The anesthetic effects of intramuscular alfaxalone in dogs premedicated with low-dose medetomidine and/or butorphanol.

We aimed to evaluate the induction, anesthesia, and cardiorespiratory effects of intramuscular (IM) anesthetic protocol with alfaxalone following premedication with low-dose medetomidine, butorphanol, or a combination of both (medetomidine-butorphanol) in dogs. Six healthy beagles were administered 1, 2.5, or 5 mg/kg alfaxalone IM following premedication with low-dose medetomidine (5 µg/kg; MA-IM), butorphanol (0.3 mg/kg; BA-IM), or medetomidine-butorphanol (5 µg/kg and 0.3 mg/kg, respectively; MBA-IM). Each dog received 9 treatments with minimum 7-day washout period between treatments. Dogs were allowed to breath room air during anesthetic induction. We attempted endotracheal intubation after alfaxalone administration. Alfaxalone produced a dose-dependent anesthetic effect in each anesthetic protocol. Intubation was achieved in 4 out of 6 dogs that received MA-IM and BA-IM with 2.5 mg/kg alfaxalone and in all dogs that received MBA-IM with 1, 2.5, and 5 mg/kg alfaxalone. The median durations [minimum-maximum] of accepting intubation were 79 [0-89], 97 [84-120], and 117 [84-217] min, respectively. Hypotension (mean arterial blood pressure <60 mmHg) did not develop, but bradycardia (heart rate <60 beats/min) was observed in all dogs that received the MA-IM and MBA-IM protocols. Severe hypoxemia (percutaneous arterial oxygen saturation <90%) developed in 2 dogs that received MBA-IM with 5 mg/kg alfaxalone. We consider that the MA-IM and BA-IM protocols with ≥2.5 mg/kg alfaxalone and the MBA-IM protocol with 1-2.5 mg/kg alfaxalone could provide clinically useful and effective anesthesia without causing severe cardiorespiratory depression in healthy dogs.

Short-Lived Radioisotope

The isotope ^{98}Tc decays to ^{98}Ru with a half-life of 4.2×10^{6} yr and could have been present in the early Solar System. In this Letter, we report on the first calculations of the production of ^{98}Tc by neutrino-induced reactions in core-collapse supernovae (the ν process). Our predicted ^{98}Tc abundance at the time of solar system formation is not much lower than the current measured upper limit raising the possibility for its detection in the not too distant future. We show that, if the initial abundance were to be precisely measured, the ^{98}Tc nuclear cosmochronometer could be used to evaluate a much more precise value of the duration time from the last core-collapse supernova to the formation of the solar system. Moreover, a unique and novel feature of the ^{98}Tc ν-process nucleosynthesis is the large contribution (∼20%) from charged current reactions with electron antineutrinos. This means that ^{98}Tc becomes a unique new ν-process probe of the temperature of the electron antineutrinos.

Correction to: Palivizumab Prophylaxis Against Respiratory Syncytial Virus Infection in Children with Immunocompromised Conditions or Down Syndrome: A Multicenter, Post-Marketing Surveillance in Japan.

"Newborns, infants, or young children aged 24 months and under who have Down syndrome, and children ≤ 24 months of age without a current hs-CHD if they had experienced persistent respiratory symptoms or regular outpatient treatment due to a respiratory tract infection in previous RSV seasons were also eligible for the study."

Palivizumab Prophylaxis Against Respiratory Syncytial Virus Infection in Children with Immunocompromised Conditions or Down Syndrome: A Multicenter, Post-Marketing Surveillance in Japan.

OBJECTIVE: The aim of this study was to assess the safety and effectiveness of palivizumab for the prevention of lower respiratory tract infection (LRI) caused by respiratory syncytial virus (RSV) in children with immunocompromised conditions or Down syndrome. METHODS: In this multicenter, post-marketing surveillance study (December 2013 to December 2015), children aged ≤24 months with immunocompromised conditions or Down syndrome (without hemodynamically significant congenital heart disease) receiving palivizumab immunoprophylaxis during two RSV seasons were observed until 30 days after the final palivizumab injection. Safety [adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs)] and effectiveness (frequency, incidence, and duration of hospitalization due to RSV infections) were assessed. RESULTS: Of 304 patients receiving palivizumab, 167 (54.9%) had immunocompromised conditions, and 138 (45.4%) had Down syndrome; 260 (85.5%) completed palivizumab immunoprophylaxis. The annual mean (±standard deviation) number of doses was 5.3 (±2.4) per season. Overall, 220 AEs occurred in 99 patients (32.6%), including 89 SAEs in 53 patients (17.4%). Of these, 33 AEs in 25 patients (8.22%) were considered ADRs, and 13 ADRs in 11 patients (3.62%) were considered SADRs. In four patients, five SADRs (nephroblastoma and asthma in the same patient, septic shock, device-related infection, and drug-induced liver injury) were previously unreported; however, none were considered drug-related. During the observation period, five RSV infections occurred and two patients required hospitalization. CONCLUSION: Palivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months.

A hybrid type Ia supernova with an early flash triggered by helium-shell detonation.

Type Ia supernovae arise from the thermonuclear explosion of white-dwarf stars that have cores of carbon and oxygen. The uniformity of their light curves makes these supernovae powerful cosmological distance indicators, but there have long been debates about exactly how their explosion is triggered and what kind of companion stars are involved. For example, the recent detection of the early ultraviolet pulse of a peculiar, subluminous type Ia supernova has been claimed as evidence for an interaction between a red-giant or a main-sequence companion and ejecta from a white-dwarf explosion. Here we report observations of a prominent but red optical flash that appears about half a day after the explosion of a type Ia supernova. This supernova shows hybrid features of different supernova subclasses, namely a light curve that is typical of normal-brightness supernovae, but with strong titanium absorption, which is commonly seen in the spectra of subluminous ones. We argue that this early flash does not occur through previously suggested mechanisms such as the companion-ejecta interaction. Instead, our simulations show that it could occur through detonation of a thin helium shell either on a near-Chandrasekhar-mass white dwarf, or on a sub-Chandrasekhar-mass white dwarf merging with a less-massive white dwarf. Our finding provides evidence that one branch of previously proposed explosion models-the helium-ignition branch-does exist in nature, and that such a model may account for the explosions of white dwarfs in a mass range wider than previously supposed.

Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage.

BACKGROUND: Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α (PDGFR α), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study. METHOD: We evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors. RESULT: Lenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100 mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100 mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p < 0.0004). Among 18 types of human primary tumors, kidney cancer had the highest MVD, while liver cancer had the lowest pericyte coverage, and cancers in Kidney and Stomach had highest vascular score. CONCLUSION: These results indicated that Lenvatinib inhibited VEGF- and FGF-driven angiogenesis and showed a broad spectrum of antitumor activity with a wide therapeutic window. MVD and pericyte-coverage of tumor vasculature might be biomarkers and suggest cases that would respond for lenvatinib therapy.

Detection of the gravitational lens magnifying a type Ia supernova.

Objects of known brightness, like type Ia supernovae (SNIa), can be used to measure distances. If a massive object warps spacetime to form multiple images of a background SNIa, a direct test of cosmic expansion is also possible. However, these lensing events must first be distinguished from other rare phenomena. Recently, a supernova was found to shine much brighter than normal for its distance, which resulted in a debate: Was it a new type of superluminous supernova or a normal SNIa magnified by a hidden gravitational lens? Here, we report that a spectrum obtained after the supernova faded away shows the presence of a foreground galaxy-the first found to strongly magnify a SNIa. We discuss how more lensed SNIa can be found than previously predicted.

Burden of menstrual symptoms in Japanese women - an analysis of medical care-seeking behavior from a survey-based study.

BACKGROUND: Menstrual symptoms are associated with various health problems in women of reproductive age, and this may impact their quality of life. Despite this, Japanese women are likely to hesitate seeking a specialist's medical help for their menstrual symptoms. PURPOSE: To study subject parameters including symptom severity, gynecological disorders, and treatments in medical care-seeking women (outpatient) and women opting for self-care (nonvisit), to identify reasons why Japanese women do not see a gynecologist, and to document the benefit of gynecologist visits by assessing the impact on women's daily lives. METHODS: Two online surveys were conducted among women aged 15-49 years. Sampling was structured to approximate the age and geographic distribution in Japan. Results of the first survey and part of the second survey on the overall current burden of menstrual symptoms are reported in a separate publication. Further outcomes from the second survey reported in this paper included data from the outpatient (n=274) and nonvisit (n=500) groups on symptom severity, gynecological disorders, medical treatment use, reasons for not seeking medical care, and the improvement of daily life. RESULTS: The outpatient group tended to have greater symptom severity compared to the nonvisit group. Uterine fibroids, dysmenorrhea, endometriosis, and premenstrual syndrome were the most commonly self-reported diagnoses, and oral contraceptives were frequently prescribed at gynecologist visits. Nonvisit group subjects felt that gynecologist consultations were unnecessary or felt resistant to them. Daily life was significantly improved after medical treatment from a gynecologist visit with associated economic savings, whilst the nonvisit group had no change after taking over-the-counter drugs to relieve their menstrual symptoms. CONCLUSION: The present study results indicate that Japanese women who were suffering from menstrual symptoms could benefit from visiting a gynecologist for easing their symptoms, hence improving their daily life.

Burden of menstrual symptoms in Japanese women: results from a survey-based study.

UNLABELLED: . OBJECTIVE: Menstrual symptoms are associated with various health problems in women and may also significantly impact their lives. This study aims to assess the current burden of menstrual symptoms in Japanese women. METHODS: Two online surveys were conducted among women aged 15-49 years, where sampling was designed to approximate the age and geographic distribution in Japan. The first survey collected data on menstrual symptom severity based on a modified, 35-item, Japanese version of the Menstrual Distress Questionnaire (mMDQ), current treatments, and impact on work productivity. The second survey collected costs of outpatient treatment within the previous 3 months. Additional outcomes of the second survey will be presented in a separate paper. RESULTS: In this study, 19,254 women had menses, with 74% suffering from menstrual symptoms. A total of 50% reported pain and 19% reported heavy bleeding. Increasing severity of menstrual symptoms and self-reported heavy bleeding were related to more outpatient visits and greater work productivity loss. Among subjects with heavy bleeding, increasing severity of symptoms was related to greater interference with daily life. The estimated annual economic burden extrapolated to the Japanese female population was 683 billion Japanese Yen (JPY) or ~8.6 billion United States Dollars (USD). LIMITATIONS: The study population may be biased due to the online survey method. CONCLUSIONS: To the authors' knowledge, this is the first large-scale research assessing outcomes by severity categories for all menstrual symptoms and women's perception of bleeding. A large proportion of women suffer from menstrual symptoms, and symptom severity impacts women's lives. Menstrual symptoms lead to significant economic burden, mainly due to work productivity loss. However, the majority of women do not visit a gynecologist, even when their menstrual symptoms are severe. Thus, increasing public awareness on the recently available medical treatments has the potential to improve the overall burden of menstrual problems.

Immunohistochemical Examination of a Resected Advanced Hilar Cholangiocarcinoma Arising in a 29-Year-Old Male without Primary Sclerosing Cholangitis.

A 29-year-old man with advanced hilar cholangiocarcinoma was successfully treated with an extended right lobectomy. The carbohydrate antigen 19-9 (CA19-9) level was elevated to 939 IU/l, and the pathological findings revealed moderately differentiated tubular adenocarcinoma which involved almost the entire thickness of the hepatic duct and the adjacent liver tissue (T3) and which was associated with lymph node metastasis (N1). It was a stage IIB (T3N1M0) tubular adenocarcinoma according to UICC pathological staging. Immunohistochemical examination revealed that Ki-67, cyclin D1, and MMP-7 were positive, and 14-3-3sigma and p27 were negative. The pathological and immunohistochemical findings indicated high malignant potential indicating poor prognosis. We administrated the postoperative adjunct gemcitabine combined with S-1 chemotherapy. The patient is alive without recurrence and doing well two years after surgery. We also review other reports of cholangiocarcinoma patients aged less than 30 years.

Tycho Brahe's 1572 supernova as a standard type Ia as revealed by its light-echo spectrum.

Type Ia supernovae are thermonuclear explosions of white dwarf stars in close binary systems. They play an important role as cosmological distance indicators and have led to the discovery of the accelerated expansion of the Universe. Among the most important unsolved questions about supernovae are how the explosion actually proceeds and whether accretion occurs from a companion or by the merging of two white dwarfs. Tycho Brahe's supernova of 1572 (SN 1572) is thought to be one of the best candidates for a type Ia supernova in the Milky Way. The proximity of the SN 1572 remnant has allowed detailed studies, such as the possible identification of the binary companion, and provides a unique opportunity to test theories of the explosion mechanism and the nature of the progenitor. The determination of the hitherto unknown spectroscopic type of this supernova is crucial in relating these results to the diverse population of type Ia supernovae. Here we report an optical spectrum of Tycho's supernova near maximum brightness, obtained from a scattered-light echo more than four centuries after the direct light from the explosion swept past the Earth. We find that SN 1572 belongs to the majority class of normal type Ia supernovae.

The metamorphosis of supernova SN 2008D/XRF 080109: a link between supernovae and GRBs/hypernovae.

The only supernovae (SNe) to show gamma-ray bursts (GRBs) or early x-ray emission thus far are overenergetic, broad-lined type Ic SNe (hypernovae, HNe). Recently, SN 2008D has shown several unusual features: (i) weak x-ray flash (XRF), (ii) an early, narrow optical peak, (iii) disappearance of the broad lines typical of SN Ic HNe, and (iv) development of helium lines as in SNe Ib. Detailed analysis shows that SN 2008D was not a normal supernova: Its explosion energy (E approximately 6x10(51) erg) and ejected mass [ approximately 7 times the mass of the Sun (M(middle dot in circle))] are intermediate between normal SNe Ibc and HNe. We conclude that SN 2008D was originally a approximately 30 M(middle dot in circle) star. When it collapsed, a black hole formed and a weak, mildly relativistic jet was produced, which caused the XRF. SN 2008D is probably among the weakest explosions that produce relativistic jets. Inner engine activity appears to be present whenever massive stars collapse to black holes.

Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies.

Nuclear receptor subfamily 5, group A, member 1 (NR5A1 previously known as SF-1/AD4BP) is a transcription factor involved in the development of adrenal/gonadal tissues and steroidogenic lineage cell differentiation in adult somatic stem cells. To understand the cellular signaling network that regulates NR5A1 gene expression, loss of function screening with an siRNA kinome library, and gain of function screening with an addressable full-length cDNA library representing one quarter of the human genome was carried out. The NR5A1 gene expression was activated in mesenchymal stem cells by siRNA directed against protein kinase C (PKC)-delta, erb-B3, RhoGAP (ARHGAP26), and hexokinase 2, none of which were previously known to be involved in the NR5A1 gene expression. Among these, we identified crosstalk between erb-B3 and PKC-delta signaling cascades. In addition, the gain of function studies indicated that sex-determining region Y (SRY)-box 15 (SOX15), TEA domain family member 4, KIAA1257 (a gene of unknown function), ADAM metallopeptidase with thrombospondin type 1 motif 6, Josephin domain containing 1, centromere protein, TATA box-binding protein-associated factor 5-like RNA polymerase, and inducible T-cell co-stimulator activate NR5A1 gene expression. These results provide new insights into the molecular mechanisms of NR5A1 gene expression.

Asphericity in supernova explosions from late-time spectroscopy.

Core-collapse supernovae (CC-SNe) are the explosions that announce the death of massive stars. Some CC-SNe are linked to long-duration gamma-ray bursts (GRBs) and are highly aspherical. One important question is to what extent asphericity is common to all CC-SNe. Here we present late-time spectra for a number of CC-SNe from stripped-envelope stars and use them to explore any asphericity generated in the inner part of the exploding star, near the site of collapse. A range of oxygen emission-line profiles is observed, including a high incidence of double-peaked profiles, a distinct signature of an aspherical explosion. Our results suggest that all CC-SNe from stripped-envelope stars are aspherical explosions and that SNe accompanied by GRBs exhibit the highest degree of asphericity.

A neutron-star-driven X-ray flash associated with supernova SN 2006aj.

Supernovae connected with long-duration gamma-ray bursts (GRBs) are hyper-energetic explosions resulting from the collapse of very massive stars ( approximately 40 M\circ, where M\circ is the mass of the Sun) stripped of their outer hydrogen and helium envelopes. A very massive progenitor, collapsing to a black hole, was thought to be a requirement for the launch of a GRB. Here we report the results of modelling the spectra and light curve of SN 2006aj (ref. 9), which demonstrate that the supernova had a much smaller explosion energy and ejected much less mass than the other GRB-supernovae, suggesting that it was produced by a star whose initial mass was only approximately 20 M\circ. A star of this mass is expected to form a neutron star rather than a black hole when its core collapses. The smaller explosion energy of SN 2006aj is matched by the weakness and softness of GRB 060218 (an X-ray flash), and the weakness of the radio flux of the supernova. Our results indicate that the supernova-GRB connection extends to a much broader range of stellar masses than previously thought, possibly involving different physical mechanisms: a 'collapsar' (ref. 8) for the more massive stars collapsing to a black hole, and magnetic activity of the nascent neutron star for the less massive stars.

The first chemical enrichment in the universe and the formation of hyper metal-poor stars.

The recent discovery of a hyper-metal-poor (HMP) star, with a metallicity Fe/H smaller than 1/100,000 of the solar ratio, together with one earlier HMP star, has raised a challenging question whether these HMP stars are the actual first-generation, low-mass stars of the universe. We argue that these HMP stars are second-generation stars formed from gases that were chemically enriched by the first-generation supernovae. The key to this solution is the very unusual abundance patterns of these HMP stars and the similarities and differences between them. We can reproduce these abundance features with core-collapse "faint" supernova models that include extensive matter mixing and fallback during explosions.

An asymmetric energetic type Ic supernova viewed off-axis, and a link to gamma ray bursts.

Type Ic supernovae, the explosions after the core collapse of massive stars that have previously lost their hydrogen and helium envelopes, are particularly interesting because of their link with long-duration gamma ray bursts. Although indications exist that these explosions are aspherical, direct evidence has been missing. Late-time observations of supernova SN 2003jd, a luminous type Ic supernova, provide such evidence. Recent Subaru and Keck spectra reveal double-peaked profiles in the nebular lines of neutral oxygen and magnesium. These profiles are different from those of known type Ic supernovae, with or without a gamma ray burst, and they can be understood if SN 2003jd was an aspherical axisymmetric explosion viewed from near the equatorial plane. If SN 2003jd was associated with a gamma ray burst, we missed the burst because it was pointing away from us.

Nucleosynthetic signatures of the first stars.

The chemically most primitive stars provide constraints on the nature of the first stellar objects that formed in the Universe; elements other than hydrogen, helium and traces of lithium present within these objects were generated by nucleosynthesis in the very first stars. The relative abundances of elements in the surviving primitive stars reflect the masses of the first stars, because the pathways of nucleosynthesis are quite sensitive to stellar masses. Several models have been suggested to explain the origin of the abundance pattern of the giant star HE0107-5240, which hitherto exhibited the highest deficiency of heavy elements known. Here we report the discovery of HE1327-2326, a subgiant or main-sequence star with an iron abundance about a factor of two lower than that of HE0107-5240. Both stars show extreme overabundances of carbon and nitrogen with respect to iron, suggesting a similar origin of the abundance patterns. The unexpectedly low Li and high Sr abundances of HE1327-2326, however, challenge existing theoretical understanding: no model predicts the high Sr abundance or provides a Li depletion mechanism consistent with data available for the most metal-poor stars.

Repeated injections of energy in the first 600 ms of the giant flare of SGR 1806-20.

The massive flare of 27 December 2004 from the soft gamma-ray repeater SGR 1806-20, a possible magnetar, saturated almost all gamma-ray detectors, meaning that the profile of the pulse was poorly characterized. An accurate profile is essential to determine physically what was happening at the source. Here we report the unsaturated gamma-ray profile for the first 600 ms of the flare, with a time resolution of 5.48 ms. The peak of the profile (of the order of 10(7) photons cm(-2) s(-1)) was reached approximately 50 ms after the onset of the flare, and was then followed by a gradual decrease with superposed oscillatory modulations possibly representing repeated energy injections with approximately 60-ms intervals. The implied total energy is comparable to the stored magnetic energy in a magnetar (approximately 10(47) erg) based on the dipole magnetic field intensity (approximately 10(15) G), suggesting either that the energy release mechanism was extremely efficient or that the interior magnetic field is much stronger than the external dipole field.