Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice.

Undernutrition during pregnancy reduces birth weight and programmes adult phenotype with consequences for life expectancy, but its effects on the phenotype of the placenta, responsible for supplying nutrients for fetal growth, remain largely unknown. Using molecular, morphological and functional analyses, placental phenotype was examined in mice during restriction of dietary intake to 80% of control from day 3 of pregnancy. At day 16, undernutrition reduced placental, but not fetal, weight in association with decreased junctional zone volume and placental expression of glucose transporter Slc2a1. At day 19, both placental and fetal weights were reduced in undernourished mice (91% and 87% of control, respectively, P < 0.01), as were the volume and surface area of the labyrinthine zone responsible for placental nutrient transfer (85% and 86%, respectively, P < 0.03). However, unidirectional materno-fetal clearance of tracer glucose was maintained and methyl-aminoisobutyric acid increased 166% (P < 0.005) per gram of undernourished placenta, relative to controls. This was associated with an 18% and 27% increased placental expression of glucose and system A amino acid transporters Slc2a1 and Slc38a2, respectively, at day 19 (P < 0.04). At both ages, undernutrition decreased expression of the placental specific transcript of the Igf2 gene by 35% (P < 0.01), although methylation of its promoter was unaffected. The placenta, therefore, adapts to help maintain fetal growth when its own growth is compromised by maternal undernutrition. Consequently, placental phenotype is responsive to environmental conditions and may help predict the risk of adult disease programmed in utero.

Ultrastructure of placental hyperplasia in mice: comparison of placental phenotypes with three different etiologies.

Hyperplastic placentas have been reported in several experimental mouse models, including animals produced by somatic cell nuclear transfer, by inter(sub)species hybridization, and by somatic cytoplasm introduction to oocytes followed by intracytoplasmic sperm injection. Of great interest are the gross and histological features common to these placental phenotypes--despite their quite different etiologies--such as the enlargement of the spongiotrophoblast layers. To find morphological clues to the pathways leading to these similar placental phenotypes, we analyzed the ultrastructure of the three different types of hyperplastic placenta. Most cells affected were of trophoblast origin and their subcellular ultrastructural lesions were common to the three groups, e.g., a heavy accumulation of cytoplasmic vacuoles in the trophoblastic cells composing the labyrinthine wall and an increased volume of spongiotrophoblastic cells with extraordinarily dilatated rough endoplasmic reticulum. Although the numbers of trophoblastic glycogen cells were greatly increased, they maintained their normal ultrastructural morphology, including a heavy glycogen deposition throughout the cytoplasm. The fetal endothelium and small vessels were nearly intact. Our ultrastructural study suggests that these three types of placental hyperplasias, with different etiologies, may have common pathological pathways, which probably exclusively affect the development of certain cell types of the trophoblastic lineage during mouse placentation.

Aberrant regulation of imprinted gene expression in Gtl2lacZ mice.

The imprinted region on mouse distal chromosome 12 covers about 1 Mb and contains at least three paternally expressed genes (Pegs: Peg9/Dlk1, Peg11/Rtl1, and Dio3) and four maternally expressed genes (Megs: Meg3/Gtl2, antiPeg11/antiRlt1, Meg8/Rian, and Meg9/Mirg). Gtl2(lacZ) (Gene trap locus 2) mice have a transgene (TG) insertion 2.3 kb upstream from the Meg3/Gtl2 promoter and show about 40% growth retardation when the TG-inserted allele is paternally derived. Quantitative RT-PCR experiments showed that the expression levels of Pegs in this region were reduced below 50%. These results are consistent with the observed phenotype in Gtl2lacZ mice, because at least two Pegs(Peg9/Dlk1 and Dio3) have growth-promoting effects. The aberrant induction of Megs from silent paternal alleles was also observed in association with changes in the DNA methylation level of a differentially methylated region (DMR) located around Meg3/Gtl2 exon 1. Interestingly, a 60 approximately 80% reduction in all Megs was observed when the TG was maternally derived, although the pups showed no apparent growth or morphological abnormalities. Therefore, the paternal or maternal inheritance of the TG results in the down-regulation in cis of either Pegs or Megs, respectively, suggesting that the TG insertion influences the mechanism regulating the entire imprinted region.

Five-year retrospective changes in hippocampal atrophy and cognitive screening test performances in very mild Alzheimer's disease: the Tajiri Project.

The medial temporal lobe, especially the hippocampus, is important for normal cognitive function. especially for memory, and is the region with the earliest and most extensive pathological changes in Alzheimer's disease (AD). We investigated the atrophic changes of the hippocampus over a 5-year period and its relation to cognitive screening test performances in normal elderly subjects, those with very mild AD, and patients with AD. Fifty-seven elderly subjects without a moderate or greater degree of cerebrovascular disease as shown by MRI were randomly selected from the town of Tajiri. Thirty-three subjects with a clinical dementia rating (CDR) of 0 (normal), 18 CDR-0.5 (very mild AD) subjects, and six CDR-1&2 (AD) subjects underwent MRI and the Mini Mental State Examination (MMSE) twice during the period. Retrospective changes in the hippocampal width and the MMSE scores were evaluated. There were significant CDR group effects for the changes in the mean bilateral hippocampal widths and the MMSE scores. Normal subjects did not show cognitive decline, although there was a slight tendency for hippocampal atrophy. A significant and meaningful Spearman's correlation was noted between left hippocampal atrophy and the MMSE scores over the 5-year period for the CDR-0.5 group. These CDR-0.5 subjects met the MCI (mild cognitive impairment) criteria as proposed by the consensus paper. Findings suggested that normal elderly subjects maintain a high level of cognitive functions for at least 5 years, although hippocampal atrophy might occur. Atrophic change of the left hippocampus might be a good marker of the very early stage of AD.

Cognitive function and frontal lobe atrophy in normal elderly adults: Implications for dementia not as aging-related disorders and the reserve hypothesis.

We examined the relations between cognitive function and age and education in the normal elderly population. As per the community-based stroke, dementia, and bed confinement prevention in the town of Tajiri, neuropsychological assessments, including the Cognitive Ability Screening Instrument (CASI), were performed for 99 randomly selected normal elderly subjects. We assessed the frontal function (working memory, word fluency, Trail-Making Tests, CASI subitems of list-generating fluency, attention, and concentration/mental manipulation), language function (proverbs, CASI subitem language), non-language function (the digit symbol test of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), CASI subitem visual construction), memory (Alzheimer's Disease Assessment Scale recall/recognition, story recall, CASI subitems short and long-term memory, the Rey-Osterrieth Complex Figure Test), and the global function (CASI subitems orientation and abstraction and judgment). We found that the only test affected by age was the digit symbol test of the WAIS-R. The effects of education were distributed among various tests. There was a significant correlation between age and the frontal lobe atrophy in the lower educated group. The present findings suggest that cognitive function is spared by the aging process itself and dementia should be considered as age-related, not aging-related disorders, and that education might have a protective effect on cognitive change, supporting the reserve hypothesis.

Depressive symptoms and associated factors in a cognitively normal elderly population: the Tajiri Project.

BACKGROUND AND OBJECTIVE: Since depression is one of the main problems of elderly subjects, it is important to examine the prevalence of this condition and to identify associated factors. METHODS: A total of 1525 cognitively normal subjects aged 65 years and over in the town of Tajiri, a typical agricultural town in Japan, were analysed. Their MMSE (mini-mental state examination) scores were 24 or over. Depressive state was assessed by Zung's SDS (self-rating depression scale) with a comprehensive interview to examine ADL, demographics and symptoms associated with illness, etc. The prevalence of depression was calculated. To determine the factors associated with depression, the t-test and the Chi-square test were used. To examine the relative strength of each factor, logistic regression analysis was performed. RESULTS: The ratio of the depressive subjects was 6.4%, lower than those of previous reports, probably due to the effect of excluding dementia subjects. The ratio for older females aged 80 years and over was 14.3%, which was significantly higher than that of the males. Among socio-demographic factors, sex, age, number of children and perception of economic status, were significantly related. For health status and ADL, such factors as perception of health and medical history of heart disease and rheumatism were related. For familial and social status, factors such as daily activity and several conversation abilities were related. The logistic regression analysis indicated that perception of health and daily activity were associated. CONCLUSIONS: In this study, we isolated some factors related to depression in a cognitively normal population. Knowledge of such factors is important for appropriate mental care of aged subjects.

A 5-year retrospective examination of cognitive screening test stages in normal older adults and patients with Alzheimer's disease: the Tajiri project.

One conception of aging and cognitive deterioration is that cognitive decline becomes common with age, and dementia may be regarded as one extreme of the continuum. An alternative conception is that the cognitive process is spared by the aging process itself and that cognitive functioning of normal older adults and those with slight cognitive impairment, a CDR (Clinical Dementia Rating) score of 0.5 (suspected dementia), should be different. We examined changes in the screening test performances of 170 older adults over a 5-year period and found the following: (a) The CDR 0 (normal) participants did not show remarkable changes even in the older groups and (b) the subitems of orientation, memory, and so forth were useful for distinguishing normal older adults from early Alzheimer's disease patients. The results support the idea that dementia is better conceptualized as an age-related than as an "aging-related" disorder and that a CDR score of 0.5 should be considered very mild Alzheimer's disease.

The changing role of health care IC card systems.

Health care researchers and professionals have had increasing interest in the development of Internet-based solutions in health care, casting doubt on the future of IC card systems. However, IC cards used in conjunction with Internet-based health information systems may be more viable than either system alone. We conducted a worldwide survey to explore the possibilities of such a combined system. Our analysis shows that there is considerable awareness of the concept of Internet-based health care services among the professionals of IC card projects. In addition, our results indicate that IC cards could play a major role in health care systems as authorization keys that permit access to health information.

Status and perspective of hospital information systems in Japan.

Questionnaire surveys were sent to hospital managers, designed to shape the policy for future hospital information systems in Japan. The answers show that many hospitals use dedicated management systems, especially for patient registration and accounting, and personnel, food control, pharmacy and financial departments. In many hospitals, order-entry systems for laboratory tests and prescriptions are well developed. Half of the hospitals have patient databases used for inquiries of basic patient information, history of outpatient care and hospital care. The most obvious benefit is the reduction of office work, due to effective hospital information system. Many hospital managers want to use the following sub systems in the future for automatic payment, waiting time display, patient records search, automatic prescription verification, drug side-effect monitoring, and graphical display of patient record data.

Prevalence of senile dementia in a rural community in Japan: the Tajiri project.

Knowledge of the prevalence of dementia in different age groups is needed for the planning of a health policy. This study shows the prevalence of dementia and magnetic resonance imaging (MRI) findings in elderly people aged 65 years and over, living in the town of Tajiri in the northern part of Japan. They were shown by two cognitive screening tests, the Mini-Mental State examination (MMS) and the Dementia Screening Test (DST) and medical diagnosis. Two subject groups were assessed, those who completed both tests (Subjects I, n=2066) and those from among the 200 'MRI-administered subjects' who were interviewed and diagnosed (Subjects II, n=170). For Subjects I, there were 6.3 and 10.2% 'dementia range' according to the severe and mild criteria, respectively. As for Subjects II, 9.4% were clinically diagnosed as having dementia. They met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria of probable Alzheimer's disease (AD) or possible AD with cerebrovascular disease. The estimated prevalence rate of dementia was 8.0%. Visual ratings of brain atrophy using MRI disclosed two distribution patterns. The 'continuous' pattern of the frontal and temporal lobes atrophy suggest that both are affected by the aging process, while a 'discontinuous' pattern of the hippocampal atrophy could indicate a pathologic background such as early changes of AD.

A normative, community-based study of Mini-Mental State in elderly adults: the effect of age and educational level.

We investigated community-based data of the Mini-Mental State Examination (MMSE) scores of elderly residents along with the effects of age and educational level. MMSE was planned for all residents over 65 years of age in a town in northern Japan. The number of elders who took the MMSE was 2,266 (90%). The score significantly declined with age and lower educational level, although no effect of sex was apparent. For the MMSE subitems, all the values except for that of naming showed effects of both age and educational level. Those screened by MMSE who fell in the range of cognitive impairment (< 24) accounted for 21.8% and those with severe cognitive impairment (< 18) constituted 6.0%. Despite the differences in language and culture, the mean scores are remarkably similar between Japan and other countries. This is the first normative, community-based study of MMSE among elderly adults in Japan.

A study on home health care support information system for health evaluation.

The need for home health care has been increasing in Japan and the application of various techniques such as medical informatics are desired to support home health care services. Therefore, we developed an information system for health evaluation of the elderly including patients at home by applying multifunctional telephone set and an IC memory card, by which complaints, symptoms, and conditions by them can be collected, recorded, and transmitted to medical facilities. We also conducted an experiment for trial use of the system with the cooperation of elderly female volunteers. It was recognized that the elderly volunteers could operate the system with the help of public health nurses and their health information could be collected by the system. Although the developed system has some problems, it was suggested that the system would be useful for the support of health evaluation of elderly at home.

An experimental study on home health care support information system construction.

The need for home health care has been increasing in Japan and the expectation is to apply advanced technology to home health care in order to promote it. We already studied the development of a home care support information system using a personal computer and a telephone set with multifunction. In the present study a new system using a new telephone terminal was developed in order to increase flexibility. To work out the concrete social system in the near future, a model of a PHD (Personal Health Data) management system was constructed and tested. Experimental studies were conducted by physicians and public health nurses. The model system would be useful for daily monitoring of home patients in the chronic stage of a disease and for dealing with their emergency states.

IgE-mediated hypersensitivity and contact sensitivity to multiple environmental allergens in atopic dermatitis.

BACKGROUND AND DESIGN: Atopic dermatitis (AD) is a chronic eczematous skin disease that develops in a patient with atopic diathesis, which is characterized by an increased liability to produce IgE antibodies for environmental allergens mostly derived from other living organisms. Experimentally, eczematous skin lesions cannot be induced by immediate IgE-mediated reactions alone. They are produced by cell-mediated allergic contact reactions, and recently contact sensitivity to various environmental allergens has been demonstrated in patients with AD. However, the pathologic role of IgE-mediated skin hypersensitivity or that of delayed-type hypersensitivity to various environmental allergens in AD is not fully evaluated. They have been studied separately and against only specific allergens. Thus, we performed a combined testing procedure consisting of radioallergosorbent test, prick, and scarification patch tests for eight environmental allergens in 97 Japanese adult patients with AD; 48 of them had a history of atopic respiratory diseases (ARD), whereas the remaining 49 had no history of ARD (pure AD). RESULTS: Patients with AD, particularly those with ARD (AD+ARD), showed a higher incidence of positive radioallergosorbent test and prick test results as well as patch test results against multiple environmental allergens than healthy age-matched control subjects. Among them, we found a significantly high positive correlation between radioallergosorbent test scores and patch test reactions to two allergens, Japanese cedar, and Dermatophagoides farinae allergens in patients with AD. However, the patients with AD displayed a significantly lower incidence of positive patch test reactions to Candida albicans allergen than the healthy control subjects. Patients with AD with negative C albicans patch tests tended to have higher levels of total serum IgE including anti-C albicans IgE antibody. We found negative correlations between total serum IgE levels including specific antibodies and patch test reactions to C albicans allergen. CONCLUSIONS: Except for the dissociated reactivities to C albicans allergen consisting of decreased contact sensitivity and heightened IgE response, generally both IgE-mediated skin hypersensitivity and delayed-type hypersensitivity to various environmental allergens are pronounced in patients with AD. The combined use of these in vivo and in vitro tests is useful to estimate the immunological state of patients with AD.

Histoanalytical study of the cellular infiltrate in the tuberculin reaction.

In contrast to the generally held view, in previous studies it has been found that the histopathological changes in delayed-type hypersensitivity reactions to intradermal purified protein derivative of tuberculin (PPD) in humans were not uniform. These were classified into three types based on their resemblance to features seen in other dermatoses, i.e.: (i) perivascular dermatitis type; (ii) basal spongiotic dermatitis type; and (iii) erythema multiforme type. These histopathological patterns correlated well with the clinical response seen in tuberculin hypersensitivity of tested subjects. In the present study, the immunohistopathological features in 44 skin biopsy specimens were assessed quantitatively by using multivariate analysis. The numbers of infiltrating cells in the epidermis and in the dermis which were immunohistologically positive to monoclonal antibodies against various mononuclear cells were counted separately to determine if there was any statistical correlation between the histopathological patterns and the phenotypes of infiltrating cells. As a result, a significant correlation was found between the histopathological patterns and the phenotypes of cells infiltrating the epidermis, such as CD8+ cells, CD4+ cells, CD11c+ cells and interleukin 2 receptor positive cells. All these cells showed a high correlation coefficient to the expression of HLA-DR antigen by keratinocytes. Next, factors that might regulate the inflammation and interaction among the infiltrating cells were assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of discriminant function concerning postoperative local recurrence or distant metastasis in 589 patients with differentiated thyroid cancer.

For the purpose of predicting postoperative local recurrence and/or distant metastasis in differentiated thyroid cancer, a discriminant analysis was done. To assess the reliability of this method and the induced function, simulation was done by using random samples under various conditions. Simulation revealed that the results obtained by this method were relatively stable. The discriminant functions Z1 and Z2 were induced, which are required at many hospitals. If the ratio of recurrence is less than 1:8 in a hospital, function Z1 should be applied. If the ratio is 1:10, function Z2 should be applied. Z1 = -(sex x 2.104) + (age x 0.032) - (diameter of tumor x 0.033)-(site of tumor x 0.871) - (histology x 0.393) + 0.249 (discriminant boundary 0.451) Z2 = -(sex x 1.967) + (age x 0.018) + (diameter of tumor x 0.025) - (site of tumor x 0.646) + (histology x 0.014) - (local invasion x 0.840) - (lymph node metastasis x 0.009) + (operation x 0.364) - (lymph node dissection x 0.235) + 1.058 (discriminant boundary 0.400). In an internal check, sensitivity was 78%, specificity 64%; and false-negative rate 5%. In an external check, sensitivity was 68%, specificity 93%, and false-negative rate 9%. In the actual application to hospitals, sensitivity was 58% to 100%, specificity 47% to 63%, and false-negative rate 0% to 16%. In clinical usage, a high sensitivity and low false-negative rate are required. These results fulfilled this condition.

A study of periventricular hyperintensity. I. Normal brain aging.

Fifty-two patients with cerebrovascular risk factors without neurological abnormalities were examined by magnetic resonance imaging and were evaluated for their periventricular hyperintensity (PVH) on T2-weighted images. We assumed that PVH was not a mere focal finding of the brain but a kind of marker for condition related to arteriosclerosis and cerebral ischemia, and we tried to devise a model screening test, using common parameters available in most ordinary hospitals, to predict PVH. Multiple regression analysis was performed by setting up the PVH% (the volume percentage of PVH to cranial cavity) as a dependent variable and twenty-seven variables associated with general medical examination and brain atrophy as explanatory variables. We found that arteriosclerotic changes in the body as well as brain atrophy were significantly correlated with PVH, and that PVH could be predicted with a high contribution ratio of 0.70. It is clinically important to examine the elderly with our screening test to predict PVH in order to detect the early stages of ischemia.

Disturbance in daily sleep/wake patterns in patients with cognitive impairment and decreased daily activity.

The sleep/wake patterns of 121 chronically ill, mentally and physically handicapped patients were visually monitored hourly for 14 consecutive days. Four types of sleep/wake patterns were found. In order to investigate how cognitive and physical functions correlated with sleep disorders, patients were classified based on a scale of mental function and the grading of daily activity. The percent of total sleep hours and the sleep rating, showing disturbances in sleep/wake pattern, were evaluated. We found a high degree of individuality in sleep/wake patterns. Sleep disturbance was associated with daily activity as well as with cognitive impairment. This monitoring system provides medical personnel with valuable information for clinical management.

Cerebral circulation and oxygen metabolism associated with subclinical periventricular hyperintensity as shown by magnetic resonance imaging.

A combined magnetic resonance imaging and positron emission tomography study was performed on 21 patients with cerebrovascular risk factors but without neurological abnormalities. Our purpose was to investigate the hypothesis that periventricular hyperintensity (PVH) reflects ischemia. Periventricular hyperintensity was evaluated with a method we devised, and cerebral circulation and oxygen metabolism were evaluated with the oxygen-15 steady-state technique. We concluded that the brain with severe periventricular hyperintensity had abnormal circulation, although oxygen metabolism was not measurably affected. The role of a compensation mechanism under conditions of decreased oxygen supply was considered.

A decision support model and analysis for hospital administrators when choosing future strategies of their hospitals.

How to allocate a hospital's finite resources to health care is an extremely important problem for hospital management. This paper shows what kind of business strategies a given hospital should consider, and present a model to support such decision making. From the model, a hospital can decide how much to emphasize different tasks in order to set a given direction for the future. We used nonlinear discriminant functions to derive a decision support model, based on findings from 831 hospital directors. This model provides a probabilistic basis for deciding how much a given hospital should emphasize any of a number of different strategies.