Summary
Background
Aspirin challenge of aspirin‐intolerant asthma (AIA) patients causes a significant increase in leukotriene E4 (LTE4) concentration in urine. However, knowledge on leukotriene B4 ...(LTB4) generation in patients with AIA is insufficient. Recent research has demonstrated that exogenously administered LTB4 is excreted as glucuronide into the urine in human healthy subjects.
Objective
The purpose of this study is to estimate urinary LTB4 glucuronide (LTBG) concentration in the clinically stable condition in healthy subjects and asthmatic patients and to investigate changes in urinary LTBG concentration in patients with AIA after aspirin challenge.
Methods
A provocation test was performed by intravenous aspirin challenge. After urine was hydrolysed by β‐glucuronidase, the fraction containing LTB4 was purified by high‐performance liquid chromatography and LTB4 concentration was quantified by enzyme immunoassay. Urinary LTBG concentration was calculated as the difference between the concentration obtained with hydrolysis and that without hydrolysis.
Results
(1) After hydrolysis, the presence of urinary LTB4 was verified by gas chromatography‐mass spectrometry‐selected ion monitoring. (2) The urinary LTBG concentration was significantly higher in the asthmatic patients than in the healthy subjects (median, 5.37 pg/mg creatinine range 1.2–13 vs. 3.32 pg/mg creatinine range, 0.14–10.5, P=0.0159). (3) The patients with AIA (n=7), but not those with aspirin‐tolerant asthma (n=6), showed significant increases in LTBG and LTE4 excretions after aspirin challenge. (4) When the concentrations after aspirin challenge were analysed simultaneously, a significant linear correlation was observed between urinary LTBG concentration and urinary LTE4 concentration in patients with AIA (Spearman's rank correlation test, r=0.817, P=0.0003).
Conclusion
LTBG is present in human urine, albeit at a concentration lower than urinary LTE4. In addition to a marked increase in cysteinyl‐leukotriene production, aspirin challenge induced LTB4 production in AIA patients.
Summary
Background
There has been no information about the concentration of 14,15‐leukotriene C4, which is generated by 15‐ and 12‐lipoxygenase and has been recently named eoxin C4, in biological ...fluids.
Objective
To determine the clinical concentrations of eoxin C4 in various respiratory inflammatory diseases, we quantified eoxin C4 in relation to the concentrations of cysteinyl‐leukotrienes (CysLTs) and 15‐hydroxyeicosatetraenoic acid (15‐HETE) in bronchoalveolar lavage fluid (BALF).
Methods
BALF fluid was obtained from patients with a number of inflammatory lung diseases. Eoxin C4 and CysLTs were quantified by enzyme immunoassay in combination with high‐performance liquid chromatography. Eoxin C4 immunoassay does not detect eoxin D4 or eoxin E4. 15‐HETE was quantified by gas chromatography–mass spectrometry using 18O‐labeled compounds as an internal standard.
Results
The concentration of eoxin C4 (median 1.4, range <1.12–6.7 pg/mL) was significantly lower than that of eoxin C4 or CysLTs (P<0.0001). The concentration of 15‐HETE significantly correlated with those of LTC4 and CysLTs or the number and the percentage of eosinophils in BALF. On the other hand, eoxin C4 concentration did not correlate with eosinophil number or CysLTs concentration in BALF.
Conclusions
This is the first study demonstrating the presence of eoxin C4 in human biological fluids. Further studies are necessary to elucidate the pathophysiological role of eoxin C4 in some respiratory inflammatory diseases.
Summary
Background
Aspirin challenge of aspirin‐intolerant asthma (AIA) patients causes a significant increase in leukotriene E
4
(LTE
4
) concentration in urine. However, knowledge on leukotriene B
...4
(LTB
4
) generation in patients with AIA is insufficient. Recent research has demonstrated that exogenously administered LTB
4
is excreted as glucuronide into the urine in human healthy subjects.
Objective
The purpose of this study is to estimate urinary LTB
4
glucuronide (LTBG) concentration in the clinically stable condition in healthy subjects and asthmatic patients and to investigate changes in urinary LTBG concentration in patients with AIA after aspirin challenge.
Methods
A provocation test was performed by intravenous aspirin challenge. After urine was hydrolysed by β‐glucuronidase, the fraction containing LTB
4
was purified by high‐performance liquid chromatography and LTB
4
concentration was quantified by enzyme immunoassay. Urinary LTBG concentration was calculated as the difference between the concentration obtained with hydrolysis and that without hydrolysis.
Results
(1) After hydrolysis, the presence of urinary LTB
4
was verified by gas chromatography‐mass spectrometry‐selected ion monitoring. (2) The urinary LTBG concentration was significantly higher in the asthmatic patients than in the healthy subjects (median, 5.37 pg/mg creatinine range 1.2–13 vs. 3.32 pg/mg creatinine range, 0.14–10.5,
P
=0.0159). (3) The patients with AIA (
n
=7), but not those with aspirin‐tolerant asthma (
n
=6), showed significant increases in LTBG and LTE
4
excretions after aspirin challenge. (4) When the concentrations after aspirin challenge were analysed simultaneously, a significant linear correlation was observed between urinary LTBG concentration and urinary LTE
4
concentration in patients with AIA (Spearman's rank correlation test,
r
=0.817,
P
=0.0003).
Conclusion
LTBG is present in human urine, albeit at a concentration lower than urinary LTE
4
. In addition to a marked increase in cysteinyl‐leukotriene production, aspirin challenge induced LTB
4
production in AIA patients.
Asthma is a phenotypically heterogeneous disorder with many etiologic factors and clinical characteristics. T-bet, a Th1-specific transcription factor of T-box family, has been found to control ...interferon-gamma (IFN-gamma) expression in T cells. Mice lacking the T-bet gene (tbx21) demonstrate multiple physiological and inflammatory features reminiscent of human asthma. In order to examine whether polymorphisms in the candidate gene, TBX21, located on chromosome 17q21.32, are related to the risk of human asthma phenotypes, we have searched for genetic variations in the human TBX21 gene and identified 24 single nucleotide polymorphisms (SNPs), including five novel SNPs, by direct sequencing in Japanese subjects. Among asthma phenotypes, a promoter -1993T-->C SNP, which is in linkage disequilibrium with a synonymous coding 390A-->G SNP in exon 1, is significantly associated with a risk of aspirin-induced asthma (AIA; P = 0.004, P(c) = 0.016). This association has also been confirmed in additional independent samples of asthma with nasal polyposis (P = 0.008), regardless of aspirin hypersensitivity. Furthermore, our data indicate that the -1993T-->C substitution increases the affinity of a particular nuclear protein to the binding site of TBX21 covering the -1993 position, resulting in increased transcriptional activity of the TBX21 gene. Thus, in addition to the antigen-driven excess Th2 response, increased T-bet (and subsequent IFN-gamma) production in human airways of individuals with the -1993T-->C polymorphism could contribute to the development of certain asthma-related phenotypes, such as AIA.
A micro pixel chamber ( mu -PIC), the development of which started in 2000 as a type of a micro pattern gas detector, has a high gas gain greater than 6000 in stable operation, a large detection area ...of 900 cm super(2), and a fine position resolution of about 120 mu m. However, for its development, simulation verification has not been very useful, because conventional simulations explain only part of the experimental data. On the other hand, some mu -PIC applications require precise understanding of the fluctuation of the gas avalanche and signal waveform for their improvement; therefore, there is a need to update the mu -PIC simulation. Hence, we adopted Garfield++, which is developed for simulating a microscopic avalanche in an effort to explain experimental data. The simulated avalanche size was well consistent with the experimental gas gain. Moreover, we calculated a signal waveform and successfully explained the pulse height and time-over-threshold. These results clearly indicate that the simulation of mu -PIC applications will improve and that Garfield++ simulation will easily facilitate the mu -PIC development.
We have developed an Electron-Tracking Compton Camera (ETCC) for use onboard a balloon to observe sub-MeV/MeV gamma rays from celestial objects. The ETCC is constructed with a three dimensional ...gaseous tracker for recoil electrons from Compton scattering, and GSO:Ce pixel scintillator arrays as absorber of the Compton-scattered gamma-ray. By using the ETCC, we can reconstruct the energy and direction of individual gamma rays. We have developed a prototype ETCC with a (30 cm) super(3) TPC, and tested its performance in the range of 356 - 835 keV in the laboratory. As the result, we succeeded in taking images of gamma ray sources and determined a detection efficiency of 9.0 x 10 super(-6) and an effective area of 8.0 x 10 super(-3) cm super(2) at 662 keV for the prototype ETCC. Furthermore, we developed a new power saving readout circuit for the scintillators that achieves the electric power consumption of 0.41 W/channel, an energy dynamic range of 81 - 1333 keV, and an energy resolution of 10.3% at full width at half maximum at 662 keV.
Summary
Background Although many studies have assumed that the overproduction of cysteinyl‐ leukotrienes (cys‐LTs) and an imbalance of arachidonic acid metabolism may be plausible causes for the ...pathogenesis of aspirin‐intolerant asthma (AIA), there has been little experimental evidence to substantiate this notion in lower airways of patients with AIA.
Objectives The purpose of this study was to compare the eicosanoid concentrations in sputum and urine from patients with AIA.
Methods The concentrations of sputum cys‐LTs, prostaglandin E2 (PGE2), PGF2α, PGD2 and thromboxane B2 were measured to assess local concentrations of eicosanoids in patients with AIA and in those with aspirin‐tolerant asthma (ATA). The concentrations of two urinary metabolites, leukotriene E4 (LTE4) and 9α11βPGF2, were also measured to corroborate the relationship between the eicosanoid biosynthesis in the whole body and that in lower airways.
Results The concentration of PGD2 in sputum was significantly higher in patients with AIA than in those with ATA (median, 5.3 pg/mL vs. 3.1 pg/mL, P < 0.05), but there was no significant difference in the concentration of the corresponding metabolite, 9α11βPGF2, between the two groups. No differences were noted in the concentrations of other prostanoids in sputum between the two groups. The sputum cys‐LT concentrations showed no differences between the two groups, in spite of the observation that the concentration of urinary LTE4 was significantly higher in patients with AIA than in those with ATA (median, 195.2 pg/mg‐cre vs. 122.1 pg/mg‐cre, P < 0.05). There was a significant correlation among the concentration of cys‐LTs, the number of eosinophils and the concentration of eosinophil‐derived neurotoxin (EDN) in sputum.
Conclusion The urinary concentration of LTE4 does not necessary reflect cys‐LT biosynthesis in lower airways. A significantly higher concentration of PGD2 in sputum from patients with AIA suggests the possible ongoing mast cell activation in lower airways.
Following success of a prototype R&D, construction of a superconducting magnet system for J-PARC neutrino beam line has been carried out since 2005. A new conceptual beam line with the ...superconducting combined function magnets demonstrated the successful beam transport to the neutrino production target.
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