Haplotype-based case-control study of receptor (calcitonin) activity-modifying protein-1 gene in cerebral infarction.

Calcitonin gene-related peptide (CGRP) receptor is a complex molecule that consists of calcitonin receptor-like receptor and receptor activity-modifying protein-1 (RAMP1). It was recently reported that RAMP1-deficient mice (RAMP1(-/-)) showed inflammatory responses with a transiently significant increase in serum CGRP levels and proinflammatory cytokines when compared with RAMP1(+/+) mice. The aim of this study was to investigate the relationship between the human RAMP1 gene and cerebral infarction (CI) using single-nucleotide polymorphisms (SNPs) in a Japanese population. We selected six SNPs in the human RAMP1 gene (rs3754701, rs3769048, rs7557078, rs1584243, rs10199956 and rs7590387) and performed a case-control study using each SNP and haplotype in 171 CI patients and 234 controls. There were no significant differences in overall distribution of genotype and allele frequencies of the SNPs between the CI and control groups. However, there was a significant difference in overall distribution between the CI and control groups (P<0.001) in the haplotype-based case-control study with the combinations of rs3754701-rs3769048-rs7590387. The T-A-C susceptibility haplotype for CI was significantly more frequent than in the control group (P=0.0024). The results suggest that the T-A-C haplotype is a genetic marker for CI, and that RAMP1 or neighbouring genes are associated with increased susceptibility to CI.

Dysmenorrhea among Japanese women.

OBJECTIVE: To investigate the epidemiology of dysmenorrhea in Japanese women of menstrual age. METHODS: A prospective cohort study was conducted using a health diary in a sample representative of Japanese women. Information on health care use was also collected. RESULTS: Among 823 enrolled participants (age range, 18-51 years), dysmenorrhea (mean duration 1.75 days; range 1-5 days) was reported in 15.8% (95% CI, 13.3-18.3) during the 1-month study period. Common associated symptoms included headache (10.77%), back pain (6.92%), and fatigue (5.38%). No participant with dysmenorrhea visited a physician, while 51.5% of the women used self-medication, and 7.7% used complementary/alternative medicine. CONCLUSION: Dysmenorrhea is common in Japanese women. In our study, about half used self-medication, while some preferred complementary/alternative medicine. Dysmenorrhea is significantly associated with younger age and employment status.

The future profile of health promotion and disease prevention in Japan: based on the study of seniors over age 75.

OBJECTIVES: One of the serious challenges for Japanese healthcare is the aging population. Analysis of health evaluation data, especially of the elderly over 75 years, is considered very important. In view of this prolonged life expectancy in Japan, our government started the new campaign of Healthy Japan 21, of which details are described, and also we will demonstrate the general profile of our perspective cohort study program concerning the new elder citizens in Japan. METHODS AND RESULTS: Our group has started a health evaluation program for those apparently healthy new elder citizens over the age of 75. A ten-year cohort study is in progress, which is designed to accumulate health check-up data annually. The study collects information on physical well being, as well as information on the individual's lifestyle, and social, emotional and spiritual environment. Such health appraisal is of primary importance. Preliminary results will be demonstrated with their special implications in clinical and epidemiological significance. The degree of frailty of the individual was also carefully evaluated, so that we can learn about the QOL of the seniors in Japan. CONCLUSIONS: At the present stage, we can only report a part of our study including the mental and spiritual environments of the individual. This kind of outcome study will give us some insights concerning the natural progress of frailty in the apparently healthy elderly.

Medicine and religion: spiritual dimension of health care.

The author probes into the origin of medicine and illuminates how religion took an essential part in the birth of ancient medicine in both East and West. In the modern age, medicine as science continues to attain a high level of progress. Yet simultaneously, medicine interacts with the spiritual and religious realm of the human mind. The hospice movement, started by Cecily Saunders in 1967, strongly encouraged this tendency, and now spiritual care is acquiring much importance in global medicine.

Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma.

We examined alterations of the p16INK4, p14ARF, p15, TP53, and MDM2 genes in 30 osteosarcomas and 24 Ewing sarcomas. Among 21 osteosarcomas and 24 Ewing sarcomas, p16INK4, p14ARF, and p15 abnormalities were found in 4 (19%), 2 (9%), and 3 (14%) osteosarcomas, respectively, and in 4 (17%), 3 (13%), and 4 (17%) Ewing sarcomas, respectively. The alterations of p16INK4, p14ARF, and p15 included homozygous deletions spanning all 3 genes, methylation of p16INK4 or p15, and a nonsense mutation of p16INK4, which simultaneously caused a missense mutation of p14ARF. Alterations of TP53 were found in 15 (50%) of 30 osteosarcomas and 1 (3%) of 24 Ewing sarcomas. None of the sarcomas showed MDM2 amplification. While TP53 abnormalities were far more frequent in osteosarcoma than in Ewing sarcoma, alterations of p16INK4, p14ARF, and p15 were present at similar frequencies in the two types of sarcoma. The event-free survival (EFS) was worse in Ewing sarcoma patients with p16INK4 and p14ARF mutation/deletion than in those without the mutation/deletion (P = 0.019), and EFS was worse in osteosarcoma patients with TP53 alterations than in those without TP53 alterations (P = 0.048). The different incidence of TP53 abnormalities in the 2 types of sarcoma may reflect differences of the molecular processes through which the 2 types of tumor develop.

Results of screening for cancer in Japanese in the prime of life--an analysis of nationwide MHTS and human dry dock statistics--Preventive Medicine Committee of the Japan Hospital Association.

The nationwide survey of institutions with MHTS and human dry dock capabilities was analyzed and the following results have been obtained. 1) The relative rates of cancer detection by sex and organ were the stomach > colon > rectum > lung > kidney > esophagus for men and the stomach > breast > uterus > colon > thyroid > lung for women. 2) Gastric cancer takes first place in the ranking of rates of cancer detection in the population of both sexes, followed by colon cancer. The difference in rate of detection between these cancers has been narrowed from year to year. In 1997, the ratio of gastric to colon cancers was 10:7. 3) Early cancers account for 74% of gastric cancer patients and 75% of colon cancer patients. 4) Since gastric and colon cancers are detected early, the proportions of persons with gastrointestinal symptoms are as low as 28% for gastric cancer patients and 26% for colon cancer patients. 5) The relative rates of cancer detection by the degree obesity are normal > obese > lean person. The rates of gastric and colon cancers are 2- and 3-fold higher for obese persons than for lean persons, respectively. Gastric and colon cancers are detected with higher frequency in well-nourished persons. The present review of the national MHTS and human dry dock statistics has confirmed the efficacy of MHTS and human dry dock, especially in the examination for gastrointestinal cancers.

Abnormalities of the FHIT transcripts in osteosarcoma and Ewing sarcoma.

In a study of FHIT gene abnormalities by reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis of the PCR products, we found normal and abnormal PCR products in 11 osteosarcomas, one osteosarcoma cell line and 3 Ewing sarcomas, and a normal PCR product only in 5 osteosarcomas and 8 Ewing sarcomas. Sequence analysis of the abnormal PCR products revealed 7 osteosarcomas lacking exons 4 to 6, 7, 8 or 9, two lacking exons 5 to 7 or 10, and two lacking exons 6 to 8 or 10. In the aberrant transcripts of the 11 osteosarcomas, fusion had occurred in the exon/intron junctions in 2 tumors, between a segment within an exon and a complete exon in 3, and between segments within exons in 6. The 3 Ewing sarcomas had lost exon 4 or 5 to exon 6 or 10, and fusion had occurred in the exon/intron junction in one, and between segments within exons in 2. These findings suggest that both abnormal or variant splicing and other mechanisms such as genomic instabilities in the FHIT locus may have resulted in the expression of aberrant transcripts. One osteosarcoma and one cell line established from this osteosarcoma showed different abnormal FHIT transcripts, indicating that the tumor cells with the initial aberrant transcripts may not have had a selective advantage for proliferation. The FHIT abnormalities did not seem to be correlated with lung metastasis or a poor clinical outcome in our patients with osteosarcoma or Ewing sarcoma.

HRA model for hypercholesterolemia based on a longitudinal health database.

To evaluate the risk factors for hypercholesterolemia, we examined 4,371 subjects (3,207 males and 1,164 females) who received medical checkups more than twice at an AMHTS in Tokyo during the period from 1976 through 1991; and whose serum total cholesterol was under 250 mg/dl. The mean follow-up duration was 6.6 years. A self-registering questionnaire was administered at the time of the health checkup. The endpoint of this study was the onset of hypercholesterolemia when the level of serum total cholesterol was 250 mg/dl and over. We compared two prognosis groups (normal and hypercholesterol) in terms of age, examination findings and lifestyle. After assessing each variable, we employed Cox's proportional hazards model analysis to determine the factors related to the occurrence of hypercholesterolemia. According to proportional hazards model analysis, total cholesterol, triglyceride and smoking at the beginning, and hypertension during the observation period were selected in males; and total cholesterol at the beginning and age were selected in females to determine the factors related to the occurrence of hypercholesterolemia.

Dietary balance chart for an on-line computerized graphical support system in MHTS.

Dietary habits are believed to play an important role in the etiology of adult disease. For this reason, it is necessary to include effective dietary guidance in multiphasic health testing and services (MHTS) programmes for primary disease prevention. We have developed such a programme of simple dietary advice, using a computer system for the MHTS. Examinees' dietary habits are checked using optical character record (OCR) questionnaire forms, and the results are displayed on the screen of a colour display terminal. They are required to prepare a menu of their usual daily dietary intake in terms of quantity and type of food. Thus the data collected relate to the nutritional composition of the examinee's usual diet. Nutritional requirements of the Japanese according to sex, height, and level of physical activity, in accordance with criteria set by the Japanese Ministry of Health and Welfare, are fed into the computer in advance. For each examinee, these criteria and the results of the assessment of the diet are displayed together on the screen in the form of colour graphs for comparison.

The Tokyo subway sarin attack: disaster management, Part 1: Community emergency response.

The Tokyo subway sarin attack was the second documented incident of nerve gas poisoning in Japan. Prior to the Tokyo subway sarin attack, there had never been such a large-scale disaster caused by nerve gas in peacetime history. This article provides details related to how the community emergency medical services (EMS) system responded from the viewpoint of disaster management, the problems encountered, and how they were addressed. The authors' assessment was that if EMTs, under Japanese law, had been allowed to maintain an airway with an endotracheal tube or use a laryngeal mask airway without physician oversight, more patients might have been saved during this chemical exposure disaster. Given current legal restrictions, advanced airway control at the scene will require that doctors become more actively involved in out-of-hospital treatment. Other recommendations are: 1) that integration and cooperation of concerned organizations be established through disaster drills; 2) that poison information centers act as regional mediators of all toxicologic information; 3) that a real-time, multidirectional communication system be established; 4) that multiple channels of communication be available for disaster care; 5) that public organizations have access to mobile decontamination facilities; and 6) that respiratory protection and chemical-resistant suits with gloves and boots be available for out-of-hospital providers during chemical disasters.

The Tokyo subway sarin attack: disaster management, Part 2: Hospital response.

The Tokyo subway sarin attack was the second documented incident of nerve gas poisoning in Japan. The authors report how St. Luke's Hospital dealt with this disaster from the viewpoint of disaster management. Recommendations derived from the experience include the following: Each hospital in Japan should prepare an emergent decontamination area and have available chemical-resistant suits and masks. Ventilation in the ED and main treatment areas should be well planned at the time a hospital is designed. Hospital disaster planning must include guidance in mass casualties, an emergency staff call-up system, and an efficient emergency medical chart system. Hospitals should establish an information network during routine practice so that it can be called upon at the time of a disaster. The long-term effects of sarin should be monitored, with such investigation ideally organized and integrated by the Japanese government.

The Tokyo subway sarin attack: disaster management, Part 3: National and international responses.

The authors report the national and international responses to the disaster produced by the Tokyo subway sarin attack. From a worldwide historical perspective, there had never been such a large-scale disaster caused by nerve gas during peacetime. Therefore, this event should be studied from various viewpoints in cooperation with members of the international community. To this end, the Japanese government should help coordinate a large-scale and detailed investigation of the Tokyo subway sarin attack, including the long-term effects of sarin. The authors also recommend that the Japanese Self Defense Forces should be used more effectively in large-scale disasters. The system of direct control of disaster management by the Japanese government could be useful in a large-scale disaster.

Health risk assessment for diabetes mellitus based on longitudinal analysis of MHTS database.

This study was designed with a follow up of 16 years to provide the epidemiological model evaluating the risk of developing diabetes mellitus in Japan. A cohort of 2573 subjects (1851 males and 722 females) from a MHTS in Tokyo, who were nondiabetic (fasting blood glucose (FBS) less than 110 mg/dl) in the initial year, were selected. This cohort was followed every year to identify the occurrence of diabetes mellitus. Diabetes Mellitus was defined as fasting blood glucose over 110 mg/dl, or the initiation of diabetic therapy. We compared two prognosis groups (a normal group and a diabetic group) in terms of age, examination findings, and prevalence of health risks (lifestyle, stress, and working form). We also assessed family history of diabetes and past histories including hypertension, hypercholesterolemia, and hyperuricemia. After assessing each variable by univariate analysis (t-test, chi 2 test), we employed Cox's proportional hazards model analysis. We used stepwise model adopting risk factors. The diabetic group had significant differences compared to the normal group in age, BMI (body mass index), FBS, smoking, drinking, not eating breakfast, dairy intake, hypertension, hypercholesterolemia, hyperuricemia, and family history by univariate analysis. According to proportional hazards model analysis, FBS, age, family history, hypertension, smoking, and BMI were incorporated into significant risk factors for diabetes in males, and not eating breakfast, FBS, age, drinking, and hypertension were incorporated in females. Diabetes seemed to be related to fixed factors (age), or genetic factors (family history and FBS) in males. For females, lifestyle (not eating breakfast and drinking habit) seemed to play an important role. It will be worthwhile to assess the risks of developing diabetes mellitus by this epidemiological model.

Left ventricular geometric patterns and QT dispersion in borderline and mild hypertension: their evolution and regression.

To investigate whether QT dispersion increases in borderline and mild hypertension during a longitudinal observation of > 3 years and whether it is improved with medications, left ventricular geometric patterns and QT dispersion were studied with special regard to their longitudinal changes in 85 male borderline and mild hypertensive subjects with left ventricular mass index < 125 g/m2. These subjects were followed for > 3 years without medication. Thirty-two patients with a left ventricular mass index > 125 g/m2 at the end of follow-up period were further observed using antihypertensive drugs for an additional 3 years. Echocardiograms and electrocardiograms were obtained at the beginning and end of the follow-up period. At the end of the follow-up period, subjects were classified into four groups based on ventricular geometric patterns determined by left ventricular mass index and relative wall thickness in diastole. The QT dispersion was greater in patients with concentric hypertrophy (56+/-18 msec) than in patients with normal geometry (41+/-17 msec) (P < .05) and increased significantly in the former group during the follow-up period. After medication, the left ventricular mass index regressed and the QT dispersion decreased (from 55+/-21 to 50+/-26 msec, P < .01) in these patients. Thus, these findings suggest that changes in the QT dispersion reflect both concentric evolution and regression of left ventricular hypertrophy.

Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16)(q23;p13) chromosome translocation.

CBP, which is located on 16p13 and encodes a transcriptional adaptor/coactivator protein, has been shown to fuse by the t(8;16)(p11;p13) translocation to MOZ on 8p11 in acute myeloid leukemia. We found a t(11;16)(q23;p13) in a child with therapy-related chronic myelomonocytic leukemia. Subsequent reverse transcriptase-polymerase chain reaction and direct sequencing analyses revealed the MLL-CBP fusion transcript in CMML cells. Because 11q23 translocations involving MLL and t(8;16) involving MOZ and CBP have been reported in therapy-related leukemias, both the MLL and CBP genes may be targets for topoisomerase II inhibitors. Accordingly, we believe that most t(11;16)-associated leukemias may develop in patients who have been treated with cytotoxic chemotherapy for primary malignant diseases.

Effects of long-term antihypertensive therapy on physical fitness of men with mild hypertension.

This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical fitness in men with mild hypertension. All subjects underwent symptom-limited treadmill stress testing and routine echocardiographic studies. Twenty-two subjects who had either a causal diastolic blood pressure of more than 105 mmHg or a left ventricular mass index (LVMI) of 125 g/m2 or more during follow-up were assigned to receive medical therapy. The other 31 men who did not meet either criterion were continuously followed-up without medication. Among the 22 treated men, the age-adjusted treadmill time (normalized treadmill time, TMTn) significantly decreased before the initiation of medication, while 31 untreated men showed no change in TMTn throughout the study. The 22 treated subjects were subsequently divided into two groups; 13 were given nifedipine and 9 were given acebutolol. All treated subjects were followed-up for more than 3 years. After treatment, the two groups showed similar reductions in blood pressure and LVMI, but a different outcome for TMTn: TMTn increased from 104 +/- 8% to 115 +/- 16% in subjects given nifedipine (p < 0.05) and decreased from 106 +/- 12% to 99 +/- 10% (p < 0.01) in those given acebutolol. Thus, the physical fitness of subjects who required medication significantly deteriorated without medication; their physical fitness improved after treatment with a calcium-channel antagonist and deteriorated after treatment with a beta-blocker.

The relationship of hyperinsulinemic state to left ventricular hypertrophy, microalbuminuria, and physical fitness in borderline and mild hypertension.

The relationship of the hyperinsulinemic state to left ventricular hypertrophy, left ventricular geometric patterns, microalbuminuria, and physical fitness were studied in 52 middle-aged unmedicated men with borderline and mild hypertension. Left ventricular mass index and relative wall thickness were assessed by echocardiography. Physical fitness was determined by symptom-limited maximal treadmill stress testings. The urinary concentration of microalbumin and C-peptide was measured in 24-h urine samples by radioimmunoassey. The 24-h urinary C-peptide excretion rate was correlated with left ventricular mass index (r = 0.46), relative wall thickness (r = 0.41), treadmill time (r = -0.35), normalized treadmill time (r = -0.52), systolic blood pressure at peak exercise (r = 0.29), and 24-h urinary microalbumin excretion (r = 0.48). Stepwise multiple regression analysis identified the left ventricular mass index, the 24-h urinary albumin excretion, and the normalized treadmill time as variables in the equation for the 24-h urinary C-peptide excretion. Thus, the hyperinsulinemic state is related to left ventricular hypertrophy, microalbuminuria, and impaired physical fitness in patients with borderline and mild hypertension.

Sarin poisoning on Tokyo subway.

On the day of the disaster, 641 victims were seen at St. Luke's International Hospital. Among those, five victims arrived with cardiopulmonary or respiratory arrest with marked miosis and extremely low serum cholinesterase values; two died and three recovered completely. In addition to these five critical patients, 106 patients, including four pregnant women, were hospitalized with symptoms of mild to moderate exposure. Other victims had only mild symptoms and were released after 6 hours of observation. Major signs and symptoms in victims were miosis, headache, dyspnea, nausea, ocular pain, blurred vision, vomiting, coughing, muscle weakness, and agitation. Almost all patients showed miosis and related symptoms such as headache, blurred vision, or visual darkness. Although these physical signs and symptoms disappeared within a few weeks, psychologic problems associated with posttraumatic stress disorder persisted longer. Also, secondary contamination of the house staff occurred, with some sort of physical abnormality in more than 20%.