Differences in fetal fractional limb volume changes in normal and gestational diabetic pregnancies: an exploratory observational study.

OBJECTIVE: Fetal fractional limb volume has been proposed as a useful measure for quantifying fetal soft tissue development. The aim of this study was to investigate the growth of fractional arm volume (AVol) and fractional thigh volume (TVol) of fetuses with maternal gestational diabetes (GDM) compared with those of fetuses with normal glucose tolerance (NGT). We hypothesised fetal fractional limb volume would be larger in the GDM group than in the NGT group in late gestation. DESIGN: Exploratory observational study. SETTING: Saitama Municipal Hospital. SAMPLE: A total of 165 (125 NGT and 40 GDM) singleton Japanese pregnant women. METHODS: AVol and TVol were assessed between 20 and 37 weeks' gestation as cylindrical limb volumes based on 50% of the fetal humeral or femoral diaphysis length. Women were diagnosed as GDM based on the criteria of the Japan Society of Obstetrics and Gynecology. MAIN OUTCOME MEASURES: AVol and TVol were compared between women with NGT and those with GDM at each gestational age period (2-week intervals from 20 to 37 weeks' gestation). RESULTS: Overall, 287 ultrasound scans were performed (NGT group, 205 scans; GDM group, 82 scans). There was no significant difference of AVol between the groups before 32 weeks' gestation. AVol was significantly larger in the GDM group than in the NGT group after 32 weeks' gestation (P < 0.05). TVol was not statistically different between the groups across gestation. CONCLUSIONS: Detection of variations in fetal AVol may provide greater insight into understanding the origins of altered fetal body proportion in GDM. TWEETABLE ABSTRACT: AVol, but not TVol, is significantly larger in fetuses with GDM than in those with NGT after 32 weeks' gestation.

Monolayer MoS2 field effect transistor with low Schottky barrier height with ferromagnetic metal contacts.

Two-dimensional MoS2 has emerged as promising material for nanoelectronics and spintronics due to its exotic properties. However, high contact resistance at metal semiconductor MoS2 interface still remains an open issue. Here, we report electronic properties of field effect transistor devices using monolayer MoS2 channels and permalloy (Py) as ferromagnetic (FM) metal contacts. Monolayer MoS2 channels were directly grown on SiO2/Si substrate via chemical vapor deposition technique. The increase in current with back gate voltage (Vg) shows the tunability of FET characteristics. The Schottky barrier height (SBH) estimated for Py/MoS2 contacts is found to be +28.8 meV (at Vg = 0V), which is the smallest value reported so-far for any direct metal (magnetic or non-magnetic)/monolayer MoS2 contact. With the application of positive gate voltage, SBH shows a reduction, which reveals ohmic behavior of Py/MoS2 contacts. Low SBH with controlled ohmic nature of FM contacts is a primary requirement for MoS2 based spintronics and therefore using directly grown MoS2 channels in the present study can pave a path towards high performance devices for large scale applications.

Prognostic nutritional index and early mortality with percutaneous endoscopic gastrostomy.

BACKGROUND: Although percutaneous endoscopic gastrostomy (PEG) is a well-accepted and less invasive method of feeding tube placement in patients with swallowing difficulties, complications and early death after PEG have been reported. AIM: This study aimed to evaluate predictive factors associated with 30-day mortality after PEG, and to assess the utility of nutritional supporting period before PEG in reducing early mortality following PEG. DESIGN: An observational study. METHODS: We retrospectively analyzed 268 patients who underwent PEG at Sapporo Shirakaba-dai Hospital from 2006 to 2010, using clinical and laboratory data to analyze predictive factors associated with early death after PEG. Then, we prospectively assessed 152 consecutive patients assessed for eligibility for PEG from 2011 to 2014. We assessed the patients' nutritional condition using Onodera's prognostic nutritional index (PNI), and supported nutrition for more than 10 days before PEG in patients with a poor nutritional index (PNI < 37). RESULTS: In both univariate and multivariate analyses in the retrospective study, Onodera's PNI of less than 37 was the only predictive factor for early mortality. In the second study, among the 115 patients who finally underwent PEG, early mortality rates improved to 1.7% from 5.2% in the first study. Conversely, 32% of patients with malnutrition who did not undergo PEG died within 30 days. CONCLUSION: Nutritional status might be a predictive factor for early mortality after PEG. In patients with poor nutritional status, nutritional supporting period before PEG might improve the outcomes and reduce unnecessary PEG.

Visualization of tumor-related blood vessels in human breast by photoacoustic imaging system with a hemispherical detector array.

Noninvasive measurement of the distribution and oxygenation state of hemoglobin (Hb) inside the tissue is strongly required to analyze the tumor-associated vasculatures. We developed a photoacoustic imaging (PAI) system with a hemispherical-shaped detector array (HDA). Here, we show that PAI system with HDA revealed finer vasculature, more detailed blood-vessel branching structures, and more detailed morphological vessel characteristics compared with MRI by the use of breast shape deformation of MRI to PAI and their fused image. Morphologically abnormal peritumoral blood vessel features, including centripetal photoacoustic signals and disruption or narrowing of vessel signals, were observed and intratumoral signals were detected by PAI in breast cancer tissues as a result of the clinical study of 22 malignant cases. Interestingly, it was also possible to analyze anticancer treatment-driven changes in vascular morphological features and function, such as improvement of intratumoral blood perfusion and relevant changes in intravascular hemoglobin saturation of oxygen. This clinical study indicated that PAI appears to be a promising tool for noninvasive analysis of human blood vessels and may contribute to improve cancer diagnosis.

Nutritional assessment using stable isotope ratios of carbon and nitrogen in the scalp hair of geriatric patients who received enteral and parenteral nutrition formulas.

BACKGROUND & AIMS: The δ13C and δ15N values in the scalp hair of geriatric patients in Japan who received the enteral or parenteral nutrition formula were measured to assess nutritional status. METHODS: The relations among δ13C, δ15N, calorie intake, BMI, albumin concentration, total cholesterol (T-CHO) and geriatric nutritional risk index (GNRI) in the patients were investigated. Furthermore, the enrichment of δ13C and δ15N from the nutrients to the hair was investigated. RESULTS: The δ13C values in the hair of patients who received enteral nutrition decreased with decreases in the calories received, while the δ15N values increased, suggesting malnutrition in some patients with a low calorie intake due to a negative nitrogen balance. The distribution of patients with a low calorie intake (below 20 kcal/kg/day) when δ13C was plotted against δ15N differed from that of control subjects, but the distribution of patients with a high calorie intake (above 20 kcal/kg/day) was similar to that of control subjects. No significant differences were observed in BMI, albumin concentration, T-CHO or GNRI between the low and high calorie groups. The enrichment of δ13C and δ15N from the enteral nutrients to the hair were inversely correlated with the δ13C and δ15N in the enteral nutrients. The enrichment levels of δ13C and δ15N tended to be higher and lower, respectively, in the high calorie group. On the other hand, the δ13C and δ15N values in the hair of patients who received parenteral nutrition were higher and lower than those in the control subjects and in the patients who received enteral nutrition, respectively, reflecting the higher δ13C and lower δ15N contents of the parenteral nutrients. CONCLUSIONS: The δ13C and δ15N values in the hair of patients who received enteral nutrition may be effective indicators for evaluating the long-term nutritional status of geriatric patients. A calorie intake of 20 kcal/kg/day may be a cut-off value for malnutrition in Japanese geriatric patients receiving enteral nutrition. However, caution is necessary when dealing with patients switching from parental nutrition as parenteral nutrition resulted in different changes in δ13C and δ15N. The enrichment levels of δ13C and δ15N from the enteral nutrients to the hair may be inversely correlated with the δ13C and δ15N values of enteral nutrients and vary according to the calorie intake.

Development of a cascade arc discharge source for an atmosphere-vacuum interface device.

To realize a novel vacuum-atmosphere interface that does not require a large differential pumping system, a robust cascade arc discharge source called a plasma window is constructed and tested for long-term operation. By modifying a test plasma with a direct current discharge, a vacuum interface with a high gas pressure ratio of 1/407 between the discharge and expansion sections is demonstrated for currents as high as 20 A. No significant damage to the electrodes is observed during the operation. Analysis of the visible emission spectra reveals that a stationary, stable argon plasma having a temperature of 1 eV and a density of 1.5 × 10(16) cm(-3) is generated in the plasma channel.

Function and Change with Aging of α-Klotho in the Kidney.

The α-Klotho mouse is an animal model that prematurely shows phenotypes resembling human aging, such as osteoporosis, arteriosclerosis, pulmonary emphysema, and kidney damage. Interestingly, these abnormalities are triggered by a deficiency of a single protein, α-Klotho. The kidney is an organ that highly expresses α-Klotho, suggesting that α-Klotho is important for kidney function. Recent studies suggest that α-Klotho is associated with phosphate, vitamin D, and calcium homeostasis. The calcium imbalance in α-Klotho mice may induce calpain overactivation, leading to cell death and tissue destruction. α-Klotho is predicted to have glycosidase activity, capable of modifying the N-glycans of channels and transporters and regulating transmembrane movement of several ions, including calcium. Interestingly, N-glycan changes are observed in the kidney of α-Klotho mice and normal aged mice in association with decreased α-Klotho levels. These results imply that glycobiology and α-Klotho function are interesting targets for future studies.

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus-the 'D-shuttle' project.

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries.

Cysteine amide adduct formation from carboxylic acid drugs via UGT-mediated bioactivation in human liver microsomes.

Although chemical trapping has been widely used to evaluate cytochrome P450-mediated drug bioactivation, thus far, only a few in vitro-trapping studies have been performed on UDP-glucuronosyltransferase (UGT)-mediated drug bioactivation. In this study, we used cysteine (Cys) as trapping agent to gain new insights into the UGT-mediated bioactivation involving acyl glucuronides of carboxylic acid drugs. Diclofenac, ketoprofen and ibuprofen were incubated in human liver microsomes with UDPGA and Cys, followed by analysis using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The N-acyl-Cys amide adduct of diclofenac was characterized by mass analysis and was detectable even in photodiode array analysis. Our data indicated that the formation of such adducts reflects the reactivity of the corresponding acyl glucuronides. In addition, it was suggested that the adduct formation requires an N-terminal Cys moiety with both a free amine and a free thiol group, from the results using various cysteine derivatives. We propose that the S-acyl-Cys thioester adduct can form via transacylation of an acyl glucuronide and can then form to an N-acyl-Cys amide adduct through intramolecular S- to N-acyl rearrangement. This series of the reactions has important implications as a possible bioactivation mechanism for covalent binding of carboxylic acid drugs to macromolecules.

Occurrence of adverse events caused by valganciclovir as pre-emptive therapy for cytomegalovirus infection after allogeneic stem cell transplantation is reduced by low-dose administration.

BACKGROUND: Pre-emptive therapy with valganciclovir (VGCV) has become the standard therapy for preventing cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The effectiveness of low-dose VGCV (900 mg per day) has been shown to be equal to that of standard-dose VGCV (900 mg twice daily); however, individualized optimal dosing and toxicity of VGCV have not been reported. METHODS: We conducted a retrospective study to evaluate the optimal dose of VGCV as pre-emptive therapy for preventing CMV infection by comparing the frequency of adverse events (AEs) and clinical efficacy in a low-dose VGCV group with those in a standard-dose VGCV group. Thirty-eight patients who were administered VGCV because of CMV antigenemia after HSCT were analyzed. RESULTS: Neutropenia (standard-dose group: 33%, low-dose group: 15%, P = 0.26) and thrombocytopenia (standard-dose group: 39%, low-dose group: 15%, P = 0.14) were frequent AEs of VGCV, and a significantly higher frequency of overall AEs was detected in the standard-dose group than in the low-dose group (P < 0.01). In comparison of dosage based on weight, dosage of VGCV >27 mg/kg was closely related to onset of AEs (P = 0.04). CONCLUSIONS: Low-dose VGCV was not inferior in clinical efficacy, including clearance rate of CMV antigenemia and incidence of consequent CMV disease, to standard-dose VGCV as was previously reported. Initial low-dose VGCV for pre-emptive CMV therapy markedly reduces hematologic toxicity and has clinical efficacy equivalent to that of standard-dose VGCV. It is therefore reasonable for patients, except for noticeably overweight patients, to be given initial low-dose VGCV.

Effect of γ-cyclodextrin as a lyoprotectant for freeze-dried actinidin.

Actinidin (ATD) is a cysteine protease found in kiwifruit. It is used to tenderize meat and to enhance the digestion of proteins in the small intestine. However, ATD is unstable during freeze-drying, which alters its bioactivity. It is well known that sugars have the ability to protect proteins from the stress of freeze-drying. In this study, we investigated the protective effect of various saccharides on the stability of ATD during freeze-drying. The ATD activities of the samples containing γ-cyclodextrin (CyD) showed only a small decrease, and compared with trehalose and sucrose, γ-CyD was a more effective stabilizer for ATD. Secondary structural changes in freeze-dried ATD were observed by circular dichroism spectroscopy and compared with the changes in stabilized samples. There was a close relationship between the α-helix content and the stabilization. The sugars stabilized the protein by suppressing the changes in the α-helix. Fourier transform infrared spectroscopy measurement showed that the amide I band of ATD with γ-CyD was shifted to a lower wavenumber compared with other sugars. Therefore, stronger hydrogen bonds may be formed between ATD and γ-CyD than between ATD and other sugars. The suppression of changes in the protein secondary structure accompanying the formation of hydrogen bonding between the protein and the sugar also contributed to the protective effect of the sugars.

Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.

Ritobegron, a selective ß3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.

An automated method for detecting architectural distortions on mammograms using direction analysis of linear structures.

Architectural distortion is one of the most important findings when evaluating mammograms for breast cancer. Abnormal breast architecture is characterized by the presence of spicules, which are distorted mammary structures that are not accompanied by an increased density or mass. We have been developing an automated method for detecting spiculated architectural distortions by analyzing linear structures extracted by normal curvature. However, some structures that are possibly related to distorted areas are not extracted using this method. The purpose of this study was to develop a new automated method for direction analysis of linear structures to improve detection performance in mammography. The direction of linear structures in each region of interest (ROI) was first determined using a direction filter and a background filter that can define one of eight directions (0°, 22.5°, 45°, 67.5°, 90°, 112.5°, 135°, and 157.5°). The concentration and isotropic indexes were calculated using the determined direction of the linear structures in order to extract the candidate areas. Discriminant analysis was performed to eliminate false positives results. Our database consisted of 168 abnormal images containing 174 distorted areas and 580 normal images. The sensitivity of the new method was 81%. There were 2.6 and 4.2 false positives per image using the new and previous methods, respectively. These findings show that our new method is effective for detecting spiculated architectural distortions.

Three-dimensional characterization of ODS ferritic steel using by FIB-SEM serial sectioning method.

Considerable attention has been paid to the research of the electron tomography due to determine the three-dimensional (3D) structure of materials [1]. One of the electron tomography techniques, focused ion beam/scanning electron microscopy (FIB-SEM) imaging has advantages of high resolutions (10 nm), large area observation (µm order) and simultaneous energy dispersive x- ray microanalysis (EDS)/ electron backscatter diffraction (EBSD) analysis. The purpose of this study, three-dimensional EBSD analysis of ODS ferritic steel which carried out cold work using FIB-SEM equipment was conducted, and it aimed at analyzing the microstructure obtained there. The zone annealing tests were conducted for ferritic steel [2,3], which were produced through mechanical alloying and hot-extrusion. After zone annealing, specimens were mechanically polished with #400∼4000 emery paper, 1 µm diamond paste and alumina colloidal silica. The serial sectioning and the 3D-electron backscattering diffraction (3D-EBSD) analysis were carried out. We made the micro pillar (30 x 30 x 15 µm). The EBSD measurements were carried out in each layer after serial sectioning at a step size and milling depth was 80 nm with 30 slices. After EBSD analysis, the series of cross-sectional images were aligned according to arbitrarily specified areas and then stacked up to form a volume. Consequently, we obtained the 3D-IPF maps for ODS ferritic steel. In this specimen, the {111} and {001} grains are layered by turns. In addition, the volume fraction value of both plane are similar. The aspect ratio increases with specimen depth. The 3D-EBSD mapping is useful to analysis of the bulk material since this method obtain many microstructure information, such a shape, volume and orientation of the crystal, grain boundary.

Antioxidant effects of carnitine supplementation on 14-3-3 protein isoforms in the aged rat hippocampus detected using fully automated two-dimensional chip gel electrophoresis.

We here described the antioxidant effects of carnitine supplementation on 14-3-3 protein isoforms in the aged rat hippocampus detected using the fully automated two-dimensional chip gel electrophoresis system (Auto2D). This system was easy and convenient to use, and the resolution obtained was more sensitive and higher than that of conventional two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). We separated and identified five isoforms of the 14-3-3 protein (beta/alpha, gamma, epsilon, zeta/delta, and eta) using the Auto2D system. We then examined the antioxidant effects of carnitine supplementation on the protein profiles of the cytosolic fraction in the aged rat hippocampus, demonstrating that carnitine supplementation suppressed the oxidation of methionine residues in these isoforms. Since methionine residues are easily oxidized to methionine sulfoxide, the convenient and high-resolution 2-D PAGE system can be available to analyze methionine oxidation avoiding artifactual oxidation. We showed here that the Auto2D system was a very useful tool for studying antioxidant effects through proteomic analysis of protein oxidation.

Hepatitis B virus (HBV) reverse seroconversion (RS) can be prevented even in non-responders to hepatitis B vaccine after allogeneic stem cell transplantation: long-term analysis of intervention in RS with vaccine for patients with previous HBV infection.

BACKGROUND: Reactivation of hepatitis B virus (HBV) infection, reverse seroconversion (RS), is a serious complication after allogeneic stem cell transplantation (alloHSCT). We previously conducted a post-transplant hepatitis B vaccine intervention trial and demonstrated the vaccine efficacy in preventing HBV-RS. This report is an update of the hepatitis B vaccine study. METHODS: In this trial, 21 patients were enrolled and received a standard 3-dose regimen of hepatitis B vaccine after discontinuation of immunosuppressants, whereas 25 transplant recipients with previous HBV infection did not receive the vaccine and served as controls. RESULTS: None of the 21 patients in the vaccine group developed HBV-RS and 12 controls developed HBV-RS in median follow-up periods of 60 months (range 13-245). HBV vaccine resulted in a positive value of hepatitis B surface antibody (HBsAb) titer in 9 patients, while HBsAb remained negative in 12 patients. Presence of a high titer of HBsAb before vaccination was associated with conversion into HBsAb positivity after vaccination. CONCLUSION: These results demonstrated the long-term effects of HBV vaccine for preventing HBV-RS after alloHSCT. Of note, no HBV-RS occurred, even in patients who did not achieve conversion into HBsAb positivity after vaccination.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Prediction of neurological recovery in spontaneous spinal epidural hematoma using apparent diffusion coefficient values.

OBJECTIVE: Magnetic resonance imaging (MRI) is useful in diagnosing spontaneous spinal epidural hematoma (SSEH). The purpose of the present study is to determine whether apparent diffusion coefficient (ADC) values could determine severity of spinal cord damage and predict functional recovery in SSEH. METHODS: The study involved four consecutive patients with SSEH (two men and two women: aged 21-76 years). Using axial slices, ADC values were determined in four separate regions of the spinal cord. These areas were classified into the following three groups based on findings in T2-weighted images: normal T2 intensity; persistent T2 abnormality; and temporary T2 abnormality. ADC values among different groups were compared. The relationship between preoperative ADC values and neurological grades were also evaluated. RESULTS: ADC values in normal T2 areas were 0.89 ± 0.10 × 10(-3) mm(2) s(-1), whereas those for the persistent T2 abnormality group were significantly lower (0.63 ± 0.14 × 10(-3)). In a patient who was Frankel A on admission and in the follow-up, the ADC value was as low as 0.41 × 10(-3). Functional recovery was also limited in the spinal cord segments with lower ADC values. In the temporary T2 abnormality group, ADC values were significantly higher (1.05 ± 0.10 × 10(-3)). CONCLUSIONS: In SSEH, if MRI demonstrated T2-hyperintensity with lower ADC values, patients may suffer from irreversible spinal cord damages. ADC values of the spinal cord can be added as a new factor that reliably indicated the severity of spinal cord damage and predicted functional recovery.