Cross-Sectional and Longitudinal Associations between Forearm Bone Mineral Density and Anthropometry in Adult Japanese Men and Women.

BACKGROUND: No consensus exists regarding which anthropometric measurements are related to bone mineral density (BMD), and this relationship may vary according to sex and age. A large Japanese cohort was analyzed to provide an understanding of the relationship between BMD and anthropometry while adjusting for known confounding factors. METHODS: Our cohort included 10,827 participants who underwent multiple medical checkups including distal forearm BMD scans. Participants were stratified into four groups according to age (≥50 years or <50 years) and sex. The BMD values were adjusted for confounding factors, after which single and partial correlation analyses were performed. The prevalence of osteopenia was plotted for each weight index (weight or body mass index [BMI]) class. RESULTS: Cross-sectional studies revealed that weight was more favorably correlated than BMI in the older group (R=0.278 and 0.212 in men and R=0.304 and 0.220 in women, respectively), whereas weight and BMI were weakly correlated in the younger age groups. The prevalence of osteopenia exhibited a negative linear relationship with weight among older women ≥50 years of age, and an accelerated increase was observed with decreasing weight in older men weighing <50 kg and younger women weighing <60 kg. When weight was replaced with BMI, the prevalence was low in most subgroups classified by weight. CONCLUSIONS: Weight, rather than BMI, was the most important indicator of osteopenia but it might not be predictive of future bone loss.

Association between screen time, including that for smartphones, and overweight/obesity among children in Japan: NICE EVIDENCE Study 4.

The association between screen time (ST), including that for smartphones, and overweight/obesity in children was examined separately for boys and girls, considering the influence of lifestyle factors. A cross-sectional study was conducted in 2,242 Japanese children (1,278 girls) aged 10-14 years. Overweight/obesity was defined by the International Obesity Task Force. Logistic regression analysis showed that only for girls, total ST (≥4 h), smartphone ST (≥3 h), and non-smartphone ST (≥2 h) were all independently and significantly associated with overweight/obesity compared to <2 h total ST, non-use of smartphones, and <1 h non-smartphone ST. Thus, smartphone ST ≥3 h and non-smartphone ST ≥2 h were additively associated with overweight/obesity in girls only. Girls having smartphone ST ≥3 h and non-smartphone ST ≥2 h were 6.79 times (95% CI: 3.11-14.81) more likely to have overweight/obesity than girls with less usage of both. In girls, when total ST was ≥4 < 5 h or smartphone ST was ≥2 h, the significant association with overweight/obesity disappeared when physical activity was ≥60 min/day and sleep time was ≥8.5 h. In addition, none of these associations was significant in boys. In Japanese girls, smartphone ST, non-smartphone ST, and total ST were all significantly associated with overweight/obesity. To avoid overweight/obesity, it is suggested to keep smartphone ST, non-smartphone ST, and total ST to <3 h, <2 h, and <4 h, respectively, and to engage in sufficient physical activity and sleep time.

Associations among metabolic health, weight status, and various physical fitness components in Japanese adolescents: a cross-sectional study (NICE EVIDENCE study- Agano 3).

Aim was to examine associations among metabolic health, weight status, and various physical fitness (PF) components in 1744 Japanese adolescents aged 13-14. Anthropometric measurements and PF tests (20 m shuttle run test [20mSRT], handgrip strength/body mass [HG], standing long jump [SLJ], and sit ups [SU]) were administered. The bottom sex-specific quintile of PF indicated "low fit". Participants were classified as non-overweight (non-OW) or overweight/obese (OW) according to the International Obesity Task Force. Clustered metabolic risk was defined as the sum of Z scores for mean arterial pressure, non-high-density lipoprotein cholesterol, and HbA1c, divided by three, and ≥ 1 SD. Combination of weight status and scores for HG or SU were additively associated with clustered metabolic risk. Compared with the non-OW-moderate-high fit group, the OW-low HG group was 3.05 (95%CI: 1.88-4.97) times more likely to have clustered metabolic risk although risk was not significantly elevated in the OW-moderate-high HG group (1.52 [95%CI: 0.88-2.62]). A similar association was observed between OW and low SU scores but not between OW and low 20mSRT or SLJ scores. Adolescents with OW and moderate-high HG or SU scores had a lower prevalence of an unfavourable metabolic state than those with OW and low HG or SU results.

Retrospective cohort study to examine the association between serum amylase and the incidence of type 2 diabetes mellitus, Toranomon Hospital Health Management Center Study 23 (TOPICS 23).

INTRODUCTION: Low serum amylase values are cross-sectionally associated with the prevalence of type 2 diabetes mellitus (T2DM) but have not been shown to be longitudinally associated with its incidence. This retrospective cohort (ie, historical cohort) study aimed to examine the association of previously lowered levels of serum amylase with incident T2DM. RESEARCH DESIGN AND METHODS: Examined were 8316 individuals who had annual health examinations for 6 years (ie, 7 times) at the Toranomon Hospital Health Management Center. The trajectory of serum amylase as the study exposure was classified into two elements: (1) serum amylase level at entry and (2) change in serum amylase, which was expressed as the annual change rate. The annual change rate was calculated by dividing the change in the amylase values according to follow-up periods. Regression analyses were performed to examine the association between low and decreased levels of serum amylase and the incidence of T2DM. RESULTS: Analyzed were 6917 individuals who had not developed T2DM within 1 year after cohort entry. T2DM thereafter occurred in 1021 patients. Cox regression indicated that the adjusted HR (95% CI) for incident T2DM for amylase ≤57 IU/L (quintile (Q) 1) was 0.97 (0.84 to 1.13) compared with amylase ≥58 IU/L (Q2-Q5). Logistic regression indicated that the adjusted OR (95% CI) for an annual change rate of amylase ≤-2.0% (Q1) vs ≥-1.9% (Q2-Q5) was 3.53 (3.00 to 4.16). The adjusted ORs were consistently significant throughout sensitivity analyses according to baseline amylase and the combination of age, body mass index, and hemoglobin A1c. CONCLUSIONS: Results showed that not low but previously decreased serum amylase was a risk factor for T2DM, suggesting the significance of periodic examinations of serum amylase values to detect individuals at high risk of T2DM.

Association between Obesity and Intake of Different Food Groups among Japanese with Type 2 Diabetes Mellitus-Japan Diabetes Clinical Data Management Study (JDDM68).

BACKGROUND: We investigated the association between various food groups and obesity in Japanese patients with type 2 diabetes. METHODS: 2070 patients with type 2 diabetes who attended 26 diabetes clinics throughout Japan were analyzed and were divided into obese and non-obese groups. Intakes of food groups determined by a food frequency questionnaire were compared. Odds ratios for obesity for quartiles of individual food groups were calculated using a logistic regression model. RESULTS: Non-obese patients consumed a larger variety of food groups than obese patients, with the diets of non-obese individuals closer to the traditional Japanese diet characterized by fish, seaweed, and soybeans/soy products. Among 21 food groups, low vegetable intake and high sweets intake were the most strongly associated with obesity in both men and women. Low intake of both fruits and vegetables and the combination of high intake of sweets and low intake of fruits were associated with obesity. CONCLUSIONS: Food groups and their combinations that were strongly associated with obesity in Japanese patients with type 2 diabetes were identified. Our findings also suggested an inverse association between the traditional Japanese diet and obesity.

Secular Trends in Dietary Intake over a 20-Year Period in People with Type 2 Diabetes in Japan: A Comparative Study of Two Nationwide Registries; Japan Diabetes Complications Study (JDCS) and Japan Diabetes Clinical Data Management Study (JDDM).

BACKGROUND: In order to provide effective dietary guidance, it is necessary to consider dietary intake, which can change over time. This study analyzed changes in the diet of Japanese patients with type 2 diabetes over a 20-year period. METHODS: We compared the results of two dietary surveys that used the food frequency questionnaire format. The first was conducted in 1996 by the Japan Diabetes Complications Study (JDCS) (n = 1509; males 53.3%), and the second in 2014-2018 by the Japan Diabetes Clinical Data Management Study (JDDM) (n = 1145; males 65.6%). Both are nationwide representative registries of outpatients with type 2 diabetes in Japan. RESULTS: Over a 20-year period, both men and women with type 2 diabetes had a significant increase in body mass index (BMI). Nonetheless, there was only a small change in energy intake. Conversely, there was a significant increase in fat intake and thus in the fat-to-energy ratio. With regard to food groups, there was a significant increase in meat intake and a decrease in the intake of fish, soybeans/soy products, vegetables, and fruits, with a particularly significant decrease in vegetables. CONCLUSIONS: Even in Japan, an industrialized country with a stable socioeconomic environment, there were many significant changes in the dietary intake of patients with type 2 diabetes over the 20-year period.

Comparing Associations of Dietary Energy Density and Energy Intake, Macronutrients with Obesity in Patients with Type 2 Diabetes (JDDM 63).

To investigate the association between dietary energy density (DED) and obesity in people with type 2 diabetes mellitus. Moreover, we compared the strength of the associations of DED with intake of energy and macronutrients in terms of obesity as well as nutritional factors that have long been used for medical nutritional therapy. Cross-sectionally investigated were 1615 outpatients with type 2 diabetes who attended 26 clinics nationwide with diabetes specialists. Odds ratios (ORs) were calculated for the association between obesity and DED, energy, and macronutrients by quintile categories and a 1 SD increment with adjustment for potential confounders. ß coefficients were calculated for the association between body mass index (BMI) and each nutritional factor by 1 SD increments in nutritional values. Multi-adjusted OR for obesity between extreme quintiles of DED was 2.99 (95% confidence interval (95% CI): 2.01-3.12). Conversely, the ORs did not differ significantly according to the quintiles of other nutrient factors. Multi-adjusted ß coefficient of BMI per 1 SD according to DED was far higher than those of other nutrient factors (ß coefficient 0.65, 95% CI: 0.41-0.88). These findings indicated that DED in persons with type 2 diabetes was positively associated with BMI and the prevalence of obesity. DED was also much more potently associated with obesity and BMI than nutritional indicators such as intake of energy or macronutrients.

Synthesis of photoreactive ivermectin B1a derivatives and their actions on Haemonchus and Bombyx glutamate-gated chloride channels.

Glutamate-gated chloride channels (GluCls) are inhibitory neurotransmitter receptors that are present only in invertebrates such as nematodes and insects. These channels are important targets of insecticidal, acaricidal, and anthelmintic macrolides such as avermectins, ivermectin (IVM), and milbemycins. To identify the amino acid residues that interact with IVM in GluCls, three IVM B1a derivatives with different photoreactive substitutions at C-13 were synthesized in the present study. These derivatives displayed low- or subnanomolar affinity for parasitic nematode (Haemonchus contortus) and silkworm (Bombyx mori) GluCls expressed in COS-1 cells. The derivatives also activated homomeric H. contortus GluCls expressed in Xenopus oocytes. The results indicate that synthesized photoreactive IVM B1a derivatives have superior affinity and functionality for chemically labeling the macrolide-binding site in GluCls. .

Competitive antagonism of insect GABA receptors by iminopyridazine derivatives of GABA.

A series of 4-(6-imino-3-aryl/heteroarylpyridazin-1-yl)butanoic acids were synthesized and examined for antagonism of GABA receptors from three insect species. When tested against small brown planthopper GABA receptors, the 3,4-methylenedioxyphenyl and the 2-naphthyl analogues showed complete inhibition of GABA-induced fluorescence changes at 100 µM in assays using a membrane potential probe. Against common cutworm GABA receptors, these analogues displayed approximately 86% and complete inhibition of GABA-induced fluorescence changes at 100 µM, respectively. The 4-biphenyl and 4-phenoxyphenyl analogues showed moderate inhibition at 10 µM in these receptors, although the inhibition at 100 µM was not complete. Against American cockroach GABA receptors, the 4-biphenyl analogue exhibited the greatest inhibition (approximately 92%) of GABA-induced currents, when tested at 500 µM using a patch-clamp technique. The second most active analogue was the 2-naphthyl analogue with approximately 85% inhibition. The 3-thienyl analogue demonstrated competitive inhibition of cockroach GABA receptors. Homology modeling and ligand docking studies predicted that hydrophobic 3-substituents could interact with an accessory binding site at the orthosteric binding site.

A photoreactive probe that differentiates the binding sites of noncompetitive GABA receptor antagonists.

γ-Aminobutyric acid (GABA) receptors are postsynaptic membrane protein complexes that are important not only in the regulation of the nervous system but also as targets of drugs and insecticides. We synthesized a photoreactive straight-chain noncompetitive antagonist (NCA), 2-nitro-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenyl 4-(4-methoxycarbonyl-1-butynyl)benzoate (NMB), to probe the NCA binding site. Our data show that this probe labels the NCA site and demonstrate that the NCA insecticide fipronil binds at a site distinct from that of other NCAs, such as picrotoxinin and 4'-ethynyl-4-n-propylbicycloorthobenzoate. The unique molecule NMB will be useful in identifying the cross-linking site of straight-chain NCAs in GABA receptors and mapping allosteric binding sites. Such studies should provide invaluable information in designing novel NCAs.

Synthesis and structure-activity relationship analysis of bicyclophosphorothionate blockers with selectivity for housefly gamma-aminobutyric acid receptor channels.

BACKGROUND: Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of gamma-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors. RESULTS: Introduction of an isopropyl group at the 3-position enhanced the affinity of bicyclophosphorothionates for housefly GABA receptors and reduced the affinity towards rat GABA receptors. The 4-isopentyl-3-isopropylbicyclophosphorothionate showed the highest affinity for housefly GABA receptors (IC(50) = 103 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC(50) = 125 nM). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC(50)(rat)/IC(50)(fly) ratio of approximately 97. Three-dimensional GABA receptor models successfully explained the structure-activity relationships of the bicyclophosphorothionates. CONCLUSION: The results indicate that minor structural modifications of blockers can change their selectivity for insect versus mammalian GABA receptors. The substituent at the 3-position of the bicyclophosphorothionates dictates selectivity for housefly versus rat GABA receptors. This information should prove useful for the design of safer insecticides and parasiticides.

Double dioxygenation by mouse 8S-lipoxygenase: specific formation of a potent peroxisome proliferator-activated receptor alpha agonist.

Mouse 8S-lipoxygenase (8-LOX) metabolizes arachidonic acid (AA) specifically to 8S-hydroperoxyeicosatetraenoic acid (8S-HPETE), which will be readily reduced under physiological circumstances to 8S-hydroxyeicosatetraenoic acid (8S-HETE), a natural agonist of peroxisome proliferator-activated receptor alpha (PPAR alpha). Here, we investigated whether 8-LOX could further oxygenate AA and whether the products could activate PPARs. The purified recombinant 8-LOX converted AA exclusively to 8S-HPETE and then to (8S,15S)-dihydroperoxy-5Z,9E,11Z,13E-eicosatetraenoic acid (8S,15S-diHPETE). The kcat/Km values for 8S-HPETE and AA were 3.3x10(3) and 2.7x10(4) M(-1) s(-1), respectively. 8-LOX also dioxygenated 8S-HETE and 15S-H(P)ETE specifically to the corresponding 8S,15S-disubstituted derivatives. By contrast, 15-LOX-2, a human homologue of 8-LOX, produced 8S,15S-diH(P)ETE from 8S-H(P)ETE but not from AA nor 15S-H(P)ETE. 8S,15S-diHETE activated PPAR alpha more strongly than 8S-HETE did. The present results suggest that 8S,15S-diH(P)ETE as well as 8S-H(P)ETE would contribute to the physiological function of 8-LOX and also that 8-LOX can function as a potential 15-LOX.

Structure-activity relationships of benzylidene anabaseines in nicotinic acetylcholine receptors of cockroach nerve cords.

Ten analogues of 6'-chloro-3-benzylideneanabaseine (CBA) bearing substituents at the ortho- and the para-positions of the phenyl group were synthesized, together with two related compounds. The affinity of the synthesized compounds for nicotinic acetylcholine receptors (nAChRs) in the nerve cord of the American cockroach (Periplaneta americana L.) was examined by the radioligand binding assay using [(3)H]epibatidine (EPI), a nAChR agonist. All 12 tested compounds inhibited [(3)H]EPI binding, showing K(i) values ranging from 14.6 to 6830nM. The potency variation of para-substituted CBA analogues was explained by the steric (Delta B(1)) and electronic (sigma(p)) parameters of the para-substituents, or by the steric parameter and the charge of the N1 nitrogen atom (qN(1)). Among the CBA analogues, only two compounds containing a dimethylamino group and a methoxy group at the para-position showed high insecticidal activity against the German cockroach (Blattella germanica) when injected after pretreatment with metabolic inhibitors. High-affinity analogues of CBA might be suitable probes for use in classifying and characterizing insect nAChR subtypes.

Effects of src-deficiency on the expression of in vivo toxicity of TCDD in a strain of c-src knockout mice procured through six generations of backcrossings to C57BL/6 mice.

The effect of TCDD was studied in c-src-deficient C57BL6-src(tm1sor) (N6 src -/- and -/+) mice, and their wild-type littermate mice (N6 src +/+). The former was created from the original strain of B6, 129-src(tm1sor) mice through six generations of backcrossings with C57BL6 mice. The results of a high dose TCDD toxicity tests in male mice indicated that N6 src-/+ mice were significantly less responsive to the toxic action of TCDD (115 microg/kg single i.p. injection) than N6 src+/+ mice in terms of reduced % body weight gain, the increase in the liver to body weight ratio, and the decrease in the adipose tissue to liver weight ratio and in the weight of pancreas. To understand the cause for these differential effects of TCDD we studied TCDD-induced changes in several biochemical parameters at day 10 and found that most drastically affected ones were glycogen depletion and phosphoenolpyruvate carboxykinase (PEPCK) downregulation. In addition, the degree of triglyceride accumulation in liver was less pronounced in N6-/+ than in N6+/+ mice. These findings suggest that the absence of c-src expression indeed affects the development of selected, TCDD-induced toxic endpoints that are related to wasting syndrome.