Search

Background: Symptoms of rhinitis and asthma can be exacerbated during Japanese cedar pollen (JCP)-scattering season, even in subjects who are not sensitized to JCP, suggesting that innate immune responses may contribute to this process. We previously reported that house dust mite directly activates the effector functions of eosinophils. Similar mechanisms may play roles in the JCP-related aggravation of allergic diseases., Objective: To investigate whether JCP or Cry j 1, a major allergen of JCP, can modify the effector functions of eosinophils., Methods: Eosinophils isolated from the peripheral blood of healthy donors were stimulated with either JCP or Cry j 1, and their adhesion to human intercellular adhesion molecule-1 was measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O 2 - ) was measured based on the superoxide dismutase-inhibitable reduction of cytochrome C. Concentrations of eosinophil-derived neurotoxin in the cell media were measured by enzyme-linked immunosorbent assay as a marker of degranulation., Results: Both JCP and Cry j 1 directly induced eosinophil adhesiveness, generation of O 2 - , and release of eosinophil-derived neurotoxin. Both anti-αM and anti-β2 integrin antibodies blocked all of these eosinophil functions induced by JCP and Cry j 1. Similarly, PAR-2 antagonists also partially suppressed all of these effector functions induced by JCP and Cry j 1., Conclusion: JCP and Cry j 1 directly activate the functions of eosinophils, and both αMβ2 integrin and partly PAR-2 are contributed to this activation. Therefore, JCP-induced eosinophil activation may play a role in the aggravation of allergic airway diseases in nonsensitized patients as well as in JCP-sensitized patients., Competing Interests: Conflict of interest: MN received fees for speaking from Torii Pharmaceutical Co., Ltd. The rest of the authors declare no conflicts of interest., (Copyright © 2021. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Reverse osmosis membranes of aromatic polyamide (PA) reinforced with a crystalline cellulose nanofiber (CNF) were synthesized and their desalination performance was studied. Comparison with plain PA membranes shows that the addition of CNF reduced the matrix mobility resulting in a molecularly stiffer membrane because of the attractive forces between the surface of the CNFs and the PA matrix. Fourier transform-infrared spectroscopy and X-ray photoelectron spectroscopy results showed complex formation between the carboxy groups of the CNF surface and the m- phenylenediamine monomer in the CNF-PA composite. Molecular dynamics simulations showed that the CNF-PA had higher hydrophilicity which was key for the higher water permeability of the synthesized nanocomposite membrane. The CNF-PA reverse osmosis nanocomposite membranes also showed enhanced antifouling performance and improved chlorine resistance. Therefore, CNF shows great potential as a nanoreinforcing material towards the preparation of nanocomposite aromatic PA membranes with longer operation lifetime due to its antifouling and chlorine resistance properties.

Background: Even in subjects who are not sensitized to house dust mite (HDM), allergic symptoms can be clinically aggravated by exposure to dust. We previously reported that Dermatophagoides farinae ( Df ), an important HDM, or Der f 1, a major allergen of Df , induced the effector functions of eosinophils, which may be an important mechanism for HDM-induced symptoms in nonsensitized patients. In a clinical setting, β2-adrenergic agonists, such as salbutamol and formoterol, are used for the treatment of asthma attacks or exacerbation to release the airway obstruction. Several reports have suggested that some β2-adrenergic agonists have an anti-inflammatory capacity., Objective: In this study, we investigated whether β2-adrenergic agonist could modify the Df - or Der f 1-induced activation of eosinophils., Methods: Blood eosinophils obtained from healthy donors were preincubated with either formoterol (1 μM), salbutamol (1 μM), or buffer control and then stimulated with Df extract (1 μg/mL) or Der f 1 (100 pg/mL). Eosinophil adhesion to intercellular adhesion molecule (ICAM)-1 was measured using eosinophil peroxidase assays. Generation of superoxide anion (O 2 - ) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) concentrations in cell media were measured by enzyme-linked immunosorbent assay., Results: Formoterol, but not salbutamol, suppressed the Df - or Der f 1-induced eosinophil adhesion to ICAM-1. Furthermore, formoterol, but not salbutamol, suppressed Df -induced O 2 - generation or EDN release. Neither formoterol nor salbutamol suppressed spontaneous eosinophil adhesion, O 2 - generation, or EDN release., Conclusion: These findings suggested that formoterol, but not salbutamol, suppressed Df - or Der f 1-induced eosinophil activation when used at the same concentration. Therefore, formoterol could potentially be used for the treatment of bronchial asthma via both bronchodilation and anti-inflammatory effect., Competing Interests: Conflict of Interest: KN received honoraria from AstraZeneca. KOD is employee of Torii Pharmaceutical Co., Ltd. MN received honoraria from AstraZeneca and KYORIN Pharmaceutical Co., Ltd. The other authors have no conflicts of interest., (Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Polyamide (PA) membranes comprise most of the reverse osmosis membranes currently used for desalination and water purification. However, their fouling mechanisms with natural organic matter (NOM) is still not completely understood. In this work, we studied three different types of PA membranes: a laboratory made PA, a commercial PA, and a multiwalled carbon nanotube (CNT-PA nanocomposite membrane during cross-flow measurements by NaCl solutions including NOM, humic acid (HA), or alginate, respectively). Molecular dynamic simulations were also used to understand the fouling process of NOM down to its molecular scale. Low molecular weight humic acid binds to the surface cavities on the PA structures that leads to irreversible adsorption induced by the high surface roughness. In addition, the larger alginate molecules show a different mechanism, due to their larger size and their ability to change shape from the globule type to the uncoiled state. Specifically, alginate molecules either bind through Ca 2+ bridges or they uncoil and spread on the surface. This work shows that carbon nanotubes can help to decrease roughness and polymer mobility on the surfaces of the membranes at the molecular scale, which represents a novel method to design antifouling membranes.

Background/aims: In this study, we investigated the severity and frequency of uremic pruritus and itch-associated insomnia in patients with end-stage renal disease (ESRD) or chronic kidney disease (CKD)., Methods: This questionnaire-based study included outpatients with ESRD or CKD who were attending Tokorozawa Renal Clinic in Saitama Prefecture or Musashi Ranzan Hospital and were stable on treatment. The questionnaire was completed by patients on hemodialysis (HD) before a dialysis session and by patients on peritoneal dialysis (PD) or conservative treatment at the time of an outpatient hospital visit., Results: Itching was reported by 61.6% of patients on HD, 61.5% on PD, and 43.2% on conservative CKD management. There was no statistically significant difference in the severity or frequency of itch according to whether patients were on HD for ESRD, PD for ESRD, or receiving conservative treatment for CKD. However, insomnia was significantly more common in the PD group than in the HD and conservative CKD groups., Conclusion: Better skin management is needed for itch in patients with ESRD or CKD. Moisturizing and lifestyle factors are important. Topical or oral medications may also be used. Nalfurafine, a κ receptor agonist, is now available in Japan for the treatment of uremic pruritus in these patients., (© 2019 S. Karger AG, Basel.)

Background: Even in subjects who are not sensitized to house dust mite (HDM), allergic symptoms can be aggravated by exposure to dust, suggesting that innate immune responses may be involved in these processes. Since eosinophils express pattern recognition receptors, HDM may directly upregulate eosinophil functions through these re ceptors. The objective of this study was to examine whether Dermatophagoides farinae (Df), a representative HDM, or Der f 1, a major allergen of Df, modifies the effector functions of eosinophils., Methods: Eosinophils isolated from the blood of healthy donors or allergic patients were stimulated with Df extract or Der f 1, and their adhesion to recombinant human intercellular adhesion molecule (ICAM)-1 was measured using eosinophil peroxidase assays. Generation of the eosinophil superoxide anion (O2-) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) concentrations in cell media were measured by ELISA as a marker of degranulation., Results: Df extract or Der f 1 directly induced eosinophil adhesion to ICAM-1, O2- generation, and EDN release. Anti-αM- or anti-β2-integrin antibodies or protease-activated receptor (PAR)-2 antagonists suppressed the eosinophil adhesion, O2- generation, and EDN release induced by Df extract or Der f 1. Eosinophils from allergic patients showed higher adhesion to ICAM-1 than those from healthy donors., Conclusions: These findings suggested that Df extract and Der f 1 directly activate eosinophil functions through αMβ2-integrin and PAR-2. Eosinophil activation by HDM may play roles in the aggravation of allergic symptoms, not only in HDM-sensitized patients, but also in nonsensitized patients., (© 2019 S. Karger AG, Basel.)

Background: Eosinophilic pneumonia (EP) is characterized by massive pulmonary infiltration by eosinophils. Although serum periostin is a novel marker for eosinophil-dominant asthma, the upregulation of periostin in the airway of asthmatics is controversial. In this study, we examined whether periostin concentrations are elevated in the bronchoalveolar lavage fluid (BALF) of patients with EP., Methods: BAL was performed in healthy volunteers and in patients with acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), and sarcoidosis. The periostin concentrations in the BALF were measured., Results: The periostin concentration in the BALF increased significantly with pulmonary eosinophil ia and was higher in AEP and CEP patients than in healthy volunteers and sarcoidosis patients, even after adjusting the albumin concentration. In pulmonary eosinophilia, the periostin concentration correlated with the eosinophil and lymphocyte counts, the concentration of albumin, and the concentration of cytokines such as IL-5, IL-13, and transforming growth factor β1., Conclusions: Although some blood leakage may be involved in the elevation of periostin in the BALF of EP, periostin can be induced locally, at least in part. Therefore, periostin may play a role in the development of EP., (© 2019 S. Karger AG, Basel.)

Background: Renal replacement therapy is vital for patients with chronic renal failure. Each type of renal replacement therapy has its own characteristics, and patients select it according on their living environment or conception of quality of life. Under the recent medical environment in Japan, economic burden of dialysis is another concern. For patients with chronic renal failure, the outcome of dialysis is vital. How to prevent or control side effects and complications is also important. One type of dialysis treatment is called peritoneal dialysis. Complications from long-term peritoneal dialysis include encapsulating peritoneal sclerosis (EPS), which can lead to life-threatening intestinal obstruction. Here, we hope to prevent the incidence of EPS through examining new possibilities in the pathogenesis during peritoneal dialysis and considering countermeasures., Summary: Membrane dialysis is a treatment methodology that makes use of the semipermeable function of body membranes. When the composition of the peritoneal dialysate is adjusted, it also removes waste products and adjusts water level. Chemical stimuli of peritoneal dialysate on peritonea can trigger inflammation and, when long-lasting, the latter is considered to cause EPS. For the body, chemical stimuli are invasive. Damaged body tissues have a capacity to repair themselves. The innate immune system is known to work in response to nonspecific stimulation, and so it is well conceivable that it is active in the abdominal cavity under peritoneal dialysis. Among many inflammatory cells involved in the innate immune system, we focus on the role of eosinophils to consider the possibility of unknown pathogenesis. Key Messages: Eosinophilic inflammation may cause EPS., (© 2018 S. Karger AG, Basel.)

We demonstrate efficient antifouling and low protein adhesion of multiwalled carbon nanotubes-polyamide nanocomposite (MWCNT-PA) reverse-osmosis (RO) membranes by combining experimental and theoretical studies using molecular dynamics (MD) simulations. Fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (FITC-BSA) was used for the fouling studies. The fouling was observed in real time by using a crossflow system coupled to a fluorescence microscope. Notably, it was observed that BSA anchoring on the smooth MWCNT-PA membrane was considerably weaker than that of other commercial/laboratory-made plain PA membranes. The permeate flux reduction of the MWCNT-PA nanocomposite membranes by the addition of FITC-BSA was 15% of its original value, whereas those of laboratory-made plain PA and commercial membranes were much larger at 34%-50%. Computational MD simulations indicated that the presence of MWCNT in PA results in weaker interactions between the membrane surface and BSA molecule due to the formation of (i) a stiffer PA structure resulting in lower conformity of the molecular structure against BSA, (ii) a smoother surface morphology, and (iii) an increased hydrophilicity involving the formation of an interfacial water layer. These results are important for the design and development of promising antiorganic fouling RO membranes for water treatment.

Background: Recent evidence has suggested that the innate immune response may play a role in the development of eosinophilic airway inflammation. We previously reported that uric acid (UA) and adenosine triphosphate (ATP), two important damage-associated molecular pattern molecules (DAMPs), activate eosinophil functions, suggesting that these molecules may be involved in the development of eosinophilic airway inflammation. The objective of this study was to measure the concentrations of DAMPs including UA and ATP in the bronchoalveolar lavage fluid (BALF) of patients with eosinophilic pneumonia (EP)., Methods: BAL was performed in patients with EP including acute and chronic eosinophilic pneumonia, and in patients with hypersensitivity pneumonia, and sarcoidosis. UA, ATP, and cytokine concentrations in the BALF were then measured., Results: The UA concentration was increased in the BALF of EP patients. UA concentrations correlated with eosinophil numbers, and with eosinophil-derived neurotoxin and interleukin (IL)-5 concentrations. Furthermore, the ATP concentration was increased in the BALF of EP patients and ATP concentrations correlated with UA concentrations. Moreover, IL-33 was increased in EP patients and IL-33 concentrations correlated with UA and ATP concentrations., Conclusions: The UA and ATP concentration was increased in the BALF of EP patients. UA concentrations correlated with eosinophil numbers, and with ATP and IL-33 concentrations. Our findings suggest that DAMPs such as UA and ATP play a role in the pathogenesis of EP., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Eosinophilic esophagitis (EoE) is related to allergic diseases such as bronchial asthma (BA), atopic dermatitis, and allergic rhinitis. The aim of this study was to examine the eosinophil infiltration in the upper gastrointestinal (GI) tract in patients with BA using esophagogastroduodenoscopy., Methods: Patients with BA who had upper GI tract symptoms were enrolled. Patients who received systemically administered steroids were excluded. Eosinophil infiltrations in the esophagus, stomach, and duodenum were examined with regard to the endoscopic findings and pathological findings of biopsy specimens (UMIN000010132)., Results: Ninety patients were enrolled from October in 2012 to September in 2014. Thirty-six were male, 54 were female, and the mean age was 57.5 years. Eighty-one (90%) used inhaled corticosteroids. Fourteen patients (15.6%) had reflux esophagitis, 8 of whom had grade A and 6 had grade B. No patient with EoE was observed. One female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic gastroenteritis, but endoscopy showed only mucosal edema in the antrum. Another female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic granulomatosis with polyangiitis, and endoscopy showed erosions in the antrum and the duodenum. Three patients had eosinophil infiltration in the stomach, but none of them had severe symptoms., Conclusions: Patients with asthma who had upper gastrointestinal symptoms rarely had eosinophilic gastrointestinal disorders. Biopsy specimens are of high importance in the diagnosis of eosinophilic gastrointestinal disorders even if there is no remarkable endoscopic finding., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.

In the airways of severe asthmatics, an increase of neutrophils and eosinophils is often observed despite high-dose corticosteroid therapy. We previously reported that interleukin-8-stimulated neutrophils induced trans-basement membrane migration (TBM) of eosinophils, suggesting the link between neutrophils and eosinophils. Concentrations of lipopolysaccharide (LPS) in the airway increase in severe asthma. As neutrophils express Toll-like receptor (TLR)4 and can release chemoattractants for eosinophils, we investigated whether LPS-stimulated neutrophils modify eosinophil TBM. Neutrophils and eosinophils were isolated from peripheral blood of healthy volunteers and severe asthmatics. Eosinophil TBM was examined using a modified Boyden's chamber technique. Eosinophils were added to the upper compartment, and neutrophils and LPS were added to the lower compartment. Migrated eosinophils were measured by eosinophil peroxidase assays. LPS-stimulated neutrophils induced eosinophil TBM (about 10-fold increase), although LPS or neutrophils alone did not. A leukotriene B 4 receptor antagonist, a platelet-activating factor receptor antagonist or an anti-TLR4 antibody decreased eosinophil TBM enhanced by LPS-stimulated neutrophils by almost half. Neutrophils from severe asthmatics induced eosinophil TBM and lower concentrations of LPS augmented neutrophil-induced eosinophil TBM. These results suggest that the combination of neutrophils and LPS leads eosinophils to accumulate in the airways, possibly involved the pathogenesis of severe asthma., Competing Interests: Conflicts of Interest: None declared.

Carbon nanotubes/polyamide (PA) nanocomposite thin films have become very attractive as reverse osmosis (RO) membranes. In this work, we used molecular dynamics to simulate the influence of single walled carbon nanotubes (SWCNTs) in the polyamide molecular structure as a model case of a carbon nanotubes/polyamide nanocomposite RO membrane. It was found that the addition of SWCNTs decreases the pore size of the composite membrane and increases the Na and Cl ion rejection. Analysis of the radial distribution function of water confined in the pores of the membranes shows that SWCNT+PA nanocomposite membranes also exhibit smaller clusters of water molecules within the membrane, thus suggesting a dense membrane structure (SWCNT+PA composite membranes were 3.9% denser than bare PA). The results provide new insights into the fabrication of novel membranes reinforced with tubular structures for enhanced desalination performance.

Clean water obtained by desalinating sea water or by purifying wastewater, constitutes a major technological objective in the so-called water century. In this work, a high-performance reverse osmosis (RO) composite thin membrane using multi-walled carbon nanotubes (MWCNT) and aromatic polyamide (PA), was successfully prepared by interfacial polymerization. The effect of MWCNT on the chlorine resistance, antifouling and desalination performances of the nanocomposite membranes were studied. We found that a suitable amount of MWCNT in PA, 15.5 wt.%, not only improves the membrane performance in terms of flow and antifouling, but also inhibits the chlorine degradation on these membranes. Therefore, the present results clearly establish a solid foundation towards more efficient large-scale water desalination and other water treatment processes.

Background: Eosinophils play important roles in the development of asthma exacerbation. Viral infection is a major cause of asthma exacerbation, and the expression of IFN-γ-inducible protein of 10 kDa (IP-10) and cysteinyl leukotrienes (cysLTs) is up-regulated in virus-induced asthma. As β2-adrenergic agonists, such as formoterol or salbutamol, are used to treat asthma exacerbation, we examined whether formoterol or salbutamol could modify eosinophil functions such as adhesiveness, particularly those activated by cysLTs or IP-10., Methods: Eosinophils were isolated from the blood of healthy subjects and were pre-incubated with either formoterol or salbutamol, and subsequently stimulated with IL-5, LTD4, or IP-10. Adhesion of eosinophils to intercellular cell adhesion molecule (ICAM)-1 was measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O2(-)) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) release was evaluated by ELISA as a marker of degranulation., Results: Neither formoterol nor salbutamol suppressed the spontaneous adhesion of eosinophils to ICAM-1. However, when eosinophils were activated by IL-5, LTD4, or IP-10, formoterol, but not salbutamol, suppressed the adhesion to ICAM-1. Formoterol also suppressed IL-5, LTD4, or IP-10 induced eosinophil O2(-) generation or EDN release., Conclusions: These findings suggest that formoterol, but not salbutamol, suppresses eosinophil functions enhanced by IL-5, LTD4, or IP-10. As these factors are involved in the development of asthma exacerbation, our results strongly support the hypothesis that administration of formoterol is a novel strategy for treating asthma exacerbation., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Eosinophils recognize various stimuli, such as cytokines, chemokines, immunoglobulins, complement, and external pathogens, resulting in their accumulation in mucosal tissues and the progression of inflammation. Eosinophils are also involved in innate Th2-type immune responses mediated through endogenous danger signals, including IL-33, uric acid (UA), or ATP, in non-sensitized mice exposed to environmental allergens. However, the mechanism involved in eosinophil responses to these danger signals remains insufficiently understood., Methods: We examined migration, adhesion, superoxide production and degranulation of human eosinophils. Isolated eosinophils were incubated with monosodium urate (MSU) crystals and ATPγS, a non-hydrolysable ATP analogue. To determine the involvement of P2 or P2Y2 receptors in eosinophil responses to UA and ATP, eosinophils were preincubated with a pan-P2 receptor inhibitor, oxidized ATP (oATP), or anti-P2Y2 antibody before incubation with MSU crystals or ATPγS., Results: MSU crystals induced adhesion of eosinophils to recombinant human (rh)-ICAM-1 and induced production of superoxide. oATP abolished eosinophil responses to MSU crystals, suggesting involvement of endogenous ATP and its receptors. Furthermore, exogenous ATP, as ATPγS, induced migration of eosinophils through a model basement membrane, adhesion to rh-ICAM-1, superoxide generation, and degranulation of eosinophil-derived neurotoxin (EDN). oATP and anti-P2Y2 significantly reduced these eosinophil responses., Conclusions: ATP serves as an essential mediator of functional responses in human eosinophils. Eosinophil responses to ATP may be implicated in airway inflammation in patients with asthma., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a central role in chronic HBV infection. However, analysis of the molecular mechanism of cccDNA formation is difficult because of the low efficiency in tissue cultured cells. In this study, we developed a more efficient cccDNA expression cell, Hep38.7-Tet, by subcloning from a tetracycline inducible HBV expression cell, HepAD38. Higher levels of cccDNA were produced in Hep38.7-Tet cells compared to HepAD38 cells. In Hep38.7-Tet cells, the cccDNA was detectable at six days after HBV induction. HBV e antigen (HBeAg) secretion was dependent upon cccDNA production. We screened chemical compounds using Hep38.7-Tet cells and HBeAg secretion as a marker. Most of the hit compounds have already been reported as anti-HBV compounds. These data suggested that Hep38.7-Tet cells will be powerful tools for analysis of the molecular mechanism of cccDNA formation/maintenance and development of novel therapeutic agents to control HBV infection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The serum level of carcinoembryonic antigen (CEA) is a marker of malignant disease but can also be increased in benign diseases. Patients with allergic bronchopulmonary aspergillosis (ABPA) have bronchial asthma showing a wide variety of radiological findings. We measured serum CEA levels in patients with ABPA and evaluated the relationships of serum CEA levels with peripheral blood eosinophil counts, total blood levels of immunoglobin (Ig) E, and findings of computed tomography (CT) in ABPA., Methods: The subjects were 13 patients (6 men and 7 women aged 34 to 76 years) who had been treated for ABPA at our hospital. Serum levels of CEA, peripheral blood eosinophil counts, total blood IgE levels, and CT findings were examined before and after treatment with prednisolone., Results: Before the start of the treatment 7 of 13 patients had serum CEA levels higher than the upper limit of normal. The serum CEA level was not correlated with eosinophil counts or total IgE values. Serum CEA levels were examined after treatment in 9 patients and were found to have significantly decreased as pulmonary consolidation improved. Furthermore, serum CEA levels before treatment in patients with pulmonary consolidation were significantly higher than those in patients without consolidation., Conclusion: Serum CEA levels are elevated in some patients with ABPA; these elevations might be associated with consolidation in the lung. Elevated serum CEA levels decrease as the consolidation decreases after treatment. The elevation of serum CEA might be attributed to the presence of local inflammation in the lung.

JTK-853, a palm site-binding NS5B nonnucleoside polymerase inhibitor, shows antiviral activity in vitro and in hepatitis C virus (HCV)-infected patients. Here, we report the results of genotypic and phenotypic analyses of resistant variants in 24 HCV genotype 1-infected patients who received JTK-853 (800, 1,200, or 1,600 mg twice daily or 1,200 mg three times daily) in a 3-day monotherapy. Viral resistance in NS5B was investigated using HCV RNA isolated from serum specimens from the patients. At the end of treatment (EOT) with JTK-853, the amino acid substitutions M414T (methionine [M] in position 414 at baseline was replaced with threonine [T] at EOT), C445R (cysteine [C] in position 445 at baseline was replaced with arginine [R] at EOT), Y448C/H (tyrosine [Y] in position 448 at baseline was replaced with cysteine [C] or histidine [H] at EOT), and L466F (leucine [L] in position 466 at baseline was replaced with phenylalanine [F] at EOT), which are known to be typical resistant variants of nonnucleoside polymerase inhibitors, were observed in a clonal sequencing analysis. These substitutions were also selected by a treatment with JTK-853 in vitro, and the 50% effective concentration of JTK-853 in the M414T-, C445F-, Y448H-, and L466V-harboring replicons attenuated the susceptibility by 44-, 5-, 6-, and 21-fold, respectively, compared with that in the wild-type replicon (Con1). These findings suggest that amino acid substitutions of M414T, C445R, Y448C/H, and L466F are thought to be viral resistance mutations in HCV-infected patients receiving JTK-853 in a 3-day monotherapy.

JTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections.

High-performance sealants using rubber composites containing multiwalled carbon nanotubes (MWNTs) were developed in order to probe and excavate oil in deeper wells. However, the stress-strain behavior and the reinforcing mechanism of highly concentrated MWNT/rubber composites subjected to large deformation remain largely unexplored. Here we report on the complete stress-strain relationships of MWNT/rubber composites under uniaxial tension before rupture, with a suggestion of a novel reinforcement effect of high concentration of MWNTs. A theoretical model is developed to understand the reinforcing mechanism and estimate the mechanical properties of MWNT/rubber composites under large deformation. We have demonstrated that persistence length and reorientation of MWNTs during stretch have a significant impact on mechanical properties, such as the modulus of the rubber composite. These results provide guidelines for developing MWNT-reinforced composites to achieve desired nonlinear and extreme mechanical performance for a wide range of applications.

Interfacial shear strengths or static frictions between carbon nanotubes (CNT) in contact at different cross angles are studied by using atomic mechanics. It is shown that the axial interfacial shear strengths between parallel CNTs in commensurate are two orders of magnitude greater than those in incommensurate. This strong chiral dependence is not surprising and is similar to that of the friction between two graphite basal planes. In contrast, we find that the interfacial shear strengths of crossly contacted CNT pairs are much less dependent upon chirality. The estimated values of interfacial shear strengths, ranging from 0.05 to 0.35 GPa, agree very well with experimentally measured results available in the literature. These results may thus be used as a basis for explaining the observed tension strengths of CNT bundles and films that are mainly bonded by van der Waals interactions and the mechanical behaviors of composite materials with highly concentrated CNTs.

Adiponectin (AdN), an adipokine derived from the adipose tissue, has an insulin-sensitizing effect, and plasma AdN is shown to be decreased in obesity and/or insulin resistant state. To clarify whether changes in AdN are also responsible for the development of glucocorticoid-induced insulin resistance, we examined AdN concentration in plasma and AdN expression in the adipose tissue, using corticotropin-releasing hormone (CRH) transgenic mouse (CRH-Tg), an animal model of Cushing syndrome. We found, unexpectedly, that plasma AdN levels in CRHTg were significantly higher than those in wild-type littermates (wild-type: 19.7+/-2.5, CRH-Tg: 32.4+/-3.1 microg/mL, p<0.01). On the other hand, AdN mRNA and protein levels were significantly decreased in the adipose tissue of CRH-Tg. Bilateral adrenalectomy in CRH-Tg eliminated both their Cushing's phenotype and their increase in plasma AdN levels (wild-type/sham: 9.4+/-0.5, CRH-Tg/sham: 15.7+/-2.0, CRH-Tg/ADX: 8.5+/-0.4 microg/mL). These results strongly suggest that AdN is not a major factor responsible for the development of insulin resistance in Cushing syndrome. Our data also suggest that glucocorticoid increases plasma AdN levels but decreases AdN expression in adipocytes, the latter being explained possibly by the decrease in AdN metabolism in the Cushing state.

Following the discovery of JTK-109 (1) as a potent inhibitor of hepatitis C virus NS5B RNA-dependent RNA polymerase, [(a) Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J. Med. Chem.2006, 49, 4721. (b) Hashimoto, H.; Mizutani, K.; Yoshida, A. Int. Patent Appl. WO 01/47883, 2001.] further studies toward the improvement of the cellular potency have been performed. A greater than 40-fold improvement was achieved through replacing the biphenyl moiety with a 2-morpholinophenyl group and the benzimidazole ring with the tetracyclic scaffold to afford compound 7 with an excellent replicon potency (EC(50)=7.6 nM).

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.

Interleukin (IL)-12 is a key factor in cell-mediated immunity that drives the development of Th1 cells and stimulates T lymphocytes and natural killer cells to produce interferon (INF)-gamma. The IL-12B gene, which encodes the p40 subunit of IL-12, is located at chromosome 5q31-33 and a linkage finding for autoimmune thyroid disease (AITD) on 5q31-33 in a Japanese population has been reported. It is also reported that the A/C polymorphism in the 3' untranslated region (UTR) of the IL-12B gene (1188A/C) is associated with IL12B mRNA expression levels. We attempted to determine whether genetic polymorphisms of the IL-12B gene are associated with AITD. One hundred three patients with Hashimoto's thyroiditis, 90 patients with Graves' disease, and 123 healthy control subjects were recruited. We detected the 1188A/C polymorphism using a PCR-RFLP method and the A/T polymorphism in intron 4 of the IL-12B gene using a cycle sequencing method. These IL-12B gene polymorphisms showed strong linkage disequilibrium, and their genotype and allele frequencies in the patients did not differ from those in the control subjects. Our results suggest that IL-12B gene polymorphisms were unlikely to have an effect on the development of Hashimoto's thyroiditis or Graves' disease in Japanese patients.

In addition to urocortin (Ucn I), Ucn II and Ucn III were identified as endogenous ligands for corticotropin-releasing factor type 2 receptor (CRF2 receptor). CRF2 receptor is abundantly located in central hypothalamic ventromedial nucleus (VMH) and in peripheral cardiovascular system. In this mini-review, we focused on the roles of these urocortins and CRF2 receptor in the hypothalamus and the cardiovascular system. Ucn II mRNA was increased in the parvocellular part or the magnocellular part of the hypothalamic paraventricular nucleus (PVN) following immobilization stress or 3 days of water deprivation, respectively. Therefore, it is thought that Ucn II may modulate CRF and vasopressin synthesis in the PVN in a paracrine or autocrine fashion through PVN CRF2 receptor. The early and later phases of Ucn I-mediated feeding suppression may be CRF1 and CRF2 receptor-mediated events, respectively. Ucn II decreases food intake at a later phase, beyond 4 h post injection. A large dose of corticosterone increased plasma leptin and insulin levels as well as the levels of CRF2 receptor mRNA. Adrenalectomy, starvation, and immobilization each lowered plasma leptin and insulin levels and were associated with decrements in CRF2 receptor mRNA levels in the VMH. Peripheral injection of leptin increased VMH CRF2 receptor mRNA, as can induce reductions of food intake and body weight, indicating that circulating leptin is involved in the regulation of VMH CRF2 receptor mRNA expression. Therefore, it is also plausible that VMH CRF2 receptor transduces the anorexogenic effects of leptin as well as those of urocortins. The systemic administration of Ucn II decreases mean arterial pressure (arterial vascular tone) and causes tachycardia via vascular CRF2 receptor in rats, similar to the effects of Ucn I. Thus, CRF2 receptor seems to mediate cardioprotective effects of urocortins.