T-705 (Favipiravir) suppresses tumor necrosis factor α production in response to influenza virus infection: A beneficial feature of T-705 as an anti-influenza drug.

Influenza virus infection induces the production of various cytokines, which play important roles in the pathogenesis of infection. Among the cytokines induced by influenza, tumor necrosis factor α (TNF-α) production has been correlated with the severity of lung lesions. We investigated the effects of T-705 (Favipiravir, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) on cytokine production due to influenza virus infection in vitro and in vivo, compared with oseltamivir or GS 4071, an active form of oseltamivir. TNF-α production in mouse macrophage-derived P388D1 cells infected with the influenza virus was lower following treatment with T-705 at concentrations of 0.3 to 100 µg/ml than treatment with GS 4071 at the same concentrations. The effect of treatment with T-705 on the cytokine production induced by the influenza virus infection was investigated in mouse influenza virus infection model. At 48 h post-infection (p.i.) T-705 significantly suppressed the viral load in the lungs and TNF-α production in the airways of infected mice even when viral loads were high. Furthermore, T-705 suppressed only TNF-α production from the early phase of infection. In this study, T-705 showed the antiviral activity of reducing pulmonary viral load compared with oseltamivir, thereby suppressing the TNF-α production. This feature of T-705 is benefit against severe influenza infection.

Large in-plane deformation of RuO6 octahedron and ferromagnetism of bulk SrRuO3.

SrRuO3 is a ferromagnetic metal with several unusual physical properties such as zero thermal expansion below Tc, so-called Invar behavior. Another anomalous feature is that the a-axis lattice constant is larger than the b-axis lattice constant, a clear deviation from the predictions of the Glazer structural description with rigid RuO6 octahedron motion. Using high resolution neutron diffraction techniques, we show how these two structural anomalies arise from the irregular in-plane deformation, i.e. plastic behavior of the RuO6 octahedron, a weak band Jahn-Teller distortion. We further demonstrate that the ferromagnetic instability of SrRuO3 is related to the temperature-induced localization of Ru 4d bands.

Distinguishing adrenal adenomas from non-adenomas on dynamic enhanced CT: a comparison of 5 and 10 min delays after intravenous contrast medium injection.

AIM: To evaluate the usefulness of several parameters of 5 min compared to 10 min delayed contrast-enhanced CT in distinguishing adenomas from non-adenomas. MATERIALS AND METHODS: The study population consisted of 94 patients (52 men and 42 women; mean age 62 years) with 103 adrenal lesions (75 adenomas and 28 non-adenomas). In each patient, unenhanced CT was followed by early, 5 and 10 min enhanced CT. Diagnostic parameters included delayed enhanced attenuation at 5 and 10 min, washout attenuation (WO) at 5 and 10 min, absolute percentage washout (APW) at 5 and 10 min, and relative percentage washout (RPW) at 5 and 10 min. The accuracy of each parameter for diagnosing adenomas from non-adenomas was calculated using receiver operating characteristic (ROC) analysis. RESULTS: Upon comparison between 5 and 10 min delayed contrast-enhanced CT for differentiating total adenomas or lipid-poor adenomas from non-adenomas, there was no significant difference in the area under the binomial ROC curve (Az) values of delayed enhanced attenuation (total adenomas versus non-adenomas, p = 0.164; lipid-poor adenomas versus non-adenomas, p = 0.178), WO (total adenomas versus non-adenomas, p = 0.216; lipid-poor adenomas versus non-adenomas, p = 0.230), APW (total adenomas versus non-adenomas, p = 0.401; lipid-poor adenomas versus non-adenomas, p = 0.870), or RPW (total adenomas versus non-adenomas, p = 0.160; lipid-poor adenomas versus non-adenomas, p = 0.780). CONCLUSION: Five minute contrast-enhanced CT was as useful as 10 min contrast-enhanced CT for differentiation of adrenal adenomas from non-adenomas.

Luminal membrane expression of mesothelin is a prominent poor prognostic factor for gastric cancer.

BACKGROUND: Mesothelin is expressed in various types of malignant tumour, and we recently reported that expression of mesothelin was related to an unfavourable patient outcome in pancreatic ductal adenocarcinoma. In this study, we examined the clinicopathological significance of the mesothelin expression in gastric cancer, especially in terms of its association with the staining pattern. METHODS: Tissue specimens from 110 gastric cancer patients were immunohistochemically examined. The staining proportion and intensity of mesothelin expression in tumour cells were analysed, and the localisation of mesothelin was classified into luminal membrane and/or cytoplasmic expression. RESULTS: Mesothelin was positive in 49 cases, and the incidence of mesothelin expression was correlated with lymph-node metastasis. Furthermore, luminal membrane staining of mesothelin was identified in 16 cases, and the incidence of luminal membrane expression was also correlated with pT factor, pStage, lymphatic permeation, blood vessel permeation, recurrence, and poor patient outcome. Multivariate analysis showed that luminal membrane expression of mesothelin was an independent predictor of overall patient survival. CONCLUSION: We described that the luminal membrane expression of mesothelin was a reliable prognostic factor in gastric cancer, suggesting the functional significance of membrane-localised mesothelin in the aggressive behaviour of gastric cancer cells.

Characterization of the Asian myopathy patients with VCP mutations.

BACKGROUND AND PURPOSE: Mutations in the valosin-containing protein (VCP) gene are known to cause inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). Despite an increasing number of clinical reports, only one Asian family with IBMPFD has been described. METHODS: To characterize patients with VCP mutations, we screened a total of 152 unrelated Asian families who were suspected to have rimmed vacuolar myopathy. RESULTS: We identified VCP mutations in seven patients from six unrelated Asian families. Five different missense mutations were found, including a novel p.Ala439Pro substitution. All patients had adult-onset progressive muscle wasting with variable involvement of axial, proximal, and distal muscles. Two of seven patients were suggested to have mild brain involvement including cerebellar ataxia, and only one showed radiological findings indicating a change in bone. Findings from skeletal muscle indicated mixed neurogenic and myogenic changes, fibers with rimmed vacuoles, and the presence of cytoplasmic and nuclear inclusions. These inclusions were immunopositive for VCP, ubiquitin, transactivation response DNA-binding protein 43, and also histone deacetylase 6 (HDAC6), of which function is regulated by VCP. Evidence of early nuclear and mitochondrial damage was also characteristic. CONCLUSIONS: Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.

Local structural properties of CuI at low temperatures.

This study examined the local structural properties of CuI at low temperatures of 10-300 K by x-ray diffraction (XRD) and extended x-ray absorption fine structure (EXAFS) measurements at the Cu K edge. The XRD data were refined using two models, split (distorted zinc-blende structure) and non-split (zinc-blende structure), using a conventional Rietveld refinement combined with a maximum entropy method (MEM). MEM/Rietveld analyses showed that both the split and non-split models could fit the data. EXAFS revealed the split model fit to be better than the non-split model. The split distance of Cu-I pairs was approximately 0.03 Å at 15 K and increased to 0.07 Å at 300 K. XRD and EXAFS combined together suggested that the CuI crystal was in a metastable state with a distorted zinc-blende structure at low temperatures.

Giant magneto-elastic coupling in multiferroic hexagonal manganites.

The motion of atoms in a solid always responds to cooling or heating in a way that is consistent with the symmetry of the given space group of the solid to which they belong. When the atoms move, the electronic structure of the solid changes, leading to different physical properties. Therefore, the determination of where atoms are and what atoms do is a cornerstone of modern solid-state physics. However, experimental observations of atomic displacements measured as a function of temperature are very rare, because those displacements are, in almost all cases, exceedingly small. Here we show, using a combination of diffraction techniques, that the hexagonal manganites RMnO3 (where R is a rare-earth element) undergo an isostructural transition with exceptionally large atomic displacements: two orders of magnitude larger than those seen in any other magnetic material, resulting in an unusually strong magneto-elastic coupling. We follow the exact atomic displacements of all the atoms in the unit cell as a function of temperature and find consistency with theoretical predictions based on group theories. We argue that this gigantic magneto-elastic coupling in RMnO3 holds the key to the recently observed magneto-electric phenomenon in this intriguing class of materials.

Does the permanent portacaval shunt for a small-for-size graft in a living donor liver transplantation do more harm than good?

In order to obviate a small-for-size graft syndrome (SFSGS), a portacaval (PC) shunt had been considered in a case of adult-to-adult living donor liver transplantation (AA-LDLT). In a recent AA-LDLT case, we adopted the PC shunt to resolve SFSGS; however, graft atrophy was observed in the late period of LDLT, thereby resulting in liver dysfunction. Due to the surgical closure of the PC shunt at 11 months post-LDLT, the graft regenerated gradually and resulted in the recovery of the liver function. This experience indicates that the portacaval shunt would overcome SFSGS in the early period of LDLT, while it would cause the graft atrophy and the graft dysfunction in the late period of LDLT.

Management and algorithm for focal nodular hyperplasia of the liver in children.

PURPOSE: The aim of this study was to determine an appropriate management plan for childhood and adolescent FNH, in particular to establish an algorithm for preoperative diagnosis and treatment. PATIENTS AND METHODS: Between 1985 and 2003, 4 children with FNH were diagnosed. Of these 4 patients, 3 (Group A) underwent tumor resection, and 1 (Group B) was treated by conservative management. Clinical data, pathological findings and follow-up were evaluated retrospectively. RESULTS: The 3 patients in Group A were symptomatic, while the 1 patient in Group B was asymptomatic. In 3 of 4 patients, a homogeneous tumor with a central stellate area was noted on abdominal ultrasonography, CT scan and MR imaging. In case 2, SPIO-enhanced MR imaging was useful for differentiating FNH from hepatocellular carcinoma. Though percutaneous needle biopsy was performed in case 3, a pathologically definitive diagnosis was impossible. An open biopsy was performed in case 4 and FNH was diagnosed. In case 4 treated by conservative management, the tumor size did not change during the 7 years after the diagnosis of FNH. CONCLUSION: FNH is usually treated conservatively because of the good evolutionary outcome of the lesion. Surgery is indicated in cases of complications, compressed adjacent organs, lesion progression, or for symptomatic patients. We advocate the use of less invasive SPIO-enhanced MR imaging instead of open biopsy when the diagnosis of focal liver lesions is not clear after contrast-enhanced CT scan and non-enhanced MR imaging.

Immune response to Japanese rabies vaccine in domestic dogs.

To evaluate the immune response induced by Japanese rabies vaccine for veterinary use as international units (IU), we measured levels of rabies antibody in serum samples from dogs by the rapid fluorescent focus inhibition test (RFFIT). In dogs immunized with a reference vaccine (potency level of 3.1 IU/ml), prepared by the same method as that used to produce commercial vaccine, and its dilutions (1 : 2 or 1 : 4), neutralizing-antibody levels increased to 1.0-2.0 IU/ml over a period of 1 month and then decreased to 0.2-1.5 IU/ml over a period of 1 year after the first vaccination and showed a remarkable increase to 12-47 IU/ml after the second vaccination. Sixty-five (74.7%) of the 87 serum samples from domestic dogs that were tested were seropositive (> or =0.1 IU/ml). However, the seropositive rate in dogs less than 1-year old at the time of vaccination was low (57.1%), and the antibody levels in these dogs were not sufficiently high for the rabies antibody titre in serum to be maintained for 1-year. Levels of rabies antibody in all serum samples were also measured by the virus neutralizing test (VNT), and a strong correlation (r > 0.95) was found between the results of the RFFIT and those of the VNT.

In vitro and in vivo activities of anti-influenza virus compound T-705.

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC(50)s) of 0.013 to 0.48 microg/ml, while it showed no cytotoxicity at concentrations up to 1,000 microg/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitor-resistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC(50)s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 x 10(2) PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.

Development of an implantable artificial anal sphincter by the use of the shape memory alloy.

In this study, we developed and assessed an artificial anal sphincter driven by an shape memory alloy actuator (AS-SMA). The performance characteristics of the device were analyzed with a measurement system. Assessment showed that the AS-SMA could generate a pressure of 55 mm Hg at an atmospheric temperature of 36 degrees C, and displacement of the SMA actuator was 7.5 mm when the temperature of the SMA plate was 55 degrees C. To evaluate opening and closing, we studied a piglet colostomy model, in which the AS-SMA was implanted around the colostomy in the extraperitoneal space. Flow control tests using living porcine intestine revealed that the AS-SMA could maintain fecal continence against an intestinal pressure of 75 mm Hg. The high pressure zone corresponding to the location of the device was demonstrated in a manometric examination. For 6 days after surgery, we activated the AS-SMA twice a day and observed the bowel movements. The animal experiment indicated that the AS-SMA is able to control the bowel movements of patients with fecal incontinence if several problems, such as burning of tissue around the device and compression injury of the intestine, are resolved.

Nicorandil, a potent cardioprotective agent, reduces QT dispersion during coronary angioplasty.

BACKGROUND: Previous studies have found that ST-segment elevation and QT dispersion are smaller in second coronary occlusions than in first occlusions, a trend that suggests ischemic preconditioning. It has not been established whether nicorandil reduces ST-segment elevation and QT dispersion during coronary angioplasty. METHODS AND RESULTS: Thirty patients with stable angina undergoing coronary angioplasty in the proximal left anterior descending artery were randomly assigned to one of two groups, receiving either 5 mg oral nicorandil 3 times daily (n = 15) or placebo (n = 15). In the control patients, the total ST-segment elevation decreased from 14 +/- 3 mm during the first inflation to 7 +/- 2 mm during the second inflation (P < .01). In contrast, in the nicorandil-treated patients, the total ST-segment elevation during the second inflation was roughly equivalent to that during the first inflation (8 +/- 3 mm vs 8 +/- 3 mm, P = not significant). After the first reperfusion, a significantly smaller increase in QT dispersion was observed in the nicorandil-treated patients than in the control patients (43 +/- 15 ms vs 54 +/- 15 ms, P < .001). However, after the second reperfusion, QT dispersion was similar for the two groups (32 +/- 15 ms vs 34 +/- 13 ms, P = not significant). CONCLUSIONS: Nicorandil may precondition the myocardium and may prevent the occurrence of ventricular arrhythmias after coronary reperfusion by suppressing the increase in QT dispersion.

Risk factors for stiffness of the wall of the thoracic aorta in patients with mild atherosis.

Previous studies have suggested that aging is associated with progressive arterial stiffness and widening of the pulse pressure, and pulse pressure has been found to be a risk factor of cardiovascular diseases. However, the effects of age, blood pressure (including pulse pressure) or atherogenic factors on thoracic aortic wall stiffness in patients with mild atherosis are unclear, so the present study used transesophageal echocardiography to examine 103 consecutive patients with various cardiovascular diseases. The extent of atherosis was evaluated in terms of intima-medial thickness (IMT), and 2 indices of wall stiffness in the aorta were calculated: elastic modulus and stiffness parameter (beta). In subjects with mild atherosis (IMT <1.0mm), age, body mass index, systolic blood pressure, pulse pressure, triglyceride level, and hypertension were factors significantly associated with high wall stiffness, and multiple logistic stepwise analysis revealed that age, pulse pressure, and triglyceride level were particularly significant.

Feeding characteristics of two tintinnid ciliate species on phytoplankton including harmful species: effects of prey size on ingestion rates and selectivity.

The feeding abilities of two tintinnid ciliates, Favella ehrenbergii and Favella taraikaensis, on 10 species of flagellates including harmful marine algae were examined under single prey conditions, and selective feeding of F. taraikaensis on two species of algae of different sizes was investigated under mixed prey conditions. Ingestion rates calculated from the rate of increases of auto-fluorescent particles inside food vacuoles in individuals ranged from 0.5 to 22.1 cells ind(-1) h(-1) for F. ehrenbergii and from 0.8 to 44.9 cells ind(-1) h(-1) for F. taraikaensis on nine species of prey algae. Significant ingestion rates of both Favella species could not be detected on Heterosigma akashiwo, although some individuals of both species were observed ingesting H. akashiwo in the initial incubation period. The relationship between prey cell volume and ingestion rate could be expressed mathematically for both Favella species, indicating that it is possible to estimate the potential feeding activity of each Favella species on specific algae using an equation, and may be applicable to evaluate the food value of prey alga for both Favella species. When F. taraikensis was fed mixtures of H. circularisquama and Pavlova lutheri, significant ingestion rates of H. circularisquama by F. taraikaensis could not be measured when H. circularisquama accounted for less than 20% of the other prey biomass. However, clear selectivity for H. circularisquama was observed when H. circularisquama reached and exceeded 34% of the other prey biomass. Under mixed prey conditions, it is likely that the selectivity of F. taraikaensis is stronger for larger prey compared to prey algae with a size near the lower limit on which F. taraikaensis can feed.

Observation of d(x2-y2)-like superconducting gap in an electron-doped high-temperature superconductor.

High-resolution angle-resolved photoemission spectroscopy of the electron-doped high-temperature superconductor Nd(2-x)Ce(x)CuO4 (x = 0.15, transition temperature T(c) = 22 K) has found the quasiparticle signature as well as the anisotropic d(x2-y2)-like superconducting gap. The spectral line shape at the superconducting state shows a strong anisotropic nature of the many-body interaction. The result suggests that the electron-hole symmetry is present in the high-temperature superconductors.

Transfusion-acquired, autochthonous human babesiosis in Japan: isolation of Babesia microti-like parasites with hu-RBC-SCID mice.

We have isolated piroplasms from a patient who developed the first case of human babesiosis in Japan by using NOD/shi-scid mice whose circulating erythrocytes (RBCs) had been replaced with human RBCs (hu-RBC-SCID mice). Following inoculation of the patient's blood specimen into hu-RBC-SCID mice, parasites proliferated within the human RBCs in the mice, resulting in a high level of parasitemia. Parasite DNA was prepared from blood samples of the patient and the mice, and the nuclear small-subunit rRNA gene (rDNA) was amplified and sequenced. Both DNA samples gave rise to identical sequences which showed the highest degree of homology (99.2%) with the Babesia microti rDNA. Because the patient had received a blood transfusion before the onset of babesiosis, we investigated the eight donors who were involved. Their archived blood samples were analyzed for specific antibody and parasite DNA; only a single donor was found to be positive by both tests, and the parasite rDNA sequence from the donor coincided with that derived from the patient. The donor's serum exhibited a high antibody titer against the isolate from the patient, whereas it exhibited only a weak cross-reaction against B. microti strains isolated in the United States. We conclude that the first Japanese babesiosis case occurred due to a blood transfusion and that the etiological agent is an indigenous Japanese parasite which may be a geographical variant of B. microti. Our results also demonstrated the usefulness of hu-RBC-SCID mice for isolation of parasites from humans and for maintenance of the parasite infectivity for human RBCs.

Association of human papillomavirus type 6 with a verruciform xanthoma.

We report a case of verruciform xanthoma (VX) associated with human papillomavirus (HPV) in a 67-year-old male. The patient had a pale-reddish, granular and verrucous tumor on the right side of his scrotum for four years. Histopathologic examination showed typical features of VX. HPV was detected by immunohistochemistry, electron microscopy, and PCR examinations. Ultrastructural examination revealed virus-like particles of 40-50 nm in the nucleus of the upper epidermal keratinocytes. HPV type 6a DNA was detected in lesional tissue by polymerase chain reaction and sequence analysis. To the best of our knowledge, this is the first case report of VX associated with HPV.