Enhancement of ectopic osteoid formation following the dual release of bone morphogenetic protein 2 and Wnt1 inducible signaling pathway protein 1 from gelatin sponges.

Bone morphogenetic protein (BMP) 2-incorporated gelatin sponge is effective for in vivo osteoinduction. However, the modeling capacity of bone decreases with age. As atrial to stimulate effective bone formation for animals with decreased osteogenic potential, Wnt1 inducible signaling pathway protein (WISP) 1, an osteoblastic regulator, was combined with gelatin sponge incorporating BMP2. Osteopontin (Opn) geneexpression was increased in vitro for mouse bone marrow stromal cells (BMSC) cultured in gelatin sponges incorporating BMP2 and WISP1 compared with those incorporating BMP2 or WISP1 alone. In vivo synergistic effect of BMP2 and WISP1 on the ectopic osteoid formation was observed when gelatin sponges incorporating BMP2 and WISP1 were implanted subcutaneously into middle-aged mice with decreased bone formation potential. It is concluded that the scaffold incorporating multiple osteoinductive agents could be effective in inducing bone formation in those with age-related decreased potential of bone formation

A Trial on Detecting Fluctuations in Bulk Metallic Glass Beams by Strain Contrast Variation Method-Use of High Energy Small-Angle Scattering

Heterogeneity in annealed Zr-Cu-Al alloys with high ductility has been examined by high-energy small-angle scattering with strain variation method. Although the statistics is still poor for detailed analysis, it was found that the heterogeneity in the sample showed clear enhancement by applied tensile strain, and the characteristic size of the heterogeneity was of the same order of magnitude as the one observed by high resolution electron microscopy. With surface insensitivity of the present method, anomalous small-angle scattering results at Cu K absorption edge for the same sample was briefly discussed

Derivation and validation of an equation to determine the optimal ventilator setting in children undergoing intracranial revascularization surgery: A single-center retrospective study

Background: It can be difficult to determine the appropriate ventilator settings to maintain normocapnia in children undergoing general anesthesia for surgery for moyamoya disease, especially immediately following anesthesia induction. Aim: We conducted this study to attempt to derive an equation to predict the appropriate ventilator settings and subsequently validated the accuracy of the equation. Methods: A retrospective study of 91 pediatric patients less than 18 years of age who underwent cerebral revascularization for moyamoya disease at our institution. Fifty‐eight patients were used to derive the equation, and the subsequent 33 patients were used to validate the equation. We calculated the required respiratory rate to attain normocapnia based on the median of all values of the minute volume during normocapnia (estimated partial pressure of arterial carbon dioxide of 38‐42 mm Hg) and the assumption that the tidal volume was 8 mL/kg body weight. We derived the regression equation from the derivation data set where the required respiratory rate to attain normocapnia was represented by age. We simplified the equation by rounding coefficients to the nearest integer. The level of agreement between the respiratory rate predicted from the equation and the actual required respiratory rate was assessed in the validation group using Bland‐Altman analysis. Results: The derived equation is tidal volume = 8 mL/kg body weight, respiratory rate = 24‐age/min. Bland‐Altman analysis in the validation group revealed that the mean bias between the predicted and actual respiratory rate was 0.29 (standard deviation, 3.67). The percentage of cases where the predicted rate was within ± 10% and ± 20% of the actual rate was 42.4% and 66.7%, respectively. Conclusions: We derived and validated a simple and easily applicable equation to predict the ventilator settings required to attain normocapnia during general anesthesia in children with moyamoya disease

Validation of the Radford Nomogram to Estimate the Minute Volume Required to Attain Normocapnia in Patients Undergoing General Anesthesia: A Single-Center Retrospective Study

Objective: The Radford nomogram, an old mathematical chart device to estimate the required ventilation for maintaining normocapnia, remains unvalidated in patients undergoing modern, balanced anesthesia. This study aims to investigate the performance of the Radford nomogram in patients undergoing general anesthesia and derive a simple equation to estimate the minute volume required to attain normocapnia (MVnorm). Methods: This single-center retrospective study enrolled 78 patients (age ≥ 18 years) undergoing cerebral revascularization for Moyamoya disease. We defi ned MVnorm as the median of all values of the minute volume during normocapnia (estimated PaCO2: 38–42 mmHg). We examined the agreement level between the estimated minute volume using the Radford nomogram and MVnorm using the Bland–Altman analysis. Furthermore, we developed and validated a simple equation predicting MVnorm based on gender and a multiple of body weight, using a split-sample validation technique. Result: The Radford nomogram tended to overestimate MVnorm with a mean bias of 560 mL/min (95% limits of agreement, -848–1, 968 mL/min). The equation developed using data from the development group (n = 52): required minute volume (mL/min) = 85 × body weight (kg) in male patients and 70 × body weight (kg) in female patients. In the validation group (n = 26), the mean bias of this simple equation was 224 mL/min (95% limits of agreement, -1, 264–1, 712 mL/min). Conclusion: The Radford nomogram overestimates MVnorm in modern, balanced anesthesia. The simple equation using gender and a multiple of body weight yields similar predictive performance to the Radford nomogram

Newly Identified CYP2C93 Is a Functional Enzyme in Rhesus Monkey, but Not in Cynomolgus Monkey

Cynomolgus monkey and rhesus monkey are used in drug metabolism studies due to their evolutionary closeness and physiological resemblance to human. In cynomolgus monkey, we previously identified cytochrome P450 (P450 or CYP) 2C76 that does not have a human ortholog and is partly responsible for species differences in drug metabolism between cynomolgus monkey and human. In this study, we report characterization of CYP2C93 cDNA newly identified in cynomolgus monkey and rhesus monkey. The CYP2C93 cDNA contained an open reading frame of 490 amino acids approximately 84–86% identical to human CYP2Cs. CYP2C93 was located in the genomic region, which corresponded to the intergenic region in the human genome, indicating that CYP2C93 does not correspond to any human genes. CYP2C93 mRNA was expressed predominantly in the liver among 10 tissues analyzed. The CYP2C93 proteins heterologously expressed in Escherichia coli metabolized human CYP2C substrates, diclofenac, flurbiprofen, paclitaxel, S-mephenytoin, and tolbutamide. In addition to a normal transcript (SV1), an aberrantly spliced transcript (SV2) lacking exon 2 was identified, which did not give rise to a functional protein due to frameshift and a premature termination codon. Mini gene assay revealed that the genetic variant IVS2-1G>T at the splice site of intron 1, at least partly, accounted for the exon-2 skipping; therefore, this genotype would influence CYP2C93-mediated drug metabolism. SV1 was expressed in 6 of 11 rhesus monkeys and 1 of 8 cynomolgus monkeys, but the SV1 in the cynomolgus monkey was nonfunctional due to a rare null genotype (c.102T>del). These results suggest that CYP2C93 can play roles as a drug-metabolizing enzyme in rhesus monkeys (not in cynomolgus monkeys), although its relative contribution to drug metabolism has yet to be validated

Establishment of a Drug Sensitivity Panel Using Human Lung Cancer Cell Lines

We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.</p

Structural basis for the fast phase change of Ge2Sb2Te5: Ring statistics analogy between the crystal and amorphous states

The three-dimensional atomic configuration of amorphous Ge2Sb2Te5 and GeTe were derived by reverse Monte Carlo simulation with synchrotron-radiation x-ray diffraction data. The authors found that amorphous Ge2Sb2Te5 can be regarded as "even-numbered ring structure," because the ring statistics is dominated by four- and six-fold rings analogous to the crystal phase. On the other hand, the formation of Ge–Ge homopolar bonds in amorphous GeTe constructs both odd- and even-numbered rings. They believe that the unusual ring statistics of amorphous Ge2Sb2Te5 is the key for the fast crystallization speed of the material

A at Single Nucleotide Polymorphism-358 Is Required for G at -420 to Confer the Highest Plasma Resistin in the General Japanese Population

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at −420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P<10−13 in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r2 = 0.98), and were tightly correlated with SNP-420 (r2 = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r2 = 0.5224, P = 4.94×10−324; G at SNP-420, r2 = 0.2616, P = 1.71×10−133). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at −358, generally had G at −420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P<0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at −420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at −358 may not exist, suggesting that SNP-358 could explain this ethnic difference

Hyperglycemia in non-obese patients with type 2 diabetes is associated with low muscle mass: The Multicenter Study for Clarifying Evidence for Sarcopenia in Patients with Diabetes Mellitus

AIMS/INTRODUCTION: Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes. MATERIALS AND METHODS: Study participants consisted of patients with type 2 diabetes (n = 746, the average age was 69.9 years) and an older general population (n = 2, 067, the average age was 68.2 years). Sarcopenia was defined as weak grip strength or slow usual gait speed and low skeletal mass index. RESULTS: Among patients with type 2 diabetes, 52 were diagnosed as having sarcopenia. The frequency of sarcopenia increased linearly with glycated hemoglobin (HbA1c) level, particularly in lean individuals (HbA1c <6.5%, 7.0%, ≥6.5% and <7.0%: 18.5%; HbA1c ≥7.0% and <8.0%: 20.3%; HbA1c ≥8.0%: 26.7%). The linear association was independent of major covariates, including anthropometric factors and duration of diabetes (HbA1c <6.5%: reference; ≥6.5% and <7.0%: odds ratio [OR] 4.38, P = 0.030; HbA1c ≥7.0% and <8.0%: 4.29, P = 0.024; HbA1c ≥8.0%: 7.82, P = 0.003). HbA1c level was specifically associated with low skeletal mass index (HbA1c ≥8.0%: OR 5.42, P < 0.001) rather than weak grip strength (OR 1.89, P = 0.058) or slow gait speed (OR 1.13, P = 0.672). No significant association was observed in the general population with a better glycemic profile. CONCLUSIONS: Poor glycemic control in patients with diabetes was associated with low muscle mass

Mechanism of primitive duct formation in the pancreas and submandibular glands: a role for SDF-1

BACKGROUND: The exocrine pancreas is composed of a branched network of ducts connected to acini. They are lined by a monolayered epithelium that derives from the endoderm and is surrounded by mesoderm-derived mesenchyme. The morphogenic mechanisms by which the ductal network is established as well as the signaling pathways involved in this process are poorly understood. RESULTS: By morphological analyzis of wild-type and mutant mouse embryos and using cultured embryonic explants we investigated how epithelial morphogenesis takes place and is regulated by chemokine signaling. Pancreas ontogenesis displayed a sequence of two opposite epithelial transitions. During the first transition, the monolayered and polarized endodermal cells give rise to tissue buds composed of a mass of non polarized epithelial cells. During the second transition the buds reorganize into branched and polarized epithelial monolayers that further differentiate into tubulo-acinar glands. We found that the second epithelial transition is controlled by the chemokine Stromal cell-Derived Factor (SDF)-1. The latter is expressed by the mesenchyme, whereas its receptor CXCR4 is expressed by the epithelium. Reorganization of cultured pancreatic buds into monolayered epithelia was blocked in the presence of AMD3100, a SDF-1 antagonist. Analyzis of sdf1 and cxcr4 knockout embryos at the stage of the second epithelial transition revealed transient defective morphogenesis of the ventral and dorsal pancreas. Reorganization of a globular mass of epithelial cells in polarized monolayers is also observed during submandibular glands development. We found that SDF-1 and CXCR4 are expressed in this organ and that AMD3100 treatment of submandibular gland explants blocks its branching morphogenesis. CONCLUSION: In conclusion, our data show that the primitive pancreatic ductal network, which is lined by a monolayered and polarized epithelium, forms by remodeling of a globular mass of non polarized epithelial cells. Our data also suggest that SDF-1 controls the branching morphogenesis of several exocrine tissues.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe