Resonant Inelastic X-Ray Scattering Reveals Hidden Local Transitions of the Aqueous OH Radical.

Resonant inelastic x-ray scattering (RIXS) provides remarkable opportunities to interrogate ultrafast dynamics in liquids. Here we use RIXS to study the fundamentally and practically important hydroxyl radical in liquid water, OH(aq). Impulsive ionization of pure liquid water produced a short-lived population of OH(aq), which was probed using femtosecond x-rays from an x-ray free-electron laser. We find that RIXS reveals localized electronic transitions that are masked in the ultraviolet absorption spectrum by strong charge-transfer transitions-thus providing a means to investigate the evolving electronic structure and reactivity of the hydroxyl radical in aqueous and heterogeneous environments. First-principles calculations provide interpretation of the main spectral features.

Functional electronic inversion layers at ferroelectric domain walls.

Ferroelectric domain walls hold great promise as functional two-dimensional materials because of their unusual electronic properties. Particularly intriguing are the so-called charged walls where a polarity mismatch causes local, diverging electrostatic potentials requiring charge compensation and hence a change in the electronic structure. These walls can exhibit significantly enhanced conductivity and serve as a circuit path. The development of all-domain-wall devices, however, also requires walls with controllable output to emulate electronic nano-components such as diodes and transistors. Here we demonstrate electric-field control of the electronic transport at ferroelectric domain walls. We reversibly switch from resistive to conductive behaviour at charged walls in semiconducting ErMnO3. We relate the transition to the formation-and eventual activation-of an inversion layer that acts as the channel for the charge transport. The findings provide new insight into the domain-wall physics in ferroelectrics and foreshadow the possibility to design elementary digital devices for all-domain-wall circuitry.

Detection of copy number variations in epilepsy using exome data.

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Indocyanine green fluorescence angiography of the reconstructed gastric tube during esophagectomy: efficacy of the 90-second rule.

By examining the reconstructed gastric tube during esophagectomy using indocyanine green fluorescence (ICG) angiography, we have established a '90-second rule' to confirm good blood perfusion at the anastomosis site. We examined the surgical outcome (rate of anastomotic leakage) of 70 consecutive patients who underwent esophagectomy with gastric tube reconstruction using ICG fluorescence angiography. All of the anastomoses were made in the area where less than 90 seconds was needed for enhancement using ICG fluorescence angiography (i.e. within the 90-second rule). In 18 cases for which the time until enhancement of the gastric tube tip exceeded 60 seconds, the anastomosis site was decided by reference to the ICG fluorescence angiogram, and the hypoperfused area was excised, and this significantly shortened the median time until enhancement of the gastric tube tip from 95.5 (60.0-204.0) seconds to 41.0 (9.0-77.0) seconds (P < 0.001). In three cases, the anastomosis was made at the site where more than 60 seconds was needed for ICG enhancement. In one case where ICG enhancement had taken 77 seconds, minor anastomotic leakage occurred. The overall rate of anastomotic leakage in this series was 1.4%. Blood flow in the reconstructed gastric tube is sufficient if the anastomosis is made in the area where ICG fluorescence angiography demonstrates enhancement within 60 seconds. Gastric tube necrosis can be avoided if the area showing an enhancement time exceeding 90 seconds is excised. The 90-second rule is a safe and effective method for deciding the site of anastomosis.

Vascular endothelial growth factors C and D and lymphangiogenesis at the early stage of esophageal squamous cell carcinoma progression.

We conducted a detailed study of lymphangiogenesis and subsequent lymph node metastasis in early-stage esophageal squamous cell carcinoma (ESCC) using immunostaining for D2-40 and vascular endothelial growth factor (VEGF)-C and D. The study materials included 13 samples of normal squamous epithelium, 6 samples of low-grade intraepithelial neoplasia (LGIN), and 60 samples of superficial ESCC (M1 and M2 cancer 24; M3 or deeper cancer 36). We assessed lymphatic vessel density (LVD) using D2-40 and immunoreactivity for VEGF-C and D in relation to histological type, lymphatic invasion, and lymph node metastasis. LVD in M1 and M2 lesions and M3 or deeper lesions was significantly higher than in normal squamous epithelium (P < 0.001). High expression of VEGF-C and D was observed in M1 and M2 cancer and in M3 or deeper cancer, but not in normal squamous epithelium or LGIN. LVD in VEGF-C- and D-positive cases was significantly higher than in negative cases (P < 0.001). In M3 or deeper cancer, the correlation between VEGF-C or D status and lymphatic invasion or lymph node metastasis was not significant. LVD in cases with positive lymphatic invasion and those with lymph node metastasis was significantly higher than in cases lacking either (P = 0.02 and 0.03, respectively). ESCC cells produce VEGF-C and D from the very early stage of progression. VEGF-C and D activate lymphangiogenesis, and this increase of lymphatic vessels leads to lymphatic invasion and subsequent lymph node metastasis.

Time-Resolved Measurement of Interatomic Coulombic Decay Induced by Two-Photon Double Excitation of Ne_{2}.

The hitherto unexplored two-photon doubly excited states [Ne^{*}(2p^{-1}3s)]_{2} were experimentally identified using the seeded, fully coherent, intense extreme ultraviolet free-electron laser FERMI. These states undergo ultrafast interatomic Coulombic decay (ICD), which predominantly produces singly ionized dimers. In order to obtain the rate of ICD, the resulting yield of Ne_{2}^{+} ions was recorded as a function of delay between the extreme ultraviolet pump and UV probe laser pulses. The extracted lifetimes of the long-lived doubly excited states, 390(-130/+450) fs, and of the short-lived ones, less than 150 fs, are in good agreement with ab initio quantum mechanical calculations.

The Neutrophil-to-Lymphocyte Ratio Predicts All-Cause Mortality in Patients with Implantable Cardioverter Defibrillators.

BACKGROUND: The relationship between the neutrophil-to-lymphocyte ratio (NLR) and outcome in patients with implantable cardioverter-defibrillators (ICDs) is unclear. METHODS AND RESULTS: Consecutive patients with cardiomyopathy who had received an ICD (n = 120, mean age 64 ± 11 years) were prospectively enrolled. Blood samples were obtained on the morning of the day of implantation. Patients were followed for a median period of 61.2 months, to an endpoint of all-cause mortality or appropriate ICD shock, which occurred in 35 (29%) and 28 (23%) patients, respectively. Multivariate Cox analysis revealed that secondary prevention was only associated with appropriate ICD shocks. The NLR, brain natriuretic peptide level, and estimated glomerular filtration rate were independent predictors of all-cause mortality but not of appropriate ICD shocks. Subgroup analysis revealed that a high NLR (≥2.1) was valuable for anticipating all-cause mortality among patients who had received ICDs for primary or secondary prevention. A high NLR was also associated with death prior to appropriate ICD shock. CONCLUSION: Evaluating the NLR may be useful for predicting outcomes in patients with cardiomyopathy who have received ICDs.

The Clinical Value of Nongated Dual-Source Computed Tomography in Atrial Fibrillation Catheter Ablation.

INTRODUCTION: Using a high-pitch dual-source CT (DSCT), we aimed to quantify the amounts of contrast media, radiation doses, and image qualities in patients undergoing pulmonary vein (PV) isolation. METHODS AND RESULTS: The study enrolled 60 patients who were randomly assigned in a 1: 1: 1 ratio to undergo ECG-gated 64-slice multidetector computed tomography (MDCT; group I, n = 20), ECG-gated 128-DSCT (group II, n = 20), and nongated 128-DSCT (group III, n = 20). The total amount of contrast media was lower in groups II and III compared with group I (I: 54.7 ± 5.6, II: 26.6 ± 2.7, and III: 28.7 ± 6.9 mL, P < 0.001). The CT dose index was lower in groups II and III compared with group I (I: 73.1 ± 5.2, II: 3.5 ± 0.1, and III: 3.7 ± 0.1 mGy, P < 0.001). The dose length product was lower in groups II and III compared with group I (I: 1154.8 ± 82.8, II: 75.4 ± 2.3, and III: 77.2 ± 1.9 mGy × cm, P < 0.001). The total CT effective radiation dose was lower in groups II and III compared with group I (I: 16.2 ± 1.2, II: 1.1 ± 0.1, and III: 1.1 ± 0.1 mSv, P < 0.001). The total CT scan duration was shorter in group III compared with groups I and II (I: 30.8 ± 2.2, II: 23.4 ± 3.6, and III: 16.0 ± 2.4 minutes, P < 0.001). There were no significant differences in quality for integrated electroanatomical mapping (EAM) and parameters associated with PV isolation among the 3 groups. CONCLUSION: Nongated 128-DSCT provides sufficient image quality to allow integrated EAM while exposing the patient to less contrast media, lower radiation doses, and shorter CT scan durations.

Slow Interatomic Coulombic Decay of Multiply Excited Neon Clusters.

Ne clusters (∼5000 atoms) were resonantly excited (2p→3s) by intense free electron laser (FEL) radiation at FERMI. Such multiply excited clusters can decay nonradiatively via energy exchange between at least two neighboring excited atoms. Benefiting from the precise tunability and narrow bandwidth of seeded FEL radiation, specific sites of the Ne clusters were probed. We found that the relaxation of cluster surface atoms proceeds via a sequence of interatomic or intermolecular Coulombic decay (ICD) processes while ICD of bulk atoms is additionally affected by the surrounding excited medium via inelastic electron scattering. For both cases, cluster excitations relax to atomic states prior to ICD, showing that this kind of ICD is rather slow (picosecond range). Controlling the average number of excitations per cluster via the FEL intensity allows a coarse tuning of the ICD rate.

The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study.

BACKGROUND: The cytokine interleukin-31 (IL-31) is considered to be responsible for the development of pruritus in humans. At present, no available evidence has been provided on the safety and efficacy of blocking the IL-31 signal in humans for the amelioration of pruritus in atopic dermatitis (AD). CIM331 is a humanized antihuman IL-31 receptor A (IL-31RA) monoclonal antibody, which binds to IL-31RA to inhibit subsequent IL-31 signalling. OBJECTIVES: To assess the tolerability, safety, pharmacokinetics and preliminary efficacy of CIM331 in healthy Japanese and white volunteers, and Japanese patients with AD. METHODS: In this randomized, double-blind, placebo-controlled phase I/Ib study, CIM331 was administered in a single subcutaneous dose. The primary outcomes were safety and tolerability; the exploratory analysis was efficacy. RESULTS: No deaths, serious adverse events (AEs) or discontinuations due to AEs were reported in any part of the study. No dose-dependent increase in the incidence of AEs occurred in any part of the study. In healthy volunteers, all AEs occurred once in the placebo groups, and increased creatine phosphokinase was more common in the CIM331 groups. In patients with AD, CIM331 reduced pruritus visual analogue scale score to about -50% at week 4 with CIM331 compared with -20% with placebo. CIM331 increased sleep efficiency and decreased the use of hydrocortisone butyrate. CONCLUSIONS: A single subcutaneous administration of CIM331 was well tolerated in healthy volunteers and patients with AD. It decreased pruritus, sleep disturbance and topical use of hydrocortisone. CIM331 may become a novel therapeutic option for AD by inhibiting IL-31.

Towards characterization of photo-excited electron transfer and catalysis in natural and artificial systems using XFELs.

The ultra-bright femtosecond X-ray pulses provided by X-ray Free Electron Lasers (XFELs) open capabilities for studying the structure and dynamics of a wide variety of biological and inorganic systems beyond what is possible at synchrotron sources. Although the structure and chemistry at the catalytic sites have been studied intensively in both biological and inorganic systems, a full understanding of the atomic-scale chemistry requires new approaches beyond the steady state X-ray crystallography and X-ray spectroscopy at cryogenic temperatures. Following the dynamic changes in the geometric and electronic structure at ambient conditions, while overcoming X-ray damage to the redox active catalytic center, is key for deriving reaction mechanisms. Such studies become possible by using the intense and ultra-short femtosecond X-ray pulses from an XFEL, where sample is probed before it is damaged. We have developed methodology for simultaneously collecting X-ray diffraction data and X-ray emission spectra, using an energy dispersive spectrometer, at ambient conditions, and used this approach to study the room temperature structure and intermediate states of the photosynthetic water oxidizing metallo-protein, photosystem II. Moreover, we have also used this setup to simultaneously collect the X-ray emission spectra from multiple metals to follow the ultrafast dynamics of light-induced charge transfer between multiple metal sites. A Mn-Ti containing system was studied at an XFEL to demonstrate the efficacy and potential of this method.

Contact Force-Guided Deep Engagement with a Steerable Sheath in the Distal Great Cardiac Vein: A Case Report.

Ablation of ventricular tachycardia originating from the great cardiac vein involves the difficult step of deep engagement with an ablation catheter. The catheter and a steerable sheath (MobiCath, Biosense Webster, Diamond Bar, CA, USA) were advanced alternately only when the contact force vector was parallel to the coronary venous system. Deep engagement with a steerable sheath ensured a powerful backup force during ablation.

Endocytoscopic observation of various esophageal lesions at ×600: can nuclear abnormality be recognized?

Endocytoscopy (ECS) is a novel endoscopic technique that allows detailed diagnostic examination of the gastrointestinal tract at the cellular level. We previously reported that use of ECS at ×380 magnification (GIF-Y0002) allowed a pathologist to diagnose esophageal squamous cell carcinoma (ESCC) with high sensitivity (94.9%) but considerably low specificity (46.7%) because this low magnification did not reveal information about nuclear abnormality. In the present study, we used the same magnifying endoscope to observe various esophageal lesions, but employed digital 1.6-fold magnification to achieve an effective magnification of ×600, and evaluated whether this improved the diagnostic accuracy in distinguishing neoplastic from non-neoplastic lesions.We examined the morphology of surface cells using vital staining with toluidine blue and compared the histological features of 40 cases, including 19 case of ESCC and 21 non-neoplastic esophageal lesions (18 cases of esophagitis, 1 case of glycogenic acanthosis, 1 case of leiomyoma, and 1 case of normal squamous epithelium). One endoscopist classified the lesions using the type classification, and we consulted one pathologist for judgment of the ECS images as 'neoplastic', 'borderline', or 'non-neoplastic'. At ×600 magnification, the pathologist confirmed that nuclear abnormality became evident, in addition to the information about nuclear density provided by observation at ×380. The overall sensitivity and specificity with which the endoscopist was able to predict neoplastic lesions using the type classification was 100% (19/19) and 90.5% (19/21), respectively, in comparison with values of 94.7% (18/19 cases) and 76.2% (16/21), respectively, for the pathologist using a magnification of ×600. The pathologist diagnosed two non-neoplastic lesions and one case of ESCC showing an apparent increase of nuclear density with weak nuclear abnormality as 'borderline'. Among the 21 non-cancerous lesions, two cases of esophagitis that were misdiagnosed by the endoscopist were also misinterpreted as 'neoplastic' by the pathologist. We have shown, by consultation with a pathologist, that an ECS magnification of ×600 (on a 19-inch monitor) is adequate for recognition of nuclear abnormality. We consider that it is feasible to diagnose esophageal neoplasms on the basis of ECS images, and that biopsy histology can be omitted if a combination of increased nuclear density and nuclear abnormality is observed.

Anisotropic conductance at improper ferroelectric domain walls.

Transition metal oxides hold great potential for the development of new device paradigms because of the field-tunable functionalities driven by their strong electronic correlations, combined with their earth abundance and environmental friendliness. Recently, the interfaces between transition-metal oxides have revealed striking phenomena, such as insulator-metal transitions, magnetism, magnetoresistance and superconductivity. Such oxide interfaces are usually produced by sophisticated layer-by-layer growth techniques, which can yield high-quality, epitaxial interfaces with almost monolayer control of atomic positions. The resulting interfaces, however, are fixed in space by the arrangement of the atoms. Here we demonstrate a route to overcoming this geometric limitation. We show that the electrical conductance at the interfacial ferroelectric domain walls in hexagonal ErMnO(3) is a continuous function of the domain wall orientation, with a range of an order of magnitude. We explain the observed behaviour using first-principles density functional and phenomenological theories, and relate it to the unexpected stability of head-to-head and tail-to-tail domain walls in ErMnO(3) and related hexagonal manganites. As the domain wall orientation in ferroelectrics is tunable using modest external electric fields, our finding opens a degree of freedom that is not accessible to spatially fixed interfaces.

A health-risk appraisal model and endoscopic mass screening for esophageal cancer in Japanese men.

A strong association between inactive aldehyde dehydrogenase-2 (ALDH2) and risk of esophageal cancer has been demonstrated in East Asian drinkers. An alcohol flushing questionnaire asking about past and current tendency for facial flushing to occur after drinking a glass (≈180 mL) of beer predicts the presence of inactive ALDH2 among Japanese aged 40 years or older with a sensitivity and specificity of approximately 90%. We invented a health-risk appraisal (HRA) model that makes it possible to identify Japanese men who are at high risk for esophageal cancer based on their past and current alcohol flushing tendency, drinking, smoking, and intake of vegetables and fruits. Between 2008 and 2009, 2221 Japanese men aged 50 years or older filled out the HRA questionnaire before undergoing a screening examination by upper gastrointestinal endoscopy at five medical facilities. The endoscopic examination resulted in a diagnosis of esophageal cancer in 19 subjects, and 117 (5.27%) subjects had an HRA score ≥ 11. The proportion of subjects with an HRA score ≥ 11 was higher in the 50-69 age group (6.11-6.88%) than in 70-89 age group (2.84-2.86%). The esophageal cancer detection rate was 4.27% among the subjects with an HRA score ≥ 11 and only 0.67% among the other subjects. Based on a receiver operating characteristic curve analysis, when an HRA score of ≥ 9 was used for subjects aged 50-69 years and of ≥ 8 for those aged 70-89 years as the cutoff value to select individuals with a high risk for esophageal cancer, its sensitivity and false-positive rate was 52.6% and 15.2%, respectively, and the cancer detection rate was 2.91% in the high-risk group, as opposed to 0.48% in the other group. In conclusion, the high detection rates for esophageal cancer in the high-risk groups encouraged screening based on our HRA model in larger Japanese populations.

Should isolated peritoneal carcinomatosis from colorectal cancer be sub-classified into stage IVB in era of modern chemotherapy?

BACKGROUND: According to the 7th edition of the TNM staging system, stage IV metastatic colorectal cancer (CRC) at the time of initial diagnosis is sub-classified into stage IVA or IVB disease. Peritoneal carcinomatosis (PC), considered to have a dismal prognosis, is exclusively sub-classified into stage IVB, even though other metastases to a sole organ are sub-classified into stage IVA, which is considered to be associated with better survival. This retrospective study was undertaken to investigate the overall survival in metastatic CRC patients, focusing on PC patients. METHODS: We reviewed data on patients with metastatic CRC at initial diagnosis surgically treated between January 2006 and June 2011. A survival analysis was performed paying special attention to PC and sub-classifying patients with PC into three categories according to metastatic sites. RESULTS: There were 69 stage IVA patients (IVA group) and 83 stage IVB. Among stage IVB patients, 20 had isolated PC (PC-I group), 28 had PC with one or more other sites of metastasis (PC-II group), and 35 had at least 2 metastatic without peritoneal involvement (NPC group). Of 152 stage IV patients, 132 (87 %) underwent resection of the primary tumor and 19 (12 %) underwent radical resection of metastatic disease with microscopic free margins (R0 resection) including 5/20 (25 %) patients in the PC1 group. A total of 139 patients received oxaliplatin-based chemotherapy in a palliative (n = 125), neoadjuvant (n = 3), or adjuvant setting after R0 resection (n = 11). Compared with 36.6 months in the PC-I group, median survival was 32.5 months (P = 0.48) in the IVA group, 14.7 months (P = 0.07) in the PC-II group, and 12.9 months (P < 0.01) in the NPC group. CONCLUSIONS: The sub-classification of isolated PC into stage IVA instead of IVB might be more appropriate in the era of modern chemotherapy. Further investigation is warranted.

Artificial placenta technology: History, potential and perception.

As presently conceptualised, the artificial placenta (AP) is an experimental life support platform for extremely preterm infants (i.e. 400-600 g; 21-23+6 weeks of gestation) born at the border of viability. It is based around the oxygenation of the periviable fetus using gas-exchangers connected to the fetal vasculature. In this system, the lung remains fluid-filled and the fetus remains in a quiescent state. The AP has been in development for some sixty years. Over this time, animal experimental models have evolved iteratively from employing external pump-driven systems used to support comparatively mature fetuses (generally goats or sheep) to platforms driven by the fetal heart and used successfully to maintain extremely premature fetuses weighing around 600 g. Simultaneously, sizable advances in neonatal and obstetric care mean that the nature of a potential candidate patient for this therapy, and thus the threshold success level for justifying its adoption, have both changed markedly since this approach was first conceived. Five landmark breakthroughs have occurred over the developmental history of the AP: i) the first human studies reported in the 1950's; ii) foundation animal studies reported in the 1960's; iii) the first extended use of AP technology combined with fetal pulmonary resuscitation reported in the 1990s; iv) the development of AP systems powered by the fetal heart reported in the 2000's; and v) the adaption of this technology to maintain extremely preterm fetuses (i.e. 500-600 g body weight) reported in the 2010's. Using this framework, the present paper will provide a review of the developmental history of this long-running experimental system and up-to-date assessment of the published field today. With the apparent acceleration of AP technology towards clinical application, there has been an increase in the attention paid to the field, along with some inaccurate commentary regarding its potential application and merits. Additionally, this paper will address several misrepresentations regarding the potential application of AP technology that serve to distract from the significant potential of this approach to greatly improve outcomes for extremely preterm infants born at or close to the present border of viability.

D1 Distal Pancreatectomy for Left-sided Pancreatic Ductal Adenocarcinoma Is Justifiable: A Propensity-score Matched Multicenter Study.

BACKGROUND/AIM: Evidence on the optimal extent of lymph node dissection for left-sided pancreatic ductal adenocarcinoma (PDAC) is scarce. The aim of the current study was to compare the long-term outcomes of patients who underwent D1 distal pancreatectomy (DP) with D2 DP for left-sided PDAC. PATIENTS AND METHODS: Patients undergoing DP for left-sided PDAC at the four institutions affiliated to The Jikei University were enrolled in this study. Patients were divided into D1 and D2 groups. Patients' clinical characteristics, overall survival (OS), and relapse-free survival (RFS) were compared between the two groups before and after propensity-score matched (PSM) analysis. RESULTS: Of 145 patients with left-sided PDAC, 55 patients underwent D1 DP and 90 underwent D2 DP, of whom 38 matched pairs were included in the PSM analytic cohort. In the unmatched cohort, no significant difference was found between the D1 and D2 groups for both OS (median 2.51 vs. 3.07 years; p=0.709) and RFS (median 1.47 vs. 1.27 years; p=0.565). After PSM, OS (median 2.37 vs. 3.56 years; p=0.407) and RFS (median 1.35 vs. 1.11 years; p=0.542) were not significantly different between the two groups. In a comparison of regional and systemic recurrence sites, no significant difference was observed between the two groups (p=0.500). CONCLUSION: The long-term survival of D1 DP for left-sided PDAC was not inferior to D2 DP. In an era in which the importance of multidisciplinary treatment for PDAC has been documented, unnecessary extended surgery should be avoided.