Evaluation of responses to immunosuppressive therapy in dogs with suspected non-regenerative immune-mediated anaemia: 11 cases (2012-2018).

OBJECTIVES: We aimed to determine the response time to immunosuppressive therapy and time required to achieve a 5% increase in haematocrit among dogs with non-regenerative immune-mediated anaemia. MATERIALS AND METHODS: Client-owned dogs diagnosed with non-regenerative immune-mediated anaemia in Hokkaido University Veterinary Teaching Hospital between December 2012 and May 2018 were enrolled. The first treatment regimen included prednisolone (2 mg/kg/day) and ciclosporin (up to 10 mg/kg/day) for 8 weeks. Dogs that did not respond to the first regimen proceeded to the second regimen comprising prednisolone and mycophenolate mofetil (15 mg/kg, twice a day). Reticulocyte count and haematocrit were monitored every 1 to 2 weeks. Treatment response was defined as an absolute reticulocyte count more than 60×103 /µL or increasing haematocrit. RESULTS: During the study period, 23 dogs fulfilled the inclusion criteria for non-regenerative immune-mediated anaemia. Twelve dogs were excluded from this study for various reasons and response to therapy was evaluated in the remaining 11 dogs. Treatment responses were observed in 8 of 11 dogs, and the median time to response was 39.5 days (range 8 to 92 days). Two responders were unable to continue the first treatment regimen and were switched to the second regimen owing to anorexia and nausea, possibly induced by ciclosporin; withdrawal of ciclosporin improved their symptoms. The time required to achieve a 5% increase in haematocrit was assessed in the other six dogs, with a median of 55.5 days (range 8 to 135 days). CLINICAL SIGNIFICANCE: Here we report the response to a standardised treatment protocol in dogs with non-regenerative immune-mediated anaemia. Knowledge of potential side effects and expected therapeutic outcomes may be of use for veterinary practitioners treating this condition.

Terahertz-field-induced polar charge order in electronic-type dielectrics.

Ultrafast electronic-phase change in solids by light, called photoinduced phase transition, is a central issue in the field of non-equilibrium quantum physics, which has been developed very recently. In most of those phenomena, charge or spin orders in an original phase are melted by photocarrier generations, while an ordered state is usually difficult to be created from a non-ordered state by a photoexcitation. Here, we demonstrate that a strong terahertz electric-field pulse changes a Mott insulator of an organic molecular compound in κ-(ET)2Cu[N(CN)2]Cl (ET = bis(ethylenedithio)tetrathiafulvalene), to a macroscopically polarized charge-order state; herein, electronic ferroelectricity is induced by the collective intermolecular charge transfers in each dimer. In contrast, in an isostructural compound, κ-(ET)2Cu2(CN)3, which shows the spin-liquid state at low temperatures, a similar polar charge order is not stabilized by the same terahertz pulse. From the comparative studies of terahertz-field-induced second-harmonic-generation and reflectivity changes in the two compounds, we suggest the possibility that a coupling of charge and spin degrees of freedom would play important roles in the stabilization of polar charge order.

DISCRIMINATION METHOD FOR GAMMA RAY DOSES IN NEUTRON FIELDS USING AN IONIZATION CHAMBER WITH ATTENUATION FILTERS.

Neutron fields produced by an accelerator-driven neutron source are generally mixed radiation fields that consist of fast neutrons and gamma rays. To estimate the biological effects of fast neutrons precisely, the gamma ray dose contamination must be evaluated in neutron fields. In this work, we developed a discrimination technique for absorbed doses (60Co gamma-ray equivalent) of fast neutrons and gamma rays using an ionization chamber. The filter thickness dependences of the absorbed doses of fast neutrons and gamma rays are different for a given filter material. Thus, the absorbed doses of each type of radiation were distinguished by fitting the dose attenuation curve, which was measured with an ionization chamber and attenuation filters, with a two-component exponential function. The absorbed dose of fast neutrons and gamma rays with no attenuation filter was evaluated from the y-intercept of the fitting function. This technique was demonstrated in two neutron fields produced by 4 MeV proton and deuteron bombardment of a 9Be target. The thicknesses of the polyethylene attenuation filters were 0-350 mm. The dose attenuation coefficients of fast neutrons obtained by the two-component exponential fitting function for the 9Be(p,n)9 and 9Be(d,n) reactions showed differences of 1.5 and 1.7%, respectively, from the reference measurements using a CR-39 plastic nuclear track detector. The absorbed dose contributions of gamma rays in neutrons fields of the 9Be(p,n)9B and 9Be(d,n) reactions were evaluated as 30.2 ± 3.24% and 20.4 ± 5.16%, respectively, without polyethylene filters.

Mott transition by an impulsive dielectric breakdown.

The transition of a Mott insulator to metal, the Mott transition, can occur via carrier doping by elemental substitution, and by photoirradiation, as observed in transition-metal compounds and in organic materials. Here, we show that the application of a strong electric field can induce a Mott transition by a new pathway, namely through impulsive dielectric breakdown. Irradiation of a terahertz electric-field pulse on an ET-based compound, κ-(ET) 2Cu[N(CN) 2]Br (ET:bis(ethylenedithio)tetrathiafulvalene), collapses the original Mott gap of ∼30 meV with a ∼0.1 ps time constant after doublon-holon pair productions by quantum tunnelling processes, as indicated by the nonlinear increase of Drude-like low-energy spectral weights. Additionally, we demonstrate metallization using this method is faster than that by a femtosecond laser-pulse irradiation and that the transition dynamics are more electronic and coherent. Thus, strong terahertz-pulse irradiation is an effective approach to achieve a purely electronic Mott transition, enhancing the understanding of its quantum nature.

Novel electronic ferroelectricity in an organic charge-order insulator investigated with terahertz-pump optical-probe spectroscopy.

In electronic-type ferroelectrics, where dipole moments produced by the variations of electron configurations are aligned, the polarization is expected to be rapidly controlled by electric fields. Such a feature can be used for high-speed electric-switching and memory devices. Electronic-type ferroelectrics include charge degrees of freedom, so that they are sometimes conductive, complicating dielectric measurements. This makes difficult the exploration of electronic-type ferroelectrics and the understanding of their ferroelectric nature. Here, we show unambiguous evidence for electronic ferroelectricity in the charge-order (CO) phase of a prototypical ET-based molecular compound, α-(ET)2I3 (ET:bis(ethylenedithio)tetrathiafulvalene), using a terahertz pulse as an external electric field. Terahertz-pump second-harmonic-generation(SHG)-probe and optical-reflectivity-probe spectroscopy reveal that the ferroelectric polarization originates from intermolecular charge transfers and is inclined 27° from the horizontal CO stripe. These features are qualitatively reproduced by the density-functional-theory calculation. After sub-picosecond polarization modulation by terahertz fields, prominent oscillations appear in the reflectivity but not in the SHG-probe results, suggesting that the CO is coupled with molecular displacements, while the ferroelectricity is electronic in nature. The results presented here demonstrate that terahertz-pump optical-probe spectroscopy is a powerful tool not only for rapidly controlling polarizations, but also for clarifying the mechanisms of ferroelectricity.

Neutron interferometric measurement and calculations of a phase shift induced by Laue transmission.

This study investigates the phase shift induced by Laue transmission in a perfect Si crystal blade in unprecedented detail. This `Laue phase' was measured at two wavelengths in the vicinity of the Bragg condition within a neutron interferometer. In particular, the sensitivity of the Laue phase to the alignment of the monochromator and interferometer (rocking angle) and beam divergence has been verified. However, the influence of fundamental quantities, such as the neutron-electron scattering length, on the Laue phase is rather small. The fascinating steep phase slope of 5.5° [(220) Bragg peak] and 11.5° [(440) Bragg peak] per 0.001 arcsec deviation from the Bragg angle has been achieved. The results are analysed using an upgraded simulation tool.

Status of ion sources at National Institute of Radiological Sciences.

The National Institute of Radiological Sciences (NIRS) maintains various ion accelerators in order to study the effects of radiation of the human body and medical uses of radiation. Two electrostatic tandem accelerators and three cyclotrons delivered by commercial companies have offered various life science tools; these include proton-induced x-ray emission analysis (PIXE), micro beam irradiation, neutron exposure, and radioisotope tracers and probes. A duoplasmatron, a multicusp ion source, a penning ion source (PIG), and an electron cyclotron resonance ion source (ECRIS) are in operation for these purposes. The Heavy-Ion Medical Accelerator in Chiba (HIMAC) is an accelerator complex for heavy-ion radiotherapy, fully developed by NIRS. HIMAC is utilized not only for daily treatment with the carbon beam but also for fundamental experiments. Several ECRISs and a PIG at HIMAC satisfy various research and clinical requirements.

Effects of subchronic inhalation exposure to ethyl tertiary butyl ether on splenocytes in mice.

Ethyl tertiary-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. The current use of ETBE in gasoline or petrol is modest but increasing. To investigate the effects of ETBE on splenocytes, mice were exposed to 0 (control), 500 ppm, 1750 ppm, or 5000 ppm of ETBE by inhalation for 6 h/day for 5 days/wk over a 6- or 13-week period. Splenocytes were harvested from the control and exposed mice, and the following cell phenotypes were quantified by flow cytometry: (1) B cells (PerCP-Cy5.5-CD45R/B220), (2) T cells (PerCP-Cy5-CD3e), (3) T cell subsets (FITC-CD4 and PE-CD8a), (4) natural killer (NK) cells (PE-NK1.1), and (5) macrophages (FITC-CD11b). Body weight and the weight of the spleen were also examined. ETBE-exposure did not affect the weight of the spleen or body weight, while it transiently increased the number of RBC and the Hb concentration. The numbers of splenic CD3+, CD4+, and CD8+ T cells, the percentage of CD4+ T cells and the CD4+/CD8+ T cell ratio in the ETBE-exposed groups were significantly decreased in a dose-dependent manner. However, ETBE exposure did not affect the numbers of splenic NK cells, B cells, or macrophages or the total number of splenocytes. The above findings indicate that ETBE selectively affects the number of splenic T cells in mice.

A neutron interferometric measurement of a phase shift induced by Laue transmission.

The phenomenon of a neutron phase shift due to Laue transmission in a perfect crystal blade is discussed. Quantitative measurements of this phase shift are presented in the vicinity of the Bragg condition well in agreement with numerical calculations. The phase shift shows a strong angular sensitivity and might constitute an interesting opportunity for precision measurements of fundamental quantities like the neutron-electron scattering length or gravitational short-range interactions.

Effects of KP-496, a novel dual antagonist of leukotriene D(4) and thromboxane A (2) receptors on nasal blockage in guinea pig models of allergic rhinitis.

OBJECTIVE AND DESIGN: KP-496 is a novel dual antagonist for leukotriene (LT) D(4) and thromboxane (TX) A(2) receptors. We investigated effects of KP-496 on antigeninduced nasal blockage in 2 guinea pig models of allergic rhinitis. SUBJECTS: Male Hartley guinea pigs were used. TREATMENT: Animals were actively sensitized with ovalbumin (OVA) or Japanese cedar pollen, and were then repeatedly challenged with OVA or pollen, respectively. KP-496 (0.003 %-0.05 %) was intranasally administered 0.5 or 1 h before and 2 h after an antigen challenge. METHODS: As an indicator of nasal blockage, specific airway resistance was measured using a double-flow plethysmograph system. Statistical analyses were performed with Dunnett's test (OVA model) or t-test (pollen model). RESULTS: Although early phase response was not affected by even a high dose (0.03 %) of KP-496, late phase nasal blockage (1.68 +/- 0.26) was inhibited by 0.01 % (0.87 +/- 0.19; p <0.05) and 0.03 % (0.44 +/- 0.12; p <0.01) of KP-496 in the OVA model. On the other hand, both early (5.60 +/- 0.77) and late phase responses (7.90 +/- 1.70) were inhibited by 0.05 % KP-496 to 2.68 +/- 0.84 (p <0.05) and 2.71 +/- 0.83 (p <0.05), respectively, in the pollen model, in which nasal hyperresponsiveness had been acquired by multiple challenges. CONCLUSIONS: KP-496 may be clinically effective for nasal blockage in allergic rhinitis.

Effects of KP-496, a novel dual antagonist at the cysteinyl leukotriene receptor 1 and the thromboxane A(2) receptor, on airway obstruction in guinea pigs.

BACKGROUND AND PURPOSE: KP-496 is a novel dual antagonist for cysteinyl leukotriene receptor 1 (CysLT(1)) and thromboxane A(2) (TXA(2)) receptor (TP). The aim of this study was to evaluate the pharmacological profile of inhaled KP-496 and its effects on airway obstruction. EXPERIMENTAL APPROACH: Antagonist activities of inhaled KP-496 were investigated using bronchoconstriction induced in guinea pigs by LTD(4) or U46619, a stable TXA(2) mimetic. Guinea pigs sensitized with injections of ovalbumin were used to assess the effects of inhaled KP-496 on bronchoconstriction induced by antigen (i.v.). Another set of guinea pigs were sensitized and challenged with ovalbumin by inhalation and the effects of inhaled KP-496 on immediate and late airway responses and airway hyperresponsiveness were investigated. KEY RESULTS: KP-496 significantly inhibited LTD(4)- and U46619-induced bronchoconstriction in a dose-dependent manner. The inhibitory effects of KP-496 (1%) were comparable to those of montelukast (a CysLT(1) antagonist, p.o., 0.3 mg kg(-1)) or seratrodast (a TP antagonist, p.o., 3 mg kg(-1)). KP-496 (1%) and oral co-administration of montelukast (10 mg kg(-1)) and seratrodast (20 mg kg(-1)) significantly inhibited antigen-induced bronchoconstriction, whereas administration of montelukast or seratrodast separately did not inhibit antigen-induced bronchoconstriction. KP-496 exhibited dose-dependent and significant inhibitory effects on the immediate and late airway responses and airway hyperresponsiveness following antigen challenge. CONCLUSIONS AND IMPLICATIONS: KP-496 exerts effects in guinea pigs which could be beneficial in asthma. These effects of KP-496 were greater than those of a CysLT(1) antagonist or a TP antagonist, in preventing antigen-induced airway obstruction.

Cerebral blood volume changes in patients with eating disorders during word fluency: a preliminary study using multi-channel near infrared spectroscopy.

OBJECTIVE: This study investigated the characteristics of cerebral oxygenation changes in eating disorders patients (ED) and normal controls during the cognitive tasks, using a highly time-resolved, and non-invasive instrument. METHOD: Eleven female patients with anorexia nervosa or bulimia nervosa were recruited, and 11 healthy females participated. The relative concentrations of oxy-hemoglobin [o-Hb] and deoxy-hemoglobin [d-Hb] were measured during word fluency task using multichannel near infrared spectroscopy (NIRS). RESULTS: The increases of o-Hb and d-Hb during the task were compared between the groups. ED patients showed lower activation and a gradual increase in o-HB during the task. In the frontal, d-HB concentrations decreased during the task in ED patients. CONCLUSION: These specific patterns of oxygenation changes may indicate less supply and less demand of cerebral blood volume. Bedside measurements of cerebral oxygenation changes using NIRS are useful on understanding of neurophysiological features of ED.

Molecular detection and quantitative analysis of the entire spectrum of human adenoviruses by a two-reaction real-time PCR assay.

Adenoviruses (AdV) can cause life-threatening infections in immunosuppressed patients. Reliable diagnostic tests are therefore of paramount importance. Apparently, any of the six AdV species (A to F), currently comprising 51 different serotypes, can play a clinically important role in patients with impaired immune response. It is imperative therefore that diagnostic assays cover the entire spectrum of these viruses. We have sequenced presumably conserved regions of the adenoviral genome in all AdV serotypes. Based on the complete sequence information of the hexon gene, we were able to develop a two-reaction real-time PCR assay covering all human adenoviruses with equally high specificity and sensitivity. The detection systems were tested using reference strains for all 51 serotypes and >1,000 clinical samples derived from peripheral blood and stool specimens from pediatric patients after allogeneic stem cell transplantation. The two-reaction assay presented permits highly specific detection and quantification of adenoviral DNA of any serotype. From the perspective of routine clinical diagnosis, the assay represents an important improvement over existing approaches by providing a sensitive and economic technique for early detection and monitoring of adenoviral infections.

Plasma des-acyl and acyl ghrelin in patients with eating disorders.

A recently recognized peptide, ghrelin, increases appetite and energy retention in human. Previous reports have shown higher plasma level in eating disorder (ED) patients and correlations with body mass index (BMI). This study examined these findings by measuring active (N-RIA) and total (C-RIA) levels of plasma ghrelin. Multipurpose assessments of symptoms were conducted for 11 ED patients and 5 control females. Results revealed significant differences of C-RIA between the groups. The BMI did not correlate with ghrelin, but demonstrated reversal correlation with the ratio of N-RIA and C-RIA (NC ratio) according to the ED or control group. The NC ratio also tended to be associated with a self-rating score. The NC ratio might be related to specific characteristics of ghrelin secretion or clearance in ED patients. Further basic and clinical investigations are necessary.

Real-time quantitative PCR assays for detection and monitoring of pathogenic human viruses in immunosuppressed pediatric patients.

A panel of 23 real-time PCR assays based on TaqMan technology has been developed for the detection and monitoring of 16 different viruses and virus families including human polyomaviruses BK virus and JC virus, human herpesviruses 6, 7, and 8, human adenoviruses, herpes simplex viruses 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, parvovirus B19, influenza A and B viruses, parainfluenza viruses 1 to 3, enteroviruses, and respiratory syncytial virus. The test systems presented have a broad dynamic range and display high sensitivity, reproducibility, and specificity. Moreover, the assays allow precise quantification of viral load in a variety of clinical specimens. The ability to use uniform PCR conditions for all assays permits simultaneous processing and detection of many different viruses, thus economizing the diagnostic work. Our observations based on more than 50,000 assays reveal the potential of the real-time PCR tests to facilitate early diagnosis of infection and to monitor the kinetics of viral proliferation and the response to treatment. We demonstrate that, in immunosuppressed patients with invasive virus infections, surveillance by the assays described may permit detection of increasing viral load several days to weeks prior to the onset of clinical symptoms. In virus infections for which specific treatment is available, the quantitative PCR assays presented provide reliable diagnostic tools for timely initiation of appropriate therapy and for rapid assessment of the efficacy of antiviral treatment strategies.

Practical quantum key distribution with polarization entangled photons.

We present an entangled-state quantum cryptography system that operated for the first time in a real-world application scenario. The full key generation protocol was performed in real-time between two distributed embedded hardware devices, which were connected by 1.45 km of optical fiber, installed for this experiment in the Vienna sewage system. The generated quantum key was immediately handed over and used by a secure communication application.

Types of programmed cell death: two variants expressed by neonatal murine hepatocytes.

Neonatal livers examined with the terminal transferase-mediated dUTP nick end labeling (TUNEL) method contained numerous positive cells. Although the majority of dying cells are either hematopoietic cells including erythroids and granulocytes or macrophages, a few hepatocytes were also positive. As for the ultrastructural features of these dying hepatocytes, two different types, type I and II, could be identified. The early features of type I appeared in the cytoplasm, which was characterized by dilated rough endoplasmic reticulum, and the cell fragments displayed a round, foamy appearance. Type II was characterized by nuclear compaction and margination of heterochromatin resulting in the formation of sharply circumscribed masses, followed by the condensation of the cytoplasm. The cell death of type I, characterized by the formation of massive vacuolization of the endoplasmic reticulum, corresponds to cytoplasmic type degeneration or nonapoptotic death, while that of type II corresponds to nuclear type cell death or classical apoptotic death. In the two types of programmed cell death, the incidence of nonapoptotic cell death was much higher than that of classical apoptosis in neonatal murine hepatocytes.