Pathological study of chronic pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): possible association of fibrosis with the development of granulomatous lesions

Introduction. Exposure to Asian sand dust (ASD) is associated with enhanced pulmonary morbidity and mor­tality, and the reporting of such cases has rapidly increased in East Asia since 2000. The purpose of the study was to assess chronic lung toxicity induced by ASD. Material and methods. A total of 174 ICR mice were randomly divided into 5 control and 17 exposure groups. Suspensions of low dose (0.2, 0.4 mg) and high dose (3.0 mg) of ASD particles in saline were intratracheally instilled into ICR mice, followed by sacrifice at 24 hours, 1 week, and 1, 2, 3 and 4 months after instillation. Paraffin sections of lung tissues were stained with hematoxylin and eosin and by immunohistochemistry to detect α-smooth muscle actin, collagen III, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), CD3, CD20, immunoglobulin G, interleukin-1β and inducible nitric oxide synthase. Results. A lung histological examination revealed similar patterns in the lesions of the groups treated with high (3.0 mg) or low dose (0.4 mg) of ASD. Acute inflammation was observed 24 h after treatment and subsided after 1 week; persistent granulomatous changes were observed at 2 months, focal lymphocytic infiltration at 3 months, and granuloma formation at 4 months. An increase in the size of granulomatous lesions was observed over time and was accompanied by collagen deposition in the lesions. The cytoplasm of macrophages in inflammatory lesions showed positive immunolabeling for MMP-9 at 24 h, 1 and 2 months after instillation of 3.0 mg of ASD. Positive immunolabeling for TIMP-1 was demonstrated in the cytoplasm of macrophages at 2 and 4 months after instillation of 3.0 mg of ASD. These findings suggest association between the expression of MMP-9 and TIMP-1 with the development of lung granulomatous lesions. Conclusions. These findings suggest that collagen deposition resulting from the altered regulation of extracel­lular matrix is associated with granuloma formation in the lungs of mice treated with ASD

Potential-Dependent Adsorption and Orientation of meso-Substituted Porphyrins at Liquid|Liquid Interfaces Studied by Polarization-Modulation Total Internal Reflection Fluorescence Spectroscopy

Potential-dependent adsorption behavior of meso-substituted water-soluble porphyrins at the polarized water|1,2-dichloroethane (DCE) interface was studied by polarization-modulation total internal reflection fluorescence (PM-TIRF) spectroscopy. In the PM-TIRF experiments, the fluorescence signal from the interfacial region was analyzed as a function of the periodic modulation of linear-polarizations (p and s) of the incident excitation beam. The potential-dependence of PM-TIRF responses for meso-substituted porphyrins, 5,10,15,20-tetrakis(N-methylpyridyl)porphyrin (H2TMPyP4+) and 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (H2TPPS4-), indicated that both free base porphyrins were adsorbed with relatively lying orientations at the polarized water|DCE interface. The average orientation angles (θ) were estimated as θ = 61 ± 1°for H2TMPyP4+ and θ = 65 ± 1°for H2TPPS4- with respect to the interface normal. The wavelength-dependence of polarization-modulated fluorescence signals (PM-TIRF spectrum), which corresponds to "pure" emission spectrum of interfacial species, clearly indicated that H2TMPyP4+ and H2TPPS4- are adsorbed with a modification of the solvation at the interface. These results demonstrated a high ability of the PM-TIRF spectroscopy for the direct characterization of fluorescent species adsorbed at polarized liquid|liquid interfaces. © 2016 American Chemical Society.Embargo Period 12 months / This article has Supplementary dat

Spectroelectrochemical characterization of dendrimer-porphyrin associates at polarized liquid|liquid interfaces

Molecular encapsulation of anionic porphyrins in NH2-terminated polyamidoamine (PAMAM) dendrimers and the interfacial behavior of the dendrimer-porphyrin associates were studied at the polarized water|1,2-dichloroethane (DCE) interface. Formation of the ion associates was significantly dependent on the pH condition and on generation of dendrimers. 5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrin (ZnTPPS4-) associated with the positively charged fourth-generation (G4) PAMAM dendrimer was highly stabilized in acidic aqueous solution without protolytic demetalation in a wide range of pH values (pH > 2). In contrast to the zinc(II) complex, the free base porphyrin (H2TPPS4-) was readily protonated under acidic conditions even in the presence of the dendrimers. In addition, the J-aggregates of diprotonated species, (H4TPPS2-) n, were preferably formed on the dendrimer. The interfacial mechanism of the dendrimer-porphyrin associates was analyzed in detail by potential-modulated fluorescence (PMF) spectroscopy. PMF results indicated that the dendrimers incorporating porphyrin molecules were transferred across the positively polarized water|DCE interface via adsorption step, whereas the transfer responses of the porphyrin ions released from the dendrimers were observed at negatively polarized conditions. A negative shift of the transfer potential of porphyrin ions compared to the intrinsic transfer potential was apparently observed for each ion association system. The ion association stability between the dendrimer and the porphyrin molecules could be estimated from a negative shift of the transfer potential. ZnTPPS4- exhibited relatively strong interaction with the higher generation dendrimer, whereas H2TPPS4- was less effectively associated with the dendrimers. © 2014 American Chemical Society

Pathological study of pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): effects of lowered serum zinc level on the toxicity

Introduction. We have previously reported that Asian sand dust (ASD) induced acute and chronic inflammatory changes in the lung of mice. Zinc (Zn) is reported to influence inflammation and wound healing. The purpose of the study was to assess the effects of lowered serum Zn levels on the lung toxicity induced by ASD. Material and methods. Mice that were fed diets containing normal (group 1) or low (group 2) content of Zn for 8 weeks were intratracheally instilled with 3.0 mg of ASD, followed by sacrifice at 24 hours, 2 weeks, and 1, 2 and 3 months after instillation. Paraffin sections of lung tissues were stained by hematoxylin and eosin and by immunohistochemistry to detect tumor necrosis factor (TNF) and interleukin (IL)-1β as well as inflammasome (NALP3), autophagy (LC-3) and lysosome (LAMP-1) markers. Selected samples of lung tissue were examined by electron microscopy. Results. Following histological examination of the lung, similar patterns of inflammatory changes were observed in mice with normal and low serum Zn concentrations; however, they were more prominent and persistent in mice with low serum Zn level. These changes were both purulent (acute) and pyogranulomatous (chronic) in nature. In the lung lesions of group 2 mice the changes within the cytoplasmic vacuoles of enlarged ASD-containing macrophages (Mo) were clearly visible. The macrophages expressed TNF and IL-1β, and semi-quantitative analysis revealed a larger number of TNF-positive Mo in mice with normal level of serum Zn and a larger number of IL-1β-positive Mo in mice with low level of serum Zn. Decreased positive LC-3 staining and dilated lysosomes containing ASD particles were observed in the cytoplasm of Mo in mice with low serum Zn concentration. Conclusions. These findings suggest that low serum zinc concentration may induce the modulation of cytokine expression and lysosomal malfunction by phagocytotic and/or autophagic mechanisms, and may result in interstitial pyogranulomatous inflammation in the lungs of mice treated with ASD

Measurement of allergen-specific secretory IgA in stool of neonates, infants and toddlers by protection against degradation of immunoglobulins and allergens

Background and aims : Measurement of secretory immunoglobulin A (SIgA) level is important to monitor various disease conditions. However SIgA in gut mucosa is degraded by pancreatic proteases and proteolytic enzymes from enteric microbiota. Currently, there is no reliable quantitation method that measures allergen-specific SIgA levels in stool of neonates, infants and toddlers. Methods : Allergen-specific SIgA levels in stool of 10 healthy neonates, infants and toddlers aged 0 to 36 months were measured by our new allergen microarray with densely carboxylated arms on a glass slide chip. Results : Protease activities in stool of 3-day-old neonates were low and no degradation of SIgA, IgA and allergens was detected. However, immunofluorescence signals of SIgA, IgA and allergen on the chip were markedly reduced by stool extracts obtained from infants and toddlers aged more than one month in dose- and time-dependent manners. Such reduction was almost completely inhibited by serine protease inhibitors, phenylmethylsulfonyl fluoride (PMSF) and partly by leupeptin, but not by a variety of other protease inhibitors tested. Conclusion : Allergen-specific SIgA levels in stool of neonates, infants and toddlers under 36 months of age could be analyzed using protease inhibitors, including PMSF and leupeptin

六角形格子上の積符号を用いた符号化変調方式によるPAPRの低減

小形通信機器を用いる無線通信においては，寸法や重量が制限されるため，より電力効率の良い通信方式が求められる．本論文では，電力利用効率の良い通信方式として，六角形格子上の整数符号を用いた積符号による符号化変調方式を提案する．六角形格子は信号点の密度が高いため，等方性の19点六角形格子のピーク対平均電力比は矩形16値直交振幅変調(QAM: Quadrature Amplitude Modulation)よりも0.56dB低く抑えることができる．また，整数符号は，訂正可能な誤りを近接点に設定でき，遠方の信号点へ誤る確率よりも近接点へ誤る確率の方が高いと言う実際的な通信路に適している．本検討では，19，37及び61点の六角形格子上で整数符号単体及び整数符号と負巡回符号またはリード・ソロモン符号の積符号のシミュレーションを行った．その結果，整数符号とリード・ソロモン符号の積符号が，負巡回符号との積符号や各符号単体の結果と比べてビット誤り率(BER: Bit Error Rate)の改善効果が大きいことを示すことができた．また，信号点数の近い矩形QAMと比較してBERが1.0×10-5において0.8dBから1dBの符号化利得を得ることができ，提案符号化変調方式による電力及びBERの改善効果を確認できた．Wireless communication using small devices requires high power efficiency schemes because of size and weight constraints. In this paper, coded modulation schemes using product codes composed of integer codes over hexagonal constellations are proposed. The peak-to-average power ratio of an isotropy 19-Hexagonal constellation is 0.56 dB lower than that of 16QAM. In addition, integer codes can define its correctable error in the vicinity of signal points. Therefore, it is suitable for the practical communication channel. Our coded modulation simulation results over 19, 37 and 61 hexagonal constellations showed lower bit error rate than the results on square QAM constellations

Early aggressive intervention for infantile atopic dermatitis to prevent development of food allergy : a multicenter, investigator‑blinded, randomized, parallel group controlled trial (PACI Study) : protocol for a randomized controlled trial

Background: Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. Methods: This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7–13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen’s egg allergy at the age of 28 weeks. Discussion: This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings