Overall survival of homebound patients without cancer receiving inpatient respite care in a hospital ward in Japan: a retrospective observational study.

OBJECTIVES: This study aimed to investigate the relationship between the use of inpatient respite care and the overall survival of homebound patients without cancer admitted to a hospital ward in order to assess the potential impact of inpatient respite care on the duration of home care. DESIGN: This was a single-centre, hospital ward-based retrospective observational study. SETTING AND PARTICIPANTS: From March 2011 to September 2018, 393 cancer-free older patients (median age, 84.0 years; 53.9% women) receiving continuous medical care at home through clinics were enrolled upon admission to a hospital ward. PRIMARY OUTCOME MEASURES: Continuous cumulative survival curves were generated using the Kaplan-Meier method for two groups: inpatient respite care users and non-users. Additionally, prognostic factors associated with all-cause mortality were assessed using the Cox proportional hazards model. RESULTS: The Kaplan-Meier curves for inpatient respite care users without cancer admitted to the hospital ward demonstrated a longer median survival time than non-users. Subgroup analyses for patients with or without neurological disorders yielded similar results. The HR for inpatient respite care use, after adjusting for age, sex and other confounding variables, was 0.480 (95% CI: 0.328 to 0.703, p<0.001). CONCLUSIONS: Homebound patients without cancer receiving inpatient respite care during the study period in Japan demonstrated higher overall survival than those who did not receive respite care. Subgroup analysis of patients with neurological disorders yielded similar results. Further studies are needed to investigate the benefits of inpatient respite care, including the exploration of appropriate methods for its use.

Comparison of the Life-Sustaining Treatment, Cardiopulmonary Resuscitation, and Palliative Care Implementation Rates between Homebound Patients with Malignant and Nonmalignant Disease Who Died in an Acute Hospital Setting: A Single-Center Retrospective Study.

OBJECTIVE: This study investigated and compared the implementation of life-support treatment (LST), cardiopulmonary resuscitation (CPR) implementation rates, and the influence of acute illnesses on the introduction of palliative care (PC) to homebound patients with malignant and nonmalignant disease, who subsequently died in an acute hospital setting. METHODS: Among the homebound patients admitted to the ward in our hospital from 2011 to 2018, we investigated and compared the attributes, underlying diseases, causes of death, and rates of implementation of LST, CPR, and PC between patients with malignant and nonmalignant disease who died in the ward, using data obtained from hospitalization records. Furthermore, acute illnesses related to the introduction of PC were examined. RESULTS: Of the 551 homebound patients admitted to the ward of an acute hospital, 119 died in the ward. Of the deceased patients, 60 had malignant disease and 59 had nonmalignant disease. Patients with nonmalignant disease had higher rates of LST implementation and CPR and a lower rate of PC. Patients with infectious disease, who required antimicrobial drugs, had significantly lower PC introduction rates. CONCLUSION: Understanding the influence of the timing of PC introduction in acute care for homebound patients with advanced chronic illness are issues to be considered.

Multi-organ carcinogenicity by inhalation exposure to 2-Bromopropane in rats.

OBJECTIVE: The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. METHODS: Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6 h/day, 5 days/week for 2 years. RESULTS: All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Death/moribundity was caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbal's gland tumors; sebaceous adenoma and basal cell carcinoma of the skin/appendage; adenocarcinoma of the small/large intestine; follicular cell adenoma of the thyroid; fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbal's gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbal's gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. CONCLUSION: Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.

Impact of the Controlling Nutritional Status (CONUT) score as a prognostic factor for all-cause mortality in older patients without cancer receiving home medical care: hospital ward-based observational cohort study.

OBJECTIVES: Malnutrition in cancer-free older patients receiving home medical care may affect prognosis, but indicators of long-term nutrition-related prognosis have not been developed. This study investigated the utility of the Controlling Nutritional Status (CONUT) score as a prognostic factor for older patients without cancer receiving home medical care. DESIGN: This was a single-centre, hospital ward-based observational cohort study. SETTING AND PARTICIPANTS: In total, 625 cancer-free older patients (median age, 81.0 years; 47.4% males) receiving continuous home medical care through clinics were enrolled on admission to a hospital ward from March 2011 to September 2018. PRIMARY OUTCOME MEASURES: Continuous cumulative survival curves were obtained using the Kaplan-Meier method after dividing the CONUT score into four groups. The prognostic factors for overall mortality were evaluated using the Cox proportional hazards model. Comparisons with other predictive tools were performed. RESULTS: The Kaplan-Meier curves of CONUT scores revealed a stepwise shortening of the median survival time with increasing scores. The HR of CONUT scores adjusted by age, sex and other confounding variables was 1.422 (95% CI 1.232 to 1.643, p<0.001). The areas under the receiver operating characteristic curve of the CONUT score for 1-year and 5-year survival were 0.684 and 0.707, respectively. The CONUT score displayed greater predictive utility than other nutrition-related predictive tools. CONCLUSIONS: The CONUT score on hospital admission could be used to predict overall mortality in older patients without cancer receiving home medical care. It is expected to be a simpler and cheaper screening tool for assessing the nutritional status in the field of home medical care.

Carcinogenicity and testicular toxicity of 2-bromopropane in a 26-week inhalation study using the rasH2 mouse model.

2-Bromopropane (2-BP) is a colorless liquid at room temperature and is used in closed systems in factories, mainly as an intermediate for medicines, pesticides, and other chemicals. However, the carcinogenicity of 2-BP is still unknown. The CByB6F1-Tg(HRAS)2Jic (rasH2) transgenic mouse model has been established as an alternative to long-term studies (1.5 years-lifetime) to detect carcinogenicity in as short a time as six months. We performed a 26-week inhalation exposure study of 2-BP using the rasH2 mouse model. Male and female rasH2 mice were exposed to 0, 67, 200, or 600 ppm of 2-BP for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. The results showed a concentration-dependent increase in lung tumor development in male and female rasH2 mice exposed by inhalation to 2-BP, which was significant by Peto's and Poly-3 trend tests. Furthermore, in male rasH2 mice, 2-BP was found to be a testicular toxin. This study is the first to demonstrate that 2-BP is carcinogenic in male and female mice and a testicular toxin in male mice using the rasH2 mouse model.

No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model.

With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. We performed a 26-week inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) mice model for detecting carcinogenicity. Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. TiO2 NPs exposure induced deposition of particles in lungs in a dose-dependent manner in each exposure group. Exposure to TiO2 NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of alveolar epithelial type 2 cells was examined, and it was not increased by exposure to TiO2 NPs. This is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO2 NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m3, which is considered to be a high concentration.

Pulmonary dust foci as rat pneumoconiosis lesion induced by titanium dioxide nanoparticles in 13-week inhalation study.

BACKGROUND: Most toxicological studies on titanium dioxide (TiO2) particles to date have concentrated on carcinogenicity and acute toxicity, with few studies focusing of pneumoconiosis, which is a variety of airspace and interstitial lung diseases caused by particle-laden macrophages. The present study examined rat pulmonary lesions associated with pneumoconiosis after inhalation exposure to TiO2 nanoparticles (NPs). METHODS: Male and female F344 rats were exposed to 6.3, 12.5, 25, or 50 mg/m3 anatase type TiO2 NPs for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. After the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. RESULTS: Numerous milky white spots were present in the lungs after exposure to 25 and 50 mg/m3 TiO2 NPs. Histopathological analysis revealed that the spots were alveolar lesions, characterized predominantly by the agglomeration of particle-laden macrophages and the presence of reactive alveolar epithelial type 2 cell (AEC2) hyperplasia. We defined this characteristic lesion as pulmonary dust foci (PDF). The PDF is an inflammatory niche, with decreased vascular endothelial cells in the interstitium, and proliferating AEC2 transformed into alveolar epithelial progenitor cells. In the present study, the AEC2 in the PDF had acquired DNA damage. Based on PDF induction, the lowest observed adverse effect concentration for pulmonary disorders in male and female rats was 12.5 mg/m3 and 6.3 mg/m3, respectively. The no observed adverse effect concentration for male rats was 6.3 mg/m3. There was a sex difference in lung lesion development, with females showing more pronounced lesion parameters than males. CONCLUSIONS: Inhalation exposure to TiO2 NPs caused PDF, an air-space lesion which is an alveolar inflammatory niche containing particle-laden macrophages and proliferating AEC2. These PDFs histopathologically resemble some pneumoconiosis lesions (pulmonary siderosis and hard metal pneumoconiosis) in workers and lung disease in smokers, suggesting that PDFs caused by exposure to TiO2 NPs in rats are an early pneumoconiosis lesion and may be a common alveolar reaction in mammals.

Two-year intermittent exposure of a multiwalled carbon nanotube by intratracheal instillation induces lung tumors and pleural mesotheliomas in F344 rats.

BACKGROUND: A mounting number of studies have been documenting the carcinogenic potential of multiwalled carbon nanotubes (MWCNTs); however, only a few studies have evaluated the pulmonary carcinogenicity of MWCNTs in vivo. A 2-year inhalation study demonstrated that MWNT-7, a widely used MWCNT, was a pulmonary carcinogen in rats. In another 2-year study, rats administered MWNT-7 by intratracheal instillation at the beginning of the experimental period developed pleural mesotheliomas but not lung tumors. To obtain data more comparable with rats exposed to MWNT-7 by inhalation, we administered MWNT-7 to F344 rats by intratracheal instillation once every 4-weeks over the course of 2 years at 0, 0.125, and 0.5 mg/kg body weight, allowing lung burdens of MWNT-7 to increase over the entire experimental period, similar to the inhalation study. RESULTS: Absolute and relative lung weights were significantly elevated in both MWNT-7-treated groups. Dose- and time-dependent toxic effects in the lung and pleura, such as inflammatory, fibrotic, and hyperplastic lesions, were found in both treated groups. The incidences of lung carcinomas, lung adenomas, and pleural mesotheliomas were significantly increased in the high-dose group compared with the control group. The pleural mesotheliomas developed mainly at the mediastinum. No MWNT-7-related neoplastic lesions were noted in the other organs. Cytological and biochemical parameters of the bronchoalveolar lavage fluid (BALF) were elevated in both treated groups. The lung burden of MWNT-7 was dose- and time-dependent, and at the terminal necropsy, the average value was 0.9 and 3.6 mg/lung in the low-dose and high-dose groups, respectively. The number of fibers in the pleural cavity was also dose- and time-dependent. CONCLUSIONS: Repeated administration of MWNT-7 by intratracheal instillation over the 2 years indicates that MWNT-7 is carcinogenic to both the lung and pleura of rats, which differs from the results of the 2 carcinogenicity tests by inhalation or intratracheal instillation.

Papillary hyperplasia of the gallbladder diagnosed as gallbladder cancer before surgery: A case report.

INTRODUCTION AND IMPORTANCE: Gallbladder cancer has a poor prognosis. Therefore, an accurate diagnosis is required, for which various tests are performed. However, in some cases, it is difficult to distinguish between benign and malignant diseases before surgery. Papillary hyperplasia of the gallbladder is known for its secondary changes. Papillary hyperplasia of the gallbladder, which is known for its secondary changes, is a benign disease. We encountered papillary hyperplasia of the gallbladder with morphological changes over the course of 1 year. In addition, the tumor was suggested to be malignant during various examinations. We present a case of papillary hyperplasia of the gallbladder showing an increasing tendency and findings indicative of malignancy on imaging. PRESENTATION OF CASE: A 70-year-old man underwent routine abdominal ultrasonography every year. We observed that the gallbladder wall was thickened. The tumor size was 24 mm. FDG-PET and other examinations indicated malignancy requiring surgery. CLINICAL DISCUSSION: Accurate diagnosis of gallbladder tumor is difficult only by diagnostic imaging. There are problems with preoperative cytology and histology. FS can be an important test to avoid extended surgery. CONCLUSION: We report a rare case of papillary hyperplasia of the gallbladder, which was difficult to diagnose. Even when morphological changes and imaging findings suggest malignancy, similar findings could appear in papillary hyperplasia of the gallbladder owing to chronic inflammation.

A Direct Aspiration First Pass Technique for Basilar Artery Occlusion Caused by Elastic-hard Tumor Embolus via the Pulmonary Vein by Metastatic Prostate Adenocarcinoma: A Case Report.

Basilar artery occlusion (BAO) accounts for only 1% of all strokes, and cerebral infarction resulting from tumor emboli has been infrequently demonstrated; therefore, few reports described BAO due to tumor embolus and its treatment experience. We report here an 83-year-old man with an acute BAO caused by embolized lung tumor invading right pulmonary vein that was revealed as metastasis of prostate adenocarcinoma. The patient underwent rapid recanalization through acute thrombectomy with a direct aspiration first pass technique (ADAPT) with Penumbra catheter. Successful recanalization was achieved in reperfusion grade of thrombolysis in cerebral infarction (TICI) 2b, and the embolus revealed a highly elastic hard tumorous mass of which texture was too tough to be caught by stent retriever. Immunohistopathologic examination of the embolus revealed adenocaricinoma of the prostate. In spite of that the recanalization was obtained, the patient died of the brain stem infarction after 7 days from the onset. We experienced a rare case of acute BAO caused by embolized prostate cancer metastasizing lung and invading pulmonary vein. When we face to patients with lung tumor invading pulmonary vein, tumor embolus should have been strongly considered and aspiration thrombectomy may be safer and more effective for the condition because of the difficulty of predicting an embolus's texture before treatment.

Associations between Exposure to Tobacco Smoke and Behavioral Problems in Preschool Japanese Children.

Background: A few studies related to pediatric behavior have measured secondhand smoke exposure in children using valid objective biochemical markers. We aimed at investigating the associations between current and cumulative exposure to tobacco smoke, measured both subjectively and objectively, and behavioral problems in children. Methods: Subjects were 437 Japanese children, aged 3-6 years in 2006. Exposure to tobacco smoke was evaluated from a parent-administered questionnaire and urinary cotinine concentrations. The cotinine concentrations were measured using first-void morning urine by liquid chromatography-tandem mass spectrometry. Children's behaviors were assessed by the parent-completed Strengths and Difficulties Questionnaire. Results: After multiple adjustments for covariates, higher total difficulty scores of children were significantly associated with the larger number of cigarettes parents smoke, more smokers among cohabiters, and more pack-years of exposure to tobacco smoke from parents and cohabiters. The total difficulty scores were 8.72, 9.09, and 10.52, respectively, for children in the low, middle, and high tertiles of creatinine-corrected cotinine concentrations in urine (p=0.002, trend p=0.005). There was no substantial sex difference in the positive associations between passive smoking and the SDQ scores. Conclusions: Exposure to tobacco smoke in early childhood may be involved in the development of pediatric behavioral problems. The importance of reducing the exposure of children to tobacco smoke, particularly in the home, was further emphasized for the prevention of psychological and behavioral problems in childhood.

Pilot study of repetitive transcranial magnetic stimulation in patients with chemotherapy-induced peripheral neuropathy.

OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients. MATERIALS AND METHODS: Eleven female patients with breast cancer or gynecologic cancer (mean age 64.8 [standard deviation 7.8]) who had neuropathic pain and/or peripheral sensory neuropathy, with a minimum two grade severity based on the scale of the National Cancer Institutes' Common Terminology Criteria for Adverse Events (version 4.0) were enrolled. Patients received rTMS (5-Hz; 500 pulses/session; figure-8 coil) on their primary motor cortex corresponding to the target extremity. The intensity of pain and dysesthesia for all extremities was evaluated using a visual analog scale for pain, dysesthesia, and the Japanese version of the short-form McGill Pain Questionnaire 2 (SFMPQ2). RESULTS: rTMS for target extremity significantly decreased the visual analog scale of pain and dysesthesia. The intensity of pain measured by the SFMPQ2 was also decreased in the target extremity. Regarding non-target extremities, only dysesthesia significantly decreased as a result of rTMS. No adverse events were observed. CONCLUSION: This is an initial report demonstrating the potential of rTMS for the treatment of CIPN. We suggest rTMS could be potentially beneficial and effective as a treatment for pain and dysesthesia in patients with CIPN.

Peptides containing the MXXCW motif inhibit oncogenic RET kinase activity with a novel mechanism of action.

REarranged during Transition (RET) is a tyrosine kinase associated with the development of several malignancies. Identification of RET kinase inhibitors promises valuable therapeutic tools for the intervention of RET-driven tumors. Most currently available tyrosine kinase inhibitors target the ATP binding site, but there are several drawbacks of these ATP-competitive drugs. Therefore, there is a need to develop new kinase inhibitors with alternative mechanisms of action. We have previously reported that a conserved cysteine in the MXXCW motif of RET is crucial to the disulfide-bonded dimerization-linked activation of RET kinases. Reagents which bind to this cysteine may inhibit the activity of RET kinases through disulfide-bond mediated dimerization. Here, we examine the potential of MXXCW motif-containing peptides as candidate kinase inhibitors. We demonstrate that MXXCW motif-containing peptides bind to RET in a redox-sensitive manner and block enzymatic activity, causing inhibition of the RET-dependent activity of extracellular signal-regulated kinases and effectively reducing the malignant potential of RET-papillary thyroid carcinoma-1 (PTC)-expressing cells. These motif-containing peptides were also found to be effective against the drug resistant mutant of RET. The inhibition of RET kinase activity by these peptides resulted in suppression of RET-PTC-1-mediated cancer growth. The great potency of these cysteine targeted peptides could indicate promising approaches for novel molecular-targeted therapies for RET-associated cancers.

Number of Teeth and All-Cause and Cancer Mortality in a Japanese Community: The Takayama Study.

BACKGROUND: The association between the number of teeth and mortality among community-dwelling people has been examined in many epidemiological studies. However, few Japanese studies have included cancer mortality as an endpoint. We prospectively investigated the association between number of remaining teeth and all-cause and cancer mortality in a Japanese community. METHODS: This study included participants in the Takayama Study who were aged 35-70 years old at baseline in 1992. Information on the number of remaining teeth was obtained from 11,273 participants via questionnaire at the second survey in 2002. The response rate was 66.9%. Deaths and their causes were ascertained during 11.8 years of follow-up. RESULTS: A total of 1,098 deaths (435 cancer-related and 235 cardiovascular-related) were identified during the follow-up period. After adjusting for covariates, participants with 0 to 9 teeth were at moderate but significantly increased risk of all-cause mortality (hazard ratio [HR] 1.19; 95% confidence interval [CI], 1.03-1.39) and cancer mortality (HR 1.31; 95% CI, 1.03-1.67) compared to those with 20 or more teeth. With regard to cancer site, a significant association was observed for lung cancer (HR for 0-9 teeth vs. 20 or more teeth, 1.75; 95% CI, 1.08-2.83). This association was somewhat strengthened among never-smokers (HR 3.56; 95% CI, 1.02-12.45). CONCLUSIONS: We observed that a lower number of remaining teeth was significantly associated with increased risk from all-cause and lung cancer mortality. Further studies on the number of teeth and lung and other types of cancer are needed.

Assessment of microvessel perfusion of pituitary adenomas: a feasibility study using turbo spin-echo-based intravoxel incoherent motion imaging.

OBJECTIVES: To evaluate the feasibility of assessment of microvessel perfusion of pituitary adenomas with intravoxel incoherent motion (IVIM) imaging using single-shot turbo spin-echo-based diffusion-weighted imaging (SS-TSE-DWI). METHODS: We examined 51 consecutive patients with pituitary adenomas (35 non-functioning and 16 functioning) and 32 patients with normal pituitary glands using SS-TSE-DWI IVIM. The diffusion coefficient (D), the perfusion fraction (f), and the pseudo-diffusion coefficient (D*) were calculated pixel-by-pixel for each adenoma and normal pituitary gland. We also obtained the pathological microvessel area (MVA) of each adenoma. The IVIM parameters in adenomas were compared with those in normal pituitary glands using the Mann-Whitney U test. The correlation between the MVA and IVIM f of adenomas was analyzed using Spearman's rank correlation coefficient. RESULTS: The mean D (× 10-3 mm2/s) in adenomas was 0.723 ± 0.253, which was significantly lower than that in normal pituitary glands (0.862 ± 0.128; p < 0.0001). The mean f (%) in adenomas was 10.74 ± 4.51, which was significantly lower than that in normal pituitary glands (13.26 ± 4.32, p = 0.0251). No significant difference was found in the mean D*. We found a significant positive correlation between MVA and f in non-functioning adenomas (ρ = 0.634, p < 0.0001) as well as in all adenomas (ρ = 0.451, p = 0.0009). CONCLUSIONS: Assessment of microvessel perfusion of pituitary adenomas based on SS-TSE-DWI IVIM is feasible. Compared to normal pituitary glands, pituitary adenomas were characterized by lower D and f. KEY POINTS: • Assessment of microvessel perfusion of pituitary adenomas based on SS-TSE-IVIM is feasible. • SS-TSE-IVIM helps with evaluation of the vascularity of pituitary lesions. • Pituitary adenomas were characterized by lower D and f than normal pituitary glands.

Associations between coffee consumption and all-cause and cause-specific mortality in a Japanese city: the Takayama study.

OBJECTIVE: Epidemiological studies suggest that coffee consumption is inversely associated with all-cause and cause-specific mortality. Evidence from studies targeting non-white, non-Western populations is still sparse, although coffee is popular and widely consumed in Asian countries. DESIGN: Population-based, prospective cohort study. We used Cox proportional hazards models with adjustment for dietary and lifestyle factors to estimate associations between coffee consumption and all-cause and cause-specific mortality. Dietary intake including coffee consumption was assessed only at baseline using a validated FFQ. SETTING: A Japanese city. PARTICIPANTS: Individuals aged 35 years or older without cancer, CHD and stroke at baseline (n 29 079) and followed from 1992 to 2008. RESULTS: From 410 352 person-years, 5339 deaths were identified (mean follow-up = 14·1 years). Coffee consumption was inversely associated with mortality from all causes and CVD among all participants, but not from cancer. Compared with the category of 'none', the multivariate hazard ratio (95 % CI) for all-cause mortality was 0·93 (0·86, 1·00) for <1 cup/d, 0·84 (0·76, 0·93) for 1 cup/d and 0·81 (0·71, 0·92) for 2-3 cups/d. The multivariate hazard ratio (95 % CI) for cardiovascular mortality were 0·87 (0·77, 0·99) for <1 cup/d, 0·76 (0·63, 0·92) for 1 cup/d and 0·67 (0·50, 0·89) for 2-3 cups/d. Inverse associations were also observed for mortality from other causes, specifically infectious and digestive diseases. CONCLUSION: Drinking coffee, even 1 cup/d, was inversely associated with all-cause mortality and mortality from cardiovascular, infectious and digestive diseases.

Dietary Soy Intake Is Inversely Associated with Risk of Type 2 Diabetes in Japanese Women but Not in Men.

BACKGROUND: Whole soy foods, as well as their components, including protein and isoflavones, have garnered attention because they may have beneficial effects against diabetes. OBJECTIVES: We examined associations between the intake of soy foods, soy protein, and soy isoflavones and the risk of diabetes in the Japanese population. METHODS: This prospective cohort study included 13,521 residents (5883 men and 7638 women; 35-69 y old) of Takayama City, Japan. The subjects responded to a self-administered baseline questionnaire in 1992 and to a follow-up questionnaire seeking information about diabetes in 2002. Their mean ± SD body mass index was 22.6 ± 2.6 kg/m2 (men) and 22.1 ± 2.7 (women). The intakes of total soy foods, fried soy foods, nonfried soy foods, soy protein, and soy isoflavones were estimated through the use of a validated food-frequency questionnaire administered in 1992. Associations between soy intake and the risk of diabetes were evaluated through the use of Cox proportional hazards models incorporating age, education level, physical activity, smoking status, alcohol consumption, history of hypertension, use of vitamin supplements, menopausal status, and dietary factors including glycemic load, total energy, total fat, meat, fruit, vegetables, and coffee. RESULTS: During a 10-y follow-up, 438 participants reported physician-diagnosed diabetes. Women in the highest tertile of intakes of total soy foods, fried soy foods, nonfried soy foods, soy protein, and soy isoflavone had significantly lower HRs, after controlling for covariates, than those with the lowest intakes. For example, HRs were 0.45 (95% CI: 0.30, 0.68; P-trend <0.001) for total soy food intake. In men, there were no significant associations between soy intake and the risk of diabetes. CONCLUSIONS: These results suggest that a high soy intake may be associated with a lower risk of diabetes in Japanese women.

Green tea intake and colorectal cancer risk in Japan: the Takayama study.

BACKGROUND: Reportedly, green tea has a preventive effect against colorectal cancer in animal models. Nevertheless, results from epidemiological studies of the association between green tea consumption and colorectal cancer have been inconsistent. We aimed to evaluate colorectal cancer risk in relation to green tea consumption in a population-based prospective cohort study. METHODS: Subjects were 13 957 men and 16 374 women aged ≥35 years in September 1992. The participants' green tea consumption was elicited by administering a food frequency questionnaire. The colorectal cancer incidence was confirmed through regional population-based cancer registries and histological identification from colonoscopy in two main hospitals in the study area. Colorectal cancer was defined as the sum of code C18 (colon cancer) and codes C19 and C20 (rectal cancer) according to ICD-10. RESULTS: Up to March 2008, 429 men and 343 women were diagnosed with colorectal cancer. No significant association was found between green tea consumption and colorectal cancer in men and women, respectively. However, for men, compared with the group of 'none or less than once per day' of green tea consumption, the multiple-adjusted relative risks (95% CIs) for colon cancer were 1.32 (0.90, 1.94), 0.76 (0.57, 1.02), and 0.78 (0.49, 1.22), respectively, in the group of 'once per day,' '2-3 times per day', and 'four times per day or more' (trend P = 0.045). CONCLUSIONS: This study observed no overall significant associations between green tea consumption and colorectal cancer risk, except that there was a weak trend for greater consumption of green tea with decreased risk of male colon cancer.

Inhibition of mast cell degranulation by melanin.

Melanin is a dark naturally occurring pigment produced in nature and in many organisms. Although several reports have demonstrated applications for melanins in various therapeutic treatments, to date, no research has examined the anti-allergic effect of melanin. In this study, we for the first time found that solubilized or synthesized soluble melanin acts as a potent inhibitor of the degranulation of mast cells. We found that squid-ink-derived melanin significantly inhibited antigen-IgE-FcεRI-mediated degranulation of the mucosal mast cell line RBL-2H3. A homogenized melanin nanoparticle prepared by laser ablation also clearly suppressed antigen-induced mast cell degranulation. We also successfully solubilized synthetic melanin in a neutral biochemical buffer and found that it also significantly inhibited IgE-sensitized mast cells. The anti-degranulation activity of synthesized melanin was abolished in the melanin fraction below 50-kD molecular weight. All melanins used in this study did not exert significant cell death. Signal transduction analysis revealed that melanin suppressed antigen-triggered phosphorylation of signaling molecules as well as calcium influx. Transmission electron microscopy revealed that homogenized melanin nanoparticles partially attached to the cell surface and some nanoparticles were internalized to the cell. Flow cytometry revealed that the number of FcεRI-bound IgE molecules was decreased by melanin. Fluorescence recovery after photobleaching analysis indicated that melanin attenuated both plasma membrane and cytoplasmic fluidity, implying that melanin increased their viscosities. In vivo experiments using passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) mouse models demonstrated that oral administration of melanin accelerated the recovery of decreased body temperature after antigen infection in PSA, and combination sensitization of IgE with melanin attenuated antigen-induced extravasation in PCA. These findings indicated that melanin exhibits preventative effects against IgE-mast cell-mediated anaphylaxis. This study provides the first evidence that homogenized melanin may be a potential therapeutic agent for diseases involving mast cells.

Association between exposure to household smoking and dental caries in preschool children: a cross-sectional study.

BACKGROUND: We aimed to examine the association of exposure to environmental tobacco smoke with dental caries among preschool children. Exposure to environmental tobacco smoke was assessed in terms of urinary cotinine concentrations and pack-years of exposure to smoking by parents and other family members at home. METHODS: This cross-sectional study included 405 preschool children aged 3-6 years from two preschools in Japan in 2006. Information on the smoking habits of family members living with the child was obtained from parent-administered questionnaires. Dental examination was conducted to assess dental caries, that is, decayed and/or filled teeth. Urinary cotinine levels were measured using first-void morning urine samples. RESULTS: Overall, 31.1% of the children had dental caries, and 29.5% had decayed teeth. Exposure to current maternal and paternal smoking was positively associated with the presence of dental caries after controlling for covariates. More than three pack-years of exposure to maternal smoking and more than five pack-years of exposure to smoking by all family members were significantly associated with the presence of dental caries as compared with no exposure (odds ratio [OR] = 5.55, 95% confidence interval [CI] = 2.17-14.22, P for trend < 0.001 and OR = 2.00, 95% CI = 1.12-3.58, P for trend = 0.004, respectively). These exposure variables were similarly associated with the presence of decayed teeth (OR = 2.92, 95% CI = 1.23-6.96, P for trend = 0.01 and OR = 1.75, 95% CI = 0.96-3.20, P for trend = 0.03, respectively). As compared with lowest tertile of the urinary cotinine level, the highest tertile of the urinary cotinine level was significantly associated with the presence of dental caries as well as decayed teeth; the ORs for the highest vs. lowest tertile of urinary cotinine levels were 3.10 (95% CI = 1.71-5.63, P for trend = 0.012) and 2.02 (95% CI = 1.10-3.70, P for trend = 0.10), respectively. CONCLUSIONS: These data suggest that exposure to tobacco smoke may have a dose-dependent influence on the development of caries.