Ultrafast time-resolved 2D imaging of laser-driven fast electron transport in solid density matter using an x-ray free electron laser.

High-power, short-pulse laser-driven fast electrons can rapidly heat and ionize a high-density target before it hydrodynamically expands. The transport of such electrons within a solid target has been studied using two-dimensional (2D) imaging of electron-induced Kα radiation. However, it is currently limited to no or picosecond scale temporal resolutions. Here, we demonstrate femtosecond time-resolved 2D imaging of fast electron transport in a solid copper foil using the SACLA x-ray free electron laser (XFEL). An unfocused collimated x-ray beam produced transmission images with sub-micron and ∼10 fs resolutions. The XFEL beam, tuned to its photon energy slightly above the Cu K-edge, enabled 2D imaging of transmission changes induced by electron isochoric heating. Time-resolved measurements obtained by varying the time delay between the x-ray probe and the optical laser show that the signature of the electron-heated region expands at ∼25% of the speed of light in a picosecond duration. Time-integrated Cu Kα images support the electron energy and propagation distance observed with the transmission imaging. The x-ray near-edge transmission imaging with a tunable XFEL beam could be broadly applicable for imaging isochorically heated targets by laser-driven relativistic electrons, energetic protons, or an intense x-ray beam.

Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment.

BACKGROUND: With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). AIM: To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. METHODS: This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. RESULTS: During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. CONCLUSIONS: For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

Erythromelalgia associated with Clitocybe acromelalga intoxication.

CONTEXT: Erythromelalgia is a rare disorder characterized by reddening, severe burning pain, and swelling of the extremities. Food poisoning by Clitocybe acromelalga, a poisonous mushroom, is known to induce erythromelalgia; however, its treatment protocol remains unclear. We describe here three cases of erythromelalgia following the consumption of C. acromelalga with varying clinical courses. CASE DETAILS: Of the three patients, the first patient presented 22 days after the onset of erythromelalgia; although he was treated with aspirin, numbness in the limbs persisted as sequela. Patient 2 presented at 3 days after the symptomatic onset and was immediately treated with high-dose intravenous nicotinic acid, with a dramatic symptomatic improvement. Patient 3, who had milder symptoms, spontaneously recovered within a week without any treatment. DISCUSSION: The clinical manifestations and varying clinical courses associated with C. acromelalga toxicity are discussed here, with the pathogenesis of this mycotoxin and a potential treatment. Detailed interviews of such patients are important, particularly because of the remarkably slow course of this mycotoxin as compared with common food poisonings. Treatment with intravenous nicotinic acid was associated with improvement in one patient. We believe that this painful disorder might thus be treatable, although the mechanism underlying the treatment remains unclear.

Obesity and aspirin intolerance are risk factors for difficult-to-treat asthma in Japanese non-atopic women.

BACKGROUND: Asthma is a clinical syndrome characterized by variabilities in disease expression and severity. The pathophysiological mechanism underlying anti-asthma treatment resistance is also assumed to be different between disease phenotypes. OBJECTIVE: To elucidate the effect of gender and atopic phenotype on the relationship between clinical factors and the risk of treatment resistance. METHODS: We compared outpatients with difficult-to-treat asthma (DTA; n = 486) in a tertiary hospital for allergic diseases in central Japan with those with controlled severe asthma (n = 621) with respect to clinical factors including body mass index (BMI) and aspirin intolerance using multivariate logistic regression analysis stratified by gender and atopic phenotype. RESULTS: When analysis was performed on the entire study populations, obesity (BMI ≥ 30 kg/m(2); adjusted odds ratio (OR) 1.92; 95% confidence interval (95% CI: 1.07-3.43) and aspirin intolerance (OR: 2.56, 95% CI: 1.44-4.57) were found to be the significant risk factors for DTA. However, after the stratification by gender and atopic phenotype, the association between obesity and DTA was significant only in women (OR: 2.76, 95% CI: 1.31-5.78), but not in men (OR: 1.03, 95% CI: 0.38-2.81), and only in non-atopics (OR: 4.03, 95% CI: 1.15-14.08), but not in atopics (OR: 1.54, 95% CI: 0.79-3.02). The similar gender and phenotypic differences were also observed in the association between aspirin intolerance and DTA: namely, the association was significant only in women (OR: 3.96, 95% CI: 1.84-8.50), but not in men (OR: 1.19, 95% CI: 0.46-3.05); and only in non-atopics (OR: 5.49, 95% CI: 1.98-15.19), but not in atopics (OR: 1.39, 95% CI: 0.65-2.98). CONCLUSIONS AND CLINICAL RELEVANCE: Significant associations of obesity and aspirin intolerance with DTA were observed only in women and in non-atopics. These findings suggest that a phenotype-specific approach is needed to treat patients with DTA.

Urinary concentrations of 15-epimer of lipoxin A(4) are lower in patients with aspirin-intolerant compared with aspirin-tolerant asthma.

BACKGROUND: Although an abnormality in arachidonic acid metabolism may be responsible for aspirin-intolerant asthma (AIA), there is little knowledge about the concentrations of urinary lipoxin A(4) (LXA(4)) and the 15-epimer of LXA(4) (15-epi-LXA(4)) in relation to asthma severity in AIA subjects. OBJECTIVE: The purpose of this study is to estimate urinary LXA(4) and the 15-epimer concentrations to investigate lipoxins in AIA. METHODS: In this study, we examined AIA, aspirin-tolerant asthma (ATA) and healthy control groups. The AIA and ATA groups were subdivided into the severe asthma and non-severe asthma subgroups. Urinary LXA(4), 15-epi-LXA(4) and leukotriene E(4) (LTE(4) ) were quantified using enzyme immunoassay after separating these compounds using high-performance liquid chromatography. RESULTS: The urinary LXA(4) concentration was significantly lower than the 15-epi-LXA(4) concentration in the asthmatic subjects. The AIA group showed significantly lower urinary 15-epi-LXA(4) (P < 0.01) and higher urinary LTE(4) concentrations (P < 0.05) than the ATA group. Comparison of 15-epi-LXA(4) concentrations between the severe asthmatic and non-severe asthmatic subjects in the AIA and ATA groups revealed that the decreased 15-epi-LXA(4) concentration may be related to aspirin intolerance, but not asthma severity. Receiver operator characteristic curves demonstrated that the concentration ratio of LTE(4) to 15-epi-LXA(4) was superior to 15-epi-LXA(4) concentration and LTE(4) concentration as a predictive factor for aspirin intolerance. CONCLUSIONS AND CLINICAL RELEVANCE: We have demonstrated for the first time that urinary 15-epi-LXA(4) concentration is significantly higher than LXA(4) concentration in both the AIA and ATA groups. 15-Epi-LXA(4) concentration was significantly lower in the AIA group with an increased urinary LTE(4) concentration than in the ATA group. An imbalance between proinflammatory cysteinyl-leukotrienes and anti-inflammatory 15-epi-LXA(4) may be involved in AIA pathogenesis.

Concentration of 14,15-leukotriene C4 (eoxin C4) in bronchoalveolar lavage fluid.

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 (18)O-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.

Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis.

BACKGROUND: Anaphylaxis is a life-threatening syndrome resulting from the sudden release of mast cell- and basophil-derived mediators into the circulation. However, pathological evidence of the association between inflammatory mediators and human anaphylaxis is insufficient. OBJECTIVE: The aim of this study was to better understand the relationship between in vivo production of inflammatory mediators and the pathogenesis of anaphylaxis. We also sought to evaluate mast cell activation in anaphylaxis. METHODS: We measured the concentrations of various inflammatory mediators in urine samples, which were collected from 32 anaphylactic patients during the onset of anaphylaxis and during clinical remission, 21 patients with asthma on acute exacerbation and 15 healthy control subjects. Blood and urine specimens were collected from the patients after provocation test. Urinary leukotriene E4 (LTE4), 9alpha, 11beta-prostaglandin F2 (9alpha, 11beta-PGF2), eosinophil-derived neurotoxin (EDN) and leukotriene B4 glucuronide (LTBG) concentrations were determined by enzyme immunoassay, and the activity of plasma platelet-activating factor acetylhydrolase and serum tryptase concentration were measured using commercially available kits. RESULTS: Significantly higher concentrations of urinary LTE4 and 9alpha, 11beta-PGF2, which immediately decreased during clinical remission, were observed in the anaphylactic patients than in asthmatic patients on acute exacerbation and healthy control subjects. Concentrations of EDN and LTBG were not significantly different among the anaphylactic patients, asthmatic patients on acute exacerbation and healthy subjects. There was a significant correlation between urinary LTE4 and 9alpha, 11beta-PGF2 concentrations in the anaphylactic patients (r=0.672, P=0.005, n=32). In addition, LTE4 concentration in patients with anaphylactic shock is significantly elevated compared with that in patients without anaphylactic shock. CONCLUSIONS: This is a report on the significant increase in urinary LTE4 and 9alpha, 11beta-PGF2 concentrations during anaphylaxis. Urinary LTE4 and 9alpha, 11beta-PGF2 concentrations may be a reliable marker of endogenous production of inflammatory mediators associated with anaphylaxis.

Comparison of cysteinyl leukotriene concentrations between exhaled breath condensate and bronchoalveolar lavage fluid.

BACKGROUND: Collection of exhaled breath condensate (EBC) is a simple, non-invasive method of obtaining samples from the airways and it can be repeated in short intervals without side effects; therefore, it provides an opportunity to monitor the changes in concentration of inflammatory mediators in the airways. However, EBC analysis still has several unresolved issues. OBJECTIVE: To better understand the characteristics of EBC, we compared cysteinyl leukotriene (CysLT) concentrations between bronchoalveolar lavage fluid (BALF) and EBC. We also attempted to correct CysLT concentrations in BALF and EBC diluted with saline and water vapour using biological markers. METHODS: EBC was collected from 14 patients with idiopathic pulmonary fibrosis before bronchoscopy. We measured CysLT concentrations and also quantified tyrosine, urea and total protein as possible biomarkers for correcting dilution. RESULTS: (1) We have validated the quantification of CysLTs in EBC. (2) Although a significant correlation was observed among tyrosine and urea concentrations in BALF, urea and total protein concentrations were below the detection limit in EBC. (3) CysLT concentrations were higher in BALF than in EBC (median, 15.96 pg/mL vs. 5.5 pg/mL; P=0.001) and there was no correlation of CysLT concentrations in BALF with those in EBC. A significant correlation of the ratio of total CysLT concentration to tyrosine concentration (CysLT/Y) in EBC with that in BALF was observed (r=0.547, P=0.043). (4) CysLT/Y in EBC correlated with serum KL-6 concentration and total cell count in BALF, and CysLT/Y in BALF also correlated with exhaled NO concentration and %VC. CONCLUSIONS: CysLT/Y in EBC significantly correlated with that in BALF and some clinical parameters correlated with CysLT/Y. Tyrosine concentration may be used to correct the dilution error for CysLT concentrations, and CysLT/Y in EBC can be a surrogate marker for CysLT concentrations in BALF.

Increased levels of cysteinyl-leukotrienes in saliva, induced sputum, urine and blood from patients with aspirin-intolerant asthma.

BACKGROUND: A diagnosis of aspirin-intolerant asthma requires aspirin provocation in specialist clinics. Urinary leukotriene E(4) (LTE(4)) is increased in aspirin-intolerant asthma. A study was undertaken to investigate new biomarkers of aspirin intolerance by comparing basal levels of cysteinyl-leukotrienes (CysLTs) and leukotriene B(4) (LTB(4)) in saliva, sputum and ex vivo stimulated blood in subjects with aspirin-intolerant and aspirin-tolerant asthma. The effects of aspirin- and allergen-induced bronchoconstriction on leukotriene levels in saliva and ex vivo stimulated blood were also compared with the effects of the provocations on urinary mediators. METHODS: Induced sputum, saliva, urine and blood were obtained at baseline from 21 subjects with asthma. At a separate visit, 11 subjects showed a positive response to lysine-aspirin inhalation and 10 were aspirin tolerant. Saliva, blood and urine were also collected on the provocation day. Analyses of CysLTs and LTB(4) and the prostaglandin D(2) metabolite 9alpha,11beta-prostaglandin F(2) were performed and the fraction of exhaled nitric oxide was measured. RESULTS: Subjects with aspirin-intolerant asthma had higher exhaled nitric oxide levels and higher baseline levels of CysLTs in saliva, sputum, blood ex vivo and urine than subjects with aspirin-tolerant asthma. There were no differences in LTB(4) levels between the groups. Levels of urinary LTE(4) and 9alpha,11beta-prostaglandin F(2) increased after aspirin provocation whereas leukotriene levels in saliva and ex vivo stimulated blood did not increase. CONCLUSION: These findings support a global and specific increase in CysLT production in aspirin-intolerant asthma. Measurement of CysLTs in saliva has the potential to be a new and convenient non-invasive biomarker of aspirin-intolerant asthma.

Increased urinary leukotriene E4 concentration in patients with eosinophilic pneumonia.

Although eosinophils produce cysteinyl leukotrienes (CysLTs) in large quantities, information on the relationship between CysLTs and eosinophilic pneumonia (EP) is lacking. Inflammatory mediator concentrations in urine were quantified to clarify the relationship between CysLT concentrations and EP severity. Leukotriene (LT)E(4), eosinophil-derived neurotoxin (EDN), 9alpha,11beta-prostaglandin F2 and LTB(4) glucuronide concentrations were quantified in the urine of: EP patients during acute exacerbation and clinical remission; asthmatic patients during acute exacerbation and under stable conditions; and healthy control subjects. The urinary LTE(4) and EDN concentrations of EP patients during acute exacerbation were significantly higher than those of asthmatic patients and healthy subjects, and decreased immediately during clinical remission. The urinary LTE(4) concentration was associated with the urinary EDN concentration of EP patients during acute exacerbation. The urinary LTE(4) concentration significantly correlated with the diffusing capacity of the lung for carbon monoxide in EP patients during acute exacerbation. The increased urinary concentrations of leukotriene and eosinophil-derived neurotoxin were associated with acute exacerbation in eosinophilic pneumonia patients. The increased leukotriene concentration significantly correlated with diffusing capacity of the lung for carbon monoxide, suggesting that the monitoring of leukotriene concentration may aid in the management of eosinophilic pneumonia patients.

Involvement of eicosanoids and surfactant protein D in extrinsic allergic alveolitis.

The pathophysiology of extrinsic allergic alveolitis (EAA) involves oxidative lung damage as well as interstitial and alveolar inflammation. Macrophages and mast cells are inflammatory components of EAA that produce both leukotrienes (LTs) and prostaglandin D2 (PGD2). In addition, PGD2 is also produced by the free-radical-catalysed peroxidation of arachidonic acid during oxidative stress. Urinary 8-iso prostaglandin F2alpha (8-isoPGF2alpha) and serum surfactant protein D (SP-D) are considered appropriate biomarkers of oxidative stress and interstitial lung disease activity, respectively. The present study aimed to assess the association of these biomarkers with the pathophysiology of EAA. Two cases of acute EAA caused by the inhalation of fungi spores were reported. Eight asthmatic patients and six healthy control subjects were also enrolled in the current study. The serum SP-D and urinary eicosanoid (LTE4, PGD2 metabolite (9alpha,11betaPGF2), 8-isoPGF2alpha) concentrations markedly increased during the acute exacerbation phase. These concentrations decreased following corticosteroid therapy in the EAA patients. There was a significant correlation between serum SP-D and urinary 9alpha,11betaPGF2 concentrations in the EAA patients. In conclusion, although the present study proposes that serum surfactant protein-D and urinary eicosanoids are new biomarkers involved in the various immunological responses in extrinsic allergic alveolitis, further large-scale studies are needed to investigate the role of these compounds, not just as biomarkers, but also as biological potentiators of extrinsic allergic alveolitis.

Increase in urinary leukotriene B4 glucuronide concentration in patients with aspirin-intolerant asthma after intravenous aspirin challenge.

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 beta-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.

Urinary 3-bromotyrosine and 3-chlorotyrosine concentrations in asthmatic patients: lack of increase in 3-bromotyrosine concentration in urine and plasma proteins in aspirin-induced asthma after intravenous aspirin challenge.

BACKGROUND: Eosinophil peroxidase and myeloperoxidase halogenate tyrosine residues in plasma proteins and generate 3-bromotyrosine (BY) and 3-chlorotyrosine (CY), respectively. OBJECTIVES: (1) To estimate urinary concentrations of BY and CY in asthmatic patients. (2) To investigate BY concentration in relation to urinary leukotriene E4 (LTE4) concentration in order to evaluate the activation of eosinophils in patients with aspirin-induced asthma (AIA). METHODS: BY and CY were quantified with a gas chromatograph-mass spectrometer using (13)C-labelled compounds as internal standards. RESULTS: (1) Activation of eosinophils and neutrophils by immobilized IgG1 induced preferential formation of BY and CY, respectively. (2) A significantly higher concentration of BY was observed in the urine from asthmatic patients than in that from healthy control subjects (45+/-21.7 vs. 22.6+/-10.8 ng/mg-creatinine, P<0.01). CY concentration was also elevated in the urine from asthmatic patients (4.4+/-3.2 vs. 1.5+/-1.0 ng/mg-creatinine, P<0.01). (3) After intravenous aspirin challenge of aspirin-induced asthmatic patients, the concentration of BY in urine did not significantly change. No significant change was also observed in the ratio of BY concentration to total tyrosine concentration in plasma proteins. In contrast, the concentration of urinary LTE4 significantly increased after the intravenous aspirin challenge. CONCLUSION: Determination of BY and CY concentrations may be useful for monitoring the activation of eosinophils and neutrophils in asthmatic patients, respectively. After aspirin challenge of AIA patients, the increased concentration of urinary LTE4 did not accompany changes in BY concentration in both urine and plasma proteins. These results may preclude the activation of eosinophils after aspirin challenge in patients with AIA.

Nasal blockage and urinary leukotriene E4 concentration in patients with seasonal allergic rhinitis.

BACKGROUND: Cysteinyl-leukotrienes have been reported to have a primary role in the induction of nasal blockage of allergic rhinitis. However, there has been little experimental evidence that substantiates the relationship between nasal blockage severity and urinary leukotriene E4 (U-LTE4) concentration in patients with seasonal allergic rhinitis (SAR). METHODS: The concentrations of urinary mediators in 20 SAR patients were measured using an enzyme immunoassay to determine the relationship between nasal blockage severity and U-LTE4 concentration in patients with SAR. RESULTS: The basal U-LTE4 concentration was significantly higher in SAR patients with severe nasal blockage than in those with mild nasal blockage and in healthy control subjects. Although U-LTE4 concentrationwas significantly higher in patients with both asthma and SAR than in SAR patients with mild nasal blockage, no significant difference in the U-LTE4 concentration between patients with both asthma and SAR and SAR patients with severe nasal blockage was found. There was a significant correlation between U-LTE4 and urinary 9alpha11beta-prostoglandin F2 (9alpha11betaPGF2) concentrations (rs = 0.51, P = 0.02) in SAR patients. CONCLUSIONS: Although specific sites and cells of cysteinyl-leukotriene biosynthesis could not be determined in this study, severe nasal blockage is associated with the increased excretion level of U-LTE4.

A comparative study of eicosanoid concentrations in sputum and urine in patients with aspirin-intolerant asthma.

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), PGF2alpha, 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 9alpha11betaPGF2, 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, 9alpha11betaPGF2, 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.

Expression and function of CD43 and CDw60 on T cells from patients with atopic dermatitis.

Signalling via the CD43 and CDw60 epitopes has been reported as providing two novel pathways of T-lymphocyte activation. In Wiskott-Aldrich syndrome, which has atopic eczema-like skin symptoms, there is a defective expression of CD43, while CDw60 is strongly expressed on T cells from rheumatoid arthritis synovial fluid and from psoriatic skin lesions, and on blood mononuclear cells from patients with cutaneous T-cell lymphoma. We therefore studied the expression and function of these phenotypes on peripheral blood mononuclear cells and on CD4+ and CD8+ T-cell subsets from patients with atopic dermatitis. We observed a significant increase in the percentage of CD43+ cells among the blood mononuclear cells in patients with atopic dermatitis and an enhanced proliferation of CD4+ T cells following stimulation with anti-CD43 antibody. There were no changes in the CDw60 expression or function after stimulation with anti-CDw60 antibody. Thus, CD43 expression was not decreased but rather increased in blood mononuclear cells from patients with atopic dermatitis, whereas CDw60 expression did not differ from healthy controls.

[Treatment of tinea unguium with terbinafine: an open study comparing twelve weeks and twenty-four weeks of continuous terbinafine therapy, and determination of terbinafine level in the target nails].

The study protocol was approved by the Ethical Committee of Sakai Municipal Hospital. A total of 40 outpatients with tinea unguium of the toenails, fingernails or both took part after giving voluntary written informed consent. Inclusion criteria were suggestive clinical appearance, a positive KOH preparation and an opaqueness of more than 50% of the nail length. The patients received 125 mg terbinafine once a day. The medication was taken after the evening meal and treatment was continued for 12 weeks. Medication stopped in twenty patients who responded well and a follow-up study was continued for 64 weeks. In the other 20 patients, medication was continued for 24 weeks and the follow-up study continued for 64 weeks. At 4-week intervals, the patients were evaluated for their clinical and mycological statuses and adverse reactions. Clipping of distal nail samples, including any attached subungual tissue, was done using nail clippers at 4-week intervals after cessation of therapy and the level of terbinafine was measured in the laboratory. No adverse reactions were detected. Tinea unguium of fingernails (1) and the third toes (2) were cured easily in the short term in the 12 week therapy group. One case in the 24 week therapy group was excluded because systemic steroid therapy was started for bullous pemphigoid at 32 weeks. The results of treatment of big toe onychomycosis were compared between the 12 week (17) and the 24 week (19). In the former group, 9 (52.9%) showed complete cure and 8 (47.1%) showed relapse or worse after cessation of therapy was. In 24 week therapy group, complete cure was achieved in 14 (73.7%) and relapse or worse in 5 (26.3%). The cure rate between the 2 groups was statistically not significant. Terbinafine was detected in the target nails up to 24 weeks after cessation of medication in both groups. Onychomycosis or tinea pedis reappeared in a few cases 12 to 16 weeks after medication ceased in the 12 week group. Topical antimycological therapy is necessary after cessation of oral terbinafine.

Expression of IL-18 mRNA and secretion of IL-18 are reduced in monocytes from patients with atopic dermatitis.

BACKGROUND: IL-18 has been found to be an IFN-gamma-inducing factor that plays an important role in T(H)1 cell activation. Recently, IL-18 has also been found to enhance a T(H)2 cellular response in a specific setting. OBJECTIVE: The aim of this study was to elucidate the role of monocytes and soluble factors, with special focus on IL-18, in the pathogenesis of atopic dermatitis (AD). METHODS: The release of cytokines from PBMCs and purified monocytes was measured through use of ELISA; mRNA expression was evaluated by RT-PCR. The results from patients with AD were compared with those from healthy controls. RESULTS: IL-18 secretion was reduced in both unstimulated and lipopolysaccharide-stimulated monocytes from patients with AD. The mRNA expression of IL-18 and IL-1 beta-converting enzyme was significantly reduced in unstimulated monocytes from patients with AD (P <.03 and P <.01, respectively). Patients with AD had an elevated secretion of prostaglandin E(2) (PGE(2)) from unstimulated PBMCs (P <.001). The anti-PGE(2) antibody reversed the suppressive effect of PGE(2) on IL-18 secretion in unstimulated PBMCs from patients with AD. CONCLUSIONS: Decreased IL-18 production, together with a significantly reduced IL-18 and ICE mRNA expression in unstimulated monocytes and elevated PGE(2) secretion from PBMCs, was associated with the pathogenesis of AD.

Nuclear deviation in hepatic parenchymal cells on sinusoidal surfaces in Arctic animals.

In normal rat and human, most of the nuclei of hepatic parenchymal cells are centrally located in the cytoplasm. However, it is reported that the nuclei of hepatic parenchymal cells are situated at a deviated position on sinusoidal surfaces under pathological situations such as chronic hepatitis, hepatocellular carcinoma, adenomatous hyperplasia, or regeneration. During a study on the mechanism of extreme vitamin A-accumulation in hepatic stellate cells of arctic animals including polar bears, arctic foxes, bearded seals, and glaucous gulls, we noticed that these arctic animals displayed the nuclear deviation in hepatic parenchymal cells on sinusoidal surfaces. In this study, we assessed the frequency of hepatic parenchymal cells showing the nuclear deviation on the sinusoidal surfaces in arctic animals. A significantly higher frequency of the nuclear deviation in hepatic parenchymal cells was seen in polar bears (89.8+/-3.4%), arctic foxes (68.6+/-10.5%), bearded seals (63.6+/-8.4%), and glaucous gulls (24.2+/-5.8%), as compared to that of control rat liver (9.8+/-3.5%). However, no pathological abnormality such as fibrosis or necrosis was observed in hepatic parenchymal and nonparenchymal cells of arctic animals, and there were no differences in the intralobular distribution of parenchymal cells displaying the nuclear deviation in the livers from either arctic animals and control rats. The hepatic sinusoidal littoral cells such as stellate cells or extracellular matrix components in the perisinusoidal spaces may influence the nuclear positioning and hence the polarity and intrinsic physiological function of parenchymal cells.