Search

The NA62 experiment at CERN, configured in beam-dump mode, has searched for dark photon decays in flight to electron-positron pairs using a sample of 1.4×10^{17} protons on dump collected in 2021. No evidence for a dark photon signal is observed. The combined result for dark photon searches in lepton-antilepton final states is presented and a region of the parameter space is excluded at 90% confidence level, improving on previous experimental limits for dark photon mass values between 50 and 600  MeV/c^{2} and coupling values in the range 10^{-6} to 4×10^{-5}. An interpretation of the e^{+}e^{-} search result in terms of the emission and decay of an axionlike particle is also presented.

Objective: To investigate the effects of a stimulus response task using virtual reality (VR) for unilateral spatial neglect (USN)., Design: Double-blind randomized controlled trial., Setting: Acute phase hospital where stroke patients are hospitalized., Participants: The participants were 42 patients (N=42) with right-hemisphere cerebral damage who had been experiencing USN in their daily lives. They were randomly assigned to 3 groups: a stimulus response task with a background shift (SR+BS group), a stimulus response task without a background shift (SR group), and an object gazing task (control group)., Interventions: The stimulus response task was to search for balloons that suddenly appeared on the VR screen. A background shift was added to highlight the search in the neglected space. The control task was to maintain a controlled gaze on a balloon that appeared on the VR screen. The intervention period was 5 days., Main Outcome Measures: The primary outcome was the participants' scores on a stimulus-driven attention test (SAT) using the reaction time. The stimuli of the SAT were divided into 6 blocks of 3 lines on each side (-3 to +3). The secondary outcomes were their scores on the Behavioral Intention Test conventional, Catherine Bergego Scale, and straight ahead pointing tests., Results: In the SAT, there were significant interaction effects of reaction time between time and group factors in left-2, right+2, and right+3. The SR+BS and SR groups showed significant improvements in the reaction time of left-2 and right+3 compared with the control group. Moreover, the SR+BS group showed a significant improvement in the reaction time of left-2, which was the neglected space, compared with the SR group. However, there were no significant interaction effects of Behavioral Intention Test conventional, Catherine Bergego Scale, and straight ahead pointing., Conclusions: Our results suggest that the use of stimulus response tasks using VR combined with background shifts may improve left-sided USN., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to clarify the effect of an intervention using a head-mounted display with a web camera set at a modified pitch angle on spatial awareness, sit-to-stand movement, and standing balance in patients with left and right hemisphere damage., Methods: The participants were 12 patients with right hemisphere damage and 12 patients with left hemisphere damage. The line bisection test, a sit-to-stand movement, and balance assessment were performed before and after the intervention. The intervention task involved pointing at targets 48 times in an upward bias condition., Results: Significant upward deviation on the line bisection test was noted in patients with right hemisphere damage. The load on the forefoot during the sit-to-stand movement was significantly increased. The range of anterior-posterior sway during forward movement in the balance assessment was reduced., Conclusions: An adaptation task performed in an upward bias condition may produce an immediate effect on upward localization, sit-to-stand movement, and balance performance in patients with right hemisphere stroke., Competing Interests: CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare., (2023 The Japanese Association of Rehabilitation Medicine.)

[Purpose] This study aimed to clarify the effect of an adaptation of a deviation of the visual field in three axes on spatial cognition in patients with unilateral spatial neglect and distorted spatial perception in three dimensions. [Participants and Methods] Fifteen patients with cerebrovascular disease and symptoms of unilateral spatial neglect were included. Forty-eight pointing movements with a camera attached to a head-mounted display changed in three axes were compared with the control condition in which the camera was deflected only in the horizontal plane as with the prism adaptation. The main outcome measures were subjective straight-ahead pointing, line bisection, line cancellation, and star cancellation. [Results] The head-mounted display adaptive therapy was performed under conditions that varied in all three axes. The results indicated that it was possible to deflect the subjective straight-ahead pointing position to the lower left direction. [Conclusion] In contrast to the prism adaptation, which deflects the visual field in a single axis in the horizontal plane, the tri-axial adaptation corrected the median cognition in the left-right direction as well as the cognition of the body center, including the vertical direction., (2022©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Here, we developed a method that randomly generates balloons in the left-right, up-down, and near-far spaces on a monitor using a head-mounted display. In this study, we evaluated a lack of stimulus-driven attention case that was undetected by conventional assessments such as the Behavioral Inattention Test. We could identify mild neglect with our virtual reality method, as later confirmed using the Catherine Bergego scale. After repeated practice under a tilted background space condition, the patient demonstrated a reduction in the time needed to perceive the appearing balloons, suggesting a therapeutic effect.

Searches for the lepton number violating K^{+}→π^{-}μ^{+}e^{+} decay and the lepton flavor violating K^{+}→π^{+}μ^{-}e^{+} and π^{0}→μ^{-}e^{+} decays are reported using data collected by the NA62 experiment at CERN in 2017-2018. No evidence for these decays is found and upper limits of the branching ratios are obtained at 90% confidence level: B(K^{+}→π^{-}μ^{+}e^{+})<4.2×10^{-11}, B(K^{+}→π^{+}μ^{-}e^{+})<6.6×10^{-11} and B(π^{0}→μ^{-}e^{+})<3.2×10^{-10}. These results improve by 1 order of magnitude over previous results for these decay modes.

Although ezetimibe has potential value as an add-on therapy to statins, it is not established whether the addition of ezetimibe to statin therapy is more effective than double-dose statin monotherapy. We conducted a crossover design study. Twenty-one coronary artery disease (CAD) patients whose lipid profiles had not achieved Japanese guideline recommendations (JAS 2017), despite receiving low-dose statin therapy, were divided into two groups. Group A received ezetimibe 10 mg in addition to the baseline dose of statin for the first 3 months and was then switched to monotherapy with a double dose of statin for the next 3 months. Group B first received a double dose of statin for 3 months and was then switched to ezetimibe 10 mg in addition to a baseline dose of statin for the next 3 months. Compared with the baseline, double-dose statin therapy reduced low-density lipoprotein (LDL)-cholesterol (from 118 ± 22 to 104 ± 15 mg/dL, P < 0.05) and malondialdehyde-modified LDL (MDA-LDL) (from 142 ± 35 to 126 ± 24 U/L, P < 0.05) but did not lower high-sensitivity C-reactive protein (hsCRP) (3.02 ± 0.47 and 2.98 ± 0.41 log [ng/ml]). The addition of ezetimibe to a baseline dose of statin further reduced LDL-cholesterol (to 89 ± 15, P < 0.0001) and MDA-LDL (to 114 ± 22 U/L, P < 0.001) and reduced hsCRP (to 2.78 ± 0.38 log (ng/ml), P < 0.05). The changes in the levels of MDA-LDL (R = 0.548, P = 0.010) and hsCRP (R = 0.473, P < 0.05) were significantly correlated with the change in the LDL-cholesterol level after the addition of ezetimibe. Add-on ezetimibe treatment appears superior to double-dose statin therapy in CAD patients with poorly controlled dyslipidemia in terms of reductions in LDL-cholesterol level, lipid peroxidation, and inflammation.

Objective: The purpose of this study was to verify the effect on spatial perception in healthy young subjects of an unconscious leftward optical shift created by a head-mounted display (HMD) with an offset camera., Methods: We recruited 40 healthy right-handed adults who were divided into four groups according to the hand used in the tests and the visual direction displayed by the HMD (centered or 10° left). Each of the four groups (n = 10) undertook line bisection tasks across four combinations of variables: using a finger/stick or a mouse to point at a touch panel located 60 or 120 cm away from the subject., Results: According to the results, regardless of the hand used, when the index finger or a stick was used (reaching condition), the line bisection point was displaced significantly to the left of the center. Additionally, a major left-displacement trend was observed in the short-distance reaching task, which did not require the use of a stick. In contrast, the long-distance task required a stick to be used, and the left displacements were all smaller than those for the short-distance tasks that used the index finger., Conclusion: This finding may be explained by the subjects having sufficient experience coordinating hand and eye movements in the condition where they used their dominant hand and reached with their own arms without using a stick., Competing Interests: CONFLICTS OF INTEREST: There are no conflicts of interest to declare., (©2019 The Japanese Association of Rehabilitation Medicine.)

Background: Although the prevalence of pneumoconiosis has been decreasing due to improvements in working conditions and regular health examinations, occupational hygiene measures are still being established. Plasterers encounter a number of hazardous materials that may be inhaled in the absence of sufficient protection., Case Presentation: A 64-year-old man who plastered without any dust protection for more than 40 years was referred to our hospital with suspected interstitial pneumonia. Mixed dust pneumoconiosis and an unusual interstitial pneumonia (UIP) pattern with fibroblastic foci were diagnosed by video-assisted thoracoscopic surgery, and an elemental analysis detected elements included in plaster work materials. Despite the cessation of plaster work and administration of nintedanib, the patient developed advanced respiratory failure., Conclusion: Plasterers are at an increased risk of pneumoconiosis and may have a poor prognosis when complicated by the UIP pattern. Thorough dust protection and careful monitoring are needed.

A new measurement of the branching ratio R&#95;{e/μ}=Γ(π^{+}→e^{+}ν+π^{+}→e^{+}νγ)/Γ(π^{+}→μ^{+}ν+π^{+}→μ^{+}νγ) resulted in R&#95;{e/μ}^{exp}=[1.2344±0.0023(stat)±0.0019(syst)]×10^{-4}. This is in agreement with the standard model prediction and improves the test of electron-muon universality to the level of 0.1%.

Background: Nontuberculous mycobacteria (NTM) are often detected in patients undergoing treatment for pulmonary tuberculosis. This clinical status is thought to represent NTM disease, contamination, or colonization, but discriminating between these three conditions is difficult., Purpose: We examined the clinical characteristics and pathogenicity of coexisting NTM among patients with pulmonary tuberculosis, as well as its impact on clinical practice., Patients and Methods: The subjects comprised 59 patients with pulmonary tuberculosis treated at the National Hospital Organization Utsunomiya National Hospital between January and December 2013. Patients in whom NTM was detected in one or more cultures were defined as the NTM group (19 patients), and they were compared to the non-NTM group (40 patients). Antiglycopeptidolipid (anti-GPL) core antibody titers were investigated in 18 patients from the NTM group., Result: We observed no significant difference in patient characteristics (age, sex, complications, history of pulmonary tuberculosis, lung disease, chest imaging findings, degree of smear positivity on admission) between the two groups. Mean duration of hospitalization was markedly longer for the NTM group, excluding those with coexisting NTM after discharge (98.8 ± 7.9 days), than for the non-NTM group (58.3 ± 3.5 days; p < 0.001). No anti-GPL core antibodies were detected in any of the 18 patients from the NTM group, including 13 patients who fulfilled the ATS/IDSA criteria., Conclusion: Coexisting NTM observed during treatment for tuberculosis likely results from colonization or contamination and usually has low pathogenicity. However, this finding is related to prolonged hospitalization.

The patient was a 27-year-old man with pulmonary tuberculosis, who was initially treated with isoniazid, rifampicin, ethambutol, and pyrazinamide. However, because of hepatic dysfunction and visual impairment, the four-drug therapy was switched to a three-drug regimen with isoniazid, rifampicin, and levofloxacin. At 9 weeks after the initiation of levofloxacin, the patient developed cervical lymphadenopathy, fever, systemic erythema, and hepatic dysfunction. He was diagnosed with drug-induced hypersensitivity syndrome (DIHS) based on positive results in the human herpesvirus (HHV)-6 DNA test, an indicator of HHV-6 reactivation. The symptoms improved after withdrawal of the antituberculosis drugs and initiation of steroid administration. However, considering the risk of relapse of DIHS, the tuberculosis treatment, which was initially planned for 9 months, was stopped at 7 months. Neither DIHS nor tuberculosis recurred.

Three events for the decay K+-->pi+ nunu have been observed in the pion momentum region below the K+-->pi+pi0 peak, 140 < Ppi < 199 MeV/c, with an estimated background of 0.93+/-0.17(stat.) -0.24+0.32(syst.) events. Combining this observation with previously reported results yields a branching ratio of B(K+-->pi+ nunu) = (1.73(-1.05)+1.15) x 10(-10) consistent with the standard model prediction.

The effect of dihydropyridine calcium channel blocker (CCB) on baroreflex sensitivity (BRS) is not well described. We studied the effect of a new CCB, azelnidipine, compared with amlodipine, on BRS and ambulatory blood pressure (BP) in newly diagnosed untreated hypertension. This study was a prospective, randomized, and open-label study. We randomized patients to either azelnidipine or amlodipine treatment. Azelnidipine 8 to 16 mg (average 14.5 mg) and amlodipine 2.5 to 7.5 mg (average 4.9 mg) were used to lower the clinical BP <140/90 mm Hg. BRS, evaluated by the spontaneous and the Valsalva methods, and clinical and ambulatory BP were evaluated at baseline and after 13 weeks of each treatment. A total of 47 patients (age 53.1 +/- 10.8 years, 51% male), 26 in the azelnidipine group and 21 in the amlodipine group, completed the study. For baseline and after therapy respectively, both Valsalva-BRS (4.8 +/- 1.7 vs. 8.4 +/- 3.1 msec/mm Hg, P = 0.001) and spontaneous-BRS (5.5 +/- 2.5 vs. 8.2 +/- 5.6 msec/mm Hg, P = 0.019) were increased by azelnidipine, but amlodipine did not change them. Clinical and awake BPs were similarly reduced by each drug therapy. In conclusion, BRS was increased by azelnidipine therapy, but not by amlodipine therapy. This differential effect may be important in cardiovascular risk reduction.

Impaired glucose tolerance (IGT) is associated with cardiovascular risk factors, but the effects of pioglitazone and metformin on IGT are not well described. We tested the hypothesis that each drug would exhibit antiatherogenic and anti-inflammatory effects in subjects with IGT and early diabetes. The study design was a prospective, randomized, open label, cross-over study. Blood tests, including a 75-g oral glucose tolerance test (OGTT), were performed at baseline and after each treatment. Pioglitazone 15 mg/day or metformin 500-750 mg/day was given for 3 months. Biochemical markers to assess insulin resistance as well as lipid, inflammatory, neurohumoral, and hemostatic factors were included. Twenty-five subjects (17 male, 8 female; age [mean+/-SD]: 61+/-9 years; 84% hypertensive) completed the protocol. Of 25 subjects, 14 were diagnosed as IGT and 11 as diabetes with 75-g OGTT. Pioglitazone significantly reduced fasting glucose (p<0.05), and homeostasis model assessment of insulin resistance (HOMA-IR) (p<0.05) and metformin (p<0.01) reduced cholesterol. Both drugs significantly reduced aldosterone (both p<0.05) and von Willebrand factor (vWF) (both p<0.05). Plasma adiponectin was increased only by pioglitazone (p<0.001). Neither drug affected BP levels. In conclusion, pioglitazone was superior to metformin for the improvement of insulin resistance and adiponectin, and both drugs were equally effective in reducing vWF and aldosterone in subjects with IGT and early diabetes. Early intervention with pioglitazone or metformin therapy may reduce the incidence of future cardiovascular disease in subjects with impaired glucose tolerance or early diabetes.

We report a case of a middle-aged man who suffered a cerebral infarction resulting from dissection of a vertebral artery associated with morning blood pressure surge. A 56-year-old man was transferred to our hospital with dizziness and vomiting in the early morning on a cold day in winter. He reported that he had been standing in front of the sink after bathing when he suddenly felt dizzy and fell down. He did not lose consciousness, and by the time he reached the hospital by ambulance, his dizziness had subsided, but he complained of severe headache and vomited 3 times. On admission, he was alert, and there were no neurological or radiological abnormalities (CT, MR angiography) in the brain. However, infarction in the left cerebellar hemisphere was detected by brain MRI on the 5th day of hospitalization. String sign of the left vertebral artery was noted by angiography, confirming the diagnosis of dissection of the left vertebral artery. Ambulatory blood pressure monitoring was performed after discharge. Although the mean 24-h blood pressure was in the normal range, a marked morning blood pressure rise was observed. We speculated that the acute rise of blood pressure in the early morning might have contributed to the dissection of the vertebral artery.

An additional event near the upper kinematic limit for K+-->pi(+)nunu; has been observed by experiment E949 at Brookhaven National Laboratory. Combining previously reported and new data, the branching ratio is B(K+-->pi(+)nunu;)=(1.47(+1.30)(-0.89))x10(-10) based on three events observed in the pion momentum region 211

The aim of present study was to compare the predictive characteristics and cost-benefit of measuring the concentration of blood brain natriuretic peptide (BNP), compared with electrocardiography (ECG), chest radiography and echocardiography, as a diagnostic test for heart disease. The study group comprised 130 untreated patients who had symptoms suggestive of heart disease. According to the results of additional examinations and follow-up checks, 86 patients were diagnosed as having heart disease and 44 patients were judged free of heart disease. Positive findings in each test suggestive of heart disease were checked in accordance with criteria, and the number of positive and negative cases for each test was calculated. The predictive characteristics, such as specificity, sensitivity, accuracy, positive and negative predictive values, of each test and the cost-benefit value were calculated and analyzed statistically. The sensitivity, specificity and accuracy of blood BNP and echocardiography were significantly greater than those of ECG and chest radiography. Echocardiography had a significantly lower cost-benefit value compared with measuring blood BNP concentration. Thus, the blood BNP concentration had significantly higher predictive characteristics than ECG and chest radiography, and a cost-benefit value significantly greater than that of echocardiography.

Additional evidence for the rare kaon decay K+-->pi+nu(nu) has been found in a new data set with comparable sensitivity to the previously reported result. One new event was observed in the pion momentum region examined, 211pi+nu(nu)) = 1.57(+1.75)(-0.82)x10(-10).

Japanese guideline for the diagnosis and management of bronchial asthma was initially reported in 1998 and revised in 2000. This guideline was based on two former guidelines which were made by Japanese Allergology Society in 1993 and NIH.NHLBI in 1995 (GINA). New version of this guideline in 2000 pointed that the efficacy and adverse reaction of leukotriene receptor antagonists, the effectiveness of new inhaled corticosteroid (fluticasone propionate), and transdermal administration of beta-2 stimulant (tulobuterol hydrochloride). The precise evaluation of this guideline in terms of propriety, reliability, applicability and so on was not performed.

Surfactant proteins (SP)-A and SP-D are collagen-like glycoproteins belonging to the "collectin" class of C-type lectins, which are primarily synthesized in type II cells. Recent studies reported the possibility of local production of SP-A and SP-D in the airways, but the amounts of surfactant proteins in patients with bronchial asthma have not been studied. The composition of surfactant proteins in mild, stable asthmatics in the first lavage as bronchial lavage (BL) and the second and third lavages consecutively as alveolar lavages (AL) were therefore, analysed separately. The co-relationships in the BL between the amounts of surfactant proteins and those of fucose, which is one of the markers of submucosal secretion were also analysed. Increased amounts of SP-A in BL and AL of in asthmatics were found as compared with those in controls. A high concentration of SP-D in the AL asthma patients was also found. The levels of SP-A correlated with those of fucose in patients with bronchial asthma (r=0.849, p<0.01). The observations in the present study suggested that surfactant protein A may be secreted from the airways with allergic inflammation in a different manner from the alveoli. The increased levels of surfactant proteins A and D may play a protective role in an allergic inflammation in the pathogenesis of bronchial asthma.

Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma.

To analyze the pulsatile movement of coronary arterial walls, intravascular ultrasound was used to measure the diameter changes in the arterial lumen of 32 patients with coronary artery disease (CAD group) and five patients with chest pain but no CAD (control group). Measurements were performed on segments of the proximal left anterior descending coronary artery that were angiographically nonstenotic. Following identification of the peak systolic and end-diastolic phases using intra-coronary pressure tracings, the luminal diameters were measured around the center at 4 degrees intervals using a computer-assisted image analyzer. The pulsatile diameter change (dD) and end-diastolic diameter (DD) at each interval were analyzed and compared between the CAD and control groups. Mean DD did not differ significantly between the CAD group (4.53 +/- 0.69 mm) and the control group (4.52 +/- 0.51 mm). In contrast, the mean dD in the CAD group (0.05 +/- 0.18 mm) was significantly lower than that of the control group (0.13 +/- 0.12 mm). The mean maximum and minimum standardized percentage pulsatile diameter changes were -10.6 +/- 6.2% and 16.2 +/- 5.9%, respectively, in the CAD group, and -2.7 +/- 4.6% and 11.7 +/- 1.3%, respectively, in the control group. The mean standard deviation of dD was significantly greater in the CAD group (0.182 +/- 0.05 mm) than in the control group (0.116 +/- 0.04 mm), which indicated dD in CAD patients varied to a greater degree than in control patients. The ratio dD/dP (dP : pulse pressure) was used as an index of vascular compliance at the site of measurement. The mean dD/dP was significantly smaller in the CAD group (1.1 +/- 2.5 x 10(-3) mm/mmHg) than in the control group (4.0 +/- 3.3 x 10(-3) mm/mmHg). Aniso-diametric wall movement in the coronary artery (as indicated by a negative dD during systolic expansion) was enhanced in the CAD group compared to the control group. This was probably caused by the early stages of the arterial sclerotic process as it progressed heterogeneously along the vessel wall. Thus, aniso-diametric movement, which is a functional abnormality of the coronary arterial wall, appears to antedate detectable morphological changes.

A 26-year-old woman was admitted to our hospital because of fever of unknown origin. She had been treated with prednisolone, elcatonin and alfacalcidol under the diagnosis of systemic lupus erythematosus (SLE) and aseptic necrosis of femoral bone head. Six months ago she began to have a fever and subsequently left low back pain, for which extensive examinations were performed in other hospital but their causes remained unclear. She was referred to our hospital for further evaluation and therapy in October 1995. Bacteriological, immunological or serological examinations did not reveal the origin of fever. CT and ultrasonic examination did not show any abnormality. However, MRI, which was taken for the evaluation of aseptic necrosis of femoral bone head, showed the abscess shadow in sacroiliac joint. Open biopsy was performed and Mycobacterium tuberculosis bacilli were detected from the abscess. To our best knowledge, this is the first report of SEE with tuberculosis sacroiliac arthritis.

Coronary angiographic and risk factor (RF) characteristics were analyzed in 133 Japanese patients with ischemic heart disease (IHD) who were less than 40 years old and who had undergone coronary angiography (CAG) during the past 10 years at six university hospitals in the Tokyo area. We compared the coronary angiographic characteristics of the subject group with those of 216 controls with coronary sclerosis detected by CAG who were more than 40 years old (older control group) and the RF characteristics with those of 133 sex- and age-matched volunteers (younger control group). Sixty seven percent of the subjects (89 cases) were diagnosed as having myocardial infarction (MI) and 33% (44 cases) had angina pectoris (AP). Coronary artery disorders in this group consisted of 103 (77%) cases of coronary sclerosis, 20 (15%) cases of coronary spasm and 10 (8%) cases of miscellaneous diseases, eg, possible vasculitis with connective tissue disease, congenital anomalies, etc. The incidences of significant (> or = 75%) sclerotic narrowing in 0 vessels (31%) and 1 vessel (49%) in the subject group were significantly (p < 0.01) higher than those in the older control group, while the incidence of multivessel disease was significantly (p < 0.05) less in the subject group than in the older control group. The incidences of the following coronary risk factors were significantly (p < 0.05) higher in the subjects than in the younger controls: smoking (83% vs 35%), hypercholesteremia (44% vs 10%), obesity (31% vs 9%), hypertension (29% vs 3%), familial IHD (28% vs 7%) and diabetes mellitus (19% vs 2%). Thus, zero- or single-vessel disease predominated in the younger subject group and the prevalence of coronary risk factors was significantly higher in the subject.

Recent in vitro studies have suggested that interleukin-4 (IL-4) may be involved in the preferential migration of eosinophils into the airways in allergic asthma through its capacity to selectively increase vascular cell adhesion molecule-1 (VCAM-1) expression on vessels. To test this hypothesis, we studied the expression of VCAM-1, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) on vascular endothelium in bronchial mucosal biopsies from 20 allergic asthmatics using an immunohistochemistry technique and related the observations to IL-4 levels in bronchoalveolar lavage (BAL) fluid simultaneously obtained and to eosinophil infiltration in the bronchial mucosa. IL-4 was detectable in BAL fluid from nine subjects (range, 15.1 to 110 pg/ml in 20-fold concentrated BAL fluid) (IL-4-positive asthmatics) but unmeasurable in the remaining 11 subjects (IL-4-negative asthmatics). The IL-4-positive asthmatics showed a significantly increased expression of VCAM-1 but not E-selectin and ICAM-1 on vessels as compared with both IL-4-negative asthmatics (P < 0.001) and diseased control subjects (P < 0.001). In asthmatics, VCAM-1 expression was positively correlated with BAL IL-4 levels (rs = 0.89; P < 0.0001). Moreover, there was a significant correlation between the endothelial expression of VCAM-1 and the number of eosinophils, but not neutrophils, in the bronchial submucosa (r2 = 0.76; P < 0.001). A significant correlation was also found between BAL IL-4 levels and the number of eosinophils. These results suggest that IL-4 is a VCAM-1-selective activator also in human airways and the VCAM-1-dependent pathways play a role in selective migration of eosinophils into the airways in allergic asthma, and support the hypothesis described above.

Eosinophils generate and release leukotrienes C4 and B4 (LTC4, LTB4) and platelet activating factor (PAF), all of which have the capacity to cause inflammation and tissue injury in the airways. This study has examined the effects of a new 5-lipoxygenase inhibitor, 6-hydroxy-2-(4-sulfamoylbenzylamino)-4,5,7-trimethylbenzothiazo le hydrochloride (CAS 120164-49-0, E6080) on the release of LTC4, LTB4 and PAF by human eosinophils, Eosinophils stimulated by 1 mumol/l calcium ionophore A23187 for 15 min released 37.5 +/- 2.2 ng, 2.3 +/- 0.3 ng and 4.0 +/- 0.3 pmol per 10(6) cells of immunoreactive LTC4, LTB4 and PAF, respectively (mean +/- SEM, n = 4). LTC4 and LTB4 releases were inhibited dose-dependently by the addition of E6080 to the cell suspension. The IC50 values were 0.26 mumol/l for LTC4 and 0.23 mumol/l for LTB4. PAF release was not inhibited. These results suggest that E6080 is a potent inhibitor of LTC4 and LTB4 release from eosinophils and may provide a protective effect against bronchoconstriction during late-phase asthmatic responses.

We measured the serum concentration of soluble interleukin-2 receptor (sIL-2R) in asthma patients and healthy controls to evaluate T-lymphocyte activation in this disease. The SIL-2R concentrations in patients with asthma irrespective of presence of acute attacks were significantly higher than those of the controls (p < 0.001). Although the sIL-2R concentrations were similar in the patients with acute asthma and those in remission, levels in patients with moderate and severe asthma attacks were significantly higher than levels for patients in remission (p < 0.001). These results suggest that T-lymphocyte activation occurs in asthma patients and becomes more prominent during moderate and severe acute attacks.

Recently direct evidence for the role of interleukin-5 (IL-5) in eosinophilic inflammation in the airways of persons with asthma has been provided by an in situ hybridization study that used radioisotope-labeled IL-5 complementary RNA probes. Radioisotope-labeled probes, although sensitive, require autoradiographic detection, which is time-consuming. In the most recent study we attempted to detect IL-5 messenger RNA in the bronchial biopsy specimens from patients with asthma using nonradioactive in situ hybridization, which gives rapid results. Bronchial biopsy specimens were obtained from eight patients with asthma and seven diseased control subjects. IL-5 complementary DNA probes were labeled with digoxigenin-deoxyuridine triphosphate and hybridized to permeabilized sections. Hybridization signals were visualized by an immunohistochemistry technique. Positive hybridization signals were observed in six of the eight biopsy specimens from patients with asthma. Pretreatment with ribonuclease or hybridization with an unrelated probe produced negative results. Immunohistochemical staining of serial sections with a monoclonal antibody to IL-5 revealed that a few cells within the mucosa positively stained, suggesting active synthesis of IL-5. Biopsy results from the seven diseased control subjects did not show any hybridization signal. These results confirm and extend previous observations of IL-5 messenger RNA expression in the airways of patients with asthma, and suggest that digoxigenin-labeled IL-5 complementary DNA probes would be a powerful research tool.

To determine whether IL-5 is locally produced in the bronchial mucosa of asthmatics, and to ascertain the precise cell type producing this cytokine, we examined bronchial biopsies by non-radioactive in situ hybridization and immunohistochemistry. IL-5 cDNA probes were labeled with digoxigenin-dUTP and hybridized to frozen or paraffin tissue sections. Hybridization signals were visualized by an immunohistochemistry technique. An IL-5-producing T cell clone derived from a patient with adult T cell leukemia was used as a positive control. Specific hybridization signals for IL-5 mRNA were observed in the bronchial mucosa of symptomatic asthmatics. No hybridization signal was detected in the control subject in whom no underlying disease was found. Immunohistochemical staining of serial sections using a panel of monoclonal antibodies directed against lymphocyte subsets strongly suggested that cells expressing mRAN for IL-5 were T cells. These results suggest that a cell-cell interaction between T cells and eosinophils through IL-5 may play an important role in the airway inflammation in asthma.

The effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the cardiovascular system were examined. When PACAP-38 (270 or 420 pmol/kg body weight) was administered intravenously to the anesthetized dogs, both mean arterial pressure and left ventricular systolic pressure increased within 2 min after a temporal depression. Pulmonary arterial systolic pressure increased promptly. These hemodynamic values and heart rates (HR) 5 min after injection were significantly higher than the corresponding values in physiological saline injected dogs, and some effects were still sustained over 15 min. Cardiac output and stroke volume also increased and the values at 5 min were significantly higher than those in controls. The high dose of PACAP-38 (420 pmol/kg) evoked greater responses than those induced by the low dose (270 pmol/kg). Plasma adrenaline, but neither noradrenaline nor dopamine concentration significantly increased 15 min after injection of 420 pmol/kg PACAP-38. Moreover, PACAP-38 clearly stimulated cyclic AMP production in rat cardiac myocytes with EC50 of 1.5 x 10(-9) M and plasma cAMP levels significantly and dose-dependently increased in dogs 5 min after administration. These results first demonstrated that PACAP has inotropic and chronotropic actions on the heart possibly by a direct stimulation of adenylate cyclase in cardiac myocytes and also that the cardiovascular functions may be possibly modified by an evoked adrenaline secretion in vivo.

In order to evaluate the role of tumor necrosis factor alpha (TNF alpha) in the recruitment of eosinophils and neutrophils into the tissues, we studied the effect of TNF alpha on the migration of those cells in vitro, employing a modified Boyden's chamber technique. TNF alpha induced a significant migration of human eosinophils in a dose-dependent manner, and the preincubation of eosinophils with TNF alpha enhanced platelet activating factor (PAF)-induced eosinophil migration. Checkerboard analysis revealed that the eosinophil migration induced by TNF alpha was mainly due to chemokinesis. On the other hand, TNF alpha induced neither neutrophil migration nor enhancement of PAF-induced neutrophil migration. These results indicate that TNF alpha possesses a chemokinetic effect on human eosinophils and that TNF alpha augments the migration of eosinophils by PAF.

Eosinophils, which are prominent inflammatory cells in the asthmatic airway, are attracted to the airway by several chemoattractants. At present, eosinophil chemotaxis is studied employing the Boyden Millipore chamber system in vitro. In the Boyden method, the number of migrated cells are evaluated by direct microscopic observation of individual cells. This microscopic procedure usually requires much time and it is difficult to obtain objective results. Therefore, we have developed a new fractional measurement technique, using the image analyzing system connected with a color video camera and a computer for counting the eosinophils which have migrated into a filter. Using this system with the Boyden method, migrated cells were observed more objectively and quickly. Therefore, this image analyzing system with the Boyden method, may be a useful technique for the fractional measurement of migrated eosinophils in a sample mixture of eosinophils and neutrophils.

To investigate the role of neuropeptides in allergic inflammation, we examined the effect of peptides on eosinophil chemotaxis. Eosinophils were purified from the blood of allergic and normal subjects using a discontinuous Percoll density gradients. Chemotaxis was induced by platelet-activating factor (PAF) and leukotriene B4, and was assayed by a modified Boyden's chamber technique. Four neuropeptides were examined in this study: substance P (SP), neurokinin A, calcitonin gene-related peptide (CGRP), and cholecystokinin octapeptide. Peptides alone (10 nM to 10 microM) were not chemotactic for eosinophils. However, when eosinophils were pre-treated with peptides (100 nM) at 37 degrees C for 30 min, chemotactic response to PAF (10 nM) was significantly enhanced (p < 0.01) in allergic subjects; % control by SP, neurokinin A, CGRP and cholecystokinin octapeptide was 269 +/- 42, 243 +/- 32, 227 +/- 21, and 251 +/- 42, respectively (n = 8). Similar results were obtained in leukotriene B4-induced eosinophil chemotaxis. In contrast, no enhancement was observed in normal subjects. Potentiating effect of SP and CGRP on PAF-induced eosinophil chemotaxis in allergic subjects was significantly attenuated by SP antagonist [D-Pro2,D-Trp7,9]-SP and human CGRP (8-37) receptor antagonist, respectively. Neutral endopeptidase inhibitors (phosphoramidon, leupeptin, and bestatin) failed to significantly augment the PAF-induced eosinophil chemotaxis when the cells were pretreated with various peptides and neutral endopeptidase inhibitors. The C-terminal fragment of SP (SP6-11) had an effect similar to that of the intact SP molecule, whereas no potentiating effect by the N-terminal of SP (SP1-9) was observed. These results suggest that neuropeptides may play a significant role in eosinophil infiltration by priming cells in allergic inflammation.

In order to clarify the role of leukotriene in the antigen-induced asthmatic response, we carried out mite-antigen, leukotriene D4 (LTD4) and histamine inhalation tests in 21 mite-sensitive atopic asthma patients, and investigated the relationship between the bronchial responsiveness to mite (PD20-Mite) and that to LTD4 and histamine (PD20-LTD4, PD20-Hist). We then compared PD20-LTD4 and PD20-Hist between the groups with and without late asthmatic response (LAR), and investigated the relationship between the peak percentage fall of FEV1.0 in LAR (magnitude of LAR) and PD20-LTD4 and PD20-Hist. There were significant correlations between PD20-LTD4 and PD20-Mite (r = 0.590, p < 0.01), and between PD20-Hist and PD20-Mite (r = 0.669, p < 0.001). The bronchial responsiveness to LTD4 and histamine was significantly higher in the group with LAR. In addition, PD20-LTD4 showed a significant negative correlation with the magnitude of LAR (r = 0.724, p < 0.001). Furthermore we analyzed the relationship between PD20-LTD and the ratio of the magnitude of LAR to that of IAR (immediate asthmatic response), because there was a significant correlation between the magnitude of IAR and that of LAR (r = 0.842, p < 0.001) in 16 asthmatic patients with dual asthmatic response, and found that the correlation coefficient was also very high (r = -0.836, p < 0.001). These results suggest an important role of leukotriene in the antigen-induced asthmatic response.

Identification of G-proteins and coupling of PAF receptors to G-proteins have been examined in the membranes of human blood eosinophils and neutrophils. Heterotrimeric G-proteins, Gi and GS, were present in both cell types, as demonstrated by immunoblotting and ADP-ribosylation with pertussis toxin. In addition, a group of low molecular mass (18-28 kDa) monomeric G-proteins was also identified. Pertussis toxin and GTP gamma S attenuated the specific binding of [3H]PAF, suggesting the occurrence of coupling between pertussis toxin-sensitive Gi protein and PAF receptors in eosinophils and neutrophils.

Compared to PAF-induced platelet aggregation, the chemotactic response to PAF of human eosinophils requires higher PAF concentrations, suggesting a lower binding affinity of PAF for the eosinophil. To test this possibility, we examined the binding of PAF by human eosinophils. The dose range of unlabeled PAF required to produce inhibition of [3H]PAF binding was roughly the same as that for induction of chemotaxis, and was much higher than that in platelets as reported in the literature. These results indicate that the affinity of PAF for the eosinophil is considerably less than that for the platelet, and may explain the higher EC50 for eosinophil chemotaxis.