Association between urinary C-megalin levels and progressive kidney dysfunction: a cohort study based on the diabetes distress and care registry at Tenri (DDCRT 24).

AIMS: The aim of this cohort study was to evaluate the association between urinary levels of C-megalin, a full-length form of megalin, and kidney dysfunction progression and its dependence on the urinary albumin-creatinine ratio (UACR) in individuals with diabetes. METHODS: We enrolled 1,547 individuals with diabetes who visited the ambulatory clinic at Tenri Hospital, a regional tertiary-care hospital in Tenri City, Nara Prefecture, Japan, with an estimated glomerular filtration (eGFR) of ≥ 30 mL/min/1.73 m2. The hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox proportional hazard models to examine the association between urinary C-megalin levels and eGFR decline by ≥ 40% from baseline. RESULTS: Urinary C-megalin level was not associated with ≥ 40% eGFR decline in an age-, sex-, eGFR-, systolic blood pressure-, hemoglobin-, and UACR-adjusted model in the 1,547 patients enrolled in the study. However, urinary C-megalin levels were associated with a ≥ 40% decline in eGFR when accounting for the relationship between urinary C-megalin levels and UACR in the model. This association was UACR-dependent. CONCLUSIONS: High urinary C-megalin levels were associated with progressive kidney dysfunction in individuals with diabetes, and this association was attenuated by high UACRs.

Urinary C-megalin as a novel biomarker of progression to microalbuminuria: A cohort study based on the diabetes Distress and Care Registry at Tenri (DDCRT 22).

AIMS: Megalin is a multiligand receptor expressed in proximal tubular cells that reabsorbs filtered albumin and correlates cross-sectionally with albuminuria. We investigated the association between urinary C-megalin levels and the incidence of microalbuminuria in patients with diabetes mellitus. METHODS: This cohort study included 752 patients with type 1 or 2 diabetes mellitus and a urinary albumin-to-creatinine (Cr) ratio (UACR) within the normoalbuminuric range (<30 mg/g Cr). The association between urinary C-megalin and persistent microalbuminuria, accounting for the possible interaction between baseline UACR and urinary C-megalin, was estimated using a Cox proportional hazards model. RESULTS: During a median follow-up period of 1.99 years, 179 cases of persistent microalbuminuria were observed. The association between urinary C-megalin and persistent microalbuminuria was UACR-dependent (P for interaction < 0.001), with the highest association observed in the absence of UACR (per 100 fM/gCr of urinary C-megalin: adjusted hazard ratio, 1.13; 95% CI 1.07-1.19), gradually decreasing as UACR increased to 30 mg/g Cr. UACR dependence was confirmed by sensitivity analyses according to low-normal (<10 mg/gCr) or high-normal (10-<30 mg/gCr) UACR. CONCLUSIONS: Urinary C-megalin is associated with progression to microalbuminuria, especially in those with low-normal UACR levels, and its usefulness to identify high risk patients requires further investigation.

A 52-week randomized controlled trial of ipragliflozin or sitagliptin in type 2 diabetes combined with metformin: The N-ISM study.

AIM: To compare the long-term efficacy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors as second-line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD). MATERIALS AND METHODS: In a 52-week randomized open-label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks. RESULTS: Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m2 , 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C-peptide and high-density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11). CONCLUSION: The HbA1c-lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.

Production of a tributyltin-binding protein 2 knockout mutant strain of Japanese medaka, Oryzias latipes.

Tributyltin-binding proteins (TBT-bps), members of the lipocalin family, bind TBT in fish blood and are presumed to contribute to detoxification of TBT. Recent studies have shown that many fish species have TBT-bp genes, and that these genes are induced by stresses such as exposure to chemicals or fish pathogenic bacteria. However, the function of TBT-bps, and the mechanisms of their induction and detoxification activity are still unclear. Here, towards elucidating the functions of TBT-bp2, we produced a TBT-bp2 knockout (TBT-bp2-/-) strain of Japanese medaka, Oryzias latipes, by using the CRISPR/Cas9 system. Gene expression of the mutated TBT-bp2 was reduced, and the cDNA sequencing and predicted protein structure suggested possible loss of function. However, the fish could be grown under normal conditions. Exposure of the TBT-bp2-/- strain of medaka to various stresses in future experiments is expected to contribute to our understanding of this novel detoxification system in aquatic organisms.

Meat intake and incidence of cardiovascular disease in Japanese patients with type 2 diabetes: analysis of the Japan Diabetes Complications Study (JDCS).

PURPOSE: Excessive meat intake has been researched as a major cause of cardiovascular disease (CVD) among healthy adults, but data on this topic in Asian patients with diabetes are sparse. The quantity and variety of available meats vary widely between Asian and Western countries. As part of a nationwide cohort study we investigated the relationship between meat intake and incidence of CVD in Japanese patients with type 2 diabetes aged 40-70 years with HbA1c ≥ 6.5%. METHODS: Analyzed were 1353 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcome was the 8-year risk of a CVD event, including coronary heart disease (CHD) and stroke. Cox regression analyses estimated hazard ratios (HRs) for dietary intake adjusted for age, gender, body mass index, HbA1c, smoking, energy intake, and other confounders. RESULTS: Mean meat intake in quartiles ranged from 9.9 to 97.7 g/day. After adjusting for confounders, HRs of CHD in the 2nd, 3rd, and 4th quartiles for meat intake compared with the 1st quartile were 2.84 (95% confidence interval 1.29-6.24, p = 0.01), 3.02 (1.36-6.70, p < 0.01), and 2.99 (1.35-6.65, p = 0.01), respectively. In two groups according to meat intake, patients consuming ≥ 20 g/day of meat had a 2.94-fold higher risk of CHD than those consuming < 20 g/day (p < 0.01). There was no significant association of stroke with meat intake. CONCLUSIONS: An elevated incidence of CHD in Japanese patients with type 2 diabetes was associated with high meat intake.

Polyoxometalate-Assisted, One-Pot Synthesis of a Pentakis[(triphenylphosphane)gold]ammonium(2+) Cation Containing Regular Trigonal-Bipyramidal Geometries of Five Bonds to Nitrogen.

Novel intercluster compounds consisting of pentakis[(triphenylphosphane)gold]ammonium(2+) cation (1) and Keggin polyoxometalate (POM) anions, i.e., {[Au(PPh3)]5(µ5-N)}3[α-PM12O40]2 (1-PW for M = W; 1-PMo for M = Mo), were synthesized in 30-36% yield by one-pot reaction of the protonic acid form of the Keggin POMs, H3[α-PM12O40]·nH2O (n = 13 for M = W; n = 15 for M = Mo) with monomeric (triphenylphosphane)gold(I) carboxylate [Au(RS-pyrrld)(PPh3)] [RS-Hpyrrld = (RS)-2-pyrrolidone-5-carboxylic acid] in the presence of aqueous NH3 at a molar ratio of 2:15:x (x = 3 for 1-PW; x = 7.5 for 1-PMo). These compounds resulted from the nitrogen-centered phosphanegold(I) clusterization of in situ generated monomeric phosphanegold(I) units, [Au(PPh3)]+ or [Au(L)(PPh3)]+ (L = NH3 or solvent), during the carboxylate elimination of [Au(RS-pyrrld)(PPh3)] in the presence of the Keggin POMs and aqueous NH3. The products 1-PW and 1-PMo were characterized by elemental analysis, Fourier transform infrared, thermogravimetric and differential thermal analyses (TGA/DTA), X-ray crystallography, and solid-state cross-polarization magic-angle-spinning (CPMAS) (31P and 15N) and solution (31P{1H} and 1H) NMR spectroscopy. The lattice contained three independent {[Au(PPh3)]5(µ5-N)}2+ cations, of which two took regular trigonal-bipyramidal (TBP) geometries and the third took a distorted, square-pyramidal (SP) geometry. These geometries are in contrast to those reported by Schmidbaur's group for {[Au(PPh3)]5(µ5-N)}2+ cations as BF4 salts. Density functional theory and ONIOM calculations for {[(L3P)Au]nN}(n-3)+ (L = H or Ph; n = 4-6) showed that the pentacoordinate cluster is energetically most stable and its TBP structure is only 1.6 kcal mol-1 more stable than its SP structure, in accordance with the experimental facts.

Relationships among cardiorespiratory fitness, muscular fitness, and cardiometabolic risk factors in Japanese adolescents: Niigata screening for and preventing the development of non-communicable disease study-Agano (NICE EVIDENCE Study-Agano) 2.

OBJECTIVE: To examine the independent and combined associations of cardiorespiratory fitness (CRF) and muscular fitness (MF) with cardiometabolic risk factors in Japanese adolescents. METHODS: A cross-sectional study including 993 Japanese adolescents (aged 13-14 years) was undertaken. Height, body mass, blood pressure, lipid profile (non-fasting), and HbA1c were measured. The physical fitness (PF) test included measurements of CRF (20 m multistage shuttle run test), upper limb strength (hand grip strength), lower limb strength (standing long jump), and muscular endurance (sit-ups). The clustered cardiometabolic risk (CCMR) was estimated by summing standardized Z-scores of body mass index (BMI), mean arterial pressure (MAP), non-high-density lipoprotein cholesterol (non-HDL-C), and HbA1c. RESULTS: Linear regression analysis showed that all PF factors except for muscular endurance were inversely correlated with CCMR (P < .001). Among metabolic risk components, HbA1c was unrelated to PF, while non-HDL-C was inversely associated with CRF (B = -2.40; P < .001), upper limb strength (B = -1.77; P < .05), and lower limb strength (B = -1.53; P < .05) after adjustment for lifestyle factors. Logistic regression showed that the probability of having high CCMR (≥1SD) was synergistically higher in those with the lowest tertiles of both CRF and upper limb strength (P for interaction = .001); however, a substantially lower likelihood of having high CCMR was observed among individuals with the lowest tertile of upper limb strength but moderate CRF. CONCLUSIONS: Lower CRF and MF were significantly and synergistically associated with an unhealthier metabolic risk profile.

Association between all-cause mortality and severity of depressive symptoms in patients with type 2 diabetes: Analysis from the Japan Diabetes Complications Study (JDCS).

OBJECTIVE: The aims of this study are to confirm whether the excess mortality caused by depressive symptoms is independent of severe hypoglycemia in patients with type 2 diabetes mellitus (T2DM) and to evaluate the association between all-cause mortality and degrees of severity of depressive symptoms in Japanese patients with T2DM. METHODS: A total of 1160 Japanese patients with T2DM were eligible for this analysis. Participants were followed prospectively for 3years and their depressive states were evaluated at baseline by the Center for Epidemiologic Studies Depression Scale (CES-D). Cox proportional hazards model was used to evaluate the relative risk of all-cause mortality and was adjusted by possible confounding factors, including severe hypoglycemia, all of which are known as risk factors for both depression and mortality. RESULTS: After adjustment for severe hypoglycemia, each 5-point increase in the CES-D score was significantly associated with excess all-cause mortality (hazard ratio 1.69 [95% CI 1.26-2.17]). The spline curve of HRs for mortality according to total CES-D scores showed that mortality risk was slightly increased at lower scores but was sharply elevated at higher scores. CONCLUSION: A high score on the CES-D at baseline was significantly associated with all-cause mortality in patients with T2DM after adjusting for confounders including severe hypoglycemia. However, only a small effect on mortality risk was found at relatively lower levels of depressive symptoms in this population. Further research is needed to confirm this relationship between the severity of depressive symptoms and mortality in patients with T2DM.

Comparison of baseline characteristics and clinical course in Japanese patients with type 2 diabetes among whom different types of oral hypoglycemic agents were chosen by diabetes specialists as initial monotherapy (JDDM 42).

Little is known about the relationships between patient factors and the antihyperglycemic agents that have been prescribed as initial therapy by diabetes specialists for patients with type 2 diabetes. Moreover, there has been little clarification of the subsequent usage patterns and related factors that influenced the continuation or discontinuation of the drug or the addition of another drug. To provide information on these issues, we evaluated the clinical characteristics of Japanese patients with type 2 diabetes for whom different types of oral hypoglycemic agents (i.e., either sulfonylureas, biguanides, or DPP-4 inhibitors (DPP-4Is)) were chosen as initial monotherapy by diabetes specialists and evaluated subsequent usage patterns.Prescription data on 3 different antidiabetic agents from December 2009 to March 2015 from diabetes specialists' patient registries were used to identify variables at baseline related to initial prescriptions; also, the addition of another hypoglycemic drug or discontinuation of the initial therapy was evaluated 1 year after the initial prescription. Analyzed were data on 2666 patients who received initial monotherapy with either a sulfonylurea (305 patients), biguanide (951 patients), or DPP-4I (1410 patients). Patients administered sulfonylureas were older, had a lower body mass index (BMI), longer duration of diabetes, and worse glycemic control than recipients of biguanides. Use of biguanides was related to younger age, short duration of diabetes, and obesity but was negatively associated with poor glycemic control. Older age but neither obesity nor poor glycemic control was associated with DPP-4Is. In all 3 groups a high HbA1c value was related to adding another hypoglycemic agent to the initial therapy. Moreover, adding another drug to a DPP-4I was related to a younger age and higher BMI.Patients' age, duration of diabetes, obesity, and glycemic control at baseline influenced the choice of hypoglycemic agents. Selection of a biguanide differs greatly from that of a sulfonylurea or DPP-4I with regard to age and obesity.

Is the Proportion of Carbohydrate Intake Associated with the Incidence of Diabetes Complications?-An Analysis of the Japan Diabetes Complications Study.

The appropriate proportions of macronutritional intake have been controversial in medical nutritional therapy for diabetes, and evidence of the effects of carbohydrate consumption on diabetes complications in prospective settings is sparse. We investigated the relationships between proportions of carbohydrate intake as the % of total energy and diabetes complications in a nationwide cohort of Japanese patients with type 2 diabetes aged 40-70 years with hemoglobin A1c ≥6.5%. The analysis was of 1516 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to overt nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) after 8 years. Hazard ratios (HRs) for proportions of carbohydrate intake were estimated by Cox regression adjusted for confounders. High carbohydrate intake was significantly related to higher intakes of grain, fruits, and sweets/snacks and lower intakes of soybean and soy products, vegetables, seaweed, meat and processed meat, fish and processed fish, eggs, milk and dairy products, oil, and alcoholic beverages. During the eight-year follow-up, there were 81, 275, and 129 events of overt nephropathy, diabetic retinopathy, and CVD, respectively. After adjustment for confounders, HRs for complications in patients with carbohydrate intake in the second or third tertiles (51.0%-56.4% and ≥56.5%, respectively) compared with carbohydrate intake in the first tertile (<50.9%, referent) were analyzed. No significant associations were shown in the second and third tertiles relative to first tertile (overt nephropathy: 1.05 (95% Confidence Interval, 0.54-2.06) and 0.98 (0.40-2.44); diabetic retinopathy: 1.30 (0.90-1.88) and 1.30 (0.78-2.15); and CVD: 0.95 (0.55-1.63) and 1.37 (0.69-2.72)). By exploring potentially nonlinear relationships, trends for the incidence of diabetes complications according to proportions of carbohydrate intake were not clearly shown. Findings suggested that proportions of carbohydrate intake were not associated with the incidence of diabetes complications among type 2 diabetes patients in Japan.

Role of calpain in eccentric contraction-induced proteolysis of Ca2+-regulatory proteins and force depression in rat fast-twitch skeletal muscle.

The aim of this study was to examine the in vivo effects of eccentric contraction (ECC) on calpain-dependent proteolysis of Ca2+-regulatory proteins and force production in fast-twitch skeletal muscles. Rat extensor digitorum longus muscles were exposed to 200 repeated ECC in situ and excised immediately [recovery 0 (REC0)] or 3 days [recovery 3 (REC3)] after cessation of ECC. Calpain inhibitor (CI)-treated rats were intraperitoneally injected with MDL-28170 before ECC and during REC3. Tetanic force was markedly reduced at REC0 and remained reduced at REC3. CI treatment ameliorated the ECC-induced force decline but only at REC3. No evidence was found for proteolysis of dihydropyridine receptor (DHPR), junctophilin (JP)1, JP2, ryanodine receptor (RyR), sarcoplasmic reticulum Ca2+-ATPase (SERCA)1a, or junctional face protein-45 at REC0. At REC3, ECC resulted in decreases in DHPR, JP1, JP2, RyR, and SERCA1a. CI treatment prevented the decreases in DHPR, JP1, and JP2, whereas it had little effect on RyR and SERCA1a. These findings suggest that DHPR, JP1, and JP2, but not RyR and SERCA1a, undergo calpain-dependent proteolysis in in vivo muscles subjected to ECC and that impaired function of DHPR and/or JP might cause prolonged force deficits with ECC.NEW & NOTEWORTHY Calpain-dependent proteolysis is one of the contributing factors to muscle damage that occurs with eccentric contraction (ECC). It is unclear, however, whether calpains account for proteolysis of Ca2+-regulatory proteins in in vivo muscles subjected to ECC. Here, we provide evidence that dihydropyridine receptor and junctophilin, but not ryanodine receptor and sarcoplasmic reticulum Ca2+-ATPase, undergo calpain-dependent proteolysis.

Patients with type 2 diabetes having higher glomerular filtration rate showed rapid renal function decline followed by impaired glomerular filtration rate: Japan Diabetes Complications Study.

AIMS: The Japan Diabetes Complications Study (JDCS), a nation-wide, multicenter, prospective study of patients with type 2 diabetes, reported that hemoglobin A1c (HbA1c), systolic blood pressure, and smoking were risk factors for the onset of macroalbuminuria. This study explored the risk factors for glomerular filtration rate (GFR) decline in the JDCS patients. METHODS: We examined the 1407 JDCS patients (667 women, mean age 59years, 974 normoalbuminuria, 433 microalbuminuria) whose urinary albumin-to-creatinine ratio (UACR) and estimated GFR (eGFR) were determined at baseline with an 8-year follow-up. We divided all the patients into four groups according to baseline eGFR: G1 (120≤eGFR), G2 (90≤eGFR<120), G3 (60≤eGFR<90), G4 (eGFR<60). RESULTS: The eGFRs in groups G1 and G2 decreased at follow-up compared to those at the baseline. The risk of annual eGFR decline rate≥3ml/min/1.73m2 (rapid decliners) increased as the baseline eGFR increased. Advanced age, high HbA1c, and UACR, or diabetic retinopathy at baseline were risk factors for the rapid decliners. Especially the G1 group had a significant risk for the rapid decliners. The frequency of the patients with GFR<60ml/min/1.73m2 at the follow-up amounted to 31.1% in the rapid decliners, which was higher than 12% in the non-rapid decliners. CONCLUSIONS: In normo- and microalbuminuric patients with type 2 diabetes, extra careful attention should be paid to patients with eGFR ≥120ml/min/1.73m2 to detect cases with rapidly decreased GFR under the normal range.

The effect of counteranions on the molecular structures of phosphanegold(i) cluster cations formed by polyoxometalate (POM)-mediated clusterization.

The effect of counteranions on the molecular structures of phosphanegold(i) cluster cations formed by polyoxometalate (POM)-mediated clusterization was investigated. A novel intercluster compound, [{(AuLCl)2(µ-OH)}2]3[α-PMo12O40]2·3EtOH (1-PMo12), was obtained as orange-yellow plate crystals in 12.0% yield from a 6 : 1 molar ratio reaction of the monomeric phosphanegold(i) carboxylato complex [Au(RS-pyrrld)(LCl)] (RS-Hpyrrld = RS-2-pyrrolidone-5-carboxylic acid; LCl = tris(4-chlorophenyl)phosphane) in CH2Cl2 with the free acid-form of Keggin polyoxometalate (POM), H3[α-PMo12O40]·14H2O. An EtOH/H2O (5 : 1, v/v) solvent mixture was used. The dimeric cation [{(AuLCl)2(µ-OH)}2](2+) in 1-PMo12 was in a parallel-edge arrangement that was formed by self-assembly through the inter-cationic aurophilic interactions of the µ-OH-bridged dinuclear phosphanegold(i) cation. The POM anion in 1-PMo12 was successfully exchanged with a smaller PF6(-) anion by the use of an anion-exchange resin. POM-free, colorless block crystals of [{(AuLCl)3(µ3-O)}2](PF6)2·4CH2Cl2 (2-PF6) were obtained by vapor diffusion in 14.1% yield. During the synthesis of 2-PF6, a compound with mixed counteranions (one POM and one PF6(-) anion), i.e. [{(AuLCl)4(µ4-O)}]2[α-PMo12O40]PF6 (3-PMo12PF6), was obtained in 66.4% yield. Both products were characterized by elemental analysis, TG/DTA, FT-IR, (31)P{(1)H} NMR, (1)H NMR, and X-ray crystallography. X-ray crystallography revealed that the countercation in 2-PF6 was the dimeric cation of the µ3-O-bridged tris{phosphanegold(i)} species, whereas that in 3-PMo12PF6 consisted of an unusual µ4-O-bridged tetragonal-pyramidal tetrakis{phosphanegold(i)} cation. Therefore, we concluded that the POM anion significantly contributed to the stabilization of these countercations (parallel-edged arrangement in 1-PMo12 and µ4-O-bridged tetragonal-pyramid in 3-PMo12PF6). Moreover, the previously reported yellow crystals of [{(AuLF)2(µ-OH)}2]3[PMo12O40]2·3EtOH (4-PMo12: LF = tris(4-fluoro phenyl)phosphane) were successfully converted to the POM-free crystalline OTf(-) salt [{(AuLF)2(µ-OH)}2](OTf)2·0.5Et2O (4-OTf) by the use of an anion-exchange resin. X-ray crystallography also revealed that the parallel-edge arrangement of the dimeric cation in 4-PMo12 was converted to the crossed-edge arrangement of that in 4-OTf. These results illustrate that the AuOPOM and hydrogen-bonding (C-HOPOM and O-HOPOM) interactions between the phosphanegold(i) cluster cation and the Keggin POM anion in the solid state significantly contribute to the structure, composition, and stability of the phosphane gold(i) cluster cations in 4-PMo12.

Utility of nonblood-based risk assessment for predicting type 2 diabetes mellitus: A meta-analysis.

OBJECTIVE: Nonblood-based risk assessment for type 2 diabetes mellitus (T2DM) that depends on data based on a questionnaire and anthropometry is expected to avoid unnecessary diagnostic testing and overdiagnosis due to blood testing. This meta-analysis aims to assess the predictive ability of nonblood-based risk assessment for future incident T2DM. METHODS: Electronic literature search was conducted using EMBASE and MEDLINE (from January 1, 1997 to October 1, 2014). Included studies had to use at least 3 predictors for T2DM risk assessment and allow reproduction of 2×2 contingency table data (i.e., true positive, true negative, false positive, false negative) to be pooled with a bivariate random-effects model and hierarchical summary receiver-operating characteristic model. Considering the importance of excluding individuals with a low likelihood of T2DM from diagnostic blood testing, we especially focused on specificity and LR-. RESULTS: Eighteen eligible studies consisting of 184,011 participants and 7038 cases were identified. The pooled estimates (95% confidence interval) were as follows: sensitivity=0.73 (0.66-0.79), specificity=0.66 (0.59-0.73), LR+=2.13 (1.81-2.50), and LR-=0.41 (0.34-0.50). CONCLUSIONS: Nonblood-based assessment of risk of T2DM could produce acceptable results although the feasibility of such a screener needs to be determined in future studies.

Synthesis and Molecular Structure of a Water-Soluble, Dimeric Tri-Titanium(IV)-Substituted Wells-Dawson Polyoxometalate Containing Two Bridging (C5Me5)Rh2+ Groups.

A novel trititanium(IV)-substituted Wells-Dawson polyoxometalate (POM)-based organometallic complex, i.e., a dimeric POM containing two bridging Cp*Rh(2+) groups (Cp* = C5Me5) or [{α-P2W15Ti3O60(OH)2}2(Cp*Rh)2](16-) (D-1) with Ci symmetry, was synthesized in an analytically pure form by a 1:2 -molar ratio reaction of the organometallic precursor [Cp*RhCl2]2 with the separately prepared, monomeric trititanium(IV)-substituted Wells-Dawson POM, "[P2W15Ti3O59(OH)3](9-)" (M-1). The crystalline sample (NaK-D-1) of the water-soluble, mixed sodium/potassium salt of D-1 was obtained in the 14.7% yield, which has been characterized by complete elemental analysis, TG/DTA, FTIR, single-crystal X-ray structure analysis, and solution ((183)W, (31)P, (1)H and (13)C{(1)H}) NMR spectroscopy. Single-crystal X-ray structure analysis revealed that the two species of the protonated Wells-Dawson subunits, "[P2W15Ti3O60(OH)2](10-)" were bridged by the two Cp*Rh(2+) groups, resulting in the an overall Ci symmetry. The Cp*Rh(2+) groups were linked to the two terminal oxygen atoms of the titanium(IV) sites and one edge-sharing oxygen atom of the surface Ti-O-Ti bond. The (183)W NMR of D-1 dissolved in D2O showed that its solution structure was represented as a dimeric POM with a formula of [{α-P2W15Ti3O60(OH)3}2{Cp*Rh(OH)}2](16-) (D-2) with Ci (or S2) symmetry. A trititanium(IV)-substituted Wells-Dawson POM-supported organometallic complex has never been reported so far, and thus D-1 in the solid state and D-2 in solution are the first example of this type of complex.

Contribution of impaired myofibril and ryanodine receptor function to prolonged low-frequency force depression after in situ stimulation in rat skeletal muscle.

The aim of this study was to examine whether prolonged low-frequency force depression (PLFFD) that occurs in situ is the result of decreased myofibrillar Ca(2+) sensitivity and/or reduced sarcoplasmic reticulum (SR) Ca(2+) release. Intact rat gastrocnemius muscles were electrically stimulated via the sciatic nerve until force was reduced to ~50% of the initial and dissected 30 min following the cessation of stimulation. Skinned fibre and whole muscle analyses were performed in the superficial region composed exclusively of type IIB fibres. Fatiguing stimulation significantly reduced the ratio of force at low frequency to that at high frequency to 65% in skinned fibres (1 vs. 50 Hz) and 73% in whole muscles (20 vs. 100 Hz). In order to evaluate changes in myofibrillar Ca(2+) sensitivity and ryanodine receptor caffeine sensitivity, skinned fibres were activated in Ca(2+)- and caffeine-containing solutions, respectively. Skinned fibres from fatigued muscles displayed decreased caffeine sensitivity together with increased myofibrillar Ca(2+) sensitivity. Treatment with 2,2'-dithiodipyridine and reduced glutathione induced a smaller increase in myofibrillar Ca(2+)sensitivity in fatigued than in rested fibres. In fatigued muscles, S-glutathionylation of troponin I was increased and submaximal SR Ca(2+) release, induced by 4-chloro-m-cresol, was decreased. These findings suggest that in the early stage of PLFFD that occurs in fast-twitch muscles of exercising animals and humans, S-glutathionylation of troponin I may attenuate PLFFD by increasing myofibrillar Ca(2+) sensitivity and that under such a circumstance, PLFFD may be ascribable to failure of SR Ca(2+) release.

Three calpain isoforms are autolyzed in rat fast-twitch muscle after eccentric contractions.

The present study investigated changes in autolysis of three calpain isoforms in skeletal muscles undergoing eccentric contractions (ECC), leading to prolonged force deficits. Rat extensor digitorum longus and tibialis anterior muscles were exposed to 200-repeated ECC in situ, excised immediately after or 3 or 6 days after cessation of ECC, and used for measures of force output and for biochemical analyses. Full restoration of tetanic force in ECC-treated muscles was not attained until 6 days of recovery. Maximal calpain activity determined by a fluorogenic substrate was unaltered immediately after ECC, but increased to 313 and 450 % after 3 and 6 days, respectively. Increases in the amount of autolyzed calpain-3 were apparent immediately and developed progressively with recovery time, whereas elevations of autolyzed µ- and m-calpain occurred after 3 and 6 days, respectively. The protein content was augmented only in m-calpain. It is suggested that the three calpain isoforms may be involved in the dismantling, repair, remodeling and/or regeneration processes in ECC-treated muscles.

Meta-analysis of the quantitative relation between pulse pressure and mean arterial pressure and cardiovascular risk in patients with diabetes mellitus.

Results of epidemiologic studies that investigated the significance of pulse pressure (PP) and mean arterial pressure (MAP) in terms of risk of cardiovascular disease (CVD) in patients with diabetes mellitus are inconsistent. We performed a quantitative meta-analysis to estimate CVD risk in relation to PP or MAP. Electronic literature search was conducted for prospective studies providing data on CVD risk for an increment in baseline MAP or PP in patients with diabetes mellitus. The pooled CVD risk for a 10-mm Hg increase in each blood pressure (BP) index was estimated with a random-effects model. There were 17 eligible studies consisting of 52,647 patients and 5,112 CVD cases. The pooled relative risk (95% confidence interval) of CVD for an increment of 10 mm Hg was 1.10 (1.04 to 1.16) for PP and 1.09 (0.98 to 1.21) for MAP. Significant between-study heterogeneity was observed (I(2) [p value]; 76.5% [p <0.001] for PP, 67.8% [p = 0.005] for MAP). In studies concurrently investigating CVD risk for the 4 indexes (i.e., PP, MAP, systolic BP, and diastolic BP), the pooled relative risk (95% confidence interval) was 1.17 (1.09 to 1.26) for PP, 1.11 (1.06 to 1.15) for MAP, 1.14 (1.06 to 1.22) for systolic BP, and 1.06 (0.94 to 1.19) for diastolic BP. In conclusion, the current meta-analysis suggested that PP was the strongest indicator among the 4 commonly used BP indexes. However, the large heterogeneity urged cautious interpretation of the study results.

Two types of tetranuclear phosphanegold(I) cations as dimers of dinuclear units, [{(Au{P(p-RPh)3})2(µ-OH)}2]2+ (R = Me, F), synthesized by polyoxometalate-mediated clusterization.

Novel intercluster compounds [{(Au{P(p-RPh)3})2(µ-OH)}2]3[α-PM12O40]2·nEtOH (R = Me, M = W for 1; R = Me, M = Mo for 2; R = F, M = Mo for 3) were synthesized by the polyoxometalate (POM)-mediated clusterization of monomeric phosphanegold(I) complexes, and unequivocally characterized by elemental analysis, TG/DTA, FTIR, X-ray crystallography, and (1)H and (31)P{(1)H} NMR. In each cluster cation, two digold(I) units, {Au{P(p-RPh)3})2(µ-OH)}(+), dimerized to form the tetragold(I) cluster cation by interdimer aurophilic interactions, i.e., a dimer of dinuclear units, and these cations showed different forms of structural dimerization, i.e., a crossed-edge arrangement for 1 and 2 and a parallel-edge arrangement for 3, depending upon the substituent on the aryl group of triarylphosphanes. The dimerization of digold(I) cations was affected by not only the type of the POMs, but also the phosphane ligand of the monomeric phosphanegold(I) precursors.