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Biomedical subjects

Hajime Orimo

Publications and source records attributed to Hajime Orimo.

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

The sample size required for intervention studies on fracture prevention can be decreased by using a bone resorption marker in the inclusion criteria: prospective study of a subset of the Nagano Cohort, on behalf of the Adequate Treatment of Osteoporosis (A-TOP) Research Group.

In drug developments for osteoporosis, large-scale and longterm fracture prevention studies have been required. We investigated whether or not it was possible to reduce the sample size and observation period under new selection criteria for an osteoporotic fracture-prevention study. A Poisson regression model was used to identify independent risks for incident vertebral fracture in 515 postmenopausal women who had had no intervention for osteoporosis; this group was a subset of Nagano Cohort participants. The total observation period for this group was 2,577 person-years, and a total of 146 new vertebral fractures were observed. Risk assessment for incident vertebral fracture among numerical covariates revealed that the following items showed significant independent risks for incident fractures; namely, baseline age (hazard ratio [HR]; 1.84; 95% confidence interval (CI), 1.44-2.35; P < 0.001), number of preexisting vertebral fractures (HR, 1.28; 95% CI, 1.17-1.40; P < 0.001), baseline lumbar bone mineral density (LBMD) (HR, 0.79; 95% CI, 0.71-0.88; P < 0.001), and urinary excretion of deoxypyridinoline (DPD) (HR, 1.18; 95% CI, 1.03-1.35; P = 0.016). Because the initial urinary excretion of DPD was found to be a risk for incident vertebral fracture, in addition to the conventional risks, we assessed whether or not the sample size or observation period could be reduced by the incorporation of the urinary excretion of DPD into the selection criteria of a fracture-prevention study. The assessment of sample size was calculated, using the log rank test, at a two-tailed significance level of 5% and with a power of 80%. When osteoporotic patients with preexisting fracture were selected (conventional criteria), the 3-year probability of vertebral fracture was estimated as 14.3% in the present population. On the other hand, the new vertebral fracture rate during 3 years in the osteoporotic patients with preexisting fracture plus high urinary DPD (HR, above 1.0); (new selection criteria) was estimated as 23.2%. When the HR between test drug and placebo was changed from 0.4 to 0.8, the required sample size for any level of HR showed a 40% reduction for the new selection criteria compared to the conventional criteria. Therefore, the addition of urinary DPD level to the selection criteria is useful to reduce sample size in an osteoporosis fracture-prevention study.

Aged↗
PubMed2006

[Reviewing the definition of elderly].

Over the past 10 years (1992-2002) the physical activity of healthy elderly (over 65) has been more youthful by 7.5 years in men and 10 years in women. Functional independence in elderly diabetic patients (over 65) has been more youthful by 15 years. pathological examination revealed that the cerebral arteries have been more youthful by 20 years in men and 10 years in women during the past 14 years (1986-2000). Based on these data, the current definition of elderly (65 year over) should be changed to those over 75 years. Changing the social system (retirement, pension, medical care etc.) to harmonize with the coming aging society is a matter of great urgency.

Activities of Daily Living↗
PubMed2006

[Current research in adequate treatment by Osteoporosis Research Group].

In 2002, Adequate Treatment of Osteoporosis (A-TOP) Research Group was organized to obtain the evidence for treatment of osteoporosis in Japan. The group has designed and carried out an intervention trial plan, Japanese Osteoporosis Intervention Trial (JOINT)-02 to demonstrate the possible combination effect of alendronate plus active vitamin D(3). In this report, we summarize the past activity and the perspective of the future of the A-TOP research group.

Alendronate↗
PubMed2005

Multi-detector row CT imaging of vertebral microstructure for evaluation of fracture risk.

UNLABELLED: We applied MDCT for in vivo evaluation of the microarchitecture of human vertebrae. Microstructure parameters, such as structure model index, Euler's number, and bone volume fraction, revealed higher relative risk for prevalent vertebral fracture than did BMD obtained by DXA. Thus, microstructure analysis by MDCT, together with simultaneously obtained volumetric BMD values, is useful for clinical assessment of fracture risk. INTRODUCTION: BMD measurement by DXA alone has limitations in predicting fracture, and methods for clinical assessment of bone quality, such as microstructure, are awaited. This study was undertaken to examine the applicability of multidetector row CT (MDCT) for in vivo evaluation of trabecular microstructure. MATERIALS AND METHODS: Optimal conditions for MDCT scanning were determined at a spatial resolution of 250 x 250 x 500 mum, using muCT data of excised human vertebra specimens as a reference. We analyzed the trabecular microstructure of the vertebrae of 82 postmenopausal women (55-76 years old), including 39 women with and 43 without a recent vertebral fracture. RESULTS: Microstructure indices obtained by MDCT scanning revealed higher relative risk for prevalent vertebral fracture (OR: 16.0 for structure model index, 13.6 for bone volume fraction, and 13.1 for Euler's number) than did spinal BMD obtained by DXA (OR: 4.8). MDCT could also provide volumetric BMD data, which had higher diagnostic value (OR: 12.7) than did DXA. CONCLUSION: Vertebral microarchitecture can be visualized by MDCT, and microstructure parameters obtained by MDCT, together with volumetric BMD, provided better diagnostic performance for assessing fracture risk than DXA measurement.

Absorptiometry, Photon↗
PubMed2005

Epidemiology of hip fracture in Japan: incidence and risk factors.

Hip fracture is the most serious complication of osteoporosis and has been recognized as a major public health problem. The prevention of hip fractures is an high-priority issue because of the rapid increase of the number of elderly people in Japan. The General Research Committee for the Prevention and Treatment of Osteoporosis in Silver Health Science Researches sponsored by the Ministry of Health and Welfare (Director, Hajime Orimo) first undertook a nationwide survey of femoral neck fracture in 1987. This nationwide survey has been continued every 5 years, in 1992, 1997, and 2002. The total number of new cases was nearly 120,000 in the latest survey, and has been rising in every survey. Total number of new cases was about 1.4 times the baseline 1987 figures in 1992, 1.7 times in 1997, and 2.2 times in 2002. The total number of new female patients was about three times higher than that of new male patients, a finding identical to those of the previous surveys. The incidences of hip fracture (per 10,000) according to sex and age was increased in both men and women, particularly among individuals 80 years old or over. The Epidemiological Research Group on Osteoporosis, Ministry of Health and Welfare (Chairman; Hajime Orimo) undertook a nation-wide case-control study to clarify the risk factors for hip fractures among Japanese in 1994. Cases of hip fracture in people aged 65-89 were selected from 21 hospitals in seven areas of Japan. Two sex- and age-matched controls were selected from the same residential area for each case using resident registration lists. During this 1-year survey, 249 cases of hip fractures (43 men and 206 women) were reported. The following risk factors for hip fractures were identified using multivariate analysis: past history of stroke with hemiplegia, sleep disturbance, sleeping in a Western-style bed, and drinking more than 3 cups of coffee daily.

Age Distribution↗
PubMed2005

Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5'-flanking region (-5229G/A) with bone mineral density.

The 12/15-lipoxygenase gene Alox15 has been identified as a susceptibility gene for bone mineral density (BMD) in mice through combined genetic and genomic analyses. Here we studied the association between bone mineral density and an ALOX15 gene single nucleotide polymorphism to assess the potential involvement of the human ALOX15 gene in postmenopausal osteoporosis. Specifically, we examined the association between a single nucleotide polymorphism at -5299G/A in the ALOX15 5'-flanking region with BMD in 319 postmenopausal Japanese women (66.7 +/- 8.9 years, mean +/- SD). We found that subjects bearing at least one variant A allele (GA + AA; n = 273) had significantly lower Z scores for lumbar spine and total body bone mineral density than did subjects with no A allele (GG; n = 46) (lumbar spine, -0.25 +/- 1.34 versus 0.48 +/- 1.70; P = 0.0014; total body, 0.25 +/- 1.01 vs 0.62 +/- 1.11; P = 0.048). These findings suggest that the ALOX15 gene is one of the genetic determinants of BMD in postmenopausal women. Accordingly, this polymorphism could be useful as a genetic marker for predicting the risk of osteoporosis.

Aged↗
PubMed2005

Association of plasma homocysteine with serum interleukin-6 and C-peptide levels in patients with type 2 diabetes.

Hyperhomocysteinemia is an independent risk factor for atherosclerotic disease. Because serum markers of inflammation and the metabolic syndrome are also associated with atherosclerotic disease and insulin resistance, we investigated whether plasma homocysteine (Hcy) levels were associated with serum markers of inflammation and factors of metabolic syndrome in 223 elderly patients with type 2 diabetes mellitus. The levels of plasma Hcy and serum interleukin-6 (IL-6), high-sensitivity C-reactive protein, and C-peptide were measured. The C677T mutation of methylenetetrahydrofolate reductase (MTHFR) gene was detected using the polymerase chain reaction-restriction fragment length polymorphism method. The number of abnormal metabolic factors (presence of diabetes, blood pressure > or =130/85 mm Hg, triglycerides > or =150 mg/dL, high-density lipoprotein cholesterol <35 mg/dL (men) or <39 mg/dL (women), or body mass index >25 kg/m 2 ) was assessed. Elevated plasma Hcy levels correlated significantly with serum IL-6 ( r = 0.25, P < .001), C-peptide ( r = 0.22, P < .01), and the number of abnormal metabolic factors ( r = 0.20, P < .01), but not with C-reactive protein. Multiple linear regression analysis revealed that log-transformed IL-6, serum C-peptide, vitamin B12 , and creatinine were significant determinants of plasma Hcy levels. The correlation between Hcy and IL-6 levels was strongest in those with TT genotype of C677T MTHFR among 3 genotypes. The association between plasma Hcy and serum IL-6 levels supports the hypothesis that the activation of innate immunity is involved in the pathogenesis of arteriosclerosis in patients with diabetes mellitus who are homozygous for the TT genotype of C677T MTHFR.

Aged↗
PubMed2005

The D-hormone analog alfacalcidol: the pioneer beyond the horizon of osteoporosis treatment.

Over the last 30 years, several clinical trials have reported the efficacy of D-hormone analogs to treat primary and secondary osteoporosis, and their genomic and nongenomic mode of action have been demonstrated with the progress of biochemical research technologies. Recent metaanalyses reviewed the preventive effect on falls and fractures of "vitamin D3" in the elderly population, mainly based on studies with alfacalcidol and calcitriol. In future a clear differentiation must be made between calcium and plain vitamin D supplementation in very old, vitamin D-deficient women and men (> 75 years) and the pharmacological treatment of patients with established osteoporosis using D-hormone analogs, independent of a patient's vitamin D status. The dual action of D-hormone analogs on bone and muscle is unique, and differentiates them from all other, bone-specific antiosteoporotic drugs. Based on its efficacy in preventing falls, alfacalcidol is an excellent partner for combination therapy to improve the antifracture efficacy, especially in elderly patients. Further research is required to elucidate the mechanism of new actions of D-hormone analogs on muscle, nerves, brain, and on the immune system, to determine their application in different diseases.

Accidental Falls↗
PubMed2004

Functional analysis of the single nucleotide polymorphism (787T>C) in the tissue-nonspecific alkaline phosphatase gene associated with BMD.

UNLABELLED: Polymorphisms of the TNSALP gene have not previously been studied as a possible determinant for variations in BMD or as a predisposing genetic factor for osteoporosis. This study showed a significantly higher association between the 787T>C (Tyr246His) TNSALP gene and BMD among 501 postmenopausal women. Furthermore, the effects of amino acid substitution on the catalytic property of the protein translated from the 787T>C gene were examined. INTRODUCTION: Alkaline phosphatase (ALP) is present mainly on the cell membrane in various tissues and hydrolyzes a variety of monophosphate esters into inorganic phosphoric acid and alcohol. Human ALPs are classified into four types: tissue-nonspecific, intestinal, placental, and germ cell types. Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from a tissue-nonspecific ALP (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization. MATERIALS AND METHODS: We explored the possibility that the TNSALP gene may contribute to age-related bone loss in humans by examining the association between TNSALP gene polymorphisms and BMD in 501 Japanese postmenopausal women. To analyze the protein translated from the TNSALP gene associated with BMD, we constructed a TNSALP cDNA expression plasmid. RESULTS: We genotyped two single nucleotide polymorphisms (787T>C[Tyr246His] and 876A>G[Pro275Pro]), which proved to be in complete linkage disequilibrium. There was a significant difference in BMD and the BMD score adjusted for age and body weight (Z score) among haplotypes (p = 0.041), which was lowest among 787T/876A homozygotes, highest among 787T>C/876A>G homozygotes, and intermediate among heterozygotes. In subgroups divided by age, haplotypes were significantly associated with BMD in older postmenopausal women (>74 years; p = 0.001), but not in younger postmenopausal women (<74 years; p = 0.964). Expression of the 787T>C TNSALP gene using COS-1 cells showed that the protein translated from 787T>C had ALP-specific activity similar to that of 787T. Interestingly, the K(m) value for TNSALP in cells transfected with the 787T>C TNSALP gene was decreased significantly compared with that of cells bearing the 787T gene, reflecting the higher affinity. CONCLUSIONS: These results suggest that variation in TNSALP may be an important determinant of age-related bone loss in humans and that the phosphate metabolism pathway may provide a novel target for the prevention and treatment of osteoporosis.

Aged↗
PubMed2004

Association of estrogen receptor alpha gene polymorphisms with neurofibrillary tangles.

Estrogen receptor alpha (ERalpha) may be implicated in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to clarify the association between ERalpha gene polymorphisms and AD-related pathologic changes. The staging of neurofibrillary tangles (NFT) and senile plaques (SP) was performed according to the method by Braak and Braak and two polymorphisms, PvuII (P or p) and XbaI (X or x), of the ERalpha gene were typed in 551 Japanese cadavers (294 men and 257 women; mean age, 80.8 years). Distributions of the NFT and SP stages significantly correlated with age (NFT: r = 0.306, p < 0.0001; SP: r = 0.237, p < 0.0001) and were significantly higher in patients with the apolipoprotein E epsilon4 allele (p < 0.0001). Possession of the P allele showed a trend to be associated with a more serious NFT stage, but had no relationship with the SP stage. In men, a significant association between PvuII polymorphism and the NFT stage (p = 0.002) was found, revealing a gene- dose effect of the P allele. Similar results were obtained in the men without the epsilon4 allele (p = 0.011). Multiple regression analyses demonstrated that age was the strongest determinant of the NFT stage, possession of the epsilon4 allele was the next strongest, and PvuII polymorphism was the third strongest (p < 0.0001, R(2) = 0.144). The XbaI polymorphism did affect neither the NFT stage nor the SP stage. In conclusion, the PvuII polymorphism of the ERalpha gene is associated with Braak NFT stages and possession of the P allele may act as a risk factor for AD in Japanese men, especially in those without the epsilon4 allele.

Aged↗
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

Impact of degenerative spinal diseases on bone mineral density of the lumbar spine in elderly women.

Degenerative diseases of lumbar spine commonly noted in elderly people may affect their lumbar spine bone mineral density (BMD). The aim of this study is to determine whether the degree of degenerative spinal diseases is correlated with lumbar spine and femoral neck BMD. This study included 630 women age 60 years or over (mean age 73.3 +/- 6.9 years) visiting the Osteoporosis Outpatient Clinic at the Tokyo Metropolitan Geriatric Medical Center. Subjects underwent anteroposterior and lateral X-rays of the lumbar spine. The score of degenerative spinal diseases for each subject was calculated according to the scores for the Kellgren-Lawrence method, osteophyte formation, bone sclerosis, disk space narrowing, and spondylolisthesis involving L1-L2 through L4-L5 interspaces. Moreover, the number of vertebral fractures at L2 through L4 was recorded. The BMD of the second to fourth lumbar spine from anteroposterior projections and femoral neck were measured using an Expert-5000 (GE Lunar, Madison, WI USA). Most subjects had degenerative diseases of the lumbar spine. Scores for the Kellgren-Lawrence method, osteophyte formation, bone sclerosis, disk space narrowing, and spondylolisthesis were positively correlated with lumbar spine BMD, while they were not correlated with femoral neck BMD. Multiple regression analysis indicated that the scores for osteophyte formation, bone sclerosis, and disk space narrowing were independently correlated with lumbar spine BMD. Thus, in this study, the scores for degenerative spinal diseases were correlated with lumbar spine BMD, while they were not correlated with femoral neck BMD. This discrepancy indicates that degenerative spinal diseases are associated with increased lumbar spine BMD measurements. Femoral neck BMD therefore may be more appropriate than lumbar spine BMD in evaluating osteoporosis in elderly women.

Aged↗
PubMed2004

Absolute height reduction and percent height ratio of the vertebral body in incident fracture in Japanese women.

Vertebral fractures are the most common complication associated with osteoporosis. The definition of prevalent or incident vertebral fractures is important in epidemiological evaluation and in clinical trials of osteoporosis treatment. There have been few reports regarding the morphometric cutoff criteria for incident fractures in Asians, and only a few reports of their occurrence in Caucasians. The aim of this study was to establish a definition for incident fractures in Japanese women. A total of 279 women, aged 64.8 +/- 9.9 (mean +/- SD) years, were recruited, and repeated thoracolumbar spinal radiographs were performed at a mean of 1.45 +/- 0.44 years after the baseline film. Vertebral fractures were graded from 0 to 3 in both baseline and follow-up films using a semiquantitative assessment by the consensus of three readers. Incident fractures were defined as an increase of grade, except grade 3, and a vertebral body height of less than 12 mm on the baseline film. As morphometric criteria, both absolute height reduction (AHr) and the percent height ratio (PHr) were calculated. Prevalent fractures were observed in 207 vertebrae (6.2%) and 85 cases (30.5%), and incident fractures in 42 vertebrae (1.3%) and 29 cases (10.4%). As morphometric criteria for incident fracture, both a PHr > or =15% and an AHr > or =3 mm or > or =4 mm indicated sensitivity of 49.17% and 50.83% and specificity of 99.92% and 99.90%, respectively. In conclusion, the morphometric criteria of incident fracture combined with a semiquantitative assessment will provide useful information in the study of clinical osteoporosis, especially for international comparisons.

Aged↗
PubMed2004

Clinical trial of risedronate in Japanese volunteers: single and multiple oral dose studies.

The tolerability and pharmacokinetics of risedronate after a single oral administration and during multiple oral administrations were examined in healthy adult male volunteers. In the single dose study, the dose was increased gradually from 1 mg to 2.5, 5, 10, or 20 mg. Subsequently, risedronate was given by multiple administration, 5 mg per dosing, once daily, for 7 days. The observed adverse events, whose causality was possibly related or unknown, included headache, diarrhea, increased body temperature, increased CK-BB, and increased urinary Beta(2)-microglobulin excretion rate. However, none of these adverse events was clinically significant. The results thus showed that risedronate was well tolerated when delivered as a single administration of up to 20 mg or as a multiple administration of up to 5 mg/day. In the multiple dose study, changes in urinary deoxypyridinoline suggested the bone antiresorptive activity of risedronate. In the single dose study, AUC and C(max), after the administration of risedronate at 1, 2.5, 5, 10, and 20 mg, increased dose dependently, and the T(max), t(1/2), and urinary excretion rates were nearly constant. Therefore, the pharmacokinetic profile of risedronate was considered to show linearity in a dosage range of up to 20 mg. Furthermore, the results obtained in the multiple administration study indicated that the plasma concentrations of risedronate reached a steady state on day 4 of administration. The plasma concentrations of risedronate after the administration of 2.5 mg risedronate to the Japanese population were nearly comparable to the serum concentrations after the administration of 5 mg risedronate to the United Kingdom study population.

Administration, Oral↗