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Aim Methods Results Conclusions To assess the feasibility, safety, and outcomes of modified laparoscopic transabdominal cerclage in patients with refractory cervical insufficiency.This single‐arm clinical trial examined women with refractory cervical insufficiency who underwent modified laparoscopic transabdominal cerclage at a specialized center in Japan between December 2017 and May 2022. Various parameters related to patient demographics, surgical techniques, outcomes, and complications were evaluated.The study enrolled 30 women with a median age of 36 years. The modified laparoscopic transabdominal cerclage was technically successful in all cases. The delivery rate and fetal survival rate at 28 days in the third trimester were both 93%. Surgical complication involving small bowel injury occurred in one case and was promptly repaired. No fetal complications or pregnancy losses occurred within 28 days of the procedure. Perinatal outcomes included a cesarean section rate of 93%, a neonatal intensive care unit admission rate of 30%, and an overall fetal survival rate of 93%. Additionally, no absence or reversal of end‐diastolic flow in the uterine artery was identified at the time of cerclage in any of the cases.This study demonstrated the feasibility and safety of modified laparoscopic transabdominal cerclage for refractory cervical insufficiency. The procedure achieved a high delivery rate in the third trimester and a good overall fetal survival rate. The study findings highlight the importance of anatomical precision during thread placement in modified laparoscopic transabdominal cerclage. This technique is promising for treating refractory cervical insufficiency and potentially preventing second‐trimester losses and extreme preterm births. [ABSTRACT FROM AUTHOR]

Background and Purpose: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201‐A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. Experimental Approach: Following the administration of M201‐A (1,4‐benzothiazepine‐1‐oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201‐A was administered intravenously at doses of 0.2 and 0.4 mg·kg−1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. Key Results: In rat heart cells, M201‐A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi‐inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201‐A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. Conclusions and Implications: The novel drug M201‐A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi‐inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure. [ABSTRACT FROM AUTHOR]

Twelve years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 5th Revised Edition was published in 2023. The 2023 Guidelines includes 5 additional clinical questions (CQs), which brings the total to 103 CQ (12 on infectious disease, 30 on oncology and benign tumors, 29 on endocrinology and infertility and 32 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated. [ABSTRACT FROM AUTHOR]

Aim: Conventionally, the skeletal muscle area with computed tomography (CT) attenuation ranging from −29 to +150 Hounsfield unit (HU) divided by height squared (the conventional skeletal muscle index [SMI]) was used as an index of skeletal muscle mass. However, it includes fat‐infiltrated skeletal muscle, which is known to have poor function. This study aims to determine whether the low‐fat SMI, which uses skeletal muscle mass with CT attenuation ranging from +30 to +150 HU, or conventional SMI appropriately reflects the function of skeletal muscle. Methods: We retrospectively analyzed 120 patients with cirrhosis whose handgrip strength was measured. Among them, 48 patients underwent a physical performance assessment such as liver frailty index (LFI) and short physical performance battery (SPPB), and 80 underwent quality of life (QOL) assessment. The relationships between each SMI and handgrip strength, LFI, SPPB, and QOL were evaluated. Results: Low‐fat SMI was significantly correlated with handgrip strength (males, R = 0.393, p = 0.002; females, R = 0.423, p < 0.001) and LFI (males, R = −0.535, p = 0.035; females, R = −0.368, p = 0.039), whereas conventional SMI was not. When using low‐fat SMI, patients with low skeletal muscle mass had significantly low handgrip strength, LFI, SPPB, and physical and social‐related QOL score than those without. By contrast, no significant differences were found for any items when using conventional SMI. Conclusions: Low‐fat SMI is a good index of skeletal muscle mass that appropriately reflects skeletal muscle function. [ABSTRACT FROM AUTHOR]

Introduction: Cryoablation has emerged as an alternative to radiofrequency ablation for treating atrioventricular nodal reentrant tachycardia (AVNRT). The aim of this prospective study was to evaluate the efficacy and safety of cryoapplication at sites within the mid/high septal region of Koch's triangle and the relation between sites of transient AV block (AVB) and sites of successful cryoablation. Methods and Results: Included were 45 consecutive patients undergoing slow‐fast AVNRT cryoablation. Initial delivery of cryoenergy was to the mid‐septal to high septal region of Koch's triangle. Transient AVB occurred during cryoenergy delivery in 62% (28/45) of patients. Median distance between sites at which cryofreezing successfully eliminated slow pathway conduction and sites of AVB was 4.0 (3.25–5.0) mm. Sites of successful cryoablation tended to be to the left and inferior to the AVB sites. The atrial/ventricular electrogram ratio was significantly lower at sites of successful cryoablation than at AVB sites (0.25 [0.17–0.56] vs. 0.80 [0.36–1.25], p <.001). Delayed discrete or fractionated atrial electrograms were recorded more frequently at sites of successful cryoablation than at AVB sites (78% vs. 20%, p <.001). No persistent AV conduction disturbance occurred, and 96% (43/45) of patients showed absence of recurrence at a median follow‐up time of 25.0 months. Conclusion: Cryoablation of slow‐fast AVNRT and targeting the mid/high septal region of Koch's triangle was highly successful. AVB frequently emerged near the site at which the slow pathway was eliminated but always resolved by regulating the energy delivery under careful monitoring, and it may be distinguishable by its local electrogram features. [ABSTRACT FROM AUTHOR]

Introduction: A new hot balloon system that registers balloon surface temperature (BST) during energy delivery is now available for clinical use in Japan. This study sought to investigate the utility of BST measurement for achievement of pulmonary vein isolation (PVI) by a single‐shot energy delivery strategy during hot balloon ablation (HBA). Methods: We applied and tested the system in 30 consecutive patients undergoing HBA for paroxysmal or early‐persistent atrial fibrillation (AF). We also performed real‐time PV potential monitoring using a circular catheter. Results: Acute PVI was achieved with single hot balloon shots in 88% (106/120) of the PVs. Real‐time BSTs and PV potentials were recorded in all cases. Mean BST at documentation of PVI was 49.4°C, and acute reconnections were observed in most cases (86%, 12/14) in which the single‐shot technique was ineffective. Time‐to‐isolation (TTI) (23.1 ± 8.7 s vs. 36.3 ± 9.3 s, p <.01) and median BST (59.9 ± 2.6°C vs. 55.7 ± 1.9°C, p <.01) differed significantly between cases in which PVI was achieved (vs. those in which PVI was not achieved). Multivariable analysis revealed strong association between both TTI and median BST and acute PVI. The best median BST cutoff value for achieving PVI with a single shot was >58.7°C (sensitivity 67.0%, specificity 100%). Conclusion: Our data suggest that real‐time BST monitoring during energy applications is useful for predicting achievement of acute PVI by a single shot during HBA. [ABSTRACT FROM AUTHOR]

The new Brain Imaging Beamline (BIB) of the Taiwan Photon Source (TPS) has been commissioned and opened to users. The BIB and in particular its endstation are designed to take advantage of bright unmonochromatized synchrotron X‐rays and target fast 3D imaging, ∼1 ms exposure time plus very high ∼0.3 µm spatial resolution. A critical step in achieving the planned performances was the solution to the X‐ray induced damaging problems of the detection system. High‐energy photons were identified as their principal cause and were solved by combining tailored filters/attenuators and a high‐energy cut‐off mirror. This enabled the tomography acquisition throughput to reach >1 mm3 min−1, a critical performance for large‐animal brain mapping and a vital mission of the beamline. [ABSTRACT FROM AUTHOR]

Background and Aim: The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV‐specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV‐TK‐NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV‐TK) mice in which the host immune system was not impaired. Methods: Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV‐treated mice were transplanted with 1 × 106 hepatocytes from HBV‐transgenic (HBV‐Tg) mice. Results: Serum alanine aminotransferase levels in HSV‐TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV‐Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)‐positive areas in the liver tissue were observed for at least 20 weeks after HBsAg‐positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV‐Tg hepatocyte‐replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV‐TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon‐γ‐producing cells were increased in non‐replaced mice. Conclusions: A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV‐infected patients and can be used to develop a new strategy to treat chronic HBV infection. [ABSTRACT FROM AUTHOR]

Introduction: Hot‐balloon ablation depends solely on thermal conduction, and myocardial tissue is ablated by only conductive heating from the balloon surface. Despite growing clinical evidence of the efficacy and safety of hot‐balloon ablation for atrial fibrillation (AF), the actual tissue temperature and the mechanism of heating during such ablation has not been clarified. To determine, by means of a porcine study, the temperatures of tissues targeted during hot‐balloon ablation of AF performed with hot‐balloon set temperatures of 73°C or 70°C, in accordance with the temperatures now used clinically. Methods: After a right thoracotomy, thermocouples with markers were implanted epicardially on the superior vena cava (SVC) and pulmonary veins (PVs) in six pigs. The tissue temperatures during hot‐balloon ablation (balloon set temperatures of 73°C and 70°C, 180 s/PV) were recorded, and the maximum tissue temperatures and fluoroscopically measured distance from the balloon surface to the target tissues were assessed. Results: Sixteen SVC‐ and 18 PV‐targeted energy deliveries were performed. Full‐thickness circumferential PV lesions were created with all hot‐balloon applications. A significant inverse relation was found between the recorded tissue temperatures and distance (r = −.67; p <.001) from the balloon surface. No tissue temperature exceeded either of the balloon set temperatures. The best distance cutoff value for achieving lethal tissue temperatures more than 50°C was 3.6 mm. Conclusion: The hot‐balloon set temperature, energy delivery time, and tissue temperature data obtained in this porcine study supported the clinical efficacy and safety of the hot‐balloon ablation as currently practiced in patients with AF. [ABSTRACT FROM AUTHOR]

Nine years after the first edition of The Guideline for Gynecological Practice, which was jointly edited by The Japan Society of Obstetrics and Gynecology and The Japan Association of Obstetricians and Gynecologists, the 4th Revised Edition was published in 2020. The 2020 Guidelines includes 4 additional clinical questions (CQ), which brings the total to 99 CQ (12 on infectious disease, 29 on oncology and benign tumors, 29 on endocrinology and infertility and 29 on healthcare for women). Currently, a consensus has been reached on the Guidelines, and therefore, the objective of this report is to present the general policies regarding diagnostic and treatment methods used in standard gynecological outpatient care that are considered appropriate. At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated. [ABSTRACT FROM AUTHOR]

SUMMARY: The Elongator complex, which is conserved in eukaryotes, has multiple roles in diverse organisms. In Arabidopsis thaliana, Elongator is shown to be involved in development, hormone action and environmental responses. However, except for Arabidopsis, our knowledge of its function is poor in plants. In this study, we initially carried out a genetic analysis to characterize a rice mutant with narrow and curled leaves, termed curled later1 (cur1). The cur1 mutant displayed a heteroblastic change, whereby the mutant leaf phenotype appeared specifically at a later adult phase of vegetative development. The shoot apical meristem (SAM) was small and the leaf initiation rate was low, suggesting that the activity of the SAM seemed to be partially reduced in cur1. We then revealed that CUR1 encodes a yeast ELP1‐like protein, the largest subunit of Elongator. Furthermore, disruption of OsELP3 encoding the catalytic subunit of Elongator resulted in phenotypes similar to those of cur1, including the timing of the appearance of mutant phenotypes. Thus, Elongator activity seems to be specifically required for leaf development at the late vegetative phase. Transcriptome analysis showed that genes involved in protein quality control were highly upregulated in the cur1 shoot apex at the later vegetative phase, suggesting the restoration of impaired proteins probably produced by partial defects in translational control due to the loss of function of Elongator. The differences in the mutant phenotype and gene expression profile between CUR1 and its Arabidopsis ortholog suggest that Elongator has evolved to play a unique role in rice development. Significance Statement: We revealed that genes encoding the subunit of Elongator complex play an important role in the differentiation of bulliform and sclerenchyma cells in leaf development and in the maintenance of the shoot apical meristem. The mutant leaf phenotypes appeared specifically at the late adult phase of the vegetative development, suggesting a unique role of the Elongator complex in rice. [ABSTRACT FROM AUTHOR]

Introduction: The clinical efficacy and safety of hot balloon ablation (HBA) for the treatment of persistent AF (PerAF) remain unclear. We aimed to evaluate the clinical efficacy and safety of HBA versus cryoballoon ablation (CBA) as a treatment for PerAF. Methods: Of 195 consecutive patients who underwent initial catheter ablation for PerAF (AF lasting for longer than 7 days but shorter than 12 months), 158 propensity score‐matched (79 HBA and 79 CBA) patients were included in our retrospective study. All patients who underwent HBA received applications of energy to the upper posterior LA wall with a larger balloon in addition to single shots to each pulmonary vein (PV) ostium, whereas those who underwent CBA received simple single‐shot applications. The electrically isolated surface area (ISA), including the PV antrum and part of the posterior LA wall, was assessed by high‐resolution mapping. Results: The success of the PV isolation with balloon shots alone did not differ between HBA and CBA (81% vs. 85%; p =.52). The ISA was generally wide in both groups and significantly larger in the HBA group than in the CBA group (61 ± 16% vs. 51 ± 12%; p <.001). The incidence of procedure‐related complications did not differ significantly (HBA 4% vs. CBA 1%; p =.62) nor did the arrhythmia recurrence rate (HBA 11% vs. CBA 18% at 18 months; p =.26). Conclusion: Despite the difference in protocols, HBA and CBA performed for PerAF appear comparable in terms of wide antral lesion creation, clinical efficacy, and safety. Further prospective studies, based on a unified methodology, are needed. [ABSTRACT FROM AUTHOR]

This paper proposes and demonstrates a simple method using the intensity correlation of X‐ray fluorescence to evaluate the focused beam size of an X‐ray free‐electron laser (XFEL). This method was applied to the sub‐micrometre focused XFEL beam at the SPring‐8 Angstrom Compact Free Electron Laser, and the beam size evaluated using the proposed method was consistent with that measured using the knife‐edge scan method. The proposed method is readily applicable to extremely small X‐ray spots and can be applied for the precise diagnostics of sub‐10 nm focused X‐ray beams which have recently emerged. [ABSTRACT FROM AUTHOR]

Ultimate focusing of an X‐ray free‐electron laser (XFEL) enables the generation of ultrahigh‐intensity X‐ray pulses. Although sub‐10 nm focusing has already been achieved using synchrotron light sources, the sub‐10 nm focusing of XFEL beams remains difficult mainly because the insufficient stability of the light source hinders the evaluation of a focused beam profile. This problem is specifically disadvantageous for the Kirkpatrick–Baez (KB) mirror focusing system, in which a slight misalignment of ∼300 nrad can degrade the focused beam. In this work, an X‐ray nanobeam of a free‐electron laser was generated using reflective KB focusing optics combined with speckle interferometry. The speckle profiles generated by 2 nm platinum particles were systematically investigated on a single‐shot basis by changing the alignment of the multilayer KB mirror system installed at the SPring‐8 Angstrom Compact Free‐Electron Laser, in combination with computer simulations. It was verified that the KB mirror alignments were optimized with the required accuracy, and a focused vertical beam of 5.8 nm (±1.2 nm) was achieved after optimization. The speckle interferometry reported in this study is expected to be an effective tool for optimizing the alignment of nano‐focusing systems and for generating an unprecedented intensity of up to 1022 W cm−2 using XFEL sources. [ABSTRACT FROM AUTHOR]

A scanning soft X‐ray spectromicroscope was recently developed based mainly on the photon‐in/photon‐out measurement scheme for the investigation of local electronic structures on the surfaces and interfaces of advanced materials under conditions ranging from low vacuum to helium atmosphere. The apparatus was installed at the soft X‐ray beamline (BL17SU) at SPring‐8. The characteristic features of the apparatus are described in detail. The feasibility of this spectromicroscope was demonstrated using soft X‐ray undulator radiation. Here, based on these results, element‐specific two‐dimensional mapping and micro‐XAFS (X‐ray absorption fine structure) measurements are reported, as well as the observation of magnetic domain structures from using a reference sample of permalloy micro‐dot patterns fabricated on a silicon substrate, with modest spatial resolution (e.g. ∼500 nm). Then, the X‐ray radiation dose for Nafion® near the fluorine K‐edge is discussed as a typical example of material that is not radiation hardened against a focused X‐ray beam, for near future experiments. [ABSTRACT FROM AUTHOR]

We consider the optimal investment problem with random endowment in the presence of defaults. For an investor with constant absolute risk aversion, we identify the certainty equivalent, and compute prices for defaultable bonds and dynamic protection against default. This latter price is interpreted as the premium for a contingent credit default swap, and connects our work with earlier articles, where the investor is protected upon default. We consider a multiple risky asset model with a single default time, at which point each of the assets may jump in price. Investment opportunities are driven by a diffusion X taking values in an arbitrary region E⊆Rd. We allow for stochastic volatility, correlation, and recovery; unbounded random endowments; and postdefault trading. We identify the certainty equivalent with a semilinear parabolic partial differential equation with quadratic growth in both function and gradient. Under minimal integrability assumptions, we show that the certainty equivalent is a classical solution. Numerical examples highlight the relationship between the factor process, market dynamics, utility‐based prices, and default insurance premium. In particular, we show that the holder of a defaultable bond has a strong incentive to short the underlying stock, even for very low default intensities. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real‐world practice. Methods: This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Results: The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha‐fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). Conclusions: The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely. [ABSTRACT FROM AUTHOR]

With each single X‐ray pulse having its own characteristics, understanding the individual property of each X‐ray free‐electron laser (XFEL) pulse is essential for its applications in probing and manipulating specimens as well as in diagnosing the lasing performance. Intensive research using XFEL radiation over the last several years has introduced techniques to characterize the femtosecond XFEL pulses, but a simple characterization scheme, while not requiring ad hoc assumptions, to address multiple aspects of XFEL radiation via a single data collection process is scant. Here, it is shown that single‐particle diffraction patterns collected using single XFEL pulses can provide information about the incident photon flux and coherence property simultaneously, and the X‐ray beam profile is inferred. The proposed scheme is highly adaptable to most experimental configurations, and will become an essential approach to understanding single X‐ray pulses. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the clinical characteristics and outcomes of candidates for second‐line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma (HCC) after sorafenib treatment. Methods: Of 122 patients, 103 were radiologically confirmed as progressive disease (PD) (sorafenib‐refractory group), and 19 discontinued sorafenib therapy due to adverse events prior to radiologic PD (sorafenib‐intolerant group). Patients in the sorafenib‐refractory group were divided into two subgroups each, according to their eligibility for second‐line treatment (second‐line‐in and ‐out group), regorafenib (RESORCE‐in and ‐out group), or ramucirumab (REACH‐2‐in and ‐out group). Results: Patients included in the non‐candidate group were those with α‐fetoprotein level <400 ng/mL (n = 51, 49.5%), daily sorafenib dose <400 mg (n = 44, 42.7%), Child–Pugh B or C (n = 40, 38.8%), and Eastern Cooperative Oncology Group performance status score ≥2 (n = 24, 23.3%). The percentages of candidates were 57.3% for second‐line, 35.0% for regorafenib, and 23.3% for ramucirumab. The median post‐progression survival (PPS) was significantly longer for the second‐line‐in and the RESORCE‐in groups than in the non‐candidate groups (12.6 and 11.0 months vs. 3.0 and 6.1 months, respectively). The PPS was not significantly different between the REACH‐2‐in and ‐out groups. A significant predictor of candidates for second‐line treatment at sorafenib initiation was a Child–Pugh score of 5 (A5). Conclusions: Not all patients refractory to sorafenib were candidates for second‐line therapy. A Child–Pugh score of A5 at sorafenib initiation was an important and favorable factor related to eligibility for second‐line therapy and good outcomes. [ABSTRACT FROM AUTHOR]

Modified laparoscopic cerclage was developed as an easy laparoscopic approach during pregnancy, with sutures placed lateral to the uterine vessels. To the best of our knowledge, its successful use in the first trimester has not been reported in Japan. Additionally, there are no published data on chronological assessment of feto‐placental circulation using Doppler. Here, we present the case of a 31‐year‐old Japanese woman (gravida 2, para 1) with refractory cervical incompetence who had a history of preterm birth at 32 weeks of gestation and cervical conization. Modified laparoscopic cervicoisthmic cerclage was performed. Doppler findings showed normal feto‐placental circulation before and after the procedure. Her pregnancy progressed uneventfully with no significant feto‐placental circulation or obstetric complications, and the baby showed normal growth. Elective cesarean section was performed at 37 + 0 weeks' gestation. Modified laparoscopic cervicoisthmic cerclage is suggested as one of the treatment methods for pregnant women with refractory cervical incompetence. [ABSTRACT FROM AUTHOR]

To supply the growing demand for high photon flux in synchrotron science including surface diffraction, a middle energy‐bandwidth monochromator covering the 10−4 to 10−3 range has been adapted by applying an asymmetric diffraction geometry to a cryogenically cooled silicon 111 double‐crystal monochromator used as a standard for the undulator source at SPring‐8. The asymmetric geometry provides a great advantage with its ability to configure flux gains over a wide energy range by simply changing the asymmetry angle, while the angular divergence of the exit beam remains unchanged. A monolithic design with three faces has been employed, having one symmetrically cut and another two asymmetrically cut surfaces relative to the same atomic plane, maintaining cooling efficiency and the capability of quickly changing the reflection surface. With the asymmetric geometry, an X‐ray flux greater than 1014 photons s−1 was available around 12 keV. A maximum gain of 2.5 was obtained relative to the standard symmetric condition. [ABSTRACT FROM AUTHOR]

Control of xylem Na+ loading has often been named as the essential component of salinity tolerance mechanism. However, it is less clear to what extent the difference in this trait may determine differential salinity tolerance between species. In this study, barley (Hordeum vulgare L. cv. CM72) and rice (Oryza sativa L. cv. Dongjin) plants were grown under two levels of salinity. Na+ and K+ concentrations in the xylem sap, and shoot and root tissues were measured at different time points after stress onset. Salt‐exposed rice plants prevented xylem Na+ loading for several days, but failed to control this process in the longer term, ultimately resulting in a massive Na+ shoot loading. Barley plants quickly increased xylem Na+ concentration and its delivery to the shoot (most likely for the purpose of osmotic adjustment) but were able to reduce this process later on, keeping most of accumulated Na+ in the root, thus maintaining non‐toxic shoot Na+ level. Rice plants increased shoot K+ concentration, while barley plants maintained higher root K+ concentration. Control of xylem Na+ loading is remarkably different between rice and barley; this difference may differentiate the extent of the salinity tolerance between species. This trait should be investigated in more detail to be used in the breeding programs aimed to improve salinity tolerance in crops. [ABSTRACT FROM AUTHOR]

There have been reports that a vitamin K2 (VK2) analog is beneficial for the prevention of recurrence in hepatocellular carcinoma (HCC) patients after curative therapy. However, the VK2 analogs in current use do not appear to show dramatic antitumor effects when given alone. Here, we report the case of a 67‐year‐old male patient with sorafenib‐failure advanced HCC who achieved complete response (CR) after VK2 analog monotherapy. At the time of sorafenib failure confirmation, the patient had multiple intrahepatic tumors, multiple lung metastases, and Vp3 portal vein tumor thrombosis. He had poor liver function (Child–Pugh score of 9, Child–Pugh class B) and poor performance status (Eastern Cooperative Oncology Group performance status 2). Both serum α‐fetoprotein (AFP) and des‐γ‐carboxy prothrombin (DCP) levels were elevated (558 900 ng/mL and 917 300 mAU/mL, respectively). Treatment with VK2 analog was initiated at 45 mg/day. Five months later, both tumor markers had decreased to normal levels (AFP 8 ng/mL and DCP 10 mAU/mL). Contrast‐enhanced computed tomography showed that all intrahepatic tumors had shrunk, there was no enhancement of tumor staining in the arterial phase, and all lung metastases and portal vein tumor thromboses had disappeared. We considered that CR was achieved according to the modified Response Evaluation Criteria in Solid Tumors. Eighteen months after the start of VK2 analog administration, the patient continues to receive treatment and has remained in CR without adverse events. Here, we report a rare case of sorafenib‐failure advanced HCC in which sustained CR was achieved by VK2 analog monotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Liver transplantation is the most effective treatment for patients with end‐stage liver diseases, but hepatocyte transplantation using spheroids is expected to become an alternative strategy owing to the limited number of liver donors. However, the effects of the transplantation route and spheroid size on cell dynamics and the organ‐specific accumulation of hepatocytes are not well characterized. In this study, the influence of three delivery routes (tail vein, portal vein, and spleen) and three spheroid sizes (50, 100, and 150 µm in diameter) on the accumulation of human fetal hepatocytes labeled with quantum dots in the liver and other organs (heart, lung, kidney, and spleen) of recipient mice is investigated. Ex vivo fluorescence imaging reveals that the accumulation of transplanted cells in the liver is highest for transplantation via the portal vein compared with other routes. The accumulation efficiency depends on spheroid size, and spheroids with a diameter of 50 µm display greater accumulation than that of spheroids of other sizes. It is concluded that hepatocyte transplantation via the portal vein using small spheroids of 50 µm in diameter may be effective for clinical applications. [ABSTRACT FROM AUTHOR]

In this study, we investigated the real‐world data of the first approved interferon‐free regimen in Japan, daclatasvir and asunaprevir (DCV+ASV), in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). Among 924 patients registered in our multicenter study, 750 patients who were proven not to be infected with NS5A‐Y93H RAS by direct sequencing and to have no or subtle amount (less than 20%) of NS5A‐Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti‐viral effect and factors associated with SVR12. In statistical analysis, P < 0.05 was considered as significant. The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were male (odds ratio: 2.128; 95%CI: 1.134‐4.000, P = 0.019); lower serum γGTP (odds ratio: 1.007; 95%CI: 1.002‐1.012, P = 0.006); lower HCV‐RNA (odds ratio: 1.848; 95%CI: 1.087‐3.145, P = 0.023), and RVR (odds ratio: 6.250; 95%CI: 2.445‐15.873, P < 0.001). No patients with γGTP ≧ 80 IU/L without RVR showed SVR12 (0/4, 0%) and one patients with γGTP ≧ 20‐< 80 IU/L and HCV‐RNA ≧ 6.5 logIU/mL without RVR (5/10, 50%) and two female patients with RVR but γGTP ≧ 80 IU/L and HCV‐RNA ≧ 6.5 logIU/mL (7/13, 53.8%) showed a low SVR12 rate. In the present study, we showed a good viral response with DCV‐ASV treatment and identified four predictive factors associated with SVR12. These four markers could be a good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A‐Y93. [ABSTRACT FROM AUTHOR]

Aim: Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)‐DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment. Methods: A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV‐DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV‐DNA disappearance. Results: Thirteen patients developed HCC during the follow‐up period. The 1‐, 3‐, and 5‐year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220–17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438–21.519; P = 0.013), and higher HBV core‐related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683–108.815; P = 0.014) at the time of HBV‐DNA disappearance were significantly associated with the development of HCC. Conclusion: Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV‐DNA disappearance. [ABSTRACT FROM AUTHOR]

Aim: The optimal duration of follow‐up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long‐term follow‐up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long‐term follow‐up of patients who achieved SVR, with molecular analysis of HCV. Methods: A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin‐based therapy and achieved SVR were enrolled. All patients were recommended for follow‐up every 6 or 12 months. Results: The mean follow‐up period was 6.0 years (range, 1.0–13.6 years). Cumulative 5‐ and 10‐year follow‐up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5‐ and 10‐year follow‐up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30 months, respectively, after SVR. Phylogenetic analyses of core, non‐structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse. Conclusions: Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin‐based therapy is durable for prolonged periods. [ABSTRACT FROM AUTHOR]

The design and performance of a soft X-ray free-electron laser (FEL) beamline of the SPring-8 Compact free-electron LAser (SACLA) are described. The SPring-8 Compact SASE Source test accelerator, a prototype machine of SACLA, was relocated to the SACLA undulator hall for dedicated use for the soft X-ray FEL beamline. Since the accelerator is operated independently of the SACLA main linac that drives the two hard X-ray beamlines, it is possible to produce both soft and hard X-ray FEL simultaneously. The FEL pulse energy reached 110 µJ at a wavelength of 12.4 nm (i.e. photon energy of 100 eV) with an electron beam energy of 780 MeV. [ABSTRACT FROM AUTHOR]

Background and Aim Virologic failure of interferon-free therapy has been associated with Y93H mutation in the non-structure 5A region in hepatitis C virus (HCV) genotype 1b, and screening is recommended. A simple assay based on Q-Invader technology was developed for Y93H mutant screening to reduce cost and effort. The present study sought to compare two methods of detection of Y93H mutation and to evaluate the effect of Y93H mutation on response to interferon-free therapy. Methods Y93H mutation was examined in 258 patients with HCV genotype 1b using both direct sequencing analysis and the polymerase chain reaction (PCR)-Invader assay. Daclatasvir and asunaprevir or ledipasvir and sofosbuvir therapy was administered to 205 patients whose sustained virological responses (SVR) were checked. Results Hepatitis C virus was detected in 232 of 258 patients by direct sequencing and in 236 of 258 patients by the PCR-Invader assay. Forty of 231 cases were defined as Y93 mutation by direct sequencing, and 46 of 236 cases were defined as Y93 mutation by the PCR-Invader assay. SVR of patients who were Y93H by direct sequencing, Y93H by the PCR-Invader assay, and Y93H by both methods was 62.5%, 82.4%, and 50%, respectively. Conclusions The sensitivity of the PCR-Invader assay was similar to that of direct sequencing analysis; however, the PCR-Invader assay had a better ability to detect minor strains. Combination of the two assays would improve prediction of the response to daclatasvir and asunaprevir, but Y93H mutation had little effect on SVR in ledipasvir and sofosbuvir therapy. [ABSTRACT FROM AUTHOR]

Background and Aim In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis. Methods Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index ≧ 3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α-fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P < 0.05 was considered as significant levels. Results Antiviral effect was lower in patients with severe fibrosis at 8 and 12 weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P = 0.002 and P = 0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P = 0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α-fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4 weeks after the start of treatment. Conclusion Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well-tolerable treatment in these populations. [ABSTRACT FROM AUTHOR]

X-ray science has greatly benefited from the progress in X-ray optics. Advances in the design and the manufacturing techniques of X-ray optics are key to the success of various microscopic and spectroscopic techniques practiced today. Here the generation of apodized X-ray illumination using a two-stage deformable Kirkpatrick-Baez mirror system is presented. Such apodized illumination is marked by the suppression of the side-lobe intensities of the focused beam. Thus generated apodized illumination was employed to improve the image quality in scanning X-ray fluorescence microscopy. Imaging of a non-isolated object by coherent X-ray diffractive imaging with apodized illumination in a non-scanning mode is also presented. [ABSTRACT FROM AUTHOR]

The existence of a 30-nm fiber as a basic folding unit for DNA packaging has remained a topic of active discussion. Here, we characterize the supramolecular structures formed by reversible Mg2+-dependent self-association of linear 12-mer nucleosomal arrays using microscopy and physicochemical approaches. These reconstituted chromatin structures, which we call 'oligomers', are globular throughout all stages of cooperative assembly and range in size from ~50 nm to a maximum diameter of ~1,000 nm. The nucleosomal arrays were packaged within the oligomers as interdigitated 10-nm fibers, rather than folded 30-nm structures. Linker DNA was freely accessible to micrococcal nuclease, although the oligomers remained partially intact after linker DNA digestion. The organization of chromosomal fibers in human nuclei in situ was stabilized by 1 mM MgCl2, but became disrupted in the absence of MgCl2, conditions that also dissociated the oligomers in vitro. These results indicate that a 10-nm array of nucleosomes has the intrinsic ability to self-assemble into large chromatin globules stabilized by nucleosome-nucleosome interactions, and suggest that the oligomers are a good in vitro model for investigating the structure and organization of interphase chromosomes. [ABSTRACT FROM AUTHOR]

A combination of plane and threefold-shape X-ray mirrors was installed in SPring-8 BL29XUL. The second mirror has parabolic cylinder surfaces that collimate X-rays in the vertical direction. A performance test was conducted, yielding highly collimated 8 keV photon beams with an effective angular divergence of 0.4 µrad, below only 5% of that of the original beams. The double-mirror system preserved 70% of the total incident flux and nearly tripled the flux density at 988 m from the light source. The values of the observations were almost similar to those of our ray-tracing simulation. Based on the results a discussion of future prospects of the mirror system is included. [ABSTRACT FROM AUTHOR]

In March 2012, SACLA started user operations of the first compact X-ray free-electron laser (XFEL) facility. SACLA has been routinely providing users with stable XFEL light over a wide photon energy range from 4 to 15 keV and an ultrafast pulse duration below 10 fs. The facility supports experimental activities in broad fields by offering high-quality X-ray optics and diagnostics, as well as reliable multiport charge-coupled-device detectors, with flexible experimental configurations. A two-stage X-ray focusing system was developed that enables the highest intensity of 1020 W cm−2. Key scientific results published in 2013 and 2014 in diverse fields are reviewed. The main experimental systems developed for these applications are summarized. A perspective on the facility upgrade is presented. [ABSTRACT FROM AUTHOR]

Total-reflection mirror devices for X-ray free-electron laser focusing are discussed in terms of optical design, mirror-fabrication technology, a wavefront diagnosis method and radiation-damage testing, as a review of the present status of the focusing optics at the SPring-8 angstrom compact free-electron laser (SACLA). Designed beam sizes of 1 µm and 50 nm, and spot sizes almost matching prediction have been achieved and used to explore topics at the forefront of natural science. The feasibility of these devices is determined to be sufficient for long-term and stable operation at SACLA by investigating the radiation-damage threshold and achievable accuracies in the mirror figure and alignment. [ABSTRACT FROM AUTHOR]

Background and Aims The population of patients chronically infected with hepatitis C virus ( HCV) is aging, and the number of older patients with HCV-related hepatocellular carcinoma ( HCC) is increasing. The purpose of this study was to elucidate the effects of peginterferon and ribavirin combination therapy on prevention of HCC in older patients with chronic hepatitis C ( CH- C). Methods We compared the sustained virological response ( SVR) and treatment discontinuation rates between older (≥ 65 years) and younger patients (< 65 years) among 1280 CH- C patients treated with peginterferon alfa-2b and ribavirin. Cumulative incidence of HCC was determined by Kaplan- Meier analysis, and factors associated with liver carcinogenesis were analyzed by Cox proportional hazards regression. Results Older patients had a significantly lower SVR rate and a significantly higher discontinuation rate of treatment than younger patients. Fifty patients developed HCC during median follow-up period of 47 months. Cox proportional hazards regression analysis indicated that the following were independent risk factors associated with the development of HCC: older age, male, advanced fibrosis, non- SVR in all patients: higher gamma-glutamyltranspeptidase, and non- SVR in older patients. Older patients who achieved SVR had a significantly reduced rate of HCC compared with those who did not achieve SVR, especially those who had gamma-glutamyltranspeptidase over 44 IU/ L. Conclusions The SVR rate was lower and the combination therapy discontinuation rate was higher in older CH- C patients than in younger patients. However, older patients who achieved SVR had a markedly lower rate of HCC development compared with older patients who did not achieve SVR. [ABSTRACT FROM AUTHOR]

Background and Aim The single nucleotide polymorphism ( SNP) of interleukin 28 B ( IL28B) and the mutations in the NS5A region of hepatitis C virus ( HCV) genotype 1 have been associated with response to interferon ( IFN) therapy. However, these relationships in patients with HCV genotype 2 are not well understood. The aim of this study was to investigate whether the SNP of IL28B (rs8099917) and amino acid substitutions in the NS5A region in patients with HCV genotype 2 affect the response to IFN and ribavirin combination therapy. Methods The study enrolled 286 patients with chronic hepatitis C genotype 2. Patients received pegylated- IFN-alpha 2b once each week plus oral ribavirin daily for 24 weeks. Results Of the 286 patients, 215 (75.2%) achieved sustained virologic response ( SVR). Rate of SVR was similar in patients with IL28B TT allele (76%) and those with TG or GG alleles (72%). Patients with SVR were younger than those without SVR ( P < 0.001). SVR was achieved in 65.9% of patients with wild-type IFN sensitivity-determining region ( ISDR) and 83.5% of patients with mutant type ( P < 0.001). There were no significant differences in other factors, including sex, alanine aminotransferase, platelet count, HCV viral load, HCV genotype, and IL28B genotype. The factors related to SVR on multivariate analysis were age ( P = 0.019) and ISDR ( P = 0.003). Conclusions ISDR sequence variations are significantly associated with IFN responsiveness in patients with HCV genotype 2. The SNP of IL28B was not associated with SVR in patients with HCV genotype 2. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) are thought to be major effectors involved in viral clearance during acute infections, including hepatitis B virus (HBV) infection. A persistent HBV infection is characterized by a lack of or a weak CTL response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific CTLs leads to the clearance of HBV in patients with a chronic HBV infection. Previously, we reported that a-galactosylceramide (α-GalCer), a specific natural killer T (NKT) cell agonist, enhanced the induction of HBV surface antigen (HBsAg)-specific CTLs. In the present study, we found that inhibition of indoleamine 2,3-dioxygenase (IDO) activity enhanced the induction of HBsAg-specific CTLs after immunization with HBsAg and α-GalCer. The administration of HBsAg and α-GalCer increased the production of interleukin- 2 and interleukin-12b, which are crucial for the induction of HBsAg-specific CTLs. The production of these cytokines was more strongly enhanced in IDO knockout mice compared with wild-type mice. In addition, α-GalCer induced the production of IDO in CD11b+ cells, and these cells inhibited proliferation of HBsAg-specific CTLs. Our results lead to strategies for improving the induction of HBsAg-specific CTLs. [ABSTRACT FROM AUTHOR]

Aim Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus ( HCV) level have a high sustained virological response ( SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon ( PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region ( ISDR) and the single-nucleotide polymorphism ( SNP) of interleukin-28 B ( IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. Methods One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/m L or less. Results SVR was achieved in 94 patients (92.2%). HCV levels (≤50 KIU/m L) and ISDR (≥2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy ( P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR ( P = 0.004). Conclusion The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels. [ABSTRACT FROM AUTHOR]

Information from structural genomics experiments at the RIKEN SPring-8 Center, Japan has been compiled and published as an integrated database. The contents of the database are (i) experimental data from nine species of bacteria that cover a large variety of protein molecules in terms of both evolution and properties (http://database.riken.jp/db/bacpedia), (ii) experimental data from mutant proteins that were designed systematically to study the influence of mutations on the diffraction quality of protein crystals (http://database.riken.jp/db/bacpedia) and (iii) experimental data from heavy-atom-labelled proteins from the heavy-atom database HATODAS (http://database.riken.jp/db/hatodas). The database integration adopts the semantic web, which is suitable for data reuse and automatic processing, thereby allowing batch downloads of full data and data reconstruction to produce new databases. In addition, to enhance the use of data (i) and (ii) by general researchers in biosciences, a comprehensible user interface, Bacpedia (http://bacpedia.harima.riken.jp), has been developed. [ABSTRACT FROM AUTHOR]

Many patients with coagulation disorders are infected with hepatitis C virus (HCV) that advances to end stage liver disease, resulting in an increased number of deaths. The efficacy of ribavirin and peginterferon combination therapy for chronic HCV infection in patients with coagulation disorders has not been clarified fully. The aim of this study was to evaluate the efficacy and tolerability of combination therapy in this patient population compared with patients who are infected with HCV and do not have coagulation disorders. A total of 226 consecutive chronic hepatitis C patients were treated with combination therapy and divided into two groups: patients with (n = 23) and without coagulation disorders (n = 203). Clinical characteristics, sustained virological response rates obtained by an intention-to-treat analysis, and combination therapy discontinuation rates were compared between the two groups. The sustained virological response rates did not differ significantly between patients with and without coagulation disorders (65.2% vs. 47.8% by intention-to-treat analysis). According to a multivariate analysis, age, alanine aminotransferase, gamma-glutamyltransferase, and HCV genotype were associated significantly with a sustained virological response, whereas whether a patient had a coagulation disorder did not affect the sustained virological response. In conclusion, combination therapy for chronic hepatitis C was comparably effective between patients with and without coagulation disorders and did not result in adverse bleeding. J. Med. Virol. 85:228-234, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The monochromatic soft X-ray femtosecond pulses of the Free Electron Laser (FEL) with wavelengths of 17.2-61.5 nm were applied for measurements of optical features of point defects photoluminescence in LiF crystals. It was observed that peak of photoluminescence spectra appears near 530 nm and is associated with emission of F3+ centers. Our results suggest that a shortening of the applied laser pulses down to pico - or femtosecond duration causes redistribution of photolumi-nescence peak intensity from the red to the green part of the spectra and does not depend on the energy of EUV or X-ray photons. Dependence of peak intensity of photoluminescence spectra on the fluence of FEL radiation was measured. Even for relatively high fluencies a quenching phenomenon was not observed. [ABSTRACT FROM AUTHOR]

How a long strand of genomic DNA is compacted into a mitotic chromosome remains one of the basic questions in biology. The nucleosome fibre, in which DNA is wrapped around core histones, has long been assumed to be folded into a 30-nm chromatin fibre and further hierarchical regular structures to form mitotic chromosomes, although the actual existence of these regular structures is controversial. Here, we show that human mitotic HeLa chromosomes are mainly composed of irregularly folded nucleosome fibres rather than 30-nm chromatin fibres. Our comprehensive and quantitative study using cryo-electron microscopy and synchrotron X-ray scattering resolved the long-standing contradictions regarding the existence of 30-nm chromatin structures and detected no regular structure >11 nm. Our finding suggests that the mitotic chromosome consists of irregularly arranged nucleosome fibres, with a fractal nature, which permits a more dynamic and flexible genome organization than would be allowed by static regular structures. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) genotype 1a is rare in Japanese patients and the clinical characteristics of this genotype remain unclear. The interferon (IFN) sensitivity-determining region (ISDR) and single-nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) among patients with HCV genotype 1b are associated with IFN response, but associations among patients with genotype 1a are largely unknown. This study investigated the clinical characteristics of genotype 1a and examined whether genomic heterogeneity of the ISDR and SNPs of IL28B among patients with HCV genotype 1a affects response to combination therapy with pegylated-IFN-α2b and ribavirin. Subjects comprised 977 patients infected with HCV genotype 1, including 574 men and 412 women (mean age, 55.2 ± 10.6 years). HCV was genotyped by direct sequencing of the 5′-untranslated region and/or core regions and confirmed by direct sequencing of the NS5A region. HCV genotypes 1a (n = 32) and 1b (n = 945) were detected. Twenty-three (71.9%) of the 32 patients with genotype 1a were patients with hemophilia who had received imported clotting factors. Prevalence of genotype 1a after excluding patients with hemophilia was thus 0.9%. Of the 23 patients with genotype 1a who completed IFN therapy, 11 (47.8%) were defined as achieving sustained virological response. Factors related to sustained virological response by univariate analysis were IL28B and ISDR. In conclusion, HCV genotype 1a is rare in Japan. The presence of IL28B genotype TT, and more than two mutations, in the ISDR are associated with a good response to IFN therapy in patients with HCV genotype 1a. J. Med. Virol. 84:438-444, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background and aims: Mutations in the core and NS5A region of hepatitis C virus (HCV) genotype 1b have been associated with response to interferon (IFN) therapy. Genome-wide association studies have revealed that the single-nucleotide polymorphism (SNP) of interleukin 28B (IL28B) contributes to IFN response. The aim of this study was to investigate whether the SNP of IL28B (rs8099917) and amino acid substitutions in the core and NS5A region affect the response to IFN therapy. Methods: A total of 299 patients (157 men, 142 women; mean age, 55.9 ± 10.3 years) infected with HCV genotype 1b were studied. The fibrosis stage was diagnosed as F0 ( n=23), F1 ( n=121), F2 ( n=62), F3 ( n=32) and F4 ( n=7) by liver biopsy. Results: Of the 299 patients, 138 achieved sustained virological response (SVR). On univariate analysis, predictors of SVR were age <60 years, male gender, higher platelet count, lack of fibrosis, non-Q at core 70, mutant-type interferon sensitivity-determining region (ISDR) and IL28B genotype TT. The factors related to SVR on multivariate analysis were IL28B ( P=0.0001), fibrosis ( P=0.0111) and mutations in the core region70 ( P=0.0267) and ISDR ( P=0.0408). The best SVR was achieved in patients with non-Q70, mutant-type ISDR and T allele (74.5%), and the worst was achieved in patients with Q70, wild-type ISDR and G allele (8.1%). Conclusions: The SNP of IL28B and mutations in the core region and NS5A are associated with IFN responsiveness. Both host and viral factors might be useful for predicting IFN response. [ABSTRACT FROM AUTHOR]

Transient elastography is a non-invasive tool to measure liver stiffness (LS), which has been reported to correlate with stage of liver fibrosis. Extrahepatic cholestasis was reported to cause elevated LS, which is considered to be attributed to the increased hydrostatic pressure in the liver. In the present study, the correlation of LS with laboratory data was investigated in extrahepatic cholestasis. The change of LS after biliary drainage was also assessed. LS was measured in 29 patients with extrahepatic cholestasis due to carcinomas in 12 and non-neoplastic diseases of biliary tract or pancreas in 17. In 15 patients, LS was 11.4 kPa or higher which suggested liver cirrhosis in chronic infection of hepatitis C virus. LS significantly correlated positively with serum bilirubin levels ( r = 0.726, P < 0.0001) and negatively with serum aspartate aminotransferase (AST) levels ( r = −0.481, P = 0.0082) and alanine aminotransferase (ALT) levels ( r = −0.631, P = 0.0002). Biliary drainage led to a reduction of bilirubin by 13.5 to 0.9 mg/dL which was significantly correlated with a reduction of LS by 14.3 to 0.5 kPa ( r = 0.524, P = 0.0257). In extrahepatic cholestasis, the elevation of LS which is probably attributed to the increased hydrostatic pressure in the liver, correlates positively with the accumulation of bilirubin but negatively with damage of hepatocytes indicated by ALT levels. Further studies on the mechanism underlying the elevation of LS should be helpful to elucidate the pathogenesis of extrahepatic cholestasis. [ABSTRACT FROM AUTHOR]

The article presents the instrumentation and experimental procedures for measuring diffraction patterns from non-crystalline specimens using an undulator beamline (BL29XUL) at SPring-8. It provides a detailed account of the instrumentation, experimental procedures and post-experimental data analysis in coherent X-ray diffraction microscopy (CXDM) that yields high-quality image reconstructions. It also discusses the estimation of the central pixel of measured diffraction patterns.

Aim: To assess the regression of liver fibrosis after interferon (IFN) treatment in patients with chronic hepatitis C, liver stiffness (LS) was measured repeatedly and the factors associated with reduction of LS were assessed. Methods: LS was measured by transient elastography before treatment, at end of treatment (EOT), and 1 year and 2 years after EOT in 145 patients with chronic hepatitis C treated by IFN with or without ribavirin. Results: In the patients with sustained virological response (SVR) ( n = 93) and relapsers ( n = 28), LS significantly decreased at EOT (median, 5.4 [interquartile range, 4.0–8.6] kilopascals [kPa], P < 0.0001 and 6.8 [4.5–8.9] kPa, P = 0.0023) and 1 year after EOT (5.3 [4.2–7.0] kPa, P < 0.0001 and 6.8 [4.5–9.3] kPa, P = 0.0204) compared with baseline (8.0 [5.0–11.9] kPa and 10.6 [7.0–16.6] kPa). In SVR patients, LS significantly decreased 2 years after EOT (5.3 [4.1–6.3] kPa) compared with baseline ( P < 0.0001) and LS at EOT ( P = 0.0034). Two points or greater reduction of deduced stage at last LS measurement was observed in 78% of SVR patients, 59% of relapsers and 15% of patients with non-virological response whose pretreatment deduced stages were F3–F4. Fibrosis stage, hyaluronic acid levels, duration of treatment, response to treatment and alanine aminotransferase levels were associated with a 2-point or greater decrease of deduced fibrosis stage. Conclusion: IFN treatment reduced LS in SVR patients and relapsers. Significant reduction of LS is associated with milder fibrosis stage, lower hyaluronic acid levels, longer IFN treatment, virological response of SVR or relapse and higher alanine aminotransferase levels. [ABSTRACT FROM AUTHOR]

An inline spectrometer has been developed to monitor shot-by-shot pulse energies of a two-color X-ray beam. A thin film of diamond allows inline operation with minimum absorption. The absolute pulse energy for each color is determined by the inline spectrometer combined with a total pulse-energy monitor. A negative correlation is found between the two-color pulse energies. [ABSTRACT FROM AUTHOR]

Aim: Human hepatocytes are known to express an array of inflammatory cytokines and chemokines. In this study, we examined the potential roles of hepatocytes in regulating immune responses in the liver, by assessing the induction of Th1- or Th2-specific chemokines in HepG2 cells after various inflammatory stimulations. Methods: HepG2 cells were stimulated with IL-1α, IFN-γ, IL-4, IL-10, and/or CCL2, harvested at several time points, and served for the analyses of cytokine/chemokine mRNA expressions by semi-quantitative RT-PCR. Results: (i) IL-1α up-regulated mRNA levels of CXCL8, CXCL10, and CCL2. IFN-γ increased those of CXCL9, CXCL10, and CCL5, while IL-4 or IL-10 had no effect. (ii) Addition of IL-4 to the culture of IFN-γ-stimulated cells, down-regulated CXCL9 and CXCL10 mRNA levels. (iii) Addition of IFN-γ to the culture of IL-1α-stimulated cells, further up-regulated CXCL9 and CXCL10 mRNA levels. Addition of IL-4 decreased CXCL8 and CXCL10 levels, and increased CCL2 level in IL-1α-stimulated cells. (iv) CCL2 induced IL-4 mRNA expression. Conclusions: IFN-γ augmented mRNA expression of Th1-specific chemokines (CXCL9 and CXCL10) in HepG2 cells. IL-4 had no effect on those of Th2-spesific chemokines (CCL17 and CCL22); however, it was supposed to augment Th2 response indirectly through the induction of CCL2 under the inflammatory condition. The findings suggest that hepatocytes have ability to promote immune responses in the liver toward the direction, initially determined by the cytokine balances in the local inflammatory region. [ABSTRACT FROM AUTHOR]