A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension

Summary The pathogenesis of diabetic cardiomyopathy is unknown. The synergistic, or enhanced, effect of hypertension on pathological changes in the heart of diabetic patients has been highly suspected. The purpose of this study was to evaluate the myocardial changes related to diabetes mellitus with and without hypertension, using biopsy specimens. We examined the ultrastructural changes in biopsy specimens of the endomyocardium obtained from 25 patients. They were divided into four groups: controls without hypertension or diabetes mellitus (n=6), and patient with hypertension (n=3), diabetes mellitus (n=8), and diabetes with hypertension (n=8). The diabetic patients showed nearly normal or mildly depressed systolic left ventricular function. Ultrastructural pictures were analyzed for thickening of the capillary basement membrane, presence of toluidine blue-positive materials (i.e., materials showing metachromasia) in the myocytes, size of myocytes, and interstitial fibrosis. The thickening of the capillary basement membrane, the accumulation of toluidine blue-positive materials, and interstitial fibrosis were all significantly greater in the patients with diabetes mellitus compared to the control subjects. The myocytes tended to be small (cell atrophy) in the diabetes group. Although these pathological changes in the heart were characteristic of diabetic patients, irrespective of the presence or absence of hypertension, the presence of hypertension increased the pathological changes of myocardial cells as well as abnormality in the capillary vessels in patients with diabetes mellitus. Alterations in the myocardial cells and capillaries, caused by diabetes mellitus, may lead to myocardial cell injury and interstitial fibrosis and, ultimately, to ventricular systolic and diastolic dysfunction, especially when the diabetes is accompanied by hypertension.     

The role of the interleukin-2 (IL-2)/IL-2 receptor pathway in MRL/lpr lymphadenopathy: The expanded CD4−8− T cell subset completely lacks functional IL-2 receptors

Autoimmune MRL/MP-lpr/lpr (MRL/lpr) mice spontaneously develop a systemic lupus erythematosus-like disease accompanied by a profound lymphadenopathy that consists of CD4^?8^?B220⁺ a P T cells. By the use of cross-linking experiments with radiolabeled interleukin-2 (IL-2), these abnormal T cells have been reported to constitutively express the IL-2 receptor β chain (IL-2Rα), a signal transducing component of IL-2R, in the absence of the a chain (IL-2Rα).To critically reevaluate the role of the IL-2/IL-2R pathway in the pathogenesis of lymphadenophathy we examined expression of the IL-2Rα and IL-2Rβ in MRL/lpr mice by ¹²⁵I-IL-2 binding analysis and also by flow cytometric analysis using monoclonal antibodies against each component of the receptor. We found that, contrary to the previous report, the CD4^?8^?B220⁺ α β T cells in lymph node (LN) of MRL/lpr mice were negative for both IL-2Rα and IL-2Rβ expression. The lpr liver CD4^?8^?B220⁺ a P T cells that had been implicated in the genesis of these abnormal LN T cells were also negative for IL-2Rβ expression. Therefore, our results indicate that the IL-2/IL-2R system plays little role, if any, in the expansion of abnormal CD4^?8^? B220⁺ α β T cells in MRL/lpr mice.     

Protection of hepatocytes from apoptosis by a novel substance from actinomycetes culture medium

A novel substance, #675, found from an Streptomyces sp. SM675 culture medium, dose-dependently stimulates the proliferation of human functional liver cell 4 (FLC4). When FLC4 cells were incubated under conditions without fetal bovine serum (FBS), typical features of apoptotic cell death such as shrinkage and nuclear condensation appeared; high molecular weight (HMW) DNA fragments were found; and caspase-3 and poly (ADP-ribose) polymerase (PARP) proteins were cleaved. When FLC4 cells were incubated with #675 and without FBS, the cells grew healthy, no HMW DNA fragments were found, and caspase-3 and PARP cleavage weakened, suggesting that #675 protects FLC4 cells from apoptosis induced by FBS-deprivation. The quantitative reverse-transcribed polymerase chain reaction did not show differences in PARP or Bcl-2 mRNA expression in FLC4 cells incubated with or without #675, indicating other genes may be involved in this anti-apoptosis effect. These results show that #675 enhances FLC4 proliferation via an apoptosis-inhibition pathway, implying potential pharmacological and clinical applications.     

Effect of aging on serum uric acid levels: longitudinal changes in a large Japanese population group

BACKGROUND: Serum uric acid (SUA) is related not only to an increased risk of gout, but also to an increased risk of cardiovascular diseases. However, real age-related changes in SUA remain unknown. METHODS: Longitudinal population-based study of epidemiological follow-up data of SUA, body mass index (BMI), and alcohol intake was conducted at a health examination center between 1989 and 1998. The subjects were 80,506 Japanese office workers or their families (50,157 men and 30,349 women) with an average age of 44.5 years for the men and 43.7 years for the women. RESULTS: SUA increased with age in all birth cohorts examined in men, and in women except for the youngest birth cohort (1960-1969). BMI and alcohol consumption positively contributed to the longitudinal changes of SUA. However, SUA also increased with age in the model controlled for BMI and alcohol consumption. There were birth cohort effects of SUA; at most ages, there were higher SUA levels in younger cohorts in men and lower SUA levels in younger cohorts in women, respectively. CONCLUSIONS: SUA levels in men and women increased with advancing age, despite changes in drinking and in the BMI. There are birth cohort effects for SUA levels in the Japanese population.     

Trends geriatric disease research evaluated by long-term longitudinal study

The number of patients with geriatric diseases will rapidly increase in our aging society. Geriatric diseases tend to progress chronically and disturb the daily activity of the elderly patients. Care for the elderly patients requires a great deal of manpower. The prevention and treatment of geriatric disease are urgent issues that must be addressed. A comprehensive longitudinal study of aging and geriatric disease was started at the National Institute for Longevity Sciences (NILS) in 1997. The participants of the NILS longitudinal study of aging (NILS-LSA) were 2,267 men and women from a local community population. The participants are examined at the NILS and followed up every two years. An outline of the system and examinations of the NILS-LSA is shown. The latest results from the NILS-LSA research including geriatric disease-related genotypes and risk factors for mild cognitive impairment (MCI) are also presented.     

The impact of health problems on depression and activities in middle-aged and older adults: age and social interactions as moderators

In this study, we compared the impact of health problems (HPs) on everyday activities and depressive symptoms between middle-aged and older adults. We also examined what type and source of social interactions moderate the noxious effects of HPs. Longitudinal analyses of data with 1,802 Japanese community-dwelling adults indicated that HPs were significantly related to (a) an increase in depressive symptoms among middle-aged adults and (b) a decline in everyday activities among older adults. The former was buffered by emotional family support, whereas the latter (b) was buffered by instrumental family support and, surprisingly, by negative interactions with family. In contrast, social interactions with other friends and acquaintances did not show any moderating effect.     

Age-associated cardiomyopathy in heterozygous carrier mice of a pathological mutation of carnitine transporter gene,OCTN2

The purpose of this study was to test whether heterozygotes of juvenile visceral steatosis mice, a model for systemic carnitine deficiency, may develop age-associated cardiomyopathy. Tissue morphological observations were carried out by light and electron microscopy to compare the heterozygous and age-matched control mice at periods of 1 and 2 years. Possible effects of the pathological mutation on lipid and glucose levels was also evaluated in humans and mice. Except mild increases in serum cholesterol levels in male heterozygous mice and humans, no changes were found in other factors, indicating that none of the confounding factors seems to be profound. Results demonstrated that heterozygous mice had larger left ventriclular myocyte diameters than the control mice. Morphological changes in cardiac muscles by electron microscopy revealed age-associated changes of lipid deposition and abnormal mitochondria in heterozygous mice. Two out of 60 heterozygous cohort and one out of nine heterozygous trim-kill mice had cardiac hypertrophy at ages older than 2 years. The present study and our previous work suggest that the carrier state of OCTN2 pathological mutations might be a risk factor for age-associated cardiomyopathy.     

Seasonal changes in activity levels among nursing care insurance service users in areas with different climates

[Purpose] To clarify seasonal changes in activity levels among nursing care insurance service users in areas with different climates using the Life Space Assessment. [Subjects] A total of 72 nursing care insurance service users aged ≥65 years, who were from areas along the Sea of Japan or those around the Inland Sea. [Methods] The subjects were divided into 2 groups according to their home prefecture, and each survey was conducted over two successive seasons (Survey I: fall and winter, n=48, Survey II: winter and spring, n=24). We investigated the subjects’ basic information, and determined their FIM, the Life Space Assessment, and Modified Falls Efficacy Scale scores. These scores were subjected to between-group and -season comparisons. [Results] In Survey I, there were no significant differences in any investigation item between the 2 groups, but the Japan Sea group showed decreases in the Life Space Assessment, Independent Life space, and Minimal Life space scores in winter. In Survey II, we did not note any between-group or -season differences. [Conclusion] Our findings suggest that the Life Space Assessment, whose scores are influenced by outdoor environments, may be used as a tool to clarify seasonal changes in activity levels of nursing care insurance service users.Key words: Life Space Assessment, Seasonal changes, Outdoor environments     

Regulation of nuclear retention of glucocorticoid receptor by nuclear Hsp90

Heat shock protein 90 (Hsp90) has been demonstrated in both cytoplasm and nucleus, and regulates cytoplasmic retention of glucocorticoid receptor (GR). However, the role of nuclear Hsp90 in GR trafficking is less characterized. The present study examined the role of Hsp90 in nuclear retention of GR after ligand withdrawal. Hsp90 inhibitors; geldanamycin (GA) and radicicol (Rad), significantly accelerated nuclear export of GR after withdrawal of ligands including dexamethasone, corticosterone and RU486. GA accelerated relocalization of GR in the cytoplasm even when reimport of GR into the nucleus was inhibited by okadaic acid or when novel GR synthesis was inhibited by cycloheximide. Overexpression of wild type or nuclear-targeted Hsp90 attenuated Hsp90 inhibitor-induced acceleration of GR nuclear export, although nuclear Hsp90 showed higher activity than the wild type. Only nuclear-targeted Hsp90 prolonged basal nuclear retention of GR after withdrawal of dexamethasone and corticosterone. These results suggest that nuclear Hsp90 regulates the nuclear retention of GR.