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101.
Elbasvir is an investigational NS5A inhibitor with in vitro activity against multiple HCV genotypes. Antiviral activity of elbasvir was measured in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The barrier to resistance was assessed by the number of resistant colonies selected by exposure to various elbasvir concentrations. In a phase 1b dose-escalating study, virologic responses were determined in 48 noncirrhotic adult men with chronic genotype 1 or 3 infections randomized to placebo or elbasvir from 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced from plasma specimens obtained before, during, and after treatment. Elbasvir suppressed the emergence of resistance-associated variants (RAVs) in vitro in a dose-dependent manner. Variants selected by exposure to high elbasvir concentrations typically encoded multiple amino acid substitutions (most commonly involving loci 30, 31, and 93), conferring high-level elbasvir resistance. In the monotherapy study, patients with genotype 1b had greater reductions in HCV RNA levels than patients with genotype 1a at all elbasvir doses; responses in patients with genotype 3 were generally less pronounced than for genotype 1, particularly at lower elbasvir doses. M28T, Q30R, L31V, and Y93H in genotype 1a, L31V and Y93H in genotype 1b, and A30K, L31F, and Y93H in genotype 3 were the predominant RAVs selected by elbasvir monotherapy. Virologic findings in patients were consistent with the preclinical observations. NS5A-RAVs emerged most often at amino acid positions 28, 30, 31, and 93 in both the laboratory and clinical trial. (The MK-8742 P002 trial has been registered at ClinicalTrials.gov under identifier NCT01532973.)  相似文献   
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Stainless steels are used as canister materials for interim storage of spent fuel. Crevice corrosion has proved to be a safety concern of 304L stainless steel spent fuel canisters, when exposed to the saline environments of coastal sites. To study the effects of chloride concentration and test duration on the crevice corrosion behavior, and the effect of relative humidity on the initiation of discrete SCC cracks, a test program was conducted on the 304L steel specimens sprayed with synthetic sea water of 3.5 wt.%. The salt-deposited specimens, wrapped up with a crevice former to form a crevice configuration, were then exposed to an environment at 45 °C with a pre-set 45%, 55%, and 70% relative humidity (RH), for 400 h and 10,000 h, respectively. The surface features and crack morphology of the tested 304L stainless-steel specimens were examined by energy-dispersive spectrometry (EDS) and electron back scatter diffraction (EBSD). For the specimens deposited with a chloride concentration of 1 g/m2, no cracks were found in the corroded regions after 400-h exposure, whereas SCC cracks were observed with the specimens tested for 10,000 h at all three pre-set relative humidity. The specimens tested at the pre-set relative humidity 45% are characterized with discrete SCC cracks, but, on the other hand, those exposed to the environments of 55% and 70% relative humidity show SCC cracks of distinct features. From the results of 10,000-h tests, it is inferred that the chloride concentration threshold for SCC initiation of 304L stainless steel at 45 °C is between 0.1 g/m2 and 1 g/m2.  相似文献   
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The hepatitis B virus (HBV) genomes in Taiwanese aborigines, whose ancestors have lived in Taiwan for over 10,000 years, have not been characterized. In order to characterize of HBV in this special population, serum samples were obtained from serologically HBsAg-positive 27 Taiwanese aborigines. The pre-S1/S2 region and the full-length 3.2 kb of the HBV genome were amplified by PCR. Obtained amplicons were sequenced and confirmed the HBV genotypes by phylogenetic analysis. By phylogenetic analysis of the sequence of pre-S1/pre-S2 region, HBV/B2 (21/27: 78 %) was the most prevalent followed by genotype D (6/27: 22 %). Two strains of HBV/B2, each having 3,215 bp genomes, had recombination with genotype C in the pre-C/C gene which is characteristic of subgenotype B2 circulating in Southeast Asia. Interestingly, six strains of genotype D formed a distinct cluster between subgenotypes D1 and D2 suggesting a novel group of HBV. A similar finding could also be confirmed based on the entire 3,182 bp genome from four strains of HBV/D. This new cluster was supported by a branch with 99 % bootstrap value and 3.4–5.8 % nucleotide divergence over the entire genome from other known subgenotypes D1 to D9. Four strains of the new D subgenotype showed serotype ayw2, but had unique amino acid sequences consisting of N115 in the preS/S gene; P41 in the X gene; S239, K/E295, V567, and P708 in the P gene, respectively. From the above results, we provisionally proposed to designate it as novel quasi-subgenotype D2 identified in Taiwanese aborigines.  相似文献   
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Klebsiella pneumoniae liver abscess (KPLA) is prevalent in East Asia. Liver abscess can develop after translocation of K. pneumoniae from a patient''s bowel into the liver via the portal circulation. TREM-1 (triggering receptor expressed on myeloid cells 1) amplifies inflammatory signaling during infection, but its role in KPLA is poorly understood. We used an animal study to characterize the role of TREM-1 in KPLA. We compared survival rates, bacterial burdens in tissues, inflammatory cytokine levels, and histology findings between wild-type and Trem-1 knockout (KO) mice after oral inoculation of capsular type K1 K. pneumoniae. Translocation of K. pneumoniae to mesenteric lymph nodes and liver was examined, and intestinal permeability, antimicrobial peptide expression, and the clearance of K. pneumoniae in the small intestine were determined. In the absence of TREM-1, KPLA model mice showed increased K. pneumoniae dissemination, enhanced liver and systemic inflammation, and reduced survival. Impaired bacterial clearance in the small intestine causes enhanced K. pneumoniae translocation, which renders Trem-1 KO mice more susceptible to K. pneumoniae oral infection. In conclusion, TREM-1-mediated bacterial clearance in the small intestine is an important immune response against K. pneumoniae. TREM-1 deficiency enhances K. pneumoniae translocation in the small intestine and increases mortality rates in mice with KPLA.  相似文献   
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Objective:To establish rabbit model of restenosis after carotid endartereclomy surgery,and to study tissue inflammatory cytokines(TNF-α,IL-61 involved in restenosis.Methods:A total of 32 rabbits were randomly divided into two groups:model group and control group.The right common carotid artery in rabbits was damaged by carotid endar terectomy in model group.The tissues were harvested at different time points respectively,the pathological changes of the vascular wall after operation were observed at different time points.The changes of expression of tissue vascular wall inflammatory cytokines(TNF-α.IL-6)at different lime points after the surgery was observed by RT-PCR,and the changes of serum inflammatory cytokines(TNT-α,IL-6)were detected by F.I.1SA.Results:The new intima appeared after 7 days of the injury and reached the peak on 28 d which is uneven and significantly thicker than the control group(P0.01).The tissue inflammatory cytokines(TNF-α,IL-6)were significantlv increased after the rabbit common carotid artery injury,which was significant difference compared with normal control group(P0.05).Conclusions:The tissue inflammatory factors significantly increase after the rabbit carotid artery injury,which suggests the mutual concurrent effects of inflammatory cytokines can result in the proliferation of vascular restenosis.  相似文献   
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The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less (“microimplants”), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.Progress in semiconductor technology has led to electronic devices that can augment or replace physiological functions; their ability to be implanted for direct interaction with organ systems relies on overall miniaturization of the device for simplified delivery (e.g., via catheter or hypodermic needle) and access to interstitial spaces. Advances over the past few decades enable most components in a biomedical device, including electrodes, oscillators, memory, and wireless communication systems, to be integrated on tiny silicon chips. However, the energy required for electronic function remains substantial and the consumption density has not been matched by existing powering technologies (1). As a result, the vast bulk of most implantable electronic devices consists of energy storage or harvesting components.Although considerable progress has been made in energy storage technologies, batteries remain a major obstacle to miniaturization (2, 3) because their lifetimes are limited and highly constrained by the available volume, requiring periodic surgical replacement once the unit is depleted. Energy-harvesting strategies have been developed to eliminate batteries or to extend their function. Previous demonstrations include thermoelectric (4), piezoelectric (57), biopotential (8), or glucose (9, 10) power extraction. However, these methods are anatomically specific and, in their existing forms, yield power densities too low (<0.1 μW/mm2) for a microimplant.Alternatively, energy can be transferred from an external source. Ideally, power transfer should be completely noninvasive and not specific to regions in the body. Most existing approaches for this type of transfer are based on electromagnetic coupling in the near field (1120). Though well-suited for large devices and prostheses (21, 22), near-field methods do not address key challenges to powering a microimplant: weak coupling between extremely asymmetric source and receiver structures (23), dissipative and heterogeneous tissue (24), and regulatory power thresholds for general safety (25). These challenges, compounded by the intrinsic exponential decay of the near field, severely limit miniaturization beyond superficial depths (>1 cm), even if the battery can be removed.Theory has indicated that these problems can be overcome in the electromagnetic midfield (23): energy transfer in this region, defined to be about a wavelength’s distance from the source, occurs through the coupling between evanescent fields in air and propagating modes in tissue. Using a patterned metal plate to control the near field, we demonstrate milliwatt levels of power transfer to a miniaturized coil deep in heterogeneous tissue (>5 cm), with exposure levels below safety thresholds for humans; this enables us to power a microimplant capable of delivering controlled electrical pulses to nearly anywhere in the body. The device consists of a multiturn coil structure, rectifying circuits for AC/DC power conversion, a silicon-on-insulator integrated circuit (IC) for pulse control, and electrodes, entirely assembled within a 2-mm diameter, 3.5-mm height device small enough to fit inside a catheter. We demonstrate wireless function by operating it in human-scale heart and brain environments, and by wirelessly regulating cardiac rhythm through a chest wall.  相似文献   
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