Biomedical subjects

Hideyo Yoshida

Publications and source records attributed to Hideyo Yoshida.

At least 19 recordsLinked to original sources

PubMed2006

A functional single nucleotide polymorphism in the vitamin-K-dependent gamma-glutamyl carboxylase gene (Arg325Gln) is associated with bone mineral density in elderly Japanese women.

The vitamin-K-dependent gamma-glutamyl carboxylase (GGCX) carboxylates vitamin-K-dependent proteins including bone Gla protein (osteocalcin) and matrix Gla protein, which play important roles in bone metabolism. Therefore, GGCX polymorphism might explain in part individual susceptibility to osteoporosis. In the present study, polymorphisms in the exons of this gene were screened in Japanese elderly women and a non-synonymous single nucleotide polymorphisms (SNP) were found; c.8762 G>A; (Arg325Gln). When the kinetic parameters of GGCX325-Gln and GGCX325-Arg were compared in vitro, Vmax/Km was significantly higher for GGCX325-Gln (944.4+/-9.21 pmol/30 min/mg/mM FLEEL) than for GGCX325-Arg (671.9+10.79 pmol/30 min/mg/mM FLEEL) (p=0.018). Then, association study of this polymorphism with forearm bone mineral density (BMD) of Japanese postmenopausal women (n=500, age 73.6+/-5.74) was conducted. As a result, the body mass index (BMI)-adjusted Z score in the subpopulation older than 75 years (n=207) was higher in those with 325-Gln (0.650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD.

Aged↗

PubMed2006

Incidence of type-2 diabetes mellitus in a large population of Japanese male white-collar workers.

Since occupation, a major socio-economic factor, may be a risk factor for type-2 diabetes mellitus (DM), we compared DM incidence among four groups of white-collar workers in a follow-up study in 13,547 Japanese men. The subjects aged 30-59 years and free from DM at baseline consisted of: (a) 3725 clerical, (b) 5575 technical/professional, (c) 3474 manager/administrative and (d) 774 sales workers. Incident DM was identified by 'fasting serum glucose >or=7.00 mmol/l' or 'under medical treatment for DM'. Hazard ratio (HR) and 95% confidence interval (CI) for incident DM were estimated using clerical workers as the reference group (HR=1.00). Baseline age, body mass index (BMI), drinking, smoking, exercise and education were computed as confounders. During mean follow-up periods of 7.4 years, 176 clerical, 264 technical/professional, 195 manager/administrative and 49 sales workers developed DM (6.0, 6.1, 8.8 and 9.4 per 1000 person-years, respectively). Sales workers aged 40-49 and 50-59 years had increased multivariate-adjusted HRs (95% CIs) of 1.55 (1.02, 2.35) and 2.01 (0.98, 4.10), respectively. Manager/administrative workers aged 50-59 years had an increased crude HR (95% CI) of 1.64 (1.02, 2.63), but the significance disappeared after BMI-adjustment (HR (95% CI: 1.46 (0.91, 2.35)). Technical/professional workers had no significant HR in any model. In conclusion, sales workers in Japan aged >or=40 years may have increased risk for DM (+55 to +100%) independent of BMI, lifestyles and education, and manager/administrative workers aged >or=50 years may have increased risk (about +65%) due to their large BMI.

Adult↗

PubMed2006

Policemen and firefighters have increased risk for type-2 diabetes mellitus probably due to their large body mass index: a follow-up study in Japanese men.

BACKGROUND: Policemen/firefighters may have increased risk for mortality from ischemic heart disease and from all causes. We compare incidence of type-2 diabetes mellitus (DM), a well-known predictor for mortality, in policemen/firefighters with that in two other worker-groups. METHODS: A follow-up study of 5,130 healthy Japanese men aged 30-49 years at baseline consisted of three worker-groups; 3,111 clerical workers, 1,122 manual/production and transport/communication workers, and 897 policemen/firefighters. Incident DM was identified by "fasting serum glucose >or=7.00 mmol/L" or/and "under medical treatment for DM." Hazard ratio (HR) and 95% confidence interval (95% CI) for incident DM was estimated by Cox's proportional hazard models using clerical workers as a reference group (HR=1.00). Baseline age, body mass index (BMI, kg/m(2)), drinking, smoking, exercise, and education were computed as confounders. RESULTS: During mean follow-up periods of 8.4 years, 155 clerical workers, 51 manual/production and transport/communication workers, and 74 policemen/firefighters had incident DM (5.9, 5.7, and 9.6 per 1,000 person-years, respectively; P=0.001 by chi(2)-test). Policemen/firefighters had significantly increased risk for incident DM against clerical workers (age-adjusted HR (95% CI): 1.65 (1.25, 2.18)), but the significance disappeared after adjustments for BMI (age- and BMI-adjusted HR (95% CI): 1.16 (0.87, 1.54)). Manual/production and transport/communication workers had no increased risk. CONCLUSIONS: Policemen/firefighters have increased risk for DM probably due to their large BMI. Body weight control may be more efficient for prevention of DM and DM-related health problems in policemen/firefighters than in other workers.

Adult↗

PubMed2006

[Correlates of change in cognitive function during a two-year follow-up period in a comprehensive health examination for the community-dwelling elderly for the prevention of geriatric syndromes and bed-ridden state].

PURPOSE: We explored correlates of change in cognitive function during a two-year follow-up period among the community-dwelling elderly in Japan, using a population-based prospective approach. METHOD: The participants analyzed in the present study were 260 men and 222 women aged 70 to 84 years at baseline, living in an urban Japanese community. Data such as change in cognitive function during two years (calculated by subtracting baseline Mini-Mental State Examination [MMSE] score from follow-up MMSE score: a negative value means a decrease in MMSE scores during the two-year period) as an outcome variable, age, education, hearing and vision problems, IADL deficit (measured by the Tokyo Metropolitan Institute of Gerontology of Index of Competence), problems related to memory complaint, living alone, hemoglobin level, as explanatory variables, and the baseline MMSE score, depressive status (measured by the Mini-International Neuropsychiatric Interview), chronic conditions (hypertension, stroke, and diabetes mellitus) as covariates, were collected during a comprehensive health examination survey for the elderly. RESULTS AND CONCLUSION: We conducted multivariate regression analysis by genders to explore correlates of change in cognitive function. The results showed that higher age (beta = -0.18), presence of hearing problem (beta = -0.21), presence of IADL deficit (beta = -0.15), and memory complaint (beta = -0.20) in men, and higher age (beta = -0.27), low education level (beta = -0.25) and lower hemoglobin level (beta = 0.16) in women, were significantly associated with change in cognitive function when adjusting for the potential confounders. These factors may be reliable predictors for cognitive decline.

Aged↗

PubMed2006

[Frequency of falls and their prevention].

In Japan, one in five elderly persons has experienced falls in the past one year, and 10%of these falls lead to fractures. In the elderly, fracture is a major factor impeding the independence of daily activities and quality of life, and hence is an important problem. Given this situation, many studies that validate the effects of exercise programs aiming at the prevention of falls have been reported recently. Especially, the strategy of disseminating falls prevention exercise programs for the elderly in the community aiming to raise the falls prevention awareness and maintain or improve physical function is expected to lower the frequency of falls as well as to prolong functional independence and extend the healthy life-span.

Accidental Falls↗

PubMed2005

Effects of cognitive function on functional decline among community-dwelling non-disabled older Japanese.

This study examined whether cognitive impairment, falls, and urinary incontinence (UI) were independent predictors of functional decline using a 2-year observation of a non-disabled older Japanese cohort living in a community from 1999 to 2001. A total of 139 men and 214 women aged 70-94 years at the baseline who were independent in both activities of daily living (ADL) and instrumental activities of daily living (IADL) were analyzed in this study. Independent variables, such as cognitive impairment, falls, UI, and other possible factors associated with functional decline were obtained from an interview survey at the baseline. A dependent variable was functional status in ADL and IADL obtained at the time of the 2-year follow-up. During the 2-year follow-up, cognitive function was a significant predictor for both IADL dependence and ADL and/or IADL dependence. Using a group of subjects with Mini Mental State Examination (MMSE) scores of 30-27 points as a reference group, a significant correlation was identified between lower MMSE scores and an increased odds ratio for functional decline. Lower cognitive function was a significant predictor of functional decline, even among those older Japanese whose cognitive function was deemed to be within the normal range.

Activities of Daily Living↗

PubMed2005

Association of single nucleotide polymorphisms in the promoter region of the pro-opiomelanocortin gene (POMC) with low bone mineral density in adult women.

Among multiple factors influencing osteoporosis, genetic variations involved in bone-mineral metabolism can affect risks predisposing to the disease onset. Here, we studied single-nucleotide polymorphisms (SNPs) in the pro-opiomelanocortin (POMC) gene for possible association with bone mineral density (BMD) among 384 adult Japanese women and observed significant correlation between adjusted BMD and three SNPs in the promoter region (r>0.14, p<0.01). The most significant correlation was observed for -2353G/A (r=-0.16, p=0.002); homozygous carriers of the major (G) allele had the highest BMD (0.405+/-0.054 g/cm2) while heterozygous carriers were intermediate (0.390+/-0.053 g/cm2) and homozygous A-allele carriers had the lowest BMDs (0.369+/-0.048 g/cm2). Although no association was detected between these SNPs and body weight or body mass index (BMI), significant association was detected between the -2313A/C genotype and plasma total cholesterol level (r=-0.12, p=0.019). We propose that POMC is among the likely susceptibility genes for osteoporosis and may also be involved in dyslipidemia.

Adult↗

PubMed2005

ATP regulation of ciliary beat frequency in rat tracheal and distal airway epithelium.

Ciliary beat frequency (CBF) was measured by video-optical microscopy in rat tracheal and distal airway ciliary cells using a slice preparation. In tracheal ciliary cells (tracheal slice), ATP or 2-methylthio ATP (MeSATP) increased CBF, which was inhibited by suramin (100 microm, an inhibitor of purinergic receptor). Ionomycin (5 microm) or thapsigargin (2 microm) increased CBF similarly. Ca2+-free solution or addition of Ni2+ (1 mm) decreased CBF gradually by approximately 25% and subsequent stimulation with ATP (10 microm) increased CBF transiently. The purinergic agonist experiments demonstrated that ATP increases CBF in tracheal ciliary cells via both P2X and P2Y receptors. ATP increased the intracellular calcium concentration ([Ca2+]i) in tracheal ciliary cells. However, in distal airway ciliary cells (lung slice), ATP did not increase CBF and [Ca2+]i, although a Ca2+-free solution decreased CBF, and ionomycin (5 microm) or thapsigargin (2 microm) increased it. Moreover, acetylcholine (100 microm) did not increase CBF in distal airway ciliary cells, although it increased CBF in tracheal ciliary cells. Terbutaline (10 microm), a selective beta2-adrenergic agonist, increased CBF in both tracheal and distal airway ciliary cells. These observations suggest that the Ca2+-mobilization mechanisms via purinergic or muscarinic receptors of the distal airway ciliary cell may be different from those of the tracheal ciliary cell. In conclusion, the CBF increase is differently regulated in the tracheal and distal airway epithelia of the rat.

Acetylcholine↗

PubMed2005

Cell shrinkage evoked by Ca2+-free solution in rat alveolar type II cells: Ca2+ regulation of Na+-H+ exchange.

The effects of intracellular Ca2+ concentration, [Ca2+]i, on the volume of rat alveolar type II cells (AT-II cells) were examined. Perfusion with a Ca2+-free solution induced shrinkage of the AT-II cell volume in the absence or presence of amiloride (1 microm, an inhibitor of Na+ channels); however, it did not in the presence of 5-(N-methyl-N-isobutyl)-amiloride (MIA, an inhibitor of Na+-H+ exchange). MIA decreased the volume of AT-II cells. Inhibitors of Cl(-)-HCO3- exchange, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) also decreased the volume of AT-II cells. This indicates that the cell shrinkage induced by a Ca2+-free solution is caused by a decrease in NaCl influx via Na+-H+ exchange and Cl(-)-HCO3- exchange. Addition of ionomycin (1 microm), in contrast, induced cell swelling when AT-II cells were pretreated with quinine and amiloride. This swelling of the AT-II cells is not detected in the presence of MIA. Intracellular pH (pHi) measurements demonstrated that the Ca2+-free solution or MIA decreases pHi, and that ionomycin increases it. Ionomycin stimulated the pHi recovery after an acid loading (NH4+ pulse method), which was not noted in MIA-treated AT-II cells. Ionomycin increased [Ca2+]i in fura-2-loaded AT-II cells. In conclusion, the Na+-H+ exchange activities of AT-II cells, which maintain the volume and pHi, are regulated by [Ca2+]i.

Animals↗

PubMed2005

[Memory complaints among community-dwelling elderly in Japan: comprehensive health examination for the community elderly for prevention of the geriatric syndrome and a bed-ridden state ("Otasha-kenshin") part III].

PURPOSE: Previous studies have indicated that memory complaints may predict cognitive decline and dementia among the elderly. The present study was therefore conducted to clarify memory complaint characteristics among elderly dwelling in an urban community in Japan. METHOD: The participants analyzed in the present study were 453 men and 385 women aged 70 to 84 years living in an urban Japanese community. Data on problems related to memory complaints, cognitive decline (below 24 points on Mini-Mental State Examination), depression (measured by Mini-International Neuropsychiatric Interview), hearing and vision problems, I-ADL (measured by TMIG Index of Competence), self-rated health, age, sex, and years of education were collected at a comprehensive mass health examination for the elderly ("Otasha-kenshin"). RESULTS AND DISCUSSION: Twenty-seven percent of male respondents and 32% of female respondents reported having current trouble remembering things (reported as "frequently" or "sometimes"). We collected specific descriptions of the memory complaint difficulties the subjects were experiencing. A quarter of the responses indicated problems with forgetting persons' names, a fifth with forgetting where things had been left, 15% with leaving things behind, and a quarter with prospective memory failure. The results of multivariate logistic regression analysis to explore correlates showed that in men self-rated health and cognitive decline, and in women hearing problems and self-rated health were significantly and independently related to the memory complaint. These findings suggest that in addition to cognitive decline, self-rated health and hearing problems may influence memory complaints, and that memory complaints in men may be a reliable, simple indicator of cognitive decline. We now need to carry out a longitudinal study to clarify predictive validity.

Activities of Daily Living↗

PubMed2004

Hypo-osmotic potentiation of acetylcholine-stimulated ciliary beat frequency through ATP release in rat tracheal ciliary cells.

The ciliary beat frequency (CBF) of rat tracheal ciliary cells in a slice preparation was measured using video-enhanced contrast (VEC) microscopy. Acetylcholine (ACh) increased CBF mediated via intracellular Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. An adequate hypo-osmotic stress (-40 mosM) potentiated ACh-stimulated CBF increase in tracheal ciliary cells and shifted the ACh dose-response curve to the left (lower concentration side). This potentiation was independent of hypo-osmotic stresses applied ranging from -20 mosM to -90 mosM. A hypo-osmotic stress induces ATP release in many cell types. The present study demonstrated that suramin (an inhibitor of purinergic receptors) and apyrase (an ATPase/ADPase) eliminate the hypo-osmotic potentiation of ACh-stimulated CBF increase and that ATP increased [Ca2+]i and CBF, as well as potentiating ACh-stimulated rises in [Ca2+]i and CBF increase. Moreover, the apical surface of tracheal ciliary cells were stained immunopositive for the P2X4 purinergic receptor. A hypo-osmotic stress (-40 mosM) transiently increased [Ca2+]i and potentiated the ACh-stimulated [Ca2+]i increase. The hypo-osmotic potentiation of ACh-stimulated CBF increase was not detected under Ca2+-free conditions. These observations suggest that a hypo-osmotic stress stimulates ATP release from the trachea. The released ATP may induce further increases in [Ca2+]i and CBF in ACh-stimulated tracheal ciliary cells, which may be mediated by purinergic receptors, such as P2X4.

Acetylcholine↗

PubMed2004

Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene (QPCT) with low radial BMD in adult women.

UNLABELLED: Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene and adjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium, R54W showed a prominent association (p = 0.0003), which was more striking when examined among 309 elder subjects (> or =50 years; p = 0.0001). Contribution for postmenopausal bone loss was suggested. INTRODUCTION: Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis (HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have been proposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene (GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essential modifier of pituitary peptide hormones, including GnRH. MATERIALS AND METHODS: Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locus with adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) was analyzed by haplotype estimation and calculation of D' and r2. Multiple regression analysis was applied for evaluating the combined effects of the variations. RESULTS AND CONCLUSIONS: LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of the QPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD, among which R54W (nt + 160C>T) presented the most prominent association (p = 0.0003). Striking association was observed for these SNPs among the 309 subjects >50 years of age (R54W, p = 0.0001; -1095T>C, p = 0.0002; -1844C>T, p = 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might act in combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are the important factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The data should provide new insight into the etiology of the disease and may suggest a new target to be considered during treatment.

Adult↗

PubMed2004

Randomized controlled trial of exercise intervention for the prevention of falls in community-dwelling elderly Japanese women.

Falls are common in elderly people. Possible consequences include serious injuries and the post-fall syndrome, with functional decline and limitation of physical activity. The present randomized controlled study sought to clarify the benefits of a combined long-term and home-based fall prevention program for elderly Japanese women. The subjects were individuals aged over 73 years, living at home in a western suburb of Tokyo, who had attended a comprehensive geriatric health check. Persons with a marked decline in the basic activities of daily living (ADL), hemiplegia, or those missing baseline data were excluded. Fifty-two subjects who expressed a wish to participate in the trial were randomized, 28 to an exercise-intervention group and 24 to a control group. Baseline data for age, handgrip force, walking speed, total serum cholesterol, serum albumin, basic ADL, visual and auditory impairments, self-rated health, and experience of falls did not differ significantly between the two groups. Beginning from June 2000, the intervention group attended a 6-month program of fall-prevention exercise classes aimed at improving leg strength, balance, and walking ability; this was supplemented by a home-based exercise program that focused on leg strength. The control group received only a pamphlet and advice on fall prevention. The average rate of attendance at exercise class was 75.3% (range, 64% to 86%). Participants showed significant improvements in tandem walk and functional reach after the intervention program, with enhanced self confidence. At the 8-month follow-up, the proportion of women with falls was 13.6% (3/22) in the intervention group and 40.9% (9/22) in the control group. At 20 months, the proportion remained unchanged, at 13.6% in the intervention group, but had increased to 54.5% (12/22) in the control group, which showed a statistically significant difference between the two groups (Fisher's exact test; P = 0.0097). The total number of falls during the 20-month follow-up period was 6 in the intervention group and 17 in the control group. We conclude that a moderate exercise intervention program plus a home-based program significantly decreases the incidence of falls in both the short and the long term, contributing to improved health and quality of life in the elderly.

Accidental Falls↗

PubMed2004

[Risk factors associated with onset of urinary incontinence in a community-dwelling elderly population: a 4-year follow-up study].

OBJECTIVE: To estimate the risk factors associated with onset of urinary incontinence in a rural community-dwelling elderly population. METHODS: The study area, village N in Akita Prefecture, is a rural community in which a baseline survey of TMIG-LISA (Tokyo Metropolitan Institute of Gerontology, Longitudinal and Interdisciplinary Study on Aging) was undertaken in 1996. Among the baseline subjects, 760 (314 males and 446 females) community-dwelling elderly people aged over 65, who did not suffer from urinary incontinence at entry of the survey were selected. This cohort has been followed for four years by multi-dimensional medical examination including interviews and physical performance tests, conducted on a yearly basis using similar methods to these for the baseline survey. RESULTS: After the 4-year follow-up, the incidence of urinary incontinence was 7.0% (22/314) in men and 12.3% (55/446) in women. The urinary incontinence group (UIG) had a significantly higher age and lower level of functional fitness at baseline for both sexes. In the UIG, the men but not the women had significantly lower serum levels of albumin and total cholesterol. By the logistic model, age (per 1-year increase: OR = 1.23, 95%CI: 1.11-1.38), and serum albumin (per 0.1 g/dl increase: OR = 0.70, 95%CI: 0.54-0.88) in men; and grip strength (per 1-kg increase: OR = 0.92, 95%CI: 0.86-0.98), social role (per 1-point decrease: OR = 1.81, 95%CI: 1.19-2.73), BMI (per 1-kg/m2 increase: OR = 1.10, 95%CI: 1.01-1.20) and smoking status (never smoker = 1.00, 3 = current smoker: OR = 7.53, 95%CI: 1.36-41.63) in women were independent variables significantly associated with onset of urinary incontinence. CONCLUSIONS: Lifestyle and functional fitness are significantly associated with onset of urinary incontinence in this population. Our findings suggest that intervention programs are needed to improve pelvic floor muscle and to provide social support for the elderly.

Aged↗

PubMed2003

Association of the -381T/C promoter variation of the brain natriuretic peptide gene with low bone-mineral density and rapid postmenopausal bone loss.

Osteoporosis is believed to result from interplay among multiple environmental and genetic determinants, including factors that regulate bone-mineral density (BMD). Recent quantitative trait locus analysis in human suggested a possible involvement of chromosomal region 1p36.2-p36.3 for determination of BMD. The brain natriuretic peptide (BNP, also named NPPB) gene lies within this candidate region for BMD determination. Overexpression of the BNP resulted in skeletal overgrowth in transgenic mice. Association analysis between nucleotide variations of the BNP gene and radial BMD in 378 Japanese postmenopausal women revealed a significant association of the -381T/C variation of the BNP gene with radial BMD (r = 0.17, P = 0.01). Homozygous T-allele carriers had the lowest BMD values (0.395 +/- 0.056 g/cm(2)), homozygous C-allele carriers had the highest (0.429 +/- 0.051 g/cm(2)), and heterozygous individuals had intermediate radial BMD values (0.405 +/- 0.048 g/cm(2)), indicating a dosage effect. Accelerated bone loss also correlated with the -381 T allele in a 5-year follow-up study (r = 0.21, P = 0.017). These results suggest that variation of BNP may be an important determinant of postmenopausal osteoporosis, in part through the mechanism of accelerated postmenopausal bone loss.

Adult↗

PubMed2003

Association of a Trp16Ser variation in the gonadotropin releasing hormone signal peptide with bone mineral density, revealed by SNP-dependent PCR typing.

Osteoporosis is believed to result from interplay among multiple environmental and genetic determinants, including factors that regulate bone mineral density (BMD). Among those factors, adequate estrogen is essential for achievement of peak bone mass as well as for postmenopausal maintenance of skeletal homeostasis. Gonadotropin-releasing hormone (GnRH) from the hypothalamus is the primary determinant in the hypothalamic-pituitary-gonadal feedback system. In genetic studies of 384 postmenopausal Japanese women, we found a significant association between BMD and an amino acid variation (Trp16Ser) located within the signal peptide of GnRH (r = 0.143, P = 0.005). These results were achieved by genotyping all subjects using a newly developed SNP-dependent PCR method. This automated, high-throughput, and inexpensive procedure is suitable for typing large numbers of samples. BMD was lowest among 16Ser/Ser homozygotes, highest among 16Trp/Trp homozygotes, and intermediate among heterozygotes. A case-control study involving 125 osteoporosis patients and 92 healthy controls revealed a significant association between the presence of a 16Ser GnRH allele and affected status (chi(2) = 4.74, P = 0.041). The results suggested that variation of the GnRH signal peptide may be an important risk factor for postmenopausal osteoporosis.

Adult↗

PubMed2003

[Ca2+]i oscillations induced by high [K+]o in acetylcholine-stimulated rat submandibular acinar cells: regulation by depolarization, cAMP and pertussis toxin.

Maintaining the extracellular K(+) concentration ([K(+)](o)) between 15 and 60 mM induced oscillations in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in rat submandibular acinar cells during stimulation with acetylcholine (ACh, 1 micro M). These [Ca(2+)](i) oscillations were also induced by 1 micro M thapsigargin and were inhibited by 50 micro M La(3+), 1 micro M Gd(3+), or the removal of extracellular Ca(2+), indicating that the [Ca(2+)](i) oscillations were generated by store-operated Ca(2+) entry (SOC). The frequency of the ACh-evoked [Ca(2+)](i) oscillations increased from 0.8 to 2.3 mHz as [K(+)](o) was increased from 15 to 50 mM. TEA (an inhibitor of K(+) channels) also induced [Ca(2+)](i) oscillations at [K(+)](o) of 4.5 or 7.5 mM in ACh-stimulated cells. These data suggest that depolarization causes [Ca(2+)](i) to oscillate in ACh-stimulated submandibular acinar cells. Pertussis toxin (PTX, an inhibitor of G proteins) caused [Ca(2+)](i) to be sustained at a high level in ACh-stimulated cells at 25 mM or 60 mM [K(+)](o). This suggests that the [Ca(2+)](i) oscillations are generated by a periodic inactivation of the SOC channels via PTX-sensitive G proteins, which are stimulated by depolarization. Moreover, in the presence of DBcAMP or forskolin which accumulated cAMP the frequency of the [Ca(2+)](i) oscillations remained constant (approximately 1.2 mHz) when [K(+)](o) was maintained in the range 25-60 mM. Based on these observations in ACh-stimulated submandibular acinar cells, we conclude that depolarization stimulates the PTX-sensitive G proteins, which inactivate the SOC channels periodically ([Ca(2+)](i) oscillation), while hyperpolarization or PTX inhibits the G proteins, maintaining the activation of the SOC channels. Accumulation of cAMP is likely to modulate the PTX-sensitive G proteins.

Acetylcholine↗

PubMed2003

Association of a haplotype (196Phe/532Ser) in the interleukin-1-receptor-associated kinase (IRAK1) gene with low radial bone mineral density in two independent populations.

Osteoporosis, a multifactorial common disease, is believed to result from the interplay of multiple environmental and genetic determinants, including factors that regulate bone mineral density. Interleukin-1 (IL-1) is one of the most potent bone-resorbing factors, and interleukin-1-associated kinase 1 (IRAK1) is an essential effector of the IL-1 receptor signaling cascade. In genetic studies of two independent populations of postmenopausal women (cohort A: 220 individuals and cohort T: 126 individuals) from separated geographical regions of Japan, we found that radial bone mineral density levels had similar associations with IRAK1 genotypes in both populations. Two amino acid-substituting variations in the gene, encoding Phe196Ser and Ser532Leu, were in complete linkage disequilibrium (D' = 1.0000, r2 = 1.0000, chi2 = 192.000, p = 1.2 x 10(-43)), and we found two exclusive haplotypes (196F/532S, frequency 0.74; 196S/532L, frequency 0.26) of the IRAK1 gene among our test subjects. In both populations, a significant association with decreased radial bone mineral density was identified with haplotype 196F/532S (in cohort A: r = 0.21, p = 0.0017; in cohort T: r = 0.23, p = 0.011). Radial bone mineral density was lowest among 196F/532S homozygotes, highest among 196S/532L homozygotes, and intermediate among heterozygotes. Accelerated bone loss also correlated with the 196F/532S haplotype in a 5-year follow-up. These results suggest that variation of IRAK1 may be an important determinant of postmenopausal osteoporosis, in part through the mechanism of accelerated postmenopausal bone loss.

Base Sequence↗