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Objective: For a general population of children, data on the relationship between vitamin D status and adiposity are limited. The aim of this study was to assess the relationships between the serum concentration of 25-hydroxyvitamin D (25-OH-D) and body fat variables measured by dual-energy X-ray absorptiometry (DXA) in a general population of Japanese children, including underweight, normal, and overweight children., Methods: The source population comprised 521 fifth-grade children who attended either of the two public schools in Hamamatsu, Japan. Total and regional body fat mass (FM) measured by DXA were evaluated along with the serum concentration of 25-OH-D., Results: We were able to analyze the FM and 25-OH-D data of 400 of the 521 children. Among boys, significant inverse relationships were observed between serum vitamin D levels and body fat variables (total FM, r = -0.201; trunk FM, r = -0.216; appendicular FM, r = -0.187; P < 0.05 for all values). Mean values of total FM and trunk FM in the vitamin D-deficient group (25-OH-D <50 nmol/L) were larger than those in the vitamin D-sufficient group (25-OH-D ≥75 nmol/L) after adjusting for confounding factors, such as sedentary behavior (P < 0.05). No relationship was observed between vitamin D status and FM among girls., Conclusions: Vitamin D deficiency was associated with higher total and trunk adiposities in a general population of Japanese children, particularly boys., (Copyright © 2013 Elsevier Inc. All rights reserved.)

End-stage renal failure deteriorates bone mass and increases fracture risk. However, there are conflicting reports in the literature regarding the effects of mild to moderate renal dysfunction on bone mineral density (BMD). We investigated the association between renal function and BMD at the spine and hip and bone metabolism markers in community-dwelling elderly Japanese men. From 2174 male volunteers aged ≥65 years, we examined 1477 men after excluding those with diseases or medications known to affect bone metabolism. Renal function was assessed by serum cystatin C and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease Study equation. Bone metabolism was evaluated using levels of serum amino-terminal propeptide of type I procollagen (PINP) and tartrate-resistant acid phosphatase isoenzyme 5b (TRACP-5b), which represent bone metabolic status independent of renal function. eGFR was inversely associated with BMD after adjusting for potential confounders (P < 0.01). Cystatin C showed a weaker but significant association with BMD. eGFR was modestly positively associated with PINP levels (P = 0.04), although cystatin C concentrations were neither associated with PINP nor TRACP-5b levels. Since BMD integrates bone metabolism from the past to present, inverse associations between renal function and BMD may be attributed to past factors, such as obesity. Our findings suggest that low renal function does not affect bone metabolism in a population of community-dwelling elderly Japanese men. Longitudinal studies will be necessary to clarify whether low renal function affects bone loss., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: We conducted a questionnaire survey among Japanese female students to explore the influence of a desire for thinness and dietary behaviors on the development of eating disorders., Methods: Self-reported measures of socio-demographic characteristics, body weight perception, height and weight, and dietary and exercise behavior were completed by 631 female university students at 6 universities in Kyoto, Japan., Results: Many students had a desire for thinness (underweight students, 51.7 %; normal-weight students, 88.8 %), whereas ideal weight and body mass index were lower in the students with a desire for thinness than the students without a desire for thinness, and were also lower in the underweight students than the normal-weight students. The eating attitude test (EAT-26) scores of underweight students with a desire for thinness were higher than those of the normal-weight students with a desire for thinness. As a result of a logistic regression analysis, underweight, desire for thinness, and experience with weight control were positively associated with eating problems. Further, the association of eating problems increased along with the increase in the number of factors (underweight, desire for thinness, and experience with weight control)., Conclusions: These results indicate that underweight females have strong associations with eating problems.

Background: In recent years in Japan, electronic games, home computers, and the internet have assumed an important place in people's lives, even for elementary school children. Subjective health complaints have also become a problem among children. In the present study, we investigated the relationship between media use and health status in elementary school children in Japan., Methods: A cross-sectional school-based population survey was conducted in 2009 with a sample of fourth-, fifth-, and sixth-grade children (age range: 10-12 years old) in elementary schools in Japan (n = 3,464). Self-reported health, lifestyle habits, and time spent using media were assessed., Results: The use of games, television, and personal computers was significantly associated with lifestyle (p < 0.05) and subjective health (p < 0.05). In addition, the use of games, the use of television, and the use of personal computers were mutually associated. The greater the number of media used for more than 1 hour was, the higher the odds ratio of the association of media use with unhealthy lifestyle and subjective health complaints was. The plural use of these media had stronger associations with unhealthy lifestyle and subjective health complaints., Conclusions: Game, television, and personal-computer use were mutually associated, and the plural use of these media had stronger associations with unhealthy lifestyle and subjective health complaints. Excessive use of media might be a risk for unhealthy lifestyle and subjective health complaints.

Objectives: The association between normal weight obesity and diet behavior and physical activity in female students was investigated in this study., Methods: The subjects were 530 female students aged 18-21 years from 6 universities in the Kyoto Prefecture, Japan. From January to July, 2010, the body fat and walk counts of these students were measured, and they answered a questionnaire. The questionnaire included questions on life environment, perception of body shape, dieting experiences, physical activities, sleeping habits, and diet behaviors. The Eating Attitude Test-26 (EAT-26) was used to evaluate diet behavior. Students with normal weight (18.5 < or = body mass index < 25 kg/m2; n = 439) were divided into high (n = 115), middle (n = 213), and low (n = 111) groups according to their percentage of body fat. Further, a comparative analysis was performed among the 3 groups., Results: From the results of the questionnaire, perception of body shape, desire for a particular body shape, reason for weight loss, success or failure in dieting, and time for sleep were significantly different among the 3 groups. Differences in physical activity were not significant among the groups. Factor III (Oral control) of EAT-26 was higher in the high group than in the low group., Conclusion: High body fat was associated with diet behavior and a desire to lose weight in normal weight students. These results indicate that health education is necessary to establish and maintain appropriate body fat composition and dietary habits.

Nitriles were found to be highly effective alkylating reagents for the selective N-alkylation of amines under catalytic hydrogenation conditions. For the aromatic primary amines, the corresponding secondary amines were selectively obtained under Pd/C-catalyzed hydrogenation conditions. Although the use of electron poor aromatic amines or bulky nitriles showed a lower reactivity toward the reductive alkylation, the addition of NH(4)OAc enhanced the reactivity to give secondary aromatic amines in good to excellent yields. Under the same reaction conditions, aromatic nitro compounds instead of the aromatic primary amines could be directly transformed into secondary amines via a domino reaction involving the one-pot hydrogenation of the nitro group and the reductive alkylation of the amines. While aliphatic amines were effectively converted to the corresponding tertiary amines under Pd/C-catalyzed conditions, Rh/C was a highly effective catalyst for the N-monoalkylation of aliphatic primary amines without over-alkylation to the tertiary amines. Furthermore, the combination of the Rh/C-catalyzed N-monoalkylation of the aliphatic primary amines and additional Pd/C-catalyzed alkylation of the resulting secondary aliphatic amines could selectively prepare aliphatic tertiary amines possessing three different alkyl groups. According to the mechanistic studies, it seems reasonable to conclude that nitriles were reduced to aldimines before the nucleophilic attack of the amine during the first step of the reaction.

Bone development up to early adulthood plays an important role in determining the risk of osteoporosis later in life. However, bone development in children has not been fully documented by longitudinal studies in Japanese children. The purpose of this study is to determine the degree of tracking of areal bone mineral density (aBMD) from pre-puberty to 6-year follow-up, and to determine the target period to achieve maximal peak aBMD. This study was conducted as the pediatric part of a larger cohort study, the Japanese Population-based Osteoporosis (JPOS) study. Of 448 children aged 9-12 years who completed the baseline survey, 225 participated in the follow-up study 6 years later (follow-up rate: 50.2%). aBMD at the forearm was measured using dual-energy X-ray absorptiometry. aBMD values in pre-pubertal children at baseline showed a significant tracking correlation with aBMD obtained at 6-year follow-up in both genders (boys r = 0.655, girls r = 0.759). Although boys and girls in the lowest quartile of aBMD pre-pubertally had greater annual increases in aBMD from pre-puberty to 6-year follow-up than those in other aBMD quartiles, they still showed the lowest mean aBMD at 6-year follow-up. Children with lower pre-pubertal aBMD showed greater increases in BMD up until 6-year follow-up, but the increase was not great enough to catch up with other children. About 50% of the variance in aBMD at 6-year follow-up was determined by the aBMD achieved during the pre-pubertal period. Activities that increase aBMD are important not only for children during puberty, but also for younger pre-pubertal children.

Background: Blood pressure examinations for health education use have been conducted at several schools in Japan. It has been reported that blood pressure is closely associated with bodyweight and height in US children. The aim of the present paper was to evaluate the association between height and blood pressure in Japanese schoolchildren., Methods: In Iwata city in Japan, blood pressure screening was conducted by the school administration. A total of 98.9% (10,152/10,270 children) of all fifth (10-year-olds) and ninth graders (14-year-olds) residing in the Old Iwata area from 2002 to 2007 were analyzed., Results: In 10-year-old and 14-year-old boys, regression analysis indicated that a positive correlation between weight and blood pressure was the strongest among the three body size indices (height, weight, and body mass index), but the association between height and blood pressure was also significant. For girls from both the 10 and 14 year age groups, the correlation of weight and blood pressure was stronger than those for the other body size indices, but there were also significant associations between height and blood pressure, except for height and diastolic blood pressure in the 14-year-olds., Conclusions: There is a significant positive relationship between height and blood pressure. Further study is necessary to provide a blood pressure reference based on height in the Japanese program to prevent children from developing lifestyle-related risk factors., (© 2010 The Authors. Pediatrics International © 2010 Japan Pediatric Society.)

Focal brain lesions such as transient focal cerebral ischemia can lead to neuronal damage in remote areas, including the ipsilateral substantia nigra and hippocampus, as well as in the ischemic core. In this study, we investigated acute changes in the ipsilateral hippocampus from 1 up to 7 days after 90 min of transient focal cerebral ischemia in rats, using anti-NeuN (neuronal nuclei), anti-Cu/Zn-superoxide dismutase (Cu/Zn-SOD), anti-Mn-SOD, anti-neuronal nitric oxide synthase (nNOS), anti-inducible NOS (iNOS), anti-glial fibrillary acidic protein (GFAP), anti-ionized calcium-binding adaptor molecule 1(Iba 1) and anti-2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) antibodies. In our western blot and histochemical analyses, present results show that transient focal cerebral ischemia in rats can cause a severe and acute damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector. The present findings also demonstrate that the expression of iNOS produced by Iba 1-immunopositive microglia precedes the damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector after transient focal cerebral ischemia. In contrast, our results suggest that increased reactive oxygen species (ROS) production during reperfusion cannot lead to damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector after transient focal cerebral ischemia, because of an insufficient expression of Cu/Zn-SOD and Mn-SOD. Our double-labeled immunohistochemical study demonstrates that the overexpression of iNOS produced by Iba 1-immunopositive microglia may play a pivotal role in the damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector at an acute stage after transient focal cerebral ischemia.

The YFL ribozyme is an artificial ligase ribozyme isolated by a 'design and selection' strategy, in which a modular catalytic unit was generated on a rationally designed modular scaffold RNA. This ligase ribozyme has a versatile catalytic unit that accepts not only beta-nicotinamide mononucleotide (beta-NMN) but also inorganic pyrophosphate as leaving groups for template-dependent RNA ligation. Although this property is interesting from an evolutionary viewpoint regarding primitive RNA ligation/polymerization systems in the RNA world, structural analysis of the YFL ribozyme has not been continued due to apparent structural nonuniformity of its folded state. To elucidate the active structure of the YFL ribozyme, we performed in vitro evolution experiments to improve its folding ability. Biochemical and phylogenetic analyses of evolved variants indicated that the catalytic unit of the YFL ribozyme is compact and the 3' single-stranded region of the parent YFL-1 ribozyme contributes to mask an element that could form an inactive structure.

Background: 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., Design: A community-based single-centre prospective cohort study with at least a 5-year follow-up., Subjects: 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., Primary Outcome: Incidence of osteoporotic fractures including vertebral and clinical non-vertebral fractures. ADDITIONAL OUTCOMES: 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. BASELINE MEASUREMENTS: 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.OUTCOME SURVEILLANCE: 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., Current Status: 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., Discussion: FORMEN baseline study was performed as designed and the FORMEN cohort study was successfully launched.

Evidence suggests a link between adiponectin, an adipocytokine, and liver tumorigenesis. Different multimer complexes of adiponectin, with low-molecular weight (LMW), middle-molecular weight (MMW) and high-molecular weight (HMW), may have different roles. Therefore the present study was performed with the aim of assessing associations between these multimers and liver cancer development. A nested case-control study (59 liver cancer cases [mean age=63.5 years] and 334 controls [62.7 years]) was conducted as a part of the Japan Collaborative Cohort (JACC) Study recruiting healthy participants, aged 40-79 years, for the follow-up period from 1988-1990 to 1999. The end point was liver cancer occurrence/death. Serum levels of HMW, MMW and LMW adiponectin were determined at baseline using an ELISA assay. Multivariate-adjusted logistic regression analyses comparing the tertile levels of adiponectin multimers showed that the groups stratified with the highest percentage of LMW tended to have lower odds ratios (ORs) than the lowest group (OR adjusted for sex, age and area=0.54 [95%CI: 0.26-1.11] and adjusted for sex, age, area, body mass index, smoking, alcohol, coffee consumption, diabetes history and HCV-antibody positivity =0.50 [95%CI: 0.22-1.15]), albeit without statistical significance (set at p<0.05). Higher percentages of circulating LMW adiponectin may lead to a reduction of liver cancer risk and relationships with multimer composition may merit further study.

The interactions of recombinant human eIF4A (4A) and its N- and C-terminal side domains (AN and AC, respectively) with the middle- and C-terminal-domain-linked fragment (GMC) of eIF4G and its middle and C-terminal domains (GM and GC, respectively) were investigated by surface plasmon resonance (SPR) analysis and isothermal titration calorimetry (ITC). It is remarkable that the kinetic parameter-dependent SPR profile observed for the 4A-GMC pair was quite different from the steady affinity profiles of the 4A-GM/GC pairs, suggesting the simultaneous contribution of the middle and C-terminal domains of eIF4G for the binding with eIF4A. On the other hand, ITC yielded the enthalpy energies of -1.5 x 10(4) to -2.5 x 10(4) J/mol for the domain-domain interactions of 4A with GMC. Although the ITC profile of the 4A-GM pair reflects well the structural feature shown previously by NMR and X-ray analyses, it was essentially different from that of the 4A-GMC pair. The present results suggest that the intimate interaction between the eIF4A N- and C-terminal domains and the eIF4G middle and C-terminal domains is necessary to reveal the biologically active function of the eIF4A-eIF4G complex.

A novel ribozyme that accelerates the ligation of beta-nicotinamide mononucleotide (beta-NMN)-activated RNA fragments was isolated and characterized. This artificial ligase ribozyme (YFL ribozyme) was isolated by a "design and selection" strategy, in which a modular catalytic unit was generated on a rationally designed modular scaffold RNA. Biochemical analyses of the YFL ribozyme revealed that it catalyzes RNA ligation in a template-dependent manner, and its activity is highly dependent on its architecture, which consists of a modular scaffold and a catalytic unit. As the design and selection strategy was used for generation of DSL ribozyme, isolation of the YFL ribozyme indicated the versatility of this strategy for generation of functional RNAs with modular architectures. The catalytic unit of the YFL ribozyme accepts not only beta-NMN but also inorganic pyrophosphate and adenosine monophosphate as leaving groups for RNA ligation. This versatility of the YFL ribozyme provides novel insight into the possible roles of beta-NMN (or NADH) in the RNA world.

To investigate the binding specificity of turnip mosaic virus (TuMV) viral protein-genome linked (VPg) with translation initiation factor 4E, we evaluated here the kinetic parameters for the interactions of human eIF4E, Caenorhabditis elegans IFE-3 and IFE-5 and Arabidopsis eIFiso4E, by surface plasmon resonance (SPR). The results indicated that TuMV VPg does not show a binding preference for Arabidopsis eIFiso4E, even though it is from a host species whereas the other eIF4E orthologues are not. Surprisingly, the effect of m(7)GTP on both the rate constants and equilibrium binding constants for the interactions of VPg differed for the four eIF4E orthologues. In the case of eIFiso4E and IFE-3, m(7)GTP increased k(on), but for eIF4E and IFE-5, it decreased k(on). To provide insight into the structural basis for these differences in VPg binding, tertiary structures of the eIF4E orthologues were predicted on the basis of the previously determined crystal structure of m(7)GpppA-bound human eIF4E. The results suggested that in cap-bound eIF4E orthologues, the VPg binds to the C-terminal region, which constitutes one side of the entrance to the cap-binding pocket, whereas in the cap-free state, VPg binds to the widely opened cap-binding pocket and its surrounding region. The binding of VPg to the C-terminal region was confirmed by the SPR analyses of N- or C-terminal residues-deleted eIF4E orthologues.

Thaumatin is a sweet-tasting protein comprising a mixture of some variants. The major variants are thaumatins I and II. Although the amino acid sequence of thaumatin I was known and the nucleotide sequence of cDNA of thaumatin II was elucidated, the nucleotide sequence of thaumatin I has been controversial. We have cloned two thaumatin cDNAs from the fruit of Thaumatococcus daniellii Benth. One is the same nucleotide sequence as that of thaumatin II already reported, and the other is a novel nucleotide sequence. The amino acid sequence deduced from the novel cDNA was the same amino acid sequence as that of thaumatin I, the only exception being the residue at position 113 (Asp instead of Asn), indicating that the novel thaumatin cDNA is that for thaumatin I. This thaumatin I cDNA was transformed into Pichia pastoris X-33, and the recombinant thaumatin I expressed was purified and characterized. The threshold value of sweetness of the recombinant thaumatin I was the same as that of the plant thaumatin I, although several unexpected amino acid residues were attached to the N-terminal of the recombinant thaumatin I. These indicate that the N-terminal portion of thaumatin is not critical for the elicitation of sweetness.

The structural change of beta-lactoglobulin A (betaLG A) on heating was measured at pH 3.0 and 7.5 with UV absorption difference spectra, differential scanning calorimetry (DSC), and circular dichroism (CD). At pH 3.0, betaLG A showed a reversible structural change by heating at 80 degrees C, while an irreversible change was observed and molecular aggregates of betaLG were formed by heating at 95 degrees C. DSC analysis of betaLG A gave endothermic peaks at 75 degrees C and 90 degrees C at pH 7.5, and 90 degrees C at pH 3.0. At pH 7.5, betaLG A modified with N-ethylmaleimide (NEM-betaLG A) gave two endothermic peaks: at 72 degrees C and 90 degrees C. CD spectra of betaLG A heated at various temperatures and pHs were measured and the spectra at pH 3.0 and 7.5 were not changed by heating to 95 degrees C and 80 degrees C, respectively. Unheated NEM-betaLG A gave a spectrum similar to that of heated betaLG A, suggesting that the secondary structure was changed by NEM treatment.

Hazard ratios (HR) of death due to hepatocellular carcinoma (HCC) were analyzed by gender and age strata (40-59 and 60-79) among smokers and ex-smokers in 65,528 eligible subjects from a large cohort of males and females aged 40-79 years, based on information about several smoking-related characteristics. Both current smokers and ex-smokers among total older males had hazard ratios (HR) for dying from HCC that were 2 to 4 times higher than those who had never smoked at the baseline survey. When subjects were restricted to those without history of liver disease (LD), older male (60-79) ex-smokers presented a statistically significant HR of 5.0. Earlier age at start of smoking (15 to 19) showed a significantly increased HR of 4 to 8 for both current and ex-smokers. Moderate number of cigarettes smoked per day showed an increased HR, and later age at cessation of smoking had a higher HR compared to earlier cessation. Larger cumulative amount of smoking resulted in an elevated HR of 11 times than in those who had never smoked. Cigarette smoking was suggested to be an important risk factor for death from HCC regardless of whether the smoking habit was in the past or was continuing at present. To eliminate confounding effects and interaction with other risk factors of HCC and to clarify the net association between smoking habits and HCC, farther careful analysis using multivariate models is needed.

Hazard ratios (HR) of death due to hepatocellular carcinoma (HCC) were analyzed by gender and age strata (40-59 and 60-79) among drinkers and ex-drinkers in 66,974 eligible subjects from a a large cohort of male and female subjects aged 40-79 years, based on information about several drinking related characteristics. The HR of dying from HCC for ex-drinkers was 4 to 8 times higher than for those who had never consumed alcohol at the baseline survey. When the subjects were restricted to those without history of liver disease (LD), the HR was still high for ex-drinkers among younger males, though the difference was not statistically significant. It appeared that the earlier drinking habits were established, the higher the HR, especially for younger males without LD. Among total current drinkers, the amount ingested per occasion and the cumulative amount ingested at the baseline did not show significantly increased HRs. Among subjects without LD, larger amounts ingested per occasion and larger cumulative amount seemed to have higher HRs in older male current drinkers. Frequent drinking and later age (50 to 79) at cessation of drinking were associated with higher HRs among both genders and both age strata. After restricting the analysis to subjects without LD, many of these increased HRs remained among males. The results suggested that the association between alcohol drinking history and HR of HCC differs depending on the presence of LD. Major confounders other than age and gender associated with both drinking and HCC, e.g. smoking, hepatitis virus infection, or history of diabetes, were not considered in this analysis, and the observed associations might be confounded by any of these factors. To clarify the net association between alcohol drinking and HCC, further analysis is needed to control potential confounders, including past history of liver disease, and to consider probable effect modifiers.

The relationship between the past history of selected diseases and the risk of dying from hepatocellular carcinoma (HCC) was analyzed using 110,792 cohort members (46,465 males and 64,327 females) recruited between 1988 and 1990 by the JACC Study (the Japan Collaborative Cohort Study for Evaluation of Cancer Risk). Significantly elevated hazard ratios (HRs) were observed in both genders for the past history of kidney diseases, liver diseases, gallstones or cholecystitis, diabetes mellitus, and blood transfusion. Further, when analyzed by age group (those 40-59 years of age were "younger" and those 60-79 years of age were "older"), although the significant associations were generally maintained, the magnitude of the HRs for liver diseases and diabetes mellitus seemed to be considerably different between the younger and older age groups for male cohort members. When the analyses were limited to cohort members without the past history of liver diseases, the past histories which had significantly elevated HRs were hypertension (HR = 3.14, 95% confidence interval (CI): 1.25-7.89), diabetes mellitus (HR = 4.17, 95% CI: 1.22-14.25), and blood transfusion (HR = 7.69, 95% CI: 3.09-19.15) in the younger male age group and gallstone or cholecystitis (HR = 2.58, 95% CI: 1.11-5.98) in the older male age group. On the other hand, for females, the significantly elevated HRs were gastric or duodenal ulcer (HR = 4.33, 95% CI: 1.09-17.25) in the younger age group and diabetes mellitus (HR = 6.16, 95%CI: 2.25-16.90) and blood transfusion (HR = 3.86, 95%CI: 1.58-9.41) in the older age group. However, since the evidence from our univariate analyses might not be decisive, multivariate Cox proportional hazards models controlling for potential confounders and effect modifiers will be required to obtain more valid or unbiased hazard ratios.