PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study.

BACKGROUND: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. METHODS: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates. RESULTS: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher's exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. CONCLUSIONS: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

Antihypertensive medication versus health promotion for improving metabolic syndrome in preventing cardiovascular events: a success rate-oriented simulation study.

BACKGROUND: In practice, it is difficult to compare the effectiveness of traditional antihypertensive treatment with that of health promotion in reducing incidence rate of cardiovascular disease (IRCVD, events/year). This simulation study compared the effectiveness of two approaches to reducing IRCVD in a sample population: a traditional approach, in which high-risk patients are treated with conventional antihypertensive medications, and a population-based approach, in which subjects participate in a health promotion program. METHODS: We constructed a simulation model for a sample population of middle-aged Japanese men whose systolic blood pressure (SBP) levels are normally distributed (130 ± 20 mm Hg). The principal assumption was that IRCVD increases exponentially according to SBP. The population IRCVD was calculated as the product of the distribution of SBP multiplied by IRCVD at each SBP. The cumulative IRCVD was calculated by the definite integral from the lowest to the highest SBP of IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. RESULTS: The reduction in IRCVD was twice as large for antihypertensive medications as it was for health promotion in several situations. For example, if adherence to antihypertensive treatment occurred at a realistic level, the decrease in IRCVD was estimated at 9.99 × 10(-4). In contrast, even if the health program was promoted optimistically, the decrease in IRCVD was estimated at 4.69 × 10(-4). CONCLUSIONS: The success rate-oriented simulation suggests that prescribing antihypertensive medications is superior to promoting the health promotion program in reducing IRCVD in virtual middle-aged Japanese men.

[Age at the onset of intractable disease: based on a clinical database for patients receiving financial aid for treatment].

OBJECTIVE: We examined a clinical database for patients receiving financial aid for treatment to elucidate age at onset of intractable disease. METHODS: Data were obtained from the clinical database of patients receiving financial aid for treatment in 2003. Age at onset of disease was calculated by subtracting the year of birth from the year of onset as registered in the database. Percentiles for age at onset and peak onset age were evaluated for each intractable disease. Peak onset ages for primary immune-deficiency syndrome, subacute sclerosing panencephalitis, lysosomal diseases, epidermolysis bullosa and neurofibromatosis I and II were under 20 years. RESULTS: Peak onset ages for aortitis syndrome, systemic lupus erythematosus, Behcet's disease, adrenoleukodystrophy, multiple sclerosis, ulcerative colitis and Crohn's disease were between 20 and 50. Distributions of age at onset for aplastic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, moyamoya disease and sarcoidosis were bimodal. Peak onset age for many other diseases were > or = 40 years. CONCLUSIONS: Using a clinical database for patients receiving financial aid for treatment, the distribution of ages at onset and peak onset ages could be systematically clarified for individual intractable diseases. Our study provides new information on the natural history of disease development.

[Age and cause of death contributing to reduction of disparity in age-adjusted overall mortality between males in Okinawa and mainland Japan].

OBJECTIVES: We here propose a new index, the difference-change contribution proportion, to quantify contributions of age and cause of death to differences in age-adjusted overall mortality disparities between two groups over time. The present study was conducted with the aim of elucidating age and cause of death contributions to the recent decrease in disparity in life expectancy between males in Okinawa and mainland Japan. The longer-term goal is to apply the findings to developing appropriate preventive measures against diseases for Okinawa people. METHODS: Changes in disparity between age-adjusted overall mortality of male populations of Okinawa and Japan nationwide during a 15-year period, between 1985 and 2000, were measured and difference-change contribution proportions for age-adjusted overall mortality were computed. RESULTS: Causes of death that showed high difference-change contribution proportions included cerebral infarction (24.26%), cardiac failure (18.45%), other cerebrovascular diseases (15.11%), malignant gastric neoplasms (11.89%), ischemic heart disease (11.06%), hepatic disease (10.93%), suicide (5.71%), and diabetes (5.36%). Of these, cerebral infarction, cardiac failure, other cerebrovascular diseases, malignant gastric neoplasm, ischemic heart disease, and diabetes indicated high difference-change contribution proportions among seniors 65 years old and above, while hepatic disease and suicide ranked highly among the middle-aged. CONCLUSION: The results of this study revealed the extent of age and cause of death contributions to the decreasing disparity observed between populations of Okinawa and Japan nationwide in male age-adjusted overall mortality. The causes of death and the age revealed by this study are critical to taking preventive measures against diseases. Moreover, this study confirmed that the difference-change contribution proportion is a useful method to quantify contributions of age and cause of death to changes in variation regarding life expectancy.

Lifestyle Modifications Versus Antihypertensive Medications in Reducing Cardiovascular Events in an Aging Society: A Success Rate-oriented Simulation.

Objective It is difficult to compare directly the practical effects of lifestyle modifications and antihypertensive medications on reducing cardiovascular disease (CVD). The purpose of this study was to compare the hypothetical potential of lifestyle modifications with that of antihypertensive medications in reducing CVD in an aging society using a success rate-oriented simulation. Methods We constructed a simulation model for virtual Japanese subpopulations according to sex and age at 10-year intervals from 40 years of age as an example of an aging society. The fractional incidence rate of CVD was calculated as the product of the incidence rate at each systolic blood pressure (SBP) level and the proportion of the SBP frequency distribution in the fractional subpopulations of each SBP. The total incidence rate was calculated by the definite integral of the fractional incidence rate at each SBP level in the sex- and age-specific subpopulations. Results If we consider the effects of lifestyle modifications on metabolic factors and transfer them onto SBP, the reductions in the total incidence rate of CVD were competitive between lifestyle modifications and antihypertensive medications in realistic scenarios. In middle-aged women, the preventive effects of both approaches were limited due to a low incidence rate. In middle-aged men and extremely elderly subjects whose adherence to antihypertensive medications is predicted to be low, lifestyle modifications could be an alternative choice. Conclusion The success rate-oriented simulation suggests that the effectiveness of lifestyle modifications or antihypertensive medications in preventing cardiovascular events largely depends on the baseline incidence rate and sex- and age-specific behavioral factors.

Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts.

OBJECTIVE: To report the age- and sex-specific prevalence of diabetes and impaired glucose regulation (IGR) according to revised World Health Organization criteria for diabetes in Asian populations. RESEARCH DESIGN AND METHODS: We performed 11 studies of 4 countries, comprising 24,335 subjects (10,851 men and 13,484 women) aged 30-89 years who attended the 2-h oral glucose tolerance test and met the inclusion criteria for data analysis. RESULTS: The prevalence of diabetes increased with age and reached the peak at 70-89 years of age in Chinese and Japanese subjects but peaked at 60-69 years of age followed by a decline at the 70 years of age in Indian subjects. At 30-79 years of age, the 10-year age-specific prevalence of diabetes was higher in Indian than in Chinese and Japanese subjects. Indian subjects also had a higher prevalence of IGR in the younger age-groups (30-49 years) compared with that for Chinese and Japanese subjects. Impaired glucose tolerance was more prevalent than impaired fasting glycemia in all Asian populations studied for all age-groups. CONCLUSIONS: Indians had the highest prevalence of diabetes among Asian countries. The age at which the peak prevalence of diabetes was reached was approximately 10 years younger in Indian compared with Chinese and Japanese subjects. Diabetes and IGR will be underestimated in Asians based on the fasting glucose testing alone.

[Chronological analysis of individually linked data for patients with intractable disease receiving public financial aid for treatment].

PURPOSE: Nationwide surveys of intractable disease patients receiving public financial aid for treatment were performed by Research Committee for Epidemiology of Intractable Disease (Ministry of Health and Welfare, Japan) 4 times in the past, in 1984, 1988, 1992 and 1997. The purpose of the present study was to clarify the features of continuance with intractable disease patients receiving public financial aid for treatment. METHODS: Individual information collected by each nationwide survey was linked using the disease, the residence, the sex, and the birth date. The proportion of intractable disease patients according to receipt duration, kind of medical insurance, sex and age was calculated with reference to the disease and an estimation of the receipt persistence rate was calculated for every year. Moreover, in consideration of variation in the data, average receipt persistence rates over years were also calculated. RESULTS: According to observation on individual patient's follow up, the proportion for which financial aid was discontinued within four years was 25%, while 70% continued receiving aid for at least four years and some 55% for eight or nine years. The proportion of those who continue receiving support long-term is high about the so-called autoimmune diseases, such as systemic lupus erythematosus, Behçet's disease, and the aortic syndrome. In contrast, with diseases having a poor prognosis, such as fulminant hepatitis, amyloidosis, and amyotrophic lateral sclerosis, periods of continuance are short. The proportion needing long-term continuation is higher in women than in men, especially with diseases which have long been eligible for support. However, with diseases for which receipt was started recently, there is a tendency for persistence to be higher in men than in women. CONCLUSION: With reform of insurance systems, including the medical system for intractable diseases, it is predicted that receipt continuation will change with alteration of social factors, and it is necessary to monitor receipt continuation carefully from now on.

Lifestyle modifications supported by regional health nurses lowered insulin resistance, oxidative stress and central blood pressure in subjects with metabolic syndrome.

BACKGROUND: This study was attempted to investigate whether lifestyle modifications supported by regional health nurses should improve cardio-metabolic factors--including adipocytokines, oxidative stress, and arterial stiffness--in subjects with metabolic syndrome. METHODS: Thirty-six subjects with metabolic syndrome were enrolled, 28 of whom completed the 6-month lifestyle modifications (male:female=19:9). Blood and urine test results were examined in relation to metabolic factors before and after 6-month nutritional and physical activity modifications. In addition, oral glucose tolerance tests were performed and arterial stiffness was measured by brachial-ankle pulse wave velocity and radial augmentation index before and after them. RESULTS: Six-month lifestyle modifications significantly reduced body weight, homeostasis model assessment index, and low-density lipoprotein cholesterol (LDL-C). They significantly attenuated oxidative stress measured by the urinary 8-hydroxy-2-deoxyguanosine/creatinine ratio. They also lowered brachial and central systolic blood pressure. They tended to decrease waist circumferences and the levels of C-reactive protein. However they did not significantly change the levels of adipocytokines, including tumour necrosis factor, soluble tumour necrosis factor receptors, and interleukin 6, or arterial stiffness measured by brachial-ankle pulse wave velocity and radial augmentation index. CONCLUSIONS: Six-month lifestyle modifications supported by regional health nurses lowered body weight, insulin resistance, LDL-C, oxidative stress, and peripheral and central blood pressure in subjects with metabolic syndrome.

[Characteristics of patients with intractable diseases receiving public financial aid for treatment--results of a nationwide survey, 1997].

OBJECTIVES: In order to clarify the characteristics of medical institutions visited by patients with selected intractable diseases, we analyzed data from the fourth nationwide survey in 1997. METHODS: We asked 47 prefectural governments to provide data concerning every patient receiving financial aid for treatment of 39 selected intractable diseases from April 1997 to March 1998. Out of 399,719 whose information was reported by prefectural governments, we analysed data of 370,232 patients whose medical institutions were reported. We performed detailed analysis on the relation between patients' residences and locations of medical institution which the patients visited, and on the characteristics of medical institutions. These analyses were respectively compared by sex and age, the beginning year of the financial aid, whether the patients were inpatients or outpatients, type of insurance, and clinical division where the patient was treated. RESULTS: 1. Analysis showed that 7.4% of all patients were treated in medical institutions outside the prefectures where they lived. Patients who lived in the neighboring prefectures of huge cities like Tokyo, tended to be treated in the medical institutions there. 2. We found that 23.5% of patients were treated in university hospitals, and 11.9% were seen in clinics. 3. There was a difference between patients with SMON and patients with myastenia gravis, pemphigus, epidermolysis bullosa or primary pulmonary hypertension. Of the two groups, the former preferred to visit clinics and be treated in medical institutions located in the same cities, towns, and villages where they lived. On the contrary, patients with the latter 4 diseases tended to visit large hospitals and be treated in those outside their prefectures. 4. Elderly patients over 70 years old tended to be treated in clinics or hospitals located in their neighborhoods. 5. Compared with past surveys, the percentage of patients treated in university hospitals had decreased, and that of patients treated in clinics had increased year by year. No change was found in the proportion of patients treated in medical institutions outside their prefectures. CONCLUSIONS: By the present analysis of a nationwide survey taken in fiscal year 1997, we were able to clarify the characteristics of medical institutions visited by patients with selected intractable diseases. This kind of analysis should be continued to obtain important information on the epidemiology of intractable diseases.

[Characteristics of social activity of the elderly who belong to senior citizens].

PURPOSE: The purpose of this study was to clarify environmental conditions determining the social activities of the elderly, by analyzing levels of activity in individuals belonging to clubs for senior citizens. METHODS: In 1998, we conducted a survey of over 10,000 elderly subjects, 65 years of age or older, who belonged to 228 clubs for senior citizens in a region of Saitama Prefecture, using a 'Check list' developed for self-evaluation of social activities. The proportions of 'active' and 'inactive' seniors, as judged by the 'Check list' for each of the four different aspects of social activities (1. individual activities, 2. social participation/volunteering, 3. education/training, 4. employment), were compared with those of the standard elderly population. RESULTS: Two hundred and seven clubs for senior citizens (90.8%) participated in this study. About 82.0% of the members of each club filled out the 'Check list'. High levels as compared to the standard population were demonstrated for two aspects of social activity: individual activity and social participation/volunteering. Women had higher levels of both types of social activity than men. Men aged 74 years or younger had lower than average levels for three aspects of social activity: social participation/volunteering, education/training, and employment. Members who resided in urban areas with easy access had higher levels of individual activity, social participation/volunteering and education/training. On the other hand, those residing in suburbs with large spaces for agriculture had higher levels for employment. CONCLUSION: Our results for social activities of elderly subjects belonging to clubs for senior citizens indicate that strong correlations exist with environmental conditions, including communication facilities and local or industrial structure.

[Nationwide survey of intractable disease patients. Analyses of patients receiving public financial aid for treatment in fiscal year 1997].

OBJECTIVE: In order to clarify epidemiologic features of selected intractable diseases, an investigation of the fourth nationwide survey, in 1998, was performed. METHODS: We asked 47 prefectural governments to provide data concerning every patient receiving financial aid for treatment of 39 selected intractable diseases from April 1997 to March 1998. The items for each patient required were the beginning year of the financial aid, the disease code, sex, date of birth, residence, type of insurance, whether an in-patient or outpatient, medical institution and the clinical division where the patient was treated. We performed a detailed analysis regarding the age distribution, the prefecture, in-patient or outpatient, the clinical division, the insurance, and the disease, for both males and females. RESULTS: 1. The total number of patients who received financial aid for treatment was 399, 719 with a sex ratio of 0.66 (males 158, 766, or female 240, 953), 60.7% being between 45 and 74 years of age. Of 214, 173 patients whose status could be confirmed regarding outpatient or inpatient. 14.7% were the latter. Of 129, 685 cases, 56, 471 (43.6%) were treated in departments of internal medicine. Of 396, 187 patients, 65, 841 (16.6%) were covered by the health and medical services law for the aged. The greatest number of patients resided in Tokyo, and the least was in Yamanashi Prefecture. 2. With regard to specific intractable diseases, the largest number of patients receiving aid for treatment were suffering from ulcerative colitis at 52, 261, while the least number was for primary pulmonary hypertension at 96. The numbers for each group had increased within the 13 years from 1984 to 1997, except for SMON. As the patients' age increased, the percentage of those receiving treatment also increased and the numbers of aged individuals were especially elevated. 3. The proportion of in-patients for the Creutzfelde-Jakob disease was 76.4 percent, which was remarkably higher than for other diseases. CONCLUSION: By the present analysis of the nationwide survey in fiscal year 1997, we could clarify changes in epidemiologic features of patients receiving financial aid for treatment. This kind of analysis should be continued to obtain important information on the epidemiology of intractable diseases.

Lipopolysaccharide-induced overproduction of nitric oxide and overexpression of iNOS and interleukin-1ß proteins in zinc-deficient rats.

Zinc deficiency leads to decreased cellular immune responses. The overproduction of nitrogen species derived from inducible nitric oxide synthase (iNOS), its enzyme, and interleukine-1 beta (IL-1ß), and inflammatory cytokine have been implicated in immune responses. The goal of this study was to investigate the effects of lipopolysaccharide (LPS)-induced changes in NO metabolites, iNOS, and IL-1ß protein expression in the lungs of zinc-deficient rats. Male Sprague-Dawley rats (body weight, 100 g) were divided into two groups and were fed either a zinc-deficient diet (ZnD) or a zinc-containing diet (Cont). After 4 weeks on these diets, rats received a 10-mg/kg dose of LPS injected via the tail vein and were then maintained for an additional 72 h. To determine total NO concentrations in the blood, serum zinc concentration, iNOS protein expression, IL-1ß, and iNOS immunohistochemistry, blood and lung samples were obtained at pre-LPS injection, 5, 24, and 72 h after injection. Total NO levels were significantly increased at 5, at 24, and at 72 h after LPS injection compared with pre-LPS injection level in ZnD group; significant changes in total NO levels was elevated at 5 h from at pre-LPS level but not significant changes from basal level at 24 and 72 h in the control group. Based on western blot analyses and immunohistochemistry, clear bands indicating iNOS and IL-1ß protein expression and iNOS antibody-stained inflammatory cells were detected at 5 and 24 h in the ZnD group and 5 h in the Cont group, not observed at 24 and 72 h in the control group. These results suggest that zinc deficiency induces overexpression of iNOS and IL-1ß proteins from inflammatory cells around the alveolar blood vessels, resulting in overproduction of total NO and persisted inflammatory response in the zinc-deficient rat lung. Taken together, overexpression of LPS-induced iNOS, overproduction of iNOS-derived NO, and overexpression of IL-1ß may induce nitrosative and oxidative stresses in the lung, and these stresses may be involved low immunity of zinc deficiency states.

Adiponectin as a biomarker of the metabolic syndrome.

BACKGROUND: The metabolic syndrome, a cluster of abdominal obesity, dyslipidemia, hypertension and hyperglycemia, is a common basis for atherosclerotic vascular diseases in industrial countries exposed to overnutrition. Adiponectin is an adipose-derived plasma protein with anti-atherogenic and insulin-sensitizing activities. METHODS AND RESULTS: A total of 661 Japanese adults (479 men, 53+/-10 years; 182 women 56+/-10 years) were enrolled. Plasma adiponectin concentrations correlated negatively with waist circumference, visceral fat area, serum triglyceride concentration, fasting plasma glucose, fasting plasma insulin, and systolic and diastolic blood pressure in both sexes. A positive correlation was found between plasma adiponectin and high-density lipoprotein cholesterol concentrations in both sexes. The mean number of components of the metabolic syndrome increased as the plasma adiponectin concentration decreased: 2.57+/-1.34 for men and 2.00+/-1.51 for women with adiponectin concentrations <4.0 microg/ml. In all, 52.3% of men and 37.5% of women with adiponectin concentrations <4.0 microg/ml fulfilled the criteria for metabolic syndrome. CONCLUSION: Hypoadiponectinemia is closely associated with the clinical phenotype of the metabolic syndrome and measuring the plasma concentration of adiponectin may be useful for management of the metabolic syndrome.