Aim
To assess the efficacy, safety and tolerability of different doses of tofogliflozin, a novel, highly selective sodium‐glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes ...mellitus (T2DM).
Methods
In a 12‐week, multicentre, multinational, randomized, double‐blind, parallel‐group, placebo‐controlled, dose‐finding study, patients with inadequate glycaemic control from diet and exercise alone, or from diet and exercise plus a stable dose of metformin, were randomized to one of five doses of tofogliflozin (2.5, 5, 10, 20, or 40 mg) or placebo. The primary efficacy endpoint was absolute change at week 12 from baseline in glycated haemoglobin (HbA1c), minus the change in the placebo group.
Results
Statistically significant dose‐dependent reductions in HbA1c were shown in all treated groups except the 2.5‐mg dose group, with a maximum reduction of 0.56% (placebo‐subtracted) at the 40‐mg dose, along with increased urinary glucose excretion. Metformin treatment had no substantial influence on tofogliflozin efficacy. Dose‐dependent reductions in fasting plasma glucose and body weight were observed, and glucose intolerance was improved, with a trend towards blood pressure reduction. Slight increases were observed for mean ketone bodies with no abnormal change in ketone body ratio. No deaths or treatment‐related serious adverse events were reported. The incidence of adverse events was similar in the placebo (37.9%) to that in the tofogliflozin group (35.9–46.3%). Withdrawal because of adverse events was rare (≤2 patients per treatment group), with similar rates of withdrawal in the placebo and tofogliflozin groups.
Conclusions
A once‐daily dose of tofogliflozin for 12 weeks was an effective, safe and well‐tolerated treatment for T2DM.
Structural phase separation in AxFe2-ySe2 system has been studied by different experimental techniques, however, it should be important to know how the electronic uniformity is influenced, on which ...length scale the electronic phases coexist, and what is their spatial distribution. Here, we have used novel scanning photoelectron microscopy (SPEM) to study the electronic phase separation in KxFe2-ySe2, providing a direct measurement of the topological spatial distribution of the different electronic phases. The SPEM results reveal a peculiar interconnected conducting filamentary phase that is embedded in the insulating texture. The filamentary structure with a particular topological geometry could be important for the high Tc superconductivity in the presence of a phase with a large magnetic moment in AxFe2-ySe2 materials.
Nosocomial infections by respiratory viruses undetected by rapid tests are not often diagnosed. For paediatric patients with background diseases, nosocomial infection could be fatal.
To determine the ...relationship between developing symptoms by respiratory viruses undetectable by rapid tests and respiratory risks and to improve the management of infection control.
Two episodes of nosocomial infection by human bocavirus (HBoV) and human rhinovirus (HRV) were retrospectively investigated in a tertiary hospital paediatric ward in Japan. Viruses were identified by polymerase chain reaction to determine infection control management. When viruses of the same species were detected from different patients, the virus homology was investigated. The relationship between respiratory risks and developing symptoms was statistically investigated.
Three and four patients with respiratory risks in the HBoV and HRV outbreaks, respectively, developed respiratory symptoms. The nucleotide sequences of two patients in the HBoV outbreak and all four patients in the HRV outbreak were phylogenetically close. In both outbreaks, the patients with respiratory risks developed significantly more symptoms than those without any risk (P = 0.035 and 0.018, respectively). After the patients with respiratory infection were separated from those with respiratory risks, no additional nosocomial infection occurred.
Patients with respiratory risks easily develop respiratory symptoms and acquire severe symptoms of nosocomial infection by those viruses. In a paediatric ward, we should adopt not only standard precautions but also isolation management of the patients with respiratory symptoms, even if they have negative results in rapid tests.
Amelogenins are the most abundant protein species in forming dental enamel, taken to regulate crystal shape and crystal growth. Unprotonated amelogenins can bind protons, suggesting that amelogenins ...could regulate the pH in enamel in situ. We hypothesized that without amelogenins the enamel would acidify unless ameloblasts were buffered by alternative ways. To investigate this, we measured the mineral and chloride content in incisor enamel of amelogenin-knockout (AmelX-/-) mice and determined the pH of enamel by staining with methyl-red. Ameloblasts were immunostained for anion exchanger-2 (Ae2), a transmembrane pH regulator sensitive for acid that secretes bicarbonate in exchange for chloride. The enamel of AmelX-/- mice was 10-fold thinner, mineralized in the secretory stage 1.8-fold more than wild-type enamel and containing less chloride (suggesting more bicarbonate secretion). Enamel of AmelX-/- mice stained with methyl-red contained no acidic bands in the maturation stage as seen in wild-type enamel. Secretory ameloblasts of AmelX-/- mice, but not wild-type mice, were immunopositive for Ae2, and stained more intensely in the maturation stage compared with wild-type mice. Exposure of AmelX-/- mice to fluoride enhanced the mineral content in the secretory stage, lowered chloride, and intensified Ae2 immunostaining in the enamel organ in comparison with non-fluorotic mutant teeth. The results suggest that unprotonated amelogenins may regulate the pH of forming enamel in situ. Without amelogenins, Ae2 could compensate for the pH drop associated with crystal formation.
We report magnetocaloric and magnetic-torque evidence that in Cs2CuBr4--a geometrically frustrated Heisenberg S=1/2 triangular-lattice antiferromagnet--quantum fluctuations stabilize a series of spin ...states at simple increasing fractions of the saturation magnetization Ms. Only the first of these states--at M=1/3Ms--has been theoretically predicted. We discuss how the higher fraction quantum states might arise and propose model spin arrangements. We argue that the first-order nature of the transitions into those states is due to strong lowering of the energies by quantum fluctuations, with implications for the general character of quantum phase transitions in geometrically frustrated systems.
Cytokines such as interleukins are known to be involved in the development of neuropathic pain through activation of neuroglia. However, the role of chemokine (C-C motif) ligand 1 (CCL-1), a ...well-characterized chemokine secreted by activated T cells, in the nociceptive transmission remains unclear. We found that CCL-1 was upregulated in the spinal dorsal horn after partial sciatic nerve ligation. Therefore, we examined actions of recombinant CCL-1 on behavioural pain score, synaptic transmission, glial cell function and cytokine production in the spinal dorsal horn. Here we show that CCL-1 is one of the key mediators involved in the development of neuropathic pain. Expression of CCL-1 mRNA was mainly detected in the ipsilateral dorsal root ganglion, and the expression of specific CCL-1 receptor CCR-8 was upregulated in the superficial dorsal horn. Increased expression of CCR-8 was observed not only in neurons but also in microglia and astrocytes in the ipsilateral side. Recombinant CCL-1 injected intrathecally (i.t.) to naive mice induced allodynia, which was prevented by the supplemental addition of N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Patch-clamp recordings from spinal cord slices revealed that application of CCL-1 transiently enhanced excitatory synaptic transmission in the substantia gelatinosa (lamina II). In the long term, i.t. injection of CCL-1 induced phosphorylation of NMDA receptor subunit, NR1 and NR2B, in the spinal cord. Injection of CCL-1 also upregulated mRNA level of glial cell markers and proinflammatory cytokines (IL-1β, TNF-α and IL-6). The tactile allodynia induced by nerve ligation was attenuated by prophylactic and chronic administration of neutralizing antibody against CCL-1 and by knocking down of CCR-8. Our results indicate that CCL-1 is one of the key molecules in pathogenesis, and CCL-1/CCR-8 signaling system can be a potential target for drug development in the treatment for neuropathic pain.
Tetragonal FeSe is a superconductor with a transition temperature
T
c of 8
K and shows a huge enhancement of
T
c with applying pressure. Tetragonal FeTe has a structure very analogous to ...superconducting FeSe, but does not show superconducting transition. We investigated the pressure effect of resistivity on FeTe. The resistivity at room temperature decreased with increasing pressure. An anomaly in resistivity around 80
K shifted towards a lower temperature with increasing pressure.
Previous studies on the spider mite
Eotetranychus smithi
Pritchard & Baker have shown that diapause in eggs is induced by low temperature alone and that females developed at ≤ 17.5 °C laid diapause ...eggs, regardless of the photoperiod. In this study, diapause eggs were kept at 5 °C and a photoperiod of 16L:8D for 0–120 days and then maintained at 25 °C to know the effect of chilling on diapause termination. Diapause eggs mostly hatched when they were maintained at 25 °C after chilling for 30–90 days at 5 °C, which suggests that diapause termination is favored by low temperatures. To clarify the hatching conditions after diapause termination, diapause eggs kept at 5 °C for 45 days were subsequently maintained at various constant temperatures (from 15 to 25 °C) under a long-day photoperiod (16L:8D). The hatchability at all temperatures tested was high (> 90%) and did not significantly differ among the high temperatures. Duration of embryonic development was shorter with increasing warming temperature after chilling. The lower thermal threshold (
t
) and thermal constant (
k
) for post-diapause egg development were 10.5 °C and 76.9 degree-days, respectively. Females, which developed from diapause eggs that were chilled at 5 °C for 45 days and then maintained at 15 °C, laid only non-diapause eggs, which indicates that they were prevented from re-entering diapause even under diapause-inducing conditions (15 °C). Thus, temperature is the main factor to control diapause termination and post-diapause development, which has also been found for other spider mites that enter diapause at the egg stage.
We study the magnetic-field-induced quantum phase transition from a gapped quantum phase that has no magnetic long-range order into a gapless phase in the spin-1/2 ladder compound ...bis(2,3-dimethylpyridinium) tetrabromocuprate (DIMPY). At temperatures below about 1 K, the specific heat in the gapless phase attains an asymptotic linear temperature dependence, characteristic of a Tomonaga-Luttinger liquid. Inelastic neutron scattering and the specific heat measurements in both phases are in good agreement with theoretical calculations, demonstrating that DIMPY is the first model material for an S=1/2 two-leg spin ladder in the strong-leg regime.
Loss-of-function mutations in the Ca2+ release-activated Ca2+ channel genes ORAI1 and STIM1 abolish store-operated Ca2+ entry (SOCE) and result in ectodermal dysplasia with amelogenesis imperfecta. ...However, because of the limited availability of patient tissue, analyses of enamel mineralization or possible changes in ameloblast function or morphology have not been possible. Here, we generated mice with ectodermal tissue-specific deletion of Stim1 (Stim1 cKO conditional knockout), Stim2 (Stim2 cKO), and Stim1 and Stim2 (Stim1/2 cKO) and analyzed their enamel phenotypes as compared with those of control (Stim1/2fl/fl) animals. Ablation of Stim1 and Stim1/2 but not Stim2 expression resulted in chalky enamel and severe attrition at the incisor tips and molar cusps. Stim1 and Stim1/2 cKO, but not Stim2 cKO, demonstrated inferior enamel mineralization with impaired structural integrity, whereas the shape of the teeth and enamel thickness appeared to be normal in all animals. The gene expression levels of the enamel matrix proteins Amelx and Ambn and the enamel matrix proteases Mmp20 and Klk4 were not altered by the abrogation of SOCE in Stim1/2 cKO mice. The morphology of ameloblasts during the secretory and maturation stages was not significantly altered in either the incisors or molars of the cKO animals. However, in Stim1 and Stim1/2 cKO incisors, the alternating modulation of maturation-stage ameloblasts between the smooth- and ruffle-ended cell types continued beyond the regular cycle and extended to the areas corresponding to the zone of postmodulation ameloblasts in the teeth of control animals. These results indicate that SOCE is essential for proper enamel mineralization, in which Stim1 plays a critical role during the maturation process.
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