Retrospective Study of IDegLira, a New Fixed-Ratio Combination, in Japanese Patients With Type 2 Diabetes Mellitus: Analysis of Background Factors Affecting Effectiveness After 6 Months of Treatment.

Background: The aim of the study was to provide real-world data on the effectiveness and safety of a new fixed-ratio combination, insulin degludec/liraglutide (IDegLira) injection in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: The primary endpoint was the change in glycated hemoglobin (HbA1c) level 6 months after the introduction of IDegLira. We also examined the rate of achievement of target HbA1c 7% and the individualized HbA1c targets set for each patient. Baseline characteristics associated with the change in HbA1c were also assessed. Seventy-five patients with T2DM were included in the analysis. Results: After the initiation of IDegLira, HbA1c decreased significantly from baseline with a change of -1.81% (baseline 9.61% and at 6 months 7.80%; P < 0.001). At baseline, the achievement rate of 7% HbA1c was 2.67% (n = 2), which increased to 36.0% (n = 27) after 6 months of IDegLira introduction (P < 0.05). The attainment rate of individualized HbA1c targets, which were set considering each patient's characteristics, improved from 2.67% (n = 2) to 49.3% (n = 37) (P < 0.001). Regardless of sex, body mass index, estimated glomerular filtration rate, duration of diabetes, or history of glucagon-like peptide-1 receptor agonist use, IDegLira significantly reduced HbA1c, but a higher C-peptide index was associated with a greater reduction in HbA1c. Conclusion: In this study, initiation of IDegLira in a real-world clinical setting was beneficial in lowering HbA1c in Japanese T2DM patients with inadequate glycemic control with existing therapy.

Retrospective Analysis of the Effectiveness of Oral Semaglutide in Type 2 Diabetes Mellitus and Its Effect on Cardiometabolic Parameters in Japanese Clinical Settings.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have a more potent glycated hemoglobin (HbA1c)-lowering effect than existing therapies and are widely used for treating type 2 diabetes mellitus (T2DM). Once-daily oral semaglutide is the world's first oral GLP-1RA. This study aimed to provide real-world data on oral semaglutide in Japanese patients with T2DM and its effects on cardiometabolic parameters. This was a single-center retrospective observational study. We examined changes in HbA1c and body weight (BW) and the rate of achieving HbA1c < 7% after 6 months of oral semaglutide treatment in Japanese patients with T2DM. Furthermore, we examined differences in the efficacy of oral semaglutide with multiple patient backgrounds. A total of 88 patients were included in this study. Overall, the mean (standard error of the mean) HbA1c at 6 months decreased by -1.24% (0.20%) from baseline, and BW at 6 months (n = 85) also decreased by -1.44 kg (0.26 kg) from baseline. The percentage of patients who achieved HbA1c < 7% changed significantly from 14% at baseline to 48%. HbA1c decreased from baseline regardless of age, sex, body mass index, chronic kidney disease, or diabetes duration. Additionally, alanine aminotransferase, total cholesterol, triglyceride, and non-high-density lipoprotein cholesterol were significantly reduced from baseline. Oral semaglutide may be an effective option for the intensification of therapy in Japanese patients with T2DM who have inadequate glycemic control with existing therapy. It may also reduce BW and improve cardiometabolic parameters.

Knockdown of D-dopachrome Tautomerase Inhibits Cell Proliferation in Human HepG2 Cell Line.

BACKGROUND/AIM: D-dopachrome tautomerase (DDT) is a macrophage migration inhibitory factor (MIF) homolog that promotes cell growth via CD74, a MIF cell surface receptor, in some types of tumors. We previously found that DDT acts as an anti-obesity adipokine independent of MIF. To understand the intrinsic properties of these two cytokines, a comparison of their actions in various tissues is necessary. In this study, we investigated the involvement of DDT in HepG2 cell (a human hepatoma cell line) proliferation, which is known to be promoted by MIF. MATERIALS AND METHODS: Cell proliferation and gene expression were evaluated in HepG2 cells expressing short hairpin RNA against the DDT gene. RESULTS: Inhibition of cell proliferation and reduced expression levels of cyclin D1 were observed in DDT-knockdown HepG2 cells. The inhibited proliferation was restored by administration of recombinant DDT. CONCLUSION: DDT promotes cell proliferation in HepG2 cells; therefore, its action may be similar to that of MIF.

Factors associated with functional rehabilitation outcomes of non-operative treatment for hip fractures: a retrospective study.

[Purpose] Limited data are available regarding the outcomes of non-operative treatment for hip fractures. We investigated the factors associated with functional rehabilitation outcomes in patients undergoing non-operative treatment for hip fractures. [Participants and Methods] We investigated 57 patients with hip fractures who underwent non-operative treatment. We retrospectively analyzed medical or rehabilitation outcomes and functional outcomes (assessed using the Functional Independence Measure tool). We examined the association between functional outcomes and other factors and compared the medical and rehabilitation outcomes between mobile and immobile patients at the time of discharge. [Results] Of the 57 patients investigated, 15 (26.3%) were mobile at discharge. We observed a significant association between the Functional Independence Measure subscores (Motor and Cognitive) and serum albumin levels. Serum albumin levels and the Functional Independence Measure subscores (Motor and Cognitive) were significantly higher in mobile than in immobile patients. [Conclusion] We observed that functional outcomes at discharge in patients undergoing non-operative treatment for hip fractures were associated with serum albumin ratios and the Functional Independence Measure-Cognitive score.

Autophagy inhibitors regulate TRAIL sensitivity in human malignant cells by targeting the mitochondrial network and calcium dynamics.

In a variety of cancer cell types, the pharmacological and genetic blockade of autophagy increases apoptosis induced by various anticancer drugs. These observations suggest that autophagy counteracts drug­induced apoptosis. We previously reported that in human melanoma and osteosarcoma cells, autophagy inhibitors, such as 3­methyladenine and chloroquine increased the sensitivity to apoptosis induced by tumor necrosis factor­related apoptosis­inducing ligand (TRAIL). In the present study, we report that different autophagy inhibitors regulate the mitochondrial network and calcium (Ca2+) dynamics in these cells. We found that compared to tumor cells, normal fibroblasts were more resistant to the cytotoxicity of TRAIL and autophagy inhibitors used either alone or in combination. Notably, TRAIL increased the autophagic flux in the tumor cells, but not in the fibroblasts. Live­cell imaging revealed that in tumor cells, TRAIL evoked modest mitochondrial fragmentation, while subtoxic concentrations of the autophagy inhibitors led to mitochondrial fusion. Co­treatment with TRAIL and subtoxic concentrations of the autophagy inhibitors resulted in severe mitochondrial fragmentation, swelling and clustering, similar to what was observed with autophagy inhibitors at toxic concentrations. The enhanced aberration of the mitochondrial network was preceded by a reduction in mitochondrial Ca2+ loading and store­operated Ca2+ entry. On the whole, the findings of this study indicate that co­treatment with TRAIL and autophagy inhibitors leads to increased mitochondrial Ca2+ and network dysfunction in a tumor­selective manner. Therefore, the co­administration of TRAIL and autophagy inhibitors may prove to be a promising tumor­targeting approach for the treatment of TRAIL­resistant cancer cells.

Four new resin glycosides, murasakimasarins I-IV, from the tuber of Ipomoea batatas.

Four new resin glycosides having macrolactone structures (jalapins), murasakimasarins I-IV, were isolated from the tubers of Ipomoea batatas (L.) Lam. ('Murasakimasari', Convolvulaceae), along with three known glycosides. Their structures were determined on the basis of spectroscopic data as well as chemical evidence. Murasakimasarin III is the first representative of a resin glycoside with 10-methylundecanoic acid as the component organic acid.

Plasma-stimulated medium kills TRAIL-resistant human malignant cells by promoting caspase-independent cell death via membrane potential and calcium dynamics modulation.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cold plasma-stimulated medium (PSM) have been shown to exhibit tumor-selective cytotoxicity and have emerged as promising new tools for cancer treatment. However, to date, at least to the best of our knowledge, no data are available as to which substance is more potent in killing cancer cells. Thus, in this study, we systematically compared their abilities to kill human malignant cells from different origins. We found that PSM dose-dependently killed TRAIL-resistant melanoma, osteosarcoma and neuroblastoma cells. Moreover, PSM had little cytotoxicity toward osteoblasts. PSM was more potent than TRAIL in inducing caspase-3/7 activation, mitochondrial network aberration and caspase-independent cell death. We also found that PSM was more potent in inducing plasma membrane depolarization (PMD) and disrupting endoplasmic-mitochondrial Ca2+ homeostasis. Moreover, persistent PMD was caused by different membrane-depolarizing agents; the use of the anti-type II diabetes drug, glibenclamide, alone caused mitochondrial fragmentation and enhanced TRAIL-induced Ca2+ modulation, mitochondrial network abnormalities and caspase-independent cell killing. These results demonstrate that PSM has a therapeutic advantage over TRAIL owing to its greater capacity to evoke caspase-independent cell death via mitochondrial network aberration by disrupting membrane potential and Ca2+ homeostasis. These findings may provide a strong rationale for developing PSM as a novel approach for the treatment of TRAIL-resistant malignant cells.

Effects of high ß-glucan barley on visceral fat obesity in Japanese individuals: A randomized, double-blind study.

OBJECTIVE: The aim of this study was to investigate whether a diet in which high ß-glucan barley was substituted for rice would reduce visceral fat obesity in Japanese individuals. METHODS: A randomized, double-blind, placebo-controlled intervention study was conducted with 100 Japanese individuals with waist circumference (WC) ≥85 cm for men or ≥90 cm for women and body mass index (BMI) ≥24 kg/m2. Participants were randomly assigned to consume a mixture of rice and either high ß-glucan barley (test group, 4.4 g/d) or ß-glucan-free barley (placebo group) for 12 wk. Blood samples and computed tomography scans were obtained before and after the trial. RESULTS: Both groups showed decreases in body weight and BMI, and these changes were significantly greater in the test group. WC and visceral fat area (VFA) significantly decreased in both groups (VFA: -10.7 cm2 in the test group; -6.8 cm2 in the placebo group). These changes did not differ significantly between the groups. However, a subgroup analysis of participants with VFA ≥100 cm2 showed a significant decrease in the test group, and this decrease was significantly greater than in the placebo group. CONCLUSIONS: The intake of high ß-glucan barley led to significant and safe reductions in VFA, body weight, BMI, and WC in individuals with visceral fat obesity with VFA ≥100 cm2. Barley high in ß-glucan may contribute to preventing visceral fat obesity.

Effect of waxy barley, Kirarimochi, consumption on bowel movements of late-stage elderly residents at Roken nursing home.

BACKGROUND: It is very important for the late-stage elderly to have the least stressful bowel movements for maintaining a good quality of life. It is generally accepted that consuming adequate dietary fiber is a promising method for the prevention and management of stressful bowel movements such as those during constipation. Therefore, we examined the effect of long-term consumption of waxy barley, which is high in dietary fiber, on the bowel movements of the late-stage elderly living at Roken nursing home (a geriatric health services facility), Japan. METHODS: We compared the defecation and laxative administration frequencies of the subjects before and after waxy barley consumption, for which we served 28 residents a boiled mixture of rice and waxy barley (variety name, Kirarimochi) as the main meals for 5 months, from November to March. In October, all residents were served boiled rice as the main meals. RESULTS: The residents were categorized into "constipated" subjects and "non-constipated" subjects according to their weekly defecation frequency during October. Among the 14 residents categorized as constipated subjects, monthly number of days with defecation in November, January, and March significantly increased in comparison to monthly number of days with defecation in October. In addition, monthly number of days with laxative administration significantly decreased in December and February in comparison to monthly number of days with laxative administration in October. In contrast, the defecation and laxative administration frequencies did not change after waxy barley consumption among the 14 residents categorized as non-constipated subjects. CONCLUSIONS: Consumption of waxy barley, Kirarimochi, for 5 months improved the bowel movements of the constipated subjects; however, the consumption had no effect on the bowel movements of the non-constipated subjects at Roken nursing home. These results indicate that consuming waxy barley, Kirarimochi, is beneficial for the management of constipation in the late-stage elderly residents at Roken nursing home.

Dermoscopic features of small size pigmented basal cell carcinomas.

Dermoscopic images of histologically proven pigmented basal cell carcinomas (BCC) were retrospectively assessed to compare the dermoscopic features of BCC of 3 mm or less in diameter (n = 6) with BCC of 4-6 mm in diameter (n = 11). All lesions lacked the presence of a pigment network. BCC with a diameter of 3 mm or less had fewer positive dermoscopic features compared with the 4-6 mm in diameter BCC. Multiple blue-gray globules and large blue-gray ovoid nests were frequently present. Dermoscopy is a useful tool for early diagnosis of pigmented BCC, even when they are small.

Ion transport in mesoporous silica SBA-16 thin films with 3D cubic structures.

Mesoporous silica SBA-16 thin films with highly ordered 3D cubic structures were synthesized on a Si substrate via the dip-coating method. After these films were filled with KCl aqueous solutions, the ionic current passing through the mesopores was measured by applying dc electric fields. At low ion concentrations, the measured I-V curves were nonlinear and the current increased exponentially with respect to voltage. As the ion concentration increased, the I-V curve approached linear behavior. The nonlinear behavior of I-V curves can be reasonably attributed to the electric potential barrier created in nanopores.

A barley Hordoindoline mutation resulted in an increase in grain hardness.

Barley seed proteins, Hordoindolines, are homologues of wheat Puroindolines, which are associated with grain hardness. Barley Hordoindoline genes are known to comprise Hina and Hinb, and Hinb consists of two Hinb genes, Hinb-1 and Hinb-2. Two types of allele were found for Hina, Hinb-1 and Hinb-2 genes, respectively, among Japanese two- and six-rowed barley lines. One of the alleles of Hinb-2 (Hinb-2b) had a frame-shift mutation resulting in an in-frame stop codon. For two-rowed barley lines, grain hardness was significantly higher among lines with the Hinb-2b than those with the wild type Hinb-2 gene (Hinb-2a). Protein spots corresponding to HINa, HINb-1, and HINb-2 were identified by 2D-gel electrophoresis among barley lines with Hinb-2a. Among the lines with Hinb-2b, HINa and HINb-1 were expressed at similar levels as those in the wild type, but HINb-2 was not detected. A DNA (cleaved amplified polymorphic sequence) marker was developed to distinguish between the Hinb-2a and Hinb-2b gene sequences. Analysis of grain hardness among F(2) lines derived from a cross between a line with Hinb-2a (Shikoku hadaka 115) and a line with the Hinb-2b (Shikoku hadaka 84) showed significantly higher grain hardness in the mutant lines. From these results, the Hinb-2b frame-shift (null) mutation might play a critical role in barley grain hardness. The DNA marker will be useful in barley breeding to select lines having harder grain texture.

Grid-based energy density analysis: implementation and assessment.

Grid-based energy density analysis (grid-EDA) that decomposes the total energy into atomic energies by a space-partitioning function is proposed. The kinetic energy, nuclear attraction, and exchange-correlation functional are evaluated on grid points and are split into atomic contributions. To reduce numerical errors in the conventional scheme of numerical integration, the electronic Coulomb and HF exchange interactions are evaluated by the pseudospectral method, which was first applied to an ab initio method by Friesner [Chem. Phys. Lett. 116, 39 (1985)], and are decomposed into atomic contributions. Grid-EDA using the pseudospectral method succeeds in ensuring less than 1 kcalmol error in total energies for small molecules and providing reliable atomic energy contributions for the problematic lithium cluster, which exhibits a strong basis-set dependence for Mulliken-type EDA. Also, site-dependent atomization energies are estimated by grid-EDA for cluster models such as Li(48), C(41)H(60), and Mg(32)O(32). Grid-EDA reveals that these models imitate crystal environments reasonably because atomization energies estimated from the inner atoms of the models are close to the experimental cohesive energies.