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Summary Background Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder. Methods In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18–74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov , NCT02073279 . Findings 95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23–0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups. Interpretation Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD. Funding Chugai Pharmaceutical (Roche).

Balanced rates of mitochondrial division and fusion are required to maintain mitochondrial function, as well as cellular and organismal homeostasis. In mammals, the cellular machines that mediate these processes are dynamin-related GTPases; the cytosolic DRP1 mediates division, while the outer membrane MFN1/2 and inner membrane OPA1 mediate fusion. Unbalanced mitochondrial dynamics are linked to varied pathologies, including cell death and neurodegeneration, raising the possibility that small molecules that target the division and fusion machines to restore balance may have therapeutic potential. Here we describe the discovery of novel small molecules that directly and selectively inhibit assembly-stimulated GTPase activity of the division dynamin, DRP1. In addition, these small molecules restore wild type mtDNA copy number in MFN1 knockout mouse embryonic fibroblast cells, a phenotype linked to deficient mitochondrial fusion activity. Thus, these compounds are unique tools to explore the roles of mitochondrial division in cells, and to assess the potential therapeutic efficacy of rebalancing mitochondrial dynamics in pathologies associated with excessive mitochondrial division.

Highlights • Endometrial and cervical adenocarcinomas may demonstrate morphologic overlap. • Distinction between these is important as it dictates treatment and prognosis. • This diagnostic dilemma can be approached with a panel of stains., In a biopsy specimen, adenocarcinomas of the endometrium and uterine cervix may demonstrate significant morphologic overlap. The distinction between these two entities prior to surgical resection is clinically significant as assigning the primary site dictates treatment and prognosis. This diagnostic dilemma is approached by the application of a panel of immunohistochemical stains, traditionally composed of CEA, vimentin, p16, ER, and PR. Most cases are successfully managed with this panel; however, in difficult cases additional tools are needed to suggest a more definitive diagnosis. In this study, we reviewed the efficacy of the customary panel of stains, as well as the added value of new stains in the diagnosis of endocervical adenocarcinoma. Our cohort included biopsy samples of 90 patients (81 endometrial and 9 endocervical adenocarcinomas) with a subsequent hysterectomy for confirmation of diagnosis. This study validated the customary panel of stains and suggests additional markers to aid in the differential diagnosis (PAX8 and CAIX). The addition of PAX8 to the traditional panel increases PPV from 85.71% to 100%. A PPV of 100% may also be attained with fewer stains (five total), with the application of a proposed new panel, which includes PAX8, CAIX, CEA, p16 and ER. This is the first-time differential expression of CAIX has been suggested in the distinction between endocervical and endometrial adenocarcinomas.

Patients with Lynch Syndrome are at an increased risk for a variety of malignancies, including ovarian cancer. Ovarian cancers associated with Lynch Syndrome are predominantly clear cell or endometrioid in histology. Lynch Syndrome is characterized by germline mutations in mismatch repair (MMR) genes. The current study aims to assess the prevalence of loss of MMR expression in patients with endometrioid and clear cell ovarian carcinoma.A retrospective review identified 90 patients with endometrioid and/or clear cell carcinomas. Slides made from tumor tissue microarray blocks were evaluated using immunohistochemical stains with antibodies against MLH1, PMS2, MSH2, and MSH6. Statistical analysis was performed.Seven of the 90 cases (7.8%) had loss of MMR expression. The mean age of patients with loss of MMR expression (47 years) was significantly younger than those with retained MMR expression (p=0.014). Loss of MMR expression was present in 20% of patients under the age of 53 with clear cell or endometrioid cancers. Genetic studies found that 3 of the 5 patients with loss of MMR expression carried mutations consistent with Lynch Syndrome; acquired hypermethylation of MLH1 was noted in one patient. Six of 7 patients (86%) whose tumors lacked MMR expression had synchronous or metachronous primary malignancies, a significantly greater prevalence than those with retained MMR expression (p0.001).Patients under the age of 53 with clear cell or endometrioid ovarian carcinomas are at a clinically significant risk for loss of MMR expression and Lynch Syndrome; routine screening with immunohistochemical staining should be considered.

Objective This study examines premenopausal and early menopause patients in a unique population with endometrial cancer and loss of mismatch repair (MMR) gene expression. The purpose is to compare clinical and pathologic differences in patients with loss of expression (LOE) to those with normal expression (NE). Methods Endometrial cancer patients under age 60 in-between 1998 and 2008 were identified from a single tumor registry. Clinical and pathologic data were abstracted from records. Staining for expression of MSH6, MSH2, MLH1, and PMS2 were performed on archived tissue blocks. Statistical analysis was performed. Results 158 patients were analyzed; 58% Asian, 34% Pacific Islander, and 8% Caucasian. 31 demonstrated LOE of at least one MMR gene; 127 retained NE. 50% Caucasian, 21.9% Asian, and 12.5% Pacific Island populations had LOE of one or more MMR genes. LOE was found to have a higher incidence of Grade III (p = 0.0013) and stage 3–4 tumors (p = 0.0079), mean depth of myometrial invasion (p = 0.0019), lymphovascular space invasion (p = 0.0020), nodal metastases (p = 0.0157), and a lower incidence of Grade I (p = 0.0020) and stage 1A tumors (p = 0.0085). LOE had a significantly lower mean BMI (p = 0.0001). 35% of patients in the NE vs zero in the LOE group had a BMI greater than 40. Conclusion Younger patients with LOE endometrial cancer appear to represent a clinically significant subgroup of patients without features characteristically found in classic type 1 endometrial cancer generally demonstrating lower BMI and tumors associated with poor prognostic characteristics. It is unclear if the distinctive ethnicity found in Hawaii has a significant impact on outcome. Further investigation is necessary to identify appropriate treatment strategies.

By monitoring the temperature inside cryogenic equipment such as superconducting magnet, we can detect the indication of failures and prevent the equipment suffered from damage. It is possible to measure the multipoint temperature by one optical fiber sensor. This sensor is suitable to measure the temperature at cryogenic temperatures because of low heat invasion and high voltage insulation. In this study, as for Fiber Bragg Grating as abbreviated FBG system of multipoint type, we investigated the reproducibility by measuring the temperature repeatedly, and multipoint measurement characteristics by measuring the temperature inside a cryogenic equipment with temperature gradient. We also investigated the improvement of the sensitivity for temperature at cryogenic temperatures by enhancing the thermal expansion coefficient using the coated optical fiber sensor.

Suzaku launched in July 2005 is equipped with the wideband instruments covering 0.3–700 keV. In addition to these main instruments, active shield counters of the hard X-ray detector are designed to be a wideband all-sky monitor (WAM). The WAM is a powerful gamma-ray burst monitor with a wide energy range of 50–5000 keV and with a large effective area of 400 cm 2 even around 1 MeV. The paper describes the strategy for the prompt GRB observation with the WAM, and the follow-up observation of X-ray afterglows with the narrow field instruments. So far, the WAM has detected 53 GRBs and half of them were detected simultaneously with other satellites. In addition to that, from at least 8 GRBs, including a bright and hard GRB 051008, it is succeeded to observe significant gamma-ray emission up to 1 MeV. The X-ray afterglow observations were carried out on January 5 and on September 4, 2006. Their results are reported in separate paper.

The outermost layer of skin, the epidermis, is cornified epithelial tissue composed of keratinocytes. To maintain the structure and function of the epidermis, the regulation of proliferation, differentiation, and cornification of keratinocytes is crucial, and various soluble factors secreted by keratinocytes are involved in these regulations. Previously, work has shown that keratinocytes secreted the protein Kdap (keratinocyte differentiation-associated protein) associated with the formation of cornified cell envelopes, a specialized protective barrier structure on the periphery of terminally differentiating keratinocytes. In the present report, the canine counterpart of human Kdap is identified and an attempt has been made to define its physiological role in canine keratinization. Canine Kdap (cKdap) showed structural features commonly observed in other counterparts and is secreted from transfected cells. The expression profile of cKdap mRNA, which was restrictively expressed in cornified epithelial tissues besides skin has also been determined. These findings indicate that there is a strong association between cKdap expression and cornification, which supports previous observations that Kdap is involved in the synthesis and/or degradation of cornified cell envelopes in humans and mice.

Final goal of this study is to develop an automatic diagnosis algorithm of the cardiac diseases using magnetocardiography (MCG) measured by SQUID system. To estimate spatial distribution and changes in time of cardiac activities, we have developed a spatial frequency analysis method for MCG. By simulations with a simple cubic model for ventricle, it was found that the spatial phase spectrum of MCG indicates the movement and the direction of the cardiac excited wave front, and the amplitude spectrum indicates the spread of the excited wave front. We preliminarily applied this method to the MCG of a healthy subject, before examining the validity of this method to the abnormal cardiac excitation. The traces of the excited wave front that are considered by the analyzed result were not inconsistent with the present electrophysiological knowledge. It is suggested that this presented method can trace the spread of cardiac excitation with sufficient accuracy.

Magnetizations and the temperature dependence of susceptibility for several kinds of Co-based Laves-phase metamagnets have been investigated. A universal linear relation between the critical field of the metamagnetic transition, BC, and the inverse of susceptibility-maximum, χ(T max ) −1 , was demonstrated. The root-mean amplitude of spin fluctuations at the susceptibility-maximum temperature, ξ p (T max ), was estimated to be about 0.4μB/Co from the B C –χ(T max ) −1 relation on the basis of the spin fluctuation theory for itinerant-electron metamagnets.

Free vibrations of a fully clamped symmetrically laminated skew plate are analyzed by a numerical approach in which the Green function for a static bending problem is used. As a numerical example, results are presented for a three-layered symmetrically laminated skew plate. The effects of the skew angle and the fiber orientation angle on natural frequencies and mode shapes are discussed.

By using the reverse transcription polymerase chain reaction and Southern blot hybridization, we demonstrated that Fc epsilon RI alpha-chain (Fc epsilon RI alpha) messenger RNA was expressed in eosinophils purified from the peripheral blood of patients with allergic rhinitis and that this expression was enhanced by IL-4. However, studies in which flow cytometry or immunostaining was used did not reveal the expression of Fc epsilon RI alpha protein on eosinophils from peripheral blood. Neither IL-4 alone nor the combination of IL-4 and other cytokines could induce detectable Fc epsilon RI alpha protein; nevertheless, they do express Fc epsilon RI alpha mRNA. Double-labeling immunostaining on cryostat sections of nasal mucosa clearly demonstrated that some Fc epsilon RI alpha-positive cells were eosinophil cationic protein-positive, which confirms their eosinophilic nature. Not all the eosinophil cationic protein-positive cells express on Fc epsilon RI alpha signal. Considering that Fc epsilon RI alpha mRNA was detectable in four of five samples of eosinophils from those patients with nasal allergy and that only one of five eosinophil samples from normal subjects expressed Fc epsilon RI alpha mRNA, the level of Fc epsilon RI expression may be correlated with the activation of eosinophils. It seems very likely that some other unidentified factors are required for the process from the expression of Fc epsilon RI alpha mRNA to that of Fc epsilon RI as a protein.

SCID mice with circulating bovine red blood cells (Bo-RBC-SCID mice) were used to isolate Babesia parasites from grazing calves in Japan. Although the initial blood samples obtained from the calves contained both Babesia and Theileria parasites, we were able to isolate only the Babesia parasites by repeated blood passages in Bo-RBC-SCID mice, taking advantage of the much more rapid growth of Babesia than of Theileria. The parasites isolated had characteristics of large-type Babesia, showing typical paired pyriform morphology. The Bo-RBC-SCID mice infected with the Babesia parasites developed a high level of parasitemia, showing severe clinical symptoms characterized by hemoglobinuria, jaundice, and hemolytic anemia. In addition, some mice exhibited nervous symptoms, particularly paralysis of both posterior limbs. The results demonstrated that the Bo-RBC-SCID mouse model was useful not only for isolating Babesia from cattle but also for studying the disease caused by the Babesia infection.

The ability of recombinant murine (rMu) interferon (IFN) -γ to activate anti- Salmonella -activity in normal mice and beige mutant ( bg / bg ) mice with Chediak-Higashi syndrome (CHS) was examined. Previous intraperitoneal (i.p.) injection of rMuIFN-γ (10 4 U per mouse) significantly hindered the bacterial growth in the peritoneal cavities, spleens and livers of the mice after the i.p. infection with Salmonella enteritidis No. 11 strain. It was also effective on the beige mice that have phagocytic cells with a genetically impaired bactericidal function, suggesting that IFN-γ activates the pathway irrelevant to the beige mutation. The effect was the maximum, when IFN-γ was given 6 h before the challenge. The effect seemed to be due to the augmentation of bactericidal capacity rather than the prevention of systemic spread of bacteria. Recombinant human IFN-αA/D (10 2 –10 6 U per mouse), which produced effects identical to those of murine IFN-β, did not show such a bactericidal effect. Bactericidal activity enhancement was also seen in mice that had been injected with a small amount of rMuIFN-γ (10 2 U) and bacterial lipopolysaccharide (LPS) (10 ng) together at 6 h before the challenge, although the IFN-γ or LPS alone at these doses produced very little if any effect. Bactericidal effect enhancement was seen in mice that had been injected with IFN-γ at 6 h and LPS at 3 h before the challenge, while it could be hardly seen in mice injected with them in a reversed order. The simultaneous injections of rMuIFN-γ and LPS at 6 h in advance could confer a good protection against the infection with the S. tryphimurium LT2 strain.

A commercial multistage batch system electrodialysis plant for desalination of brackish groundwater was installed at Hatsushima, Atami City in April 1973. The plant has three stages each of which is operated at a constant voltage. Each stage has a dialyzer which is provided with 150 pairs of ion exchange membranes having an effective area of 1 m2 each. This plant is used for drinking water supply and has a capacity of 200 m3/day when the raw water has a saline concentration of 6,000 ppm TDS. The operation was very stable and easy, and it was possible to produce water of constant quality at all times regardless of fluctuations in the raw water concentration. The dialyzer was chemically cleaned for removal of deposits on membranes thereby reducing the maintenance cost by 62% without adversely influencing ion exchange membranes.

Refuse incineration plant operations involve many kinds of uncertain factors, such as the variable physical properties of refuse as fuel and the complexity of the burning phenomenon. That makes it very difficult to apply conventional control methods to the combustion control of the refuse. This paper describes a fuzzy control system for the refuse combustion process, which applies sensing and controlling rules of skilled operators. From a simulation analysis and some test-runs on an actual incineration plant, it is concluded that the fuzzy control system is effective and practical toward plant automation.

From January 1, 1946, through January 1, 1986, at the University of Michigan, 60 patients were treated with Stage IB (FIGO) carcinoma of the cervix with lymph node metastases. Clinical variables were examined with regard to long-term survival. Prognostically significant variables were (1) highest level of lymph node involvement and (2) tumor histology. Patients with common iliac or periaortic node involvement had an actuarial survival at 5 years of 14%; 5-year survival for patients with only pelvic node involvement (external iliac, hypogastric, or obturator) was 68%. Patients with adenocarcinoma or adenosquamous histology had an actuarial survival at 5 years of 16%; 5-year survival for patient with squamous cell carcinoma was 71%. Overall survival for all patients with lymph node involvement was 61%. For patients undergoing radical hysterectomy as primary treatment, postoperative adjuvant radiotherapy did not significantly improve survival.

In patients treated for ovarian cancer it is crucial to distinguish recurrent malignancy from a benign process. Presented herein is a patient who developed bilateral pelvic lymphoceles following a second-look laparotomy for ovarian cancer. Indications for surgical intervention are discussed and the preferred surgical approach is outlined.

The binary systems that have been detected in gamma rays have proven very useful to study high-energy processes, in particular particle acceleration, emission and radiation reprocessing, and the dynamics of the underlying magnetized flows. Binary systems, either detected or potential gamma-ray emitters, can be grouped in different subclasses depending on the nature of the binary components or the origin of the particle acceleration: the interaction of the winds of either a pulsar and a massive star or two massive stars; accretion onto a compact object and jet formation; and interaction of a relativistic outflow with the external medium. We evaluate the potentialities of an instrument like the Cherenkov telescope array (CTA) to study the non-thermal physics of gamma-ray binaries, which requires the observation of high-energy phenomena at different time and spatial scales. We analyze the capability of CTA, under different configurations, to probe the spectral, temporal and spatial behavior of gamma-ray binaries in the context of the known or expected physics of these sources. CTA will be able to probe with high spectral, temporal and spatial resolution the physical processes behind the gamma-ray emission in binaries, significantly increasing as well the number of known sources. This will allow the derivation of information on the particle acceleration and emission sites qualitatively better than what is currently available., Comment: 23 pages, 13 figures, accepted for publication in Astroparticle Physics, special issue on Physics with the Cherenkov Telescope Array