Coffee and caffeine intake reduces risk of ulcerative colitis: a case-control study in Japan.

BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

IL12B rs6887695 polymorphism and interaction with alcohol intake in the risk of ulcerative colitis in Japan.

BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

Active and passive smoking and risk of ulcerative colitis: A case-control study in Japan.

BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.

Serum Globulin Is Associated with Endoscopic Findings and Mucosal Healing in Japanese Patients with Ulcerative Colitis.

BACKGROUND: Serum globulin is an inflammation marker. To date, no evidence regarding the association between serum globulin and disease activity in patients with ulcerative colitis has been reported. AIMS: We evaluated the association between serum globulin and endoscopic activity in patients with ulcerative colitis. METHODS: Serum globulin was divided into tertiles based on the distribution of study subjects (low globulin, ≤ 2.7 g/dl (reference); moderate globulin, 2.7-3.1 g/dl; and high globulin, > 3.1 g/dl). A single endoscopic specialist evaluated the endoscopic findings, and mucosal healing was based on Mayo endoscopic subscore. RESULTS: A total of 277 patients with ulcerative colitis were included in the study. Serum globulin was independently positively associated with diminished or absent vascular markings [moderate: adjusted odds ratio (OR) 3.70 (95% confidence interval, CI: 1.82-7.88) and high: adjusted OR 2.40 (95%CI: 1.20-4.94), p for trend = 0.005]. A similar positive association between globulin and erosion was found [high: adjusted OR 2.00 (95%CI: 1.05-3.86)]. Serum globulin was independently inversely associated with mucosal healing [moderate: adjusted OR 0.37 (95%CI: 0.18-0.73) and high: adjusted OR 0.31 (95%CI: 0.14-0.64), p for trend = 0.001] and adjusted partial mucosal healing [moderate: OR 0.51 (95%CI: 0.26-0.98), p for trend = 0.048]. The inverse association between globulin and mucosal healing was significant in the low but not the high C-reactive protein group. CONCLUSIONS: In patients with ulcerative colitis, serum globulin was significantly positively associated with endoscopic activity, and was significantly inversely associated with mucosal healing, especially in the low C-reactive protein group.

Association between platelet count and mucosal healing in Japanese patients with ulcerative colitis: a cross-sectional study.

BACKGROUND: Mucosal healing (MH) has been indicated as the therapeutic goal for ulcerative colitis (UC). Platelet count is known as an inflammation evaluation. However, the association between platelet count and MH among patients with UC is still scarce. We therefore assessed this issue among Japanese patients with UC. METHODS: The study subjects consisted of 345 Japanese patients with UC. Platelet count was divided into quartiles on the basis of the distribution of all study subjects (low, moderate, high, and very high). Several endoscope specialists were responsible for evaluating MH and partial MH, which was defined as a Mayo endoscopic subscore of 0 and 0-1, respectively. Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for partial MH and MH in relation to platelet count were performed using logistic regression analysis. Age, sex, CRP, steroid use, and anti-Tumor necrosis factor α (TNFα) preparation were selected a priori as potential confounding factors. RESULTS: The percentage of partial MH and MH were 63.2 and 26.1%, respectively. Moderate and very high was independently inversely associated with partial MH (moderate: OR 0.40 [95%CI 0.19-0.810], very high: OR 0.37 [95%CI 0.17-0.77], p for trend = 0.034). Similarly, moderate, high, and very high were independently inversely associated with MH (moderate: OR 0.37 [95% CI 0.18-0.73], high: OR 0.41 [95% CI 0.19-0.83], and very high: OR 0.45 [95% CI 0.21-0.94], p for trend = 0.033) after adjustment for confounding factors. CONCLUSIONS: Among patients with UC, platelet count was independently inversely associated with MH.

Immunohistochemical analysis of invasive micropapillary carcinoma pattern in four cases of gastric cancer.

Gastric cancer with the invasive micropapillary carcinoma (IMPC) pattern has been reported to be a variant with poor prognosis and rapid progression. To the best of our knowledge, only 4 cases of gastric cancer from Japan and 11 cases from Korea have been reported to contain the IMPC pattern. In the present study, 4 cases of gastric cancer containing the IMPC pattern from 2 Japanese men and 2 Japanese women are reported. The cancer tissues, including a recurrent lesion in 1 case and lymph node metastases in 2 other cases, were examined immunohistochemically to identify suitable markers for demonstrating the peculiar "inside out" pattern of IMPC and for analyzing HER2 expression. A characteristic IMPC pattern occupied more than 10% of each cancer tissue in these 4 cases. Lymphatic invasions were very often detected; in fact, lymph node metastases were detected in 3 out of 4 cases. The unique "inside out" pattern in IMPC was clearly revealed in all cases by staining with antibodies to both epithelial membrane antigen (EMA) and KL-6, but not with an antibody to CD10. HER2 was positive in 3 of 4 cases with the IMPC pattern, including cases with a recurrent lesion or lymph node metastases. Fluorescence in situ hybridization (FISH) analyses disclosed positive results in case 1, and case 3 including lymph node metastatic foci. Highest FISH titer was 6.8 in case 1, revealing marked amplification of HER-2 gene. Four cases of gastric cancer with the IMPC pattern were reported. EMA and KL-6, but not CD10, were particularly useful markers for visualizing the characteristic "inside out" pattern of the IMPC pattern in stomach cancers, similar to the markers for breast and urinary bladder cancers.

International comparison of cross-disciplinary integration in industry 4.0: A co-authorship analysis using academic literature databases.

In innovation strategy, a type of Schumpeterian competitive strategy in business administration, "intra-individual diversity" has attracted attention as one factor for creating innovation. In this study, we redefine "framework for identifying researchers' areas of expertise" as "a framework for quantifying intra-individual diversity among researchers. Note that diversity here refers to authorship of articles in multiple research fields. The application of this framework then made it possible to visualize organizational diversity by accumulating the intra-individual diversity of researchers and to discuss the innovation strategy of the organization. The analysis in this study discusses how countries are promoting research on the topics of artificial intelligence (AI), big data, and Internet of Things (IoT) technologies, which are at the core of Industry 4.0, from an innovation perspective. Note that Industry 4.0 is a technological framework that aims to "improve the efficiency of all social systems," "create new industries," and "increase intellectual productivity." For the analysis, we used 19-year bibliographic data (2000-2018) from the top 20 countries in terms of the number of papers in AI, big data, and IoT technologies. As the results, this study classified the styles of cross-disciplinary fusion into four patterns in AI and three patterns in big data. This study did not consider the results in IoT because of only small differences between countries. Furthermore, regional differences in the style of cross-disciplinary fusion were also observed, and the global innovation patterns in Industry 4.0 were classified into seven categories. In Europe and North America, the cross-disciplinary integration style was similar to that between the United States, Germany, the Netherlands, Spain, England, Italy, Canada, and France. In Asia, the cross-disciplinary fusion style was similar between China, Japan, and South Korea.

Dietary intake of vegetables, fruit, and antioxidants and risk of ulcerative colitis: A case-control study in Japan.

OBJECTIVES: Oxidative stress is considered one of the etiologic factors involved in ulcerative colitis (UC), yet there is limited epidemiologic information regarding the relationship between antioxidant intake and the risk of UC. The aim of the present case-control study in Japan was to examine the association between intake of green and yellow vegetables, other vegetables, fruit, vitamin C, vitamin E, retinol, alpha-carotene, beta-carotene, and cryptoxanthin and UC risk. METHODS: A total of 384 cases within 4 y of diagnosis with UC and 665 controls were included in the study. Data on dietary intake and confounders were obtained using a self-reported questionnaire. Information on dietary factors was collected using a 169-item semiquantitative food-frequency questionnaire. Adjustment was made for sex, age, pack-y of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Higher intake levels of other vegetables, vitamin C, and retinol were independently associated with a reduced risk of UC. The adjusted odds ratio between extreme quartiles was 0.51 (95% confidence interval [CI], 0.34-0.76; P for trend ≤ 0.001) for other vegetables, 0.45 (95% CI, 0.30-0.69, P for trend ≤ 0.001) for vitamin C, and 0.64 (95% CI, 0.43-0.95, P for trend = 0.04) for retinol. There were no associations between intake of green and yellow vegetables, fruit, vitamin E, alpha-carotene, beta-carotene, or cryptoxanthin and UC risk (P for trend = 0.29, 0.56, 0.89, 0.20, 0.69, and 0.22, respectively). CONCLUSIONS: Intake of other vegetables, vitamin C, and retinol was inversely associated with UC risk.

Immunohistochemical and electron microscopic studies of a case of duodenal gangliocytic paraganglioma.

Gangliocytic paraganglioma (GPG) is a rare tumor, occurring almost exclusively in the duodenum. In the present case, a submucosal tumor 2.5 x 2 x 1.5 cm in size was located on the anal side of the papilla of Vater, with clear margins and without capsule on cut-surface examination. Tumor cells included three types of cells: ganglion-like cells (GCs), endocrine cells (ECs), and Schwann cells (SCs). The GCs were large with eccentric nuclei with large nucleoli and clear abundant cytoplasm. ECs were detected in small nests, surrounded by bundles of SCs. Immunohistochemically, GCs were positive for synaptophysin, neuron-specific enolase (NSE), and CD56. ECs were positive for chromogranin A, NSE, somatostatin, pancreatic polypeptide, and CD56, and were associated with S100 protein-positive SCs. On fine structural examination, ECs contained numerous membrane-bounded secretory granules, 250-450 nm in diameter, in their cytoplasm, surrounded by a branched, complex basal lamina. SCs possessed basal lamina along their long interlacing cytoplasmic processes. The histogenesis of GPG most likely involves proliferation and differentiation of pluripotent stem cells in the duodenal crypts in the duodenum as a true tumor, although it is also possible that the retroperitoneal components of both GCs and SCs proliferate, together with ECs, from ventral primordial tissue of the pancreas in the duodenum. The immunohistochemical and ultrastructural findings of a case of GPG are reported, focusing on three major cellular components: GCs, ECs, and SCs.

Glycogen-rich clear cell carcinoma of the breast: a case report.

Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare malignant breast tumor. We recently encountered a case of GRCC and report our imaging findings here. The patient was a 49-year-old woman with a mass in her right breast. Mammographic study showed no definite mass shadow because the breast was dense. No calcifications were identified. Ultrasonography disclosed a hypoechoic mass that had a diameter of 1.3 cm, partially irregular borders, heterogeneous internal echoes, and posterior acoustic enhancement, suggesting an invasive carcinoma. Histologic study of core needle biopsy specimens showed a solid proliferation of large clear carcinoma cells, suggestive of a ductal carcinoma. The carcinoma cells possessed clear cytoplasm larger than that typical of ductal carcinoma cells. Breast-conserving surgery was performed with axillary sentinel lymph node biopsy. Macroscopically, the tumor was a solid, white-yellow mass with fairly well defined margins. Histologic examination of the tumor showed a characteristic feature of GRCC: the tumor cells were positive for estrogen receptor but negative for progesterone receptor and Her 2, and the sentinel lymph node was histologically negative. The patient remains well and has had no clinical recurrence of the disease after 2.5 years of follow-up without radiotherapy or adjuvant therapy. Noteworthy is the usefulness of mammography and ultrasonography, which should be used as complementary imaging tools.

Pleomorphic adenoma of the breast.

Pleomorphic adenoma is a very rare benign tumor of the breast. Only 70 cases have been reported in the world literature. Recently, we encountered a case of pleomorphic adenoma of the breast and thus present here the mammographic and ultrasonographic findings with the pathology of this rare breast tumor. The patient was a 76-year-old Japanese woman with a right breast mass. The mammography showed a 1.5-cm, lobulated high-density mass with partially ill-defined margins. Ultrasonography revealed an irregularly shaped mass with partially ill defined borders, hypoechoic and heterogeneous internal echoes, and posterior acoustic enhancement. These findings suggested an invasive carcinoma. Awareness of this type of tumor will help in correct diagnosis, in spite of the rarity of this disease.

Primary small-cell carcinoma of the breast: a case report.

We report a case of small-cell carcinoma of the breast. The patient was a 54-year-old Japanese woman with a left breast mass. Mammography revealed a 1.2-cm microlobulated mass with partially ill-defined borders. Ultrasonography disclosed a hypoechoic mass measuring 1.8 × 1.2 × 1.2 cm with heterogeneous internal echoes and partially ill-defined borders. The shape of the mass was round and taller than it was wide in the orthogonal section to the longest axis of the mass. These imaging findings suggested a malignant tumor. Fine-needle aspiration cytology of the tumor also suggested a ductal carcinoma. Breast-conserving surgery was performed with axillary sentinel lymph node biopsy. A diagnosis of small-cell carcinoma of the breast was made based on the histologic and immunohistochemical findings. This rare breast tumor has been reported to be aggressive and associated with a poor prognosis; however, our patient is currently well and has had no clinical recurrence of the disease after 5 years of follow-up without radiotherapy or chemotherapy. Therefore, the prognosis may be better if the tumor is detected early and there is an absence of lymph node metastasis.

Arachidonic acid promotes glutamate-induced cell death associated with necrosis by 12- lipoxygenase activation in glioma cells.

Glutamate induced glutathione (GSH) depletion in C6 rat glioma cells, which resulted in cell death. This cell death seemed to be apoptosis through accumulation of reactive oxygen species (ROS) or hydroperoxides representing cytochrome c release from mitochondria and internucleosomal DNA fragmentation. A significant increase of 12-lipoxygenase enzyme activity was observed in the presence of arachidonic acid (AA) under GSH depletion induced by glutamate. AA promoted the glutamate-induced cell death, which reduced caspase-3 activity and diminished internucleosomal DNA fragmentation. Furthermore, AA reduced intracellular NAD, ATP and membrane potentials, which indicated dysfunction of the mitochondrial membrane. Protease inhibitors such as N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and 3, 4-dichloroisocumarin (DCI) but no Ac-DEVD, a caspase inhibitor, suppressed the glutamate-induced cell death. AA reduced the inhibitory effect of TPCK and DCI on the glutamate-induced cell death. These results suggest that AA promotes cell death by inducing necrosis from caspase-3-independent apoptosis. This might occur through lipid peroxidation initiated by ROS or lipid hydroperoxides generated during GSH depletion in C6 cells.

A case of adenoid cystic carcinoma of the breast.

A 57-year-old woman was referred to our institution 4 months after she noticed a palpable, painless mass in her left breast. Physical examination revealed a mobile and elastic mass. An axillary or subclavicular lymph node was not palpable. Mammography revealed a lobulated mass with a partially ill-defined border. Ultrasonography depicted a 2.5 × 1.5 cm irregularly shaped mass with heterogeneous internal echo and posterior acoustic enhancement. The border of the mass was poorly defined at the anterior and lateral aspects of the mass. Results of ultrasonography-guided fine-needle aspiration cytology were strongly suggestive of a malignant tumor. Thus, the patient underwent breast-conserving surgery with axillary lymph node dissection. The gross resected specimen revealed a gray-to-white and well-demarcated solid tumor measuring 3 × 2 × 2.5 cm, with an irregular border and heterogeneous internal structure. Histological examination showed the characteristic patterns of adenoid cystic carcinoma of the breast. Immunohistochemical studies for both estrogen receptors (ER) and progesterone receptors (PgR) were negative. The patient remains well and has no clinical recurrence of the disease after 5 years of follow-up without radiotherapy or adjuvant therapy.

Cytologic features of nipple adenoma: a report of four cases of adenoma of the nipple.

We report four cases of adenoma of the nipple, a rare benign epithelial benign tumor occurring under the nipple and areola. Clinically, erosion findings of the nipple require discrimination from Paget's disease. In addition, a mass found in the nipple warrants discrimination from ductal carcinoma. Two cases underwent aspiration biopsy cytology and the other underwent tumor imprint cytology, respectively, revealing a large number of epithelial cell populations in the necrotic background material. These large cell clusters had a papillary or sheet structure and exhibited decreased cell cohesiveness at the cluster part. In addition, small clusters and solitary epithelial cells were also present. Furthermore, a two-cell pattern comprising both duct epithelial and myoepithelial cells was observed in the cell clusters. Two other cases underwent nipple brush cytology, revealing a few small papillary clusters with isolated epithelial cells in the hemorrhagic background. The clusters appeared as benign duct proliferative lesions such as papilloma, papillomatosis, and adenosis. An accurate diagnosis warrants the recognition of regular nuclei with bland chromatin and myoepithelial cells and the identification of the lesion location.

Ultraviolet ray induces chromosomal giant DNA fragmentation followed by internucleosomal DNA fragmentation associated with apoptosis in rat glioma cells.

Giant DNA fragments (1-2 Mbp) were found in C6 rat glioma cells irradiated by a lethal dose of ultraviolet-C (UV-C, 254 nm) at 50 J/m(2). After irradiation, the fragments mutated into high-molecular-weight (100-800 kbp) DNA fragments and then into ladder-formed internucleosomal DNA fragments. Poly-ADP-ribose polymerase (PARP) activity and NAD levels were reduced during DNA fragmentation. Some inhibitors of caspase and protease inhibited DNA ladder formation, but not giant DNA fragmentation, whereas antioxidants did not inhibit DNA fragmentation. These results suggest that a lethal dose of UV radiation induces giant DNA fragmentation and leads to internucleosomal DNA fragmentation associated with apoptosis through some caspases and nonreactive oxygen species in cells.

Subacute thyroiditis with highly positive thyrotropin receptor antibodies and high thyroidal radioactive iodine uptake.

A 48-year-old woman with transient thyrotoxicosis, having a slightly high thyroidal 99mTc uptake (3.9% at 20 m) or radioactive iodine uptake (RAIU) (17.3% at 4 hour) and subacute thyroiditis (SAT)-like symptoms, signs and histological diagnosis (extensive cellular destruction and granulomatous inflammatory change), showed positive TRAb (59.9%) and TSAb (194%) activity. The high levels of TRAb and slightly high RAIU were still observed after one month of prednisolone treatment. Nine months later, the TRAb and TSAb levels finally normalized and her thyroid function has remained normal since then. We suspect that the slightly high RAIU were due to the presence of both the TRAb and the TSAb and the course of this case might mimic neonatal Graves' disease.

[Mucoepidermoid carcinoma of the intrahepatic bile duct with metastasis to the cranial skin].

Mucoepidermoid carcinoma of the intrahepatic bile duct is a rare variant of cholangiocarcinoma: it is composed of mucus-secreting squamous cells and glandular cells within the same nests. This tumor is very aggressive, with high-grade malignancy, and has a poor prognosis. In the international literature, only 17 cases of mucoepidermoid carcinoma originating in the hepatic bile duct system have been reported until now. We report an autopsy case of mucoepidermoid carcinoma of the intrahepatic bile duct with metastasis to the cranial skin in a Japanese man who was more than 70 years old. This cancer metastasizes to many organs, but skin metastasis is extremely rare.

Primary malignant lymphoma of the breast.

Primary malignant lymphoma of the breast is a rare tumor. Recently, we encountered a case of primary malignant lymphoma of the breast and present here the mammographic and ultrasonographic (US) findings with the pathology of this rare breast tumor. The patient was a 47-year-old woman with a left breast mass. Mammography showed a 3.0 x 1.5 cm, lobulated high-density mass with well-defined margins. US revealed a lobulated mass with fairly well-defined borders, hypoechoic and heterogenous internal echoes, and posterior acoustic enhancement. It was difficult to differentiate malignant lymphoma from breast carcinoma by imaging studies. This type of breast cancer should be added to a differential diagnosis when a solitary tumor is found in the breast on mammography.