Studies of Alzheimer's disease (AD) strongly support the hypothesis that amyloid-β (Aβ) deposition in the brain is the initiating event in the progression of AD. Aβ peptides easily form long ...insoluble amyloid fibrils, which accumulate in deposits known as senile plaques. On the other hand, recent work indicated that soluble Aβ oligomers, rather than monomers or insoluble Aβ fibrils, might be responsible for neuronal and synaptic dysfunction in AD. Curcumin, a low molecular weight yellow-orange pigment derived from the turmeric plant, has shown therapeutic effects in transgenic mouse models of AD. However, it remains unclear whether curcumin interacts directly with the Aβ oligomers. This study investigated any interaction between curcumin and Aβ oligomers such as globulomer and Aβ-derived diffusible ligand (ADDL). Globulomer was observed as a cluster of spherical structures by electron microscopic analysis, and ADDL was also detected as small spherical structures. Fluorescence analysis revealed a significant increase in the fluorescence of curcumin when reacted with both oligomers. Furthermore quartz crystal microbalance analysis showed significant frequency decreases in oligomer-immobilized electrodes following the addition of curcumin. These results strongly suggested that curcumin binds to Aβ oligomers and to Aβ fibrils. The association of curcumin with Aβ oligomers may contribute to the therapeutic effect on AD. Based on these findings, curcumin could provide the basis of a novel concept in AD therapies targeting Aβ oligomers.
Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its ...potential contributions to early diagnosis and monitoring of disease progress. Fluorine‐19 magnetic resonance imaging (19F‐MRI) may be extremely useful for tau imaging once a high‐quality probe has been formulated. In this investigation, a novel fluorine‐19–labeling compound has been developed as a probe for tau imaging using 19F‐MRI. This compound is a buta‐1,3‐diene derivative with a polyethylene glycol side chain bearing a CF3 group and is known as Shiga‐X35. Female rTg4510 mice (a mouse model of tauopathy) and wild‐type mice were intravenously injected with Shiga‐X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0‐T horizontal‐bore magnetic resonance scanner. The 19F‐MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine‐19 magnetic resonance signal in the rTg4510 mice compared with the wild‐type mice. Histological analysis showed fluorescent signals of Shiga‐X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that 19F‐MRI using Shiga‐X35 could be a promising tool to evaluate tau pathology in the brain.
We have synthesized a buta‐1,3‐diene derivative Shiga‐X35. In vivo MRI with a 7‐T MR scanner successfully detected significant 19F‐MR signals in the brain of a tauopathy mouse model after the injection of Shiga‐X35. 19F‐MRI using Shiga‐X35 represents a promising approach to evaluating tau pathology in the brain.
OBJECTIVE
To investigate the relationship between fasting insulin levels and metabolic risk factors (MRFs) in type 2 diabetic patients at the first clinic/hospital visit in Japan over the years 2000 ...to 2009.
RESEARCH DESIGN AND METHODS
In total, 4,798 drug-naive Japanese patients with type 2 diabetes were registered on their first clinic/hospital visits. Conventional clinical factors and fasting insulin levels were observed at baseline within the Japan Diabetes Clinical Data Management (JDDM) study between consecutive 2-year groups. Multiple linear regression analysis was performed using a model in which the dependent variable was fasting insulin values using various clinical explanatory variables.
RESULTS
Fasting insulin levels were found to be decreasing from 2000 to 2009. Multiple linear regression analysis with the fasting insulin levels as the dependent variable showed that waist circumference (WC), BMI, mean blood pressure, triglycerides, and HDL cholesterol were significant, with WC and BMI as the main factors. ANCOVA after adjustment for age and fasting plasma glucose clearly shows the decreasing trend in fasting insulin levels and the increasing trend in BMI.
CONCLUSIONS
During the 10-year observation period, the decreasing trend in fasting insulin was related to the slight increase in WC/BMI in type 2 diabetes. Low pancreatic β-cell reserve on top of a lifestyle background might be dependent on an increase in MRFs.
Aims/Introduction
To investigate the current status of achieved blood pressure levels in association with the number of antihypertensive drug classes as of 2013, and to explore the clinical ...correlates with achievement of target blood pressure in a large‐scale cohort of Japanese individuals with type 2 diabetes.
Materials and Methods
A nationwide survey was carried out including 12,811 individuals with type 2 diabetes. Participants were divided by achieved blood pressure, <130/80 or 140/90 mmHg, and the number of drug classes taken.
Results
The percentages achieving a blood pressure of <130/80 or 140/90 mmHg were 52.0% and 86.1%, respectively. The prevalence of hypertension, if defined as ≥130/80 mmHg or treated, became 67.9%. Among participants taking antihypertensive drugs, a blood pressure of <130/80 or <140/90 mmHg was 46.7% and 83.2%, respectively. The percentages of <130/80 mmHg were 55.9% without drugs, 47.1% on one drug, 42.5% on two drugs, 47.2% on three drugs and 56.8% on four or more drugs, respectively. The most prescribed drugs were renin–angiotensin system inhibitors, followed by calcium channel blockers, diuretics and beta‐blockers. The multiple logistic regression analysis showed that a blood pressure <130/80 mmHg was associated with lower values in age, body mass index, albuminuria and glomerular filtration rate, higher proportions on targets for glycosylated hemoglobin A1c and lipids, and less retinopathy.
Conclusions
In type 2 diabetes, hypertension is common, and just 52% achieved <130/80 mmHg, indicating a difficulty in blood pressure lowering. This was correlated with difficulties in glycemic and lipid management, obesity, and vascular complications, implying this clustering to be a serious problem.
A nationwide large‐scale survey was performed to investigate the current status of achieved blood pressure levels in association with the number of antihypertensive drugs. The percentages achieving a blood pressure of <130/80 or 140/90 mmHg were 52.0% and 86.1%, respectively. A difficulty in blood pressure lowering was correlated with difficulties in glycemic and lipid management, obesity, and vascular complications, implying these clustering to be a serious problem.
IntroductionWe investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with ...type 2 diabetes.Research design and methodsA serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model.ResultsThe proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin.ConclusionsDuring the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care.
Fluorine-19 magnetic resonance imaging (19F MRI) could be a promising approach for imaging amyloid deposition in the brain. However, the required features of a 19F MRI probe for amyloid detection ...remain unclear. In the present study, we investigated a series of compounds as potent 19F probes that could prevent the reduction in MR signal when bound to amyloid plaques in the brain. Each compound consists of styrylbenzoxazole as a core structure linked by a different length of polyethylene glycol (PEG) chain to one of three types of fluorine-labeled group: a trifluoroethoxy group, a hexafluoroisopropoxy group, or a 3',5'-bis(trifluoromethyl)benzylamino group. Among these compounds, 6-(3',6',9',15',18',21'-heptaoxa-23',23',23'-trifluoro tricosanyloxy)-2-(4'-dimethylaminostyryl)benzoxazole compound 3b (m = 6), which has a trifluoroethoxy group with seven ethylene glycol groups in the PEG chain, showed significant 19F MR signals in the brains of AβPPswe/PS1dE9 double-transgenic mice, but not wild-type mice. This suggested that compound 3b (m = 6) could be a useful 19F MRI probe for amyloid detection. Furthermore, this study identified the most effective length of PEG chain between the fluorine-labeled group and the core structure to ensure a strong MR signal when the probe is bound to amyloid plaques.
Introduction
The present study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes.
Materials and Methods
This ...was a randomized, single‐center, double‐blind, two‐period, crossover, multiple‐dose trial. Patients were randomized into two treatment sequences, and received IDeg or insulin detemir for 6 days and a washout period (7–21 days) before switching treatment. Blood samples for pharmacokinetic measurements were obtained before each dose and up to 120 h after the last dose of each treatment period. Pharmacodynamic measurements were obtained using a 26‐h euglycemic clamp procedure after the last dose of each treatment period.
Results
A total of 22 patients were randomized (14 men, 8 women; mean glycosylated hemoglobin at baseline of 7.5% based on Japanese Diabetes Society value). At steady state, total glucose‐lowering effect (area under the glucose infusion rate GIR curve during one dosing interval τ, 0–24 h at steady state AUCGIR,τ,SS) was 1,446 mg/kg and total exposure (geometric mean) of IDeg (AUCIDeg,τ,SS) was 81,270 pmol h/L. Both the glucose‐lowering effect and the exposure of IDeg were evenly distributed over the dosing interval, with AUC for the first 12‐h intervals being approximately 50% of the total (geometric mean; AUCGIR,0–12h,SS/AUCGIR,τ,SS = 48%; AUCIDeg,0–12h,SS/AUCIDeg,τ,SS = 53%).
Conclusions
IDeg has a flat, consistent and ultra‐long glucose‐lowering effect that is evenly distributed across a 24‐h interval and an ultra‐long duration of action in Japanese patients with type 1 diabetes. These data support once‐daily dosing of IDeg in all patients. Overall, the pharmacodynamic and pharmacokinetic end‐points and safety observations are consistent with those previously reported in Caucasian patients.
This study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes mellitus (T1DM). Patients were randomized into two treatment sequences and received IDeg or insulin detemir (IDet) for 6 days and a washout period (7–21 days) before switching treatment. IDeg has a flat, consistent and ultra‐long glucose‐lowering effect that is evenly distributed across a 24‐h interval and an ultra‐long duration of action in Japanese patients with type 1 diabetes mellitus; overall, the pharmacodynamic and pharmacokinetic endpoints and safety observations are consistent with those previously reported in Caucasian patients.
Poly(
l-lactic acid) (PLLA) was hydrolyzed using microwave irradiation, and yields of the resultant lactic acid and reaction time were compared with those obtained by conventional heating. In both ...cases, the reaction temperature was maintained at 170 °C and the weight ratio of PLLA:H
2O was 3:1. Under conventional heating, the lactic acid yield reached saturation after 800 min at 45%, whereas only 120 min was required to reach the same yield level under microwave irradiation. The optical purity under conventional heating decreased with hydrolysis of the PLLA and dropped to 94%ee when the lactic acid yield reached at 45%. Under microwave irradiation, however, the optical purity decreased only after the equilibrium state of hydrolysis was attained. Therefore, to maintain the optical purity at 98%ee, it was necessary to stop microwave irradiation when the lactic acid yield reached 45%.
Mechanical reinforcement of environmentally friendly composite, composed of kenaf fibers as reinforcement and poly-
l-lactic acid (PLLA) resin as matrix, was investigated. The stress on the ...incorporated fibers in the composite under transverse load was monitored in situ and non-destructively using X-ray diffraction. The outer applied stress was found to be well transferred to the incorporated kenaf fibers through the PLLA matrix, which suggests a strong interaction between the fiber and the matrix. In addition, it was also revealed that a silane-coupling treatment to the kenaf fiber was effective for the improvement of interfacial adhesion.
Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be ...preferable for patients. To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study. The present study was performed on 928 patients with T2DM who started insulin therapy in 2007. Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin. Of the 928 patients, 37 had stopped insulin therapy within 1 year. In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin. In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan. Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan.
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