Very-Low-Dose Pegylated Interferon a2a Plus Ribavirin Therapy for Advanced Liver Cirrhosis Type C: A Possible Therapeutic Alternative without Splenic Intervention

Despite the recent progress in interferon (IFN) therapies for chronic hepatitis C, liver cirrhosis remains refractory. One of the major obstacles to successful IFN therapy is low platelet count. Currently, splenic interventions, such as partial splenic embolization (PSE) or surgical splenectomy, have been applied effectively and make standard IFN therapy possible. However, there may be a group of patients with low platelet counts who can be treated without splenic intervention. We here report two patients with advanced type C liver cirrhosis who were successfully treated using very-low-dose pegylated interferon a2a plus ribavirin. One patient had a very low platelet count (2.5 × 104/μl) due to splenomegaly before treatment. However, pretreatment serum HCV titers were low in both patients and early viral responses were obtained in both. Because PSE or splenectomy may still have some safety concerns, this attenuated IFN treatment protocol can be an alternative therapeutic option for patients with advanced type C liver disease, but good virological factors for sustained virological response

A Fungal Metabolite Asperparaline A Strongly and Selectively Blocks Insect Nicotinic Acetylcholine Receptors: The First Report on the Mode of Action

Asperparalines produced by Aspergillus japonicus JV-23 induce paralysis in silkworm (Bombyx mori) larvae, but the target underlying insect toxicity remains unknown. In the present study, we have investigated the actions of asperparaline A on ligand-gated ion channels expressed in cultured larval brain neurons of the silkworm using patch-clamp electrophysiology. Bath-application of asperparaline A (10 µM) had no effect on the membrane current, but when delivered for 1 min prior to co-application with 10 µM acetylcholine (ACh), it blocked completely the ACh-induced current that was sensitive to mecamylamine, a nicotinic acetylcholine receptor (nAChR)-selective antaogonist. In contrast, 10 µM asperparaline A was ineffective on the γ-aminobutyric acid- and L-glutamate-induced responses of the Bombyx larval neurons. The fungal alkaloid showed no-use dependency in blocking the ACh-induced response with distinct affinity for the peak and slowly-desensitizing current amplitudes of the response to 10 µM ACh in terms of IC50 values of 20.2 and 39.6 nM, respectively. Asperparaline A (100 nM) reduced the maximum neuron response to ACh with a minimal shift in EC50, suggesting that the alkaloid is non-competitive with ACh. In contrast to showing marked blocking action on the insect nAChRs, it exhibited only a weak blocking action on chicken α3β4, α4β2 and α7 nAChRs expressed in Xenopus laevis oocytes, suggesting a high selectivity for insect over certain vertebrate nAChRs

The fungal alkaloid Okaramine-B activates an L-glutamate-gated chloride channel from Ixodes scapularis, a tick vector of Lyme disease

This work was supported by Merial Ltd., The Japan Society for the Promotion of Sciences (KAKENHI, Grant number: 17H01472) and The UK Medical Research Council.A novel L-glutamate-gated anion channel (IscaGluCl1) has been cloned from the black-legged tick, Ixodes scapularis, which transmits multiple pathogens including the agents of Lyme disease and human granulocytic anaplasmosis. When mRNA encoding IscaGluCl1 was expressed in Xenopus laevis oocytes, we detected robust 50–400 nA currents in response to 100 μM L-glutamate. Responses to L-glutamate were concentration-dependent (pEC50 3.64 ± 0.11). Ibotenate was a partial agonist on IscaGluCl1. We detected no response to 100 μM aspartate, quisqualate, kainate, AMPA or NMDA. Ivermectin at 1 μM activated IscaGluCl1, whereas picrotoxinin (pIC50 6.20 ± 0.04) and the phenylpyrazole fipronil (pIC50 6.90 ± 0.04) showed concentration-dependent block of the L-glutamate response. The indole alkaloid okaramine B, isolated from fermentation products of Penicillium simplicissimum (strain AK40) grown on okara pulp, activated IscaGluCl1 in a concentration-dependent manner (pEC50 5.43 ± 0.43) and may serve as a candidate lead compound for the development of new acaricides.Publisher PDFPeer reviewe

Heating duration of igneous rim formation on a chondrule in the Northwest Africa 3118 CV3(oxA) carbonaceous chondrite inferred from micro-scale migration of the oxygen isotopes

Due to their common occurrence in various types of chondrites, igneous rims formed on pre-existing chondrules throughout chondrule-forming regions of the solar nebula. Although the peak temperatures are thought to reach similar values to those achieved during chondrule formation events, the heating duration in chondrule rim formation has not been well defined. We determined the two-dimensional chemical and oxygen isotopic distributions in an igneous rim of a chondrule within the Northwest Africa 3118 CV3(oxA) chondrite with sub-micrometer resolution using secondary ion mass spectrometry and scanning electron microscopy. The igneous rim experienced aqueous alteration on the CV parent body. The aqueous alteration resulted in precipitation of the secondary FeO-rich olivine (Fa(40-49)) and slightly disturbed the Fe-Mg distribution in the MgO-rich olivine phenocrysts (Fa(11-22)) at about a 1 mu m scale. However, no oxygen isotopic disturbances were observed at a scale greater than 100 nm. The MgO-rich olivine, a primary phase of igneous rim formation, has delta O-17 = -6 +/- 3 parts per thousand and delta O-18 = -1 +/- 4 parts per thousand, and some grains contain extreme O-16-rich areas (delta O-17, delta O-18 = similar to -30 parts per thousand) nearly 10 mu m across. We detected oxygen isotopic migration of approximately 1 mu m at the boundaries of the extreme O-16-rich areas. Using oxygen self-diffusivity in olivine, the heating time of the igneous rim formation could have continued from several hours to several days at near liquidus temperatures (similar to 2000 K) in the solar nebula suggesting that the rim formed by a similar flash heating event that formed the chondrules

A method for the frequency control in time-resolved two-dimensional gigahertz surface acoustic wave imaging

We describe an extension of the time-resolved two-dimensional gigahertz surface acoustic wave imaging based on the optical pump-probe technique with periodic light source at a fixed repetition frequency. Usually such imaging measurement may generate and detect acoustic waves with their frequencies only at or near the integer multiples of the repetition frequency. Here we propose a method which utilizes the amplitude modulation of the excitation pulse train to modify the generation frequency free from the mentioned limitation, and allows for the first time the discrimination of the resulted upper- and lower-side-band frequency components in the detection. The validity of the method is demonstrated in a simple measurement on an isotropic glass plate covered by a metal thin film to extract the dispersion curves of the surface acoustic waves