wheelchair athletes and comparing them with 25 male physically able healthy athletes as the controls. The DXA method was used to measure bone mineral density (BMD), percentage of body fat (% body fat), and lean body mass (LBM). Possible factors affecting the BMD of the wheelchair athletes with spinal injuries were analyzed including age, body part, type of sport, area of injury, length of injury, and the length of time it took before restarting sports activity after injury. BMD in the arms, body trunk, legs, and entire body was measured. There were no significant differences in the BMD of the wheelchair athletes by age group (from 20 to 29, from 30 to 39, and 40 years and older), by sports (basketball, track and field, and tennis), and by area of injury (high and low paraplegia). BMD in the legs (r = −0.549, P < 0.01), body trunk (r = −0.414, P < 0.05), and entire body (r = −0.452, P < 0.05) of the wheelchair athletes was negatively correlated with the period since injury; however, no such a relationship was observed in the arms. In addition, the multiple regression analysis for BMD of each body region showed that the earlier the wheelchair athletes restarted sports after injury, the higher values the BMD of legs (r = −0.467, P < 0.05), body trunk (r = −0.469, P < 0.05), and entire body (r = −0.488, P < 0.05), independent of age and sports. The leg BMD of the wheelchair athletes was lower than that of the physically able athletes, with a BMD 76.5% of the controls. The present study suggests that restarting sports activity in a timely manner after treatment and rehabilitation for the injury is useful in preventing loss of BMD in wheelchair athletes and ultimately improving their quality of life.

Allergic airway inflammation by nasal inoculation of particulate matter (PM2.5) in NC/Nga mice.

To evaluate the effect of airborne particulate matter 2.5 (PM2.5) in winter on airway inflammation, water-soluble supernatant (Sup) and water-insoluble precipitate (Pre) in PM2.5 were inoculated in NC/Nga mice with high sensitivity to mite allergens. Sup with aluminum oxide was injected intraperitoneally for sensitization. Five days later, Sup, Pre or both Sup and Pre were inoculated via the nasal route five times for more sensitization and a challenge inoculation on the 11th day in NC/Nga mice. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), BALF cell count and IL-1β concentration, mRNA expression of Th1 and Th2 cytokines, chemokines such as eotaxin 1 and eotaxin 2, inflammasomal complex molecules such as IL-1β, caspase 1 and the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) in lung tissue as well as histopathology. The synergistic effect of Sup and Pre was observed in terms of increases in AHR, BALF cells, the mRNA expression of IL-13, eotaxin1 and IL-1β, and the IL-1β concentration in BALF. Intracellular deposits of insoluble particulates were observed in macrophages around inflammatory granulation of the mouse group treated with Sup and Pre. These results suggest that PM2.5 can induce airway hyperresponsiveness in mice with genetically high sensitivity to mite allergens by an inflammasome-associated mechanism and synergistic action of insoluble particulates and soluble components.