Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis

Exposure to dioxins and polychlorinated biphenyls (PCBs) has been suggested as a possible etiologic factor for endometriosis, but the association remains highly controversial. To assess whether cytochrome P450 (CYP) gene polymorphisms modulate the effect of dioxins and/or PCBs in endometriosis risk, we conducted a case-control study among infertile Japanese women. A total of 138 eligible women aged 20-45 were diagnosed laparoscopically and classified into three subgroups: control (no endometriosis), early endometriosis (stages I-II) and advanced endometriosis (stages III-IV). Neither CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms (genotypes with versus genotypes without the minor allele) nor serum dioxin and PCB toxic equivalency (TEQ) levels (low versus high) were independently associated with either early or advanced endometriosis risk. However, genotypes with the CYP1A1 462Val allele showed a statistically significant reduced risk of advanced endometriosis in combination with high serum dioxin TEQ levels (adjusted odds ratio = 0.13, 95% confidence interval: 0.02-0.76) (P for interaction = 0.08). Although no association was found between serum PCB TEQ level and advanced endometriosis in any stratum of CYP1B1 Leu432Val polymorphism, a statistically significant interaction was found (P for interaction = 0.05). CYP1A1 and CYP1B1 polymorphisms may modify the relation between environmental exposure to organochlorine and advanced endometriosis risk.     

Cruciferous vegetables, mushrooms, and gastrointestinal cancer risks in a multicenter, hospital-based case-control study in Japan

We assessed the possible association of gastrointestinal cancers with cruciferous vegetables and mushrooms in a multicenter, hospital-based case-control study in an agricultural area of Japan. One hundred forty-nine cases and 287 controls for stomach cancer and 115 cases and 230 controls for colorectal cancer were matched by age, sex, and residential area. In stomach cancer, the protective effect of vegetables (consumption of total vegetable) was obscure, but it became clearer when we examined specific kinds of vegetables. Marginal associations were observed in the group of the highest consumption of Chinese cabbage (odds ratio [OR] = 0.61; 95% confidence interval [CI] = 0.35-1.07), broccoli (OR = 0.60; 95% CI = 0.34-1.08), Hypsizigus marmoreus (Bunashimeji) (OR = 0.57; 95% CI = 0.31-1.04) and Pholita nameko (Nameko) (OR = 0.56; 95% CI = 0.30-1.06). In colorectal cancer, we observed decreased risks from the highest tertile of total vegetables (OR = 0.22; 95% CI = 0.08-0.66) and low-carotene-containing vegetables (OR = 0.28; 95% CI = 0.08-0.77), and inverse associations were observed in the group of the highest consumption of broccoli (OR = 0.18; 95% CI = 0.06-0.58). Although the sample size was limited, subgroup analyses showed that the associations differed with the histopathological subtype. These findings suggest that cruciferous vegetables decrease the risk of both stomach and colorectal cancer, and that mushrooms are associated with a decreased risk of stomach cancer.     

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m²); normal (18.5-22.9 kg/m²); overweight (23-24.9 kg/m²); and obese (25+ kg/m²). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.     

Activation of Akt by mechanical stretching in human epidermal keratinocytes

Mechanical stretching represents an important part of the signaling in skin. We have previously demonstrated that mechanical stretching induced proliferative phenotypes in human keratinocytes, as shown in increased 5-bromo-2'-deoxyuridine (BrdU) incorporation, ERK1/2 activation, and keratin K6 induction. Here we have further investigated the antiapoptotic signals in human keratinocytes provoked by mechanical stretching in vitro. Keratinocytes were plated on flexible silicone supports to transmit mechanical stretching to keratinocytes, involving continuous stretching by +20%. Stretching of these cells for 15-30 min caused the phosphorylation and activation of Akt. Inhibition of mitogen and extracellular signal-regulated kinase (MEK1/2) with U0126 and phosphoinositide 3-OH kinase (PI 3-K) with Wortmannin attenuated Akt activation. The epidermal growth factor (EGF) receptor kinase inhibitor, AG1478, and calcium channel inhibitor, gadolinium (Gd3+), also inhibited Akt activation. In summary, our results demonstrate the activation of the Akt signaling pathway by mechanical stretching, generating not only proliferative but also antiapoptotic signals in human keratinocytes.     

Complex anomalies of type 1 proatlantal intersegmental artery and aortic arch variations

Purpose

We report a case of type 1 proatlantal intersegmental artery (PIA) associated with multiple anomalies of the aortic arch, and discuss the possible embryonic mechanism and clinical importance of the multiple cerebrovascular variants in this patient.

Methods

A 65-year-old woman with dizziness underwent cerebral magnetic resonance (MR) imaging and head and neck MR angiography using a 3-tesla scanner and computed tomography (CT) angiography using a 64-slice multidetector CT scanner.

Results

MR and CT angiography demonstrated an aneurysm of the distal end of the azygos anterior cerebral arteries and hypoplasia of the proximal right vertebral artery (VA) with an anastomotic artery, between the right internal carotid artery (ICA) and distal right VA that passed through the foramen magnum, indicating a type 1 PIA. She also demonstrated an aberrant right subclavian artery (ARSA) with hypoplasia of the right VA, and the left VA arose directly from the aortic arch.

Conclusion

To our knowledge, this is the first report of a type 1 PIA associated with multiple vascular anomalies of the aortic arch, such as ARSA and origin of the left VA from the arch. In cases of persistent anastomoses between the carotid and vertebrobasilar arteries, such as PIAs, imaging examination should include the aortic arch to identify associated vascular variations.     

Endocrine disrupting chemicals in Hungarian canned foods

The aim of this study was to clarify the worldwide residual levels of organochloride compounds, such as BHC and DDT, which were reportedly concentrated in animal tissues by biological food chains. As a part of the investigation of endocrine disrupting chemicals (EDCs), we had a chance to measure the level of these compounds in Hungarian canned foods. Seven kinds of canned foods were purchased at a market in Budapest, Hungary, and the concentrations of eighteen organochloride compounds (α-BHC; β-BHC; γ-BHC; δ-BHC; p,p'-DDT; p,p'-DDE; p,p'-DDD; o,p'-DDT; heptachlor; heptachlor-epoxide; aldrin; dieldrin; endrin; oxychlordane; trans-chlordane; cischlordane; trans-nonachlor; and cis-nonachlor) were measured. Other than DDT and its metabolites, none of the EDCs were detected (levels <0.4 ppb). DDT and its metabolites, however, were detected in fish, meat and chicken liver pate. One of the DDT metabolites was detected quite frequently: p,p'-DDE was detected at a level of 1.8 ppb in fish soup concentrate, 2.3 ppb in Hungarian luncheon meat, 0.5 ppb in special luncheon meat, and 0.6 ppb in chicken liver pate. Of eighteen organochloride compounds examined, only DDT and its metabolites were detected in fish, animal meat, and animal liver. It is suggested that the DDT contamination in fish and meat is worldwide even after the ban of its use.     

Exploratory Research on Determinants of Place of Death in a Large-scale Cohort Study: The JPHC Study

BackgroundThe place of death and related factor, such as diseases, symptoms, family burden, and cost, has been examined, but social background and lifestyle were not considered in most studies. Here, we assessed factors that are associated with the place of death using the largest cohort study in Japan.MethodsA total of 17,781 deaths from the cohort study were assessed. The study database was created from the Japan Public Health Center-based Prospective Study (JPHC Study), in which demographic data were collected from Japanese Vital Statistics. Adjusted odds ratios for home death were calculated using logistic regression.ResultsMultivariate analysis adjusted for various factors showed that unmarried status (odds ratio [OR] 2.4; 95% confidence interval [CI], 2.0–2.9), unemployed male (OR 1.3; 95% CI, 1.1–1.5), and high drinking level in male (OR 1.3; 95% CI, 1.1–1.6) were associated with home death. Regarding the cause of death, cardiovascular disease (OR 3.3; 95% CI, 2.9–3.8), cerebrovascular disease (OR 1.9; 95% CI, 1.6–2.2), and external factors (OR 4.1; 95% CI, 3.5–4.8) were significantly associated with home death, compared with cancer. The risk of death at home was significantly higher among unmarried subjects stratified by cause of death (cardiovascular disease: OR 3.2; 95% CI, 2.2–4.7; cerebrovascular disease: OR :5.1; 95% CI, 2.9–9.1; respiratory disease: OR 3.4; 95% CI, 1.6–7.6; and external factors: OR 2.3; 95% CI, 1.4–3.7), but for cancer, the risk of death at home tended to be higher among married participants.ConclusionThis study found that various factors are associated with home death using the largest cohort study in Japan. There is a high possibility of home deaths in people with fewer social connections and in those with diseases leading to sudden death.Key words: place of death, large-cohort study, factors influencing home death     

P57kip2 immunohistochemical expression and ultrastructural findings of gestational trophoblastic disease and related disorders

Gestational trophoblastic disease (GTD) is a unique spectrum of diseases ranging from complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), and invasive mole (IM) to choriocarcinoma (CC). Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) have been classified as related disorders. Mesenchymal dysplasia (MD) may be misdiagnosed as PHM; however, it is said to have a quite different histogenesis from PHM. P57kip2 is the protein product of a paternally imprinted or maternal gene that inhibits cyclin-dependent kinases (CDK), thus serving to inhibit cell proliferation and to suppress tumor growth. Its lack of expression in trophoblastic disease plays a role in its abnormal proliferation and differentiation. In this study, P57kip2 immunostaining was absent in the trophoblastic layers of CHM and was positive in the trophoblast layer of nonmolar villi and MD. Ultrastructure of complete molar cystic villi showed tree-like branching of microvillous processes and intracytoplasmic lacunae without capillaries in the stroma, whereas MD contained many newly formed blood vessels and collagen. Also, large lacunae with microvilli and polymorphic nuclei of syncytiotrophoblast cells with well-developed organelles were observed in IM. Lung ETT following CHM and normal deliveries showed two types of large mononuclear cells and binuclear cells with abundant organelles and bundles of intermediate-type filaments in the stroma.     

Adenomatous polyposis coli (APC) protein regulates epithelial cell migration and morphogenesis via PDZ domain-based interactions with plasma membranes

The tumor suppressor adenomatous polyposis coli (APC) protein is localized at the plus ends of microtubules (MTs) at the migrating edges of cells. Here, we established Xenopus A6 epithelial cell transfectants expressing GFP-fused full-length APC (GFP-fAPC) or truncated APC lacking the COOH-terminal PDZ-binding motif TSV (GFP-APC(DeltaTSV)). Although both APC proteins were similarly accumulated at the MT ends, GFP-fAPC, but not GFP-APC(DeltaTSV), was associated with the basal and lateral plasma membranes and co-localized with a PDZ protein, DLG1. Stable over-expression of GFP-fAPC enforced cell-substrate attachment and thereby enhanced cell spreading on the substratum and induced polarized extension of lamellipodia and MTs during scratch-induced migration. Truncation of the PDZ-binding motif was sufficient to abolish these effects of GFP-fAPC. Furthermore, expression of GFP-APC(DeltaTSV) disturbed the establishment of a continuous epithelial monolayer. These results suggest that APC links MTs to plasma membranes through interactions with PDZ proteins, such that the migration and morphogenesis of epithelial cells can be properly regulated.     

Prospective study showing that dietary vitamin C reduced the risk of age-related cataracts in a middle-aged Japanese population

Background In Western countries, many epidemiological studies have demonstrated that specific dietary nutrients are associated with the risk of developing age-related cataracts. These reports have suggested that dietary antioxidant vitamins, in particular vitamin C, can play a role in preventing the onset or progression of age-related visual impairment. However, few prospective studies have examined this relationship in a general Asian population. Therefore, in this study, we investigated whether dietary vitamin C was associated with a lower incidence of age-related cataracts by performing a 5-year prospective population-based analysis using data from a cohort of over 30,000 Japanese residents recruited to the Japan Public Health Center-based Prospective Study (JPHC Study) cohort I. Aim of the study We carried out a prospective analysis of the association between vitamin C intake and age-related cataracts among middle-aged Japanese, to study the effects of dietary antioxidants in an Asian population. Methods This 5-year population-based study included 16,415 men and 18,771 women (aged 45–64 years), who were recruited onto the JPHC Study and had not reported cataracts in baseline surveys. Vitamin C was calculated from the nutrient intake assessed by self-administered food-frequency questionnaires (FFQ). Self-reported questionnaires were used to assess two endpoints: diagnosis or extraction of cataracts. Results At follow-up, 216 men and 551 women reported new diagnoses, and 110 men and 187 women reported extractions of cataracts. For both endpoints, a higher vitamin C intake was associated with a reduced incidence of cataracts in both sexes. After adjusting for potential confounding factors, the multivariate odds ratios (ORs) for men and women in the highest quintiles of energy-adjusted vitamin C intake, relative to the lowest quintiles, were 0.65 (95% CI, 0.42–0.97) and 0.59 (95% CI, 0.43–0.89) for cataract diagnoses, and 0.70 (95% CI, 0.44–1.20) and 0.64 (95% CI, 0.41–0.94) for cataract extractions, respectively. Conclusions Dietary vitamin C intake might lower the risk of age-related cataracts among middle-aged Japanese. Study Group Members: Members of the Japan Public Health Center-based Prospective Study Group are: S. Tsugane, M. Inoue, T. Sobue, T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; K. Matsui, T. Abe, M. Katagiri, M. Suzuki, Niigata Prefectural Kashiwazki and Nagaoka Public Health Center, Kashiwazaki and Nagaoka; M. Doi, A. Terao, Y. Ishikawa, Kochi Prefectural Chuo-higashi Public Health Center, Tosayamada; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima, S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, Ehime University, Matsuyama; H. Iso, Y. Honda, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi Medical School, Nankoku; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; the late M. Yamaguchi, Y. Matsumura, S. Sasaki, S. Watanabe, National Institute of Health and Nutrition, Tokyo; and T. Kadowaki, Tokyo University, Tokyo.