Design and baseline characteristics of a prospective cohort study for determinants of osteoporotic fracture in community-dwelling elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study

<p>Abstract</p> <p>Background</p> <p>Osteoporosis and osteoporotic fracture in men are significant public health problems in an aging society. However, information on male osteoporosis remains impressively lacking, especially for Asians. We designed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study as an ancillary study of a cohort study, the Fujiwara-kyo study, to determine risk factors for osteoporotic fractures in Japanese men.</p> <p>Methods/Design</p> <p><it><b>Design</b></it>: A community-based single-centre prospective cohort study with at least a 5-year follow-up</p> <p><it><b>Subjects</b></it>: All the male participants of the Fujiwara-kyo study who were living in the four cities studied, aged 65 years and older, and able to walk without aid from others.</p> <p><it><b>Primary outcome</b></it>: Incidence of osteoporotic fractures including vertebral and clinical non-vertebral fractures.</p> <p><it><b>Additional outcomes</b></it>: Change in bone mineral density (BMD), change in hip geometry, onset of receiving benefits from Long-term Care Insurance (LCI), health-related quality of life, and mortality.</p> <p><it><b>Baseline measurements</b></it>: BMD at the lumbar spine (LS) and hip (TH), hip geometry, vertebral deformity assessment, bone turnover markers, physical and cognitive performance, various medical and lifestyle factors, and geriatric psychosocial measures confirmed by interviews based on self-administrated questionnaires.</p> <p><it><b>Outcome surveillance</b></it>: Annual mail surveys and a follow-up survey at the fifth year comprising similar items to the baseline study will be used to determine the outcomes. Receipt of benefits from LCI and mortality will be obtained from the city governments.</p> <p><it><b>Current status</b></it>: The baseline study was conducted for 2174 eligible men, and 2012 completed the study and were eligible for follow-up. Prevalence rates of osteoporosis (BMD 2.5 SD or more below the young adult mean (YAM)) and low BMD (BMD 1 SD or more below YAM) in at least one of LS and TH were calculated to be 4.4% and 41.8%, respectively. The proportion of men with low BMD only at TH showed a significant increasing trend with aging (p < 0.0001) while that only at LS showed a decreasing trend (p = 0.0386). The prevalence rate of osteoporosis was underestimated when diagnosed using only BMD at LS. Other baseline measurements were successfully obtained.</p> <p>Discussion</p> <p>FORMEN baseline study was performed as designed and the FORMEN cohort study was successfully launched.</p

Use of anthropometric indicators in screening for undiagnosed vertebral fractures: A cross-sectional analysis of the Fukui Osteoporosis Cohort (FOC) study

<p>Abstract</p> <p>Background</p> <p>Vertebral fractures are the most common type of osteoporotic fracture. Although often asymptomatic, each vertebral fracture increases the risk of additional fractures. Development of a safe and simple screening method is necessary to identify individuals with asymptomatic vertebral fractures.</p> <p>Methods</p> <p>Lateral imaging of the spine by single energy X-ray absorptiometry and vertebral morphometry were conducted in 116 Japanese women (mean age: 69.9 ± 9.3 yr). Vertebral deformities were diagnosed by the McCloskey-Kanis criteria and were used as a proxy for vertebral fractures. We evaluated whether anthropometric parameters including arm span-height difference (AHD), wall-occiput distance (WOD), and rib-pelvis distance (RPD) were related to vertebral deformities. Positive findings were defined for AHD as ≥ 4.0 cm, for WOD as ≥ 5 mm, and for RPD as ≤ two fingerbreadths. Receiver operating characteristics curves analysis was performed, and cut-off values were determined to give maximum difference between sensitivity and false-positive rate. Expected probabilities for vertebral deformities were calculated using logistic regression analysis.</p> <p>Results</p> <p>The mean AHD for those participants with and without vertebral deformities were 7.0 ± 4.1 cm and 4.2 ± 4.2 cm (p < 0.01), respectively. Sensitivity and specificity for use of AHD-positive, WOD-positive and RPD-positive values in predicting vertebral deformities were 0.85 (95% CI: 0.69, 1.01) and 0.52 (95% CI: 0.42, 0.62); 0.70 (95% CI: 0.50, 0.90) and 0.67 (95% CI: 0.57, 0.76); and 0.67 (95% CI: 0.47, 0.87) and 0.59 (95% CI: 0.50, 0.69), respectively. The sensitivity, specificity, and likelihood ratio for a positive result (LR) for use of combined AHD-positive and WOD-positive values were 0.65 (95% CI: 0.44, 0.86), 0.81 (95% CI: 0.73, 0.89), and 3.47 (95% CI: 3.01, 3.99), respectively. The expected probability of vertebral deformities (P) was obtained by the equation; P = 1-(exp [-1.327-0.040 × body weight +1.332 × WOD-positive + 1.623 × AHD-positive])^-1. The sensitivity, specificity and LR for use of a 0.306 cut-off value for probability of vertebral fractures were 0.65 (95% CI: 0.44, 0.86), 0.87 (95% CI: 0.80, 0.93), and 4.82 (95% CI: 4.00, 5.77), respectively.</p> <p>Conclusion</p> <p>Both WOD and AHD effectively predicted vertebral deformities. This screening method could be used in a strategy to prevent additional vertebral fractures, even when X-ray technology is not available.</p

Pancreatic alpha cell mass in European subjects with type 2 diabetes

AIMS/HYPOTHESIS: Type 2 diabetes is a bi-hormonal disease characterised by relative hypoinsulinaemia and hyperglucagonaemia with elevated blood glucose levels. Besides pancreatic beta cell defects, a low number of beta cells (low beta cell mass) may contribute to the insufficient secretion of insulin. In this study our aim was to determine whether the alpha cell mass is also altered. METHODS: Using a point counting method, we measured the ratio of alpha to beta cell areas in pancreas samples obtained at autopsy from 50 type 2 diabetic subjects, whose beta cell mass had previously been found to be 36% lower than that of 52 non-diabetic subjects. RESULTS: The topography of alpha and beta cells was similar in both groups: many alpha cells were localised in the centre of the islets and the ratio of alpha/beta cell areas increased with islet size. The average ratio was significantly higher in type 2 diabetic subjects (0.72) than in non-diabetic subjects (0.42), with, however, a large overlap between the two groups. In contrast, the alpha cell mass was virtually identical in type 2 diabetic subjects (366 mg) and non-diabetic subjects (342 mg), and was not influenced by sex, BMI or type of diabetes treatment. CONCLUSIONS: The higher proportion of alpha to beta cells in the islets of some type 2 diabetic subjects is due to a decrease in beta cell number rather than an increase in alpha cell number. This imbalance may contribute to alterations in the normal inhibitory influence exerted by beta cells on alpha cells, and lead to the relative hyperglucagonaemia observed in type 2 diabete

Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population

<p>Abstract</p> <p>Background</p> <p>Telomerase expression is one of the characteristics of gastric cancer (GC) cells and telomerase activity is frequently up-regulated by a variety of mechanisms during GC development. Therefore, we hypothesized that elevated levels of activated telomerase might enhance GC risk due to increased propagation of cells with DNA damage, such as induced by γ-radiation.</p> <p>Methods</p> <p>To explore this hypothesis, 246 GC cases and 246 matched controls were recruited in our case-control study. TRAP-ELISA was used to assess the levels of telomerase activity at baseline and after γ-radiation and the γ-radiation-induced telomerase activity (defined as after γ-irradiation/baseline) in cultured peripheral blood lymphocytes (PBLs).</p> <p>Results</p> <p>Our data showed that there was no significant difference for the baseline telomerase activity between GC cases and controls (10.17 ± 7.21 <it>vs. </it>11.02 ± 8.03, <it>p </it>= 0.168). However, after γ-radiation treatment, γ-radiation-induced telomerase activity was significantly higher in the cases than in the controls (1.51 ± 0.93 <it>vs</it>. 1.22 ± 0.66, <it>p </it>< 0.001). Using the median value of γ-radiation-induced telomerase activity in the controls as a cutoff point, we observed that high γ-radiation-induced telomerase activity was associated with a significantly increased GC risk (adjusted odds ratio, 2.45; 95% confidence interval, 1.83-3.18). Moreover, a dose response association was noted between γ-radiation-induced telomerase activity and GC risk. Age, but not sex, smoking and drinking status seem to have a modulating effect on the γ-radiation-induced telomerase activities in both cases and controls.</p> <p>Conclusion</p> <p>Overall, our findings for the first time suggest that the increased γ-radiation-induced telomerase activity in PBLs might be associated with elevated GC risk. Further confirmation of this association using a prospective study design is warranted.</p

Comparative Genomics Reveals Two Novel RNAi Factors in Trypanosoma brucei and Provides Insight into the Core Machinery

The introduction ten years ago of RNA interference (RNAi) as a tool for molecular exploration in Trypanosoma brucei has led to a surge in our understanding of the pathogenesis and biology of this human parasite. In particular, a genome-wide RNAi screen has recently been combined with next-generation Illumina sequencing to expose catalogues of genes associated with loss of fitness in distinct developmental stages. At present, this technology is restricted to RNAi-positive protozoan parasites, which excludes T. cruzi, Leishmania major, and Plasmodium falciparum. Therefore, elucidating the mechanism of RNAi and identifying the essential components of the pathway is fundamental for improving RNAi efficiency in T. brucei and for transferring the RNAi tool to RNAi-deficient pathogens. Here we used comparative genomics of RNAi-positive and -negative trypanosomatid protozoans to identify the repertoire of factors in T. brucei. In addition to the previously characterized Argonaute 1 (AGO1) protein and the cytoplasmic and nuclear Dicers, TbDCL1 and TbDCL2, respectively, we identified the RNA Interference Factors 4 and 5 (TbRIF4 and TbRIF5). TbRIF4 is a 3′-5′ exonuclease of the DnaQ superfamily and plays a critical role in the conversion of duplex siRNAs to the single-stranded form, thus generating a TbAGO1-siRNA complex required for target-specific cleavage. TbRIF5 is essential for cytoplasmic RNAi and appears to act as a TbDCL1 cofactor. The availability of the core RNAi machinery in T. brucei provides a platform to gain mechanistic insights in this ancient eukaryote and to identify the minimal set of components required to reconstitute RNAi in RNAi-deficient parasites

Prevalence of osteoporosis and incidence of hip fracture in women - secular trends over 30 years

<p>Abstract</p> <p>Background</p> <p>The number of hip fractures during recent decades has been reported to be increasing, partly because of an increasing proportion of elderly women in the society. However, whether changes in hip fracture annual incidence in women are attributable to secular changes in the prevalence of osteoporosis is unclear.</p> <p>Methods</p> <p>Bone mineral density was evaluated by single-photon absorptiometry at the distal radius in 456 women aged 50 years or above and living in the same city. The measurements were obtained by the same densitometer during three separate time periods: 1970-74 (n = 106), 1987-93 (n = 175) and 1998-1999 (n = 178), and the age-adjusted prevalence of osteoporosis in these three cohorts was calculated. Additionally, all hip fractures sustained in the target population of women aged 50 years or above between 1967 and 2001 were registered, whereupon the crude and the age-adjusted annual incidence of hip fractures were calculated.</p> <p>Results</p> <p>There was no significant difference in the age-adjusted prevalence of osteoporosis when the three cohorts were compared (P = 1.00). The crude annual incidence (per 10,000 women) of hip fracture in the target population increased by 110% from 40 in 1967 to 84 in 2001. The overall trend in the crude incidence between 1967 and 2001 was increasing (1.58 per 10,000 women per year; 95 percent confidence interval, 1.17 to 1.99), whereas the age-adjusted incidence was stable over the same period (0.22 per 10,000 women per year; 95 percent confidence interval, -0.16 to 0.60).</p> <p>Conclusions</p> <p>The increased number of hip fracture in elderly women is more likely to be attributable to demographic changes in the population than to secular increase in the prevalence of osteoporosis.</p

Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity

Clinical risk factor assessment had better discriminative ability than bone mineral density in identifying subjects with vertebral fracture

Summary: This study evaluated the characteristics of patients with vertebral fractures and examined the discriminative ability of clinical risk factors. The findings provide further insights into possible development of a simple, cost-effective scheme for fracture risk assessment using clinical risk factors to identify high-risk patients for further evaluation. Introduction: Vertebral fractures are the most common complication of osteoporosis. The aim of this study was to evaluate the characteristics of patients with vertebral fractures and to determine the discriminative ability of bone mineral density (BMD) and other clinical risk factors. Methods: Postmenopausal Southern Chinese women (2,178) enrolled in the Hong Kong Osteoporosis Study since 1995 were prospectively followed up for fracture outcome. Subjects (1,372) with lateral spine radiographs were included in this study. Baseline demographic, BMD, and clinical risk factor information were obtained from a structured questionnaire. Results: Subjects (299; 22%) had prevalent vertebral fractures. The prevalence of vertebral fractures increased with increasing age, number of clinical risk factors, and decreasing BMD. The odds of having a prevalent vertebral fracture per SD reduction in BMD after adjustment for age in Hong Kong Southern Chinese postmenopausal women was 1.5 for the lumbar spine and femoral neck. Analysis of the receiver operating characteristic curve revealed that bone mineral apparent density did not enhance fracture risk prediction. Subjects with ≥4 clinical risk factors had 2.3-fold higher odds of having a prevalent vertebral fracture while subjects with ≥4 clinical risk factors plus a low BMD (i.e., femoral neck T-score <-2.5) had 2.6-fold. Addition of BMD to clinical risk factors did not enhance the discriminative ability to identify subjects with vertebral fracture. Conclusions: Based on these findings, we recommend that screening efforts should focus on older postmenopausal women with multiple risk factors to identify women who are likely to have a prevalent vertebral fracture. © 2010 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201