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Diagnosing and treating elite and Olympic athletes with exercise-induced bronchoconstriction has been well established. However, a subset of elite and Olympic athletes with exercise-induced bronchoconstriction experience symptoms of breathlessness due to lack of adherence, improper medications, and/or generalized breathing dysfunction. A short review of traditional treatment plans for elite and Olympic athletes is presented along with the challenges of adherence, managing dysfunctional breathing, and measuring and treating mental skills deficits that may impact breathing. Elite and Olympic athletes may not respond to traditional treatment for exercise-induced bronchospasm, and we present some of the reasons why the athletes fail to respond. Furthermore, we present information on how to detect and treat elite and Olympic athletes with difficult-to-treat asthma. As part of this review we developed a flow diagram for medical providers to identify the reasons for lack of response to traditional treatment plans for exercise-induced bronchoconstriction with options for other treatment modalities., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective : To investigate whether once-daily (OD) fluticasone furoate (FF)/vilanterol (VI) provides greater long-term protection from postexercise fall in forced expiratory volume in 1 s (FEV 1 ) than twice-daily (BD) fluticasone propionate (FP) in patients with asthma and exercise-induced bronchoconstriction. Methods : A randomized, double-blind, crossover study was conducted in patients (aged 12-50 years) on low-/mid-dose maintenance inhaled corticosteroid. Following a 4-week run-in period (FP 250 µg BD), patients with a ≥ 20% decrease in postexercise FEV 1 received FF/VI 100/25 µg OD or FP 250 µg BD for 2 weeks. Exercise challenges were carried out 23 h after the first dose of study medication, and 12 and 23 h after evening clinic dose at the end of the 2-week treatment period. After a 2-week washout period (FP 250 µg), patients crossed over treatments, with procedures and tests repeated. The primary endpoint was mean maximal percentage decrease from pre-exercise FEV 1 following exercise challenge 12-h postevening dose on Day 14. Results: The mean maximal percentage decrease from pre-exercise FEV 1 after the 12-h exercise challenge (Day 14) was 15.02% with FF/VI, and 16.71% with FP (difference, -1.69; 95% confidence interval, -3.76 to 0.39; p = 0.109). After the 23-h exercise challenge (Day 14), respective mean maximal decreases were 11.90% and 14.05% (difference, -2.15; 95% confidence interval, -4.31 to 0.01). Conclusion: The study failed to show a difference between FF/VI and FP at providing long-term protection from exercise-induced bronchoconstriction.

This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted. Subjects attended a clinic visit daily on consecutive mornings during each of 3 1-week treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 fluticasone propionate/salmeterol combination product (Advair ® Diskus). Daily eNO value recorded was the highest of 3 measurements; 1 inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washouts. A total of 105 subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percentage eNO decrease (standard deviation) from day 1 baseline for each treatment period was 36.6 (±18.7), 45.3 (±16.5), and 54.6 (±12.5) with Advair ® 100/50, 250/50, and 500/50, respectively. Mean percentage decrease in eNO across each treatment (dose) was modeled using a mixed-model ANOVA. Although the overall treatment was significant (P = .0015), because of the relatively small sample size and within-subject variability, only the 100/50 vs 500/50 (P = .0003) and 250/50 vs 500/50 (P = .047) treatments were significantly different., (© 2017, The American College of Clinical Pharmacology.)

The first practice parameter on exercise-induced bronchoconstriction (EIB) was published in 2010. This updated practice parameter was prepared 5 years later. In the ensuing years, there has been increased understanding of the pathogenesis of EIB and improved diagnosis of this disorder by using objective testing. At the time of this publication, observations included the following: dry powder mannitol for inhalation as a bronchial provocation test is FDA approved however not currently available in the United States; if baseline pulmonary function test results are normal to near normal (before and after bronchodilator) in a person with suspected EIB, then further testing should be performed by using standardized exercise challenge or eucapnic voluntary hyperpnea (EVH); and the efficacy of nonpharmaceutical interventions (omega-3 fatty acids) has been challenged. The workgroup preparing this practice parameter updated contemporary practice guidelines based on a current systematic literature review. The group obtained supplementary literature and consensus expert opinions when the published literature was insufficient. A search of the medical literature on PubMed was conducted, and search terms included pathogenesis, diagnosis, differential diagnosis, and therapy (both pharmaceutical and nonpharmaceutical) of exercise-induced bronchoconstriction or exercise-induced asthma (which is no longer a preferred term); asthma; and exercise and asthma. References assessed as relevant to the topic were evaluated to search for additional relevant references. Published clinical studies were appraised by category of evidence and used to document the strength of the recommendation. The parameter was then evaluated by Joint Task Force reviewers and then by reviewers assigned by the parent organizations, as well as the general membership. Based on this process, the parameter can be characterized as an evidence- and consensus-based document., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Racehorses may experience exercise-induced bronchodilation or bronchoconstriction, with potential differences between healthy and asthmatic individuals., Objectives: To identify exercise-related lung function variations by oscillometry in racehorses, compare lung function between healthy and mild equine asthma (MEA) horses, assess oscillometry's potential as a predictor of racing fitness., Study Design: Prospective case-control clinical study., Methods: Fourteen Thoroughbred racehorses (5 healthy, 9 MEA) underwent a protocol including respiratory oscillometry at rest, exercise with fitness monitoring, oscillometry at 15 and 45 min post-exercise, and bronchoalveolar lavage fluid (BALf) cytology. Oscillometry parameters (resistance [Rrs] and reactance [Xrs]) were compared within and between healthy and MEA groups at different timepoints. Associations between Rrs and Xrs at rest and 15 min post-exercise and BALf cytology and fitness indices were evaluated., Results: MEA horses showed higher Rrs at 15 min post-exercise (0.6 ± 0.2 cmH 2 O/L/s) than healthy horses (0.3 ± 0.1 cmH 2 O/L/s) (p < 0.01). In healthy horses, Rrs decreased at 15 min post-exercise compared with resting values (0.5 ± 0.1 cmH 2 O/L/s) (p = 0.04). In MEA horses, oscillometry parameters did not vary with time. Post-exercise Xrs inversely correlated with total haemosiderin score (p < 0.01, r 2  = 0.51). Resting Rrs inversely correlated with speed at 200 bpm (p = 0.03, r 2  = -0.61), and Xrs with maximum heart rate (HR) during exercise (p = 0.02, r 2  = -0.62). Post-exercise Rrs inversely correlated with mean (p = 0.04, r 2  = -0.60) and maximum speed (p = 0.04, r 2  = -0.60), and HR variability (p < 0.01, r 2  = -0.74)., Main Limitations: Small sample size, oscillometry repeatability not assessed, potential interference of upper airway obstructions, external variables influencing fitness indices., Conclusions: Oscillometry identified lung function differences between healthy and MEA horses at 15 min post-exercise. Only healthy horses exhibited exercise-induced bronchodilation. Oscillometry showed potential in predicting subclinical airway obstruction., (© 2024 EVJ Ltd.)

Objective: To present guidelines for the recognition, prophylaxis, and management of asthma that lead to improvement in the quality of care certified athletic trainers and other health care providers can offer to athletes with asthma, especially exercise-induced asthma.Background: Many athletes have difficulty breathing during or after athletic events and practices. Although a wide variety of conditions can predispose an athlete to breathing difficulties, the most common cause is undiagnosed or uncontrolled asthma. At least 15% to 25% of athletes may have signs and symptoms suggestive of asthma, including exercise-induced asthma. Athletic trainers are in a unique position to recognize breathing difficulties caused by undiagnosed or uncontrolled asthma, particularly when asthma follows exercise. Once the diagnosis of asthma is made, the athletic trainer should play a pivotal role in supervising therapies to prevent and control asthma symptoms. It is also important for the athletic trainer to recognize when asthma is not the underlying cause for respiratory difficulties, so that the athlete can be evaluated and treated properly.Recommendations: The recommendations contained in this position statement describe a structured approach for the diagnosis and management of asthma in an exercising population. Athletic trainers should be educated to recognize asthma symptoms in order to identify patients who might benefit from better management and should understand the management of asthma, especially exercise-induced asthma, to participate as active members of the asthma care team. [ABSTRACT FROM AUTHOR]

Background: Sedating antihistamines may impair driving performance as seriously as alcohol.Objective: To compare the effects of fexofenadine, diphenhydramine, alcohol, and placebo on driving performance.Design: Randomized, double-blind, double-dummy, four-treatment, four-period crossover trial.Setting: The Iowa Driving Simulator.Participants: 40 licensed drivers with seasonal allergic rhinitis who were 25 to 44 years of age.Intervention: One dose of fexofenadine (60 mg), diphenhydramine (50 mg), alcohol (approximately 0.1% blood alcohol concentration), or placebo, given at weekly intervals before participants drove for 1 hour in the Iowa Driving Simulator.Measurements: The primary end point was coherence, a continuous measure of participants' ability to match the varying speed of a vehicle that they were following. Secondary end points were drowsiness and other driving measures, including lane keeping and response to a vehicle that unexpectedly blocked the lane ahead.Results: Participants had significantly better coherence after taking alcohol or fexofenadine than after taking diphenhydramine. Lane keeping (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine use compared with fexofenadine use. Mean response time to the blocking vehicle was slowest after alcohol use (2.21 seconds) compared with fexofenadine use (1.95 seconds). Self-reported drowsiness did not predict lack of coherence and was weakly associated with minimum following distance, steering instability, and leftlane excursion.Conclusions: Participants had similar performance when treated with fexofenadine or placebo. After alcohol use, participants performed the primary task well but not the secondary tasks; as a result, overall driving performance was poorer. After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did. Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive. [ABSTRACT FROM AUTHOR]

Background: Physical exercise has been shown to improve asthma symptoms, QoL, exercise capacity, bronchial hyperresponsiveness and lung function and is recommended as a supplementary treatment to pharmacotherapy for asthma. Clinicians are well placed to promote physically active lifestyles, but their role and practice towards promoting physically active lifestyles among patients has not been fully investigated. This study was designed to investigate the knowledge, propensity, attitude and practices of clinicians towards the promotion of physical activity among patients with asthma and allergies., Methods: Two hundred and eighty clinicians (mean age; 46 ± 13 years; with a clinical experience of practice for 15 ± 7 years) participated in a global survey. The survey comprised a 29-item questionnaire, which gathered information on attitudes of the clinicians towards promoting physical activity, their knowledge and their beliefs regarding evidence for benefits of physical activity as a supplementary treatment in patients with asthma and allergies., Results: Almost all respondents were aware of the strong evidence in favor of physical activity for the psychological well-being, weight control, decreased risk of diabetes, ischemic heart disease and arterial hypertension. Evidence for reduction in the risk for developing asthma and for better asthma control were reported by 60.0% and 85.4% of participants, respectively. The majority (85.0%) of clinicians strongly agreed that promoting physical activity is important to health care, although 95.5% considered they required more educational training. Although two thirds of them usually recommended exercise to their asthmatic/allergic patients, only 24.0% reported having previous training on the subject of such counseling. Almost all believed that effective counseling about a healthy diet, exercise and weight management would be easier if the clinician himself/herself was physically fit and healthy., Conclusions: The results of this global survey indicate that clinicians working in the field of allergy and respiratory diseases are well aware of the evidence supporting the benefits of physical activity for asthma and allergic diseases although they need more training in such counseling. Therefore, concerted efforts are needed towards educating clinicians towards promoting physical activity and weight management, as a supplementary treatment for asthma and allergies.

Severe pulmonary vasoconstriction induced by protamine is a rare complication. We report a case of a 77-year-old male patient with a history of mitral valve plasty (MVP). He underwent redo MVP via right thoracotomy under the totally endoscopic procedure (MICS redo-MVP). Immediately after weaning cardiopulmonary bypass (CPB), protamine was administrated. 10 min later peak systolic pulmonary arterial pressure (sys PAP) rose to 62 mmHg, and 30 min later to 80 mmHg. Due to the negative impact of protamine administration, nitric oxide inhalation (iNO) therapy was started with a concentration of 20 ppm. 10 min after iNO therapy started, sys PAP decreased to 63 mmHg. After entering the intensive care unit (ICU), sys PAP decreased to 35 mmHg. Here, we present an effective iNO therapy case for pulmonary hypertension due to protamine and the patient had a good postoperative recovery. This study was approved by the Institutional Review Board at Kitaharima Medical Center (IRB-0602) with the waiver of informed consent. [ABSTRACT FROM AUTHOR]

Fexofenadine is a second-generation inverse agonist of H1-receptor of histamine which is highly selective with proven efficacy in relieving symptoms associated with allergic conditions. It has an additional benefit of not penetrating the blood–brain barrier and therefore do not induce sedation and not impair the cognitive function/psychomotor performance. This review aimed at providing evidence based on available controlled studies to reinforce the non-sedative property of fexofenadine for treating patients with allergic rhinitis and urticaria. We performed an electronic literature search using keywords such as fexofenadine, drowsiness, somnolence, sedation, fatigue, cognitive, impairment, psychomotor, driving performances, sleep, rapid eye movement, alertness, clinical study, in vitro study, in vivo study, and pharmacodynamics in the Embase search engine. The review included randomized controlled trials, review articles, systematic reviews, and meta-analyses, together with post-marketing analysis conducted in healthy subjects and patients with allergy and were focused on comparing the antihistaminic potential or safety of fexofenadine with other antihistamines or placebo. Positron emission tomography (PET) and proportional impairment ratio (PIR) data along with other objective tests from various studies confirmed the non-sedative property of fexofenadine. Results of brain H1-receptor occupancy (H1RO) obtained from PET showed no H1RO by fexofenadine, the receptor which is known to cause sedation of H1 antihistamines. Most studies calculating PIR value as 0 showed fexofenadine to be a non-impairing oral antihistamine regardless of dose. Clinical trials in adults and children showed fexofenadine to be well tolerated without sedative effect or impairment of cognitive/psychomotor function even at higher than recommended doses. Published literature based on various parameters and clinical trials conducted for evaluating the effect of fexofenadine on sedation and central nervous system shows fexofenadine is both clinically effective and non-sedating. [ABSTRACT FROM AUTHOR]

This article summarizes the findings of an expert panel of nationally recognized allergists and pulmonologists who met to discuss how to improve detection and diagnosis of exercise-induced bronchoconstriction (EIB), a transient airway narrowing that occurs during and most often after exercise in people with and without underlying asthma. EIB is both commonly underdiagnosed and overdiagnosed. EIB underdiagnosis may result in habitual avoidance of sports and physical activity, chronic deconditioning, weight gain, poor asthma control, low self-esteem, and reduced quality of life. Routine use of a reliable and valid self-administered EIB screening questionnaire by professionals best positioned to screen large numbers of people could substantially improve the detection of EIB. The authors conducted a systematic review of the literature that evaluated the accuracy of EIB screening questionnaires that might be adopted for widespread EIB screening in the general population. Results of this review indicated that no existing EIB screening questionnaire had adequate sensitivity and specificity for this purpose. The authors present a call to action to develop a new EIB screening questionnaire, and discuss the rigorous qualitative and quantitative research necessary to develop and validate such an instrument, including key methodological pitfalls that must be avoided., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma., Methods: To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB. The evidence was appraised and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach., Results: Recommendations for the treatment of EIB were developed. The quality of evidence supporting the recommendations was variable, ranging from low to high. A strong recommendation was made for using a short-acting β(2)-agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting β(2)-agonist before exercise, strong recommendations were made for a daily inhaled corticosteroid, a daily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise., Conclusions: The recommendations in this Guideline reflect the currently available evidence. New clinical research data will necessitate a revision and update in the future.

Background: Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB) is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions., Methods: Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval., Results: Of 373 subjects challenged twice 161 were positive (≥ 10% fall FEV1 on at least one challenge). The EIB was mild and 77% of subjects had <15% fall on both challenges. Agreement between results was 76.1% with 56.8% (212) negative (< 10% fall FEV1) and 19.3% (72) positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30 min for the 72 subjects with two tests ≥ 10% fall FEV1 was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥ 15% fall FEV1 it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative., Conclusions: Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when prescribing prophylactic treatment to prevent EIB and when designing protocols for clinical trials.

Background: The pharmacological stress agents adenosine and dipyridamole are contraindicated in asthma patients because of the risk of adenosine receptor-mediated bronchospasm. Binodenoson, a selective adenosine A(2A) receptor agonist, produces maximal coronary hyperemia during pharmacological stress testing yet has a low affinity for the adenosine A(1), A(2B), and A(3) receptors that are probably responsible for bronchospasm. This study was conducted to assess the safety of binodenoson in 87 healthy young adult volunteers with documented mild, intermittent asthma., Methods and Results: This study consisted of a dose-escalating, single-blinded phase and a placebo-controlled, double-blinded phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blinded phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 microg/kg). In the double-blinded phase, commenced after medical review of results from the single-blinded phase, subjects were randomly assigned 2:1 to either binodenoson 1.5 microg/kg (n=41) or placebo (n=22). The primary end point was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second of >/=20% from the preinjection measure. Secondary safety end points were changes from preinjection measure in forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow during the middle 50% of the forced vital capacity; vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing., Conclusions: Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.

Background: Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma., Methods: 509 people (6-50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a > or = 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 < or = 16 mg/ml and to mannitol a 15% fall in FEV1 at < or = 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results., Results: Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6) mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive., Conclusion: In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations., Trial Registration: This was a multi-center trial comprising 25 sites across the United States of America.

Exercise-induced (EI) hypersensitivity disorders are significant problems for both recreational and competitive athletes. These include EI-asthma, EI-bronchoconstriction, EI-rhinitis, EI-anaphylaxis and EI-urticaria. A group of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy Asthma and Immunology met to discuss the pathogenesis of these disorders and how to diagnose and treat them, and then to develop a consensus report. Key words (exercise with asthma, bronchoconstriction, rhinitis, urticaria or anaphylaxis) were used to search Medline, the Cochrane database and related websites through February 2008 to obtain pertinent information which, along with personal reference databases and institutional experience with these disorders, were used to develop this report. The goal is to provide physicians with guidance in the diagnosis, understanding and management of EI-hypersensitivity disorders to enable their patients to safely return to exercise-related activities.

Background: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. Methods: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. Results: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. Conclusions: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs. [ABSTRACT FROM AUTHOR]

Excessive dynamic airway collapse (EDAC) is a recognized cause of exertional dyspnea arising due to invagination of the trachea and/or main bronchi. EDAC is typically assessed by evaluating large airway movement with forced expiratory maneuvers. This differs from the respiratory response to exercise hyperpnea. We aimed to evaluate large airway movement during physical activity, with continuous bronchoscopy during exercise (CBE), in healthy subjects and compare findings with resting bronchoscopic maneuvers and imaging techniques. Twenty-eight individuals were recruited to complete two visits including treadmill-based CBE, to voluntary exhaustion, and cine magnetic resonance imaging (MRI) with forced expiratory maneuvers at rest. Twenty-five subjects [aged 29 (26–33) yr, 52% female] completed the study (n = 2 withdrew before bronchoscopy, and one was unable to tolerate insertion of bronchoscope). The majority (76%) achieved a peak heart rate of >90% predicted during CBE. The procedure was prematurely terminated in five subjects (n = 3; elevated blood pressure and n = 2; minor oxygen desaturation). The CBE assessment enabled adequate tracheal visualization in all cases. Excessive dynamic airway collapse (tracheal collapse ≥50%) was identified in 16 subjects (64%) on MRI, and in six (24%) individuals during resting bronchoscopy, but in no cases with CBE. No serious adverse events were reported, but minor adverse events were evident. The CBE procedure permits visualization of large airway movement during physical activity. In healthy subjects, there was no evidence of EDAC during strenuous exercise, despite evidence during forced maneuvers on imaging, thus challenging conventional approaches to diagnosis. NEW & NOTEWORTHY: This study demonstrates that large airway movement can be visualized with bronchoscopy undertaken during vigorous exercise. This approach does not require sedation and permits characterization of the behavior of the large airways and the tendency toward collapse during upright, ambulatory exercise. In healthy individuals, the response pattern of the large airways during exercise appears to differ markedly from the pattern of airway closure witnessed during forced expiratory maneuvers, assessed via imaging. [ABSTRACT FROM AUTHOR]

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter-and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site. [ABSTRACT FROM AUTHOR]

Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors' blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro, as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 - the human FH analog expressed in moss - will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade. [ABSTRACT FROM AUTHOR]

Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery. We identify an oral commensal strain of Lactobacillus plantarum with an intrinsic cancer-binding mechanism and engineer the strain to enable the surface loading of anticancer prodrugs, with nasopharyngeal carcinoma (NPC) as a model cancer. The engineered commensals show specific binding to NPC via OppA-mediated recognition of surface heparan sulfate, and the loaded prodrugs are activated by tumor-associated biosignals to release SN-38, a chemotherapy compound, near NPC. In vitro experiments demonstrate that the prodrug-loaded microbes significantly increase the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered L. plantarum leads to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%. The chemotherapeutic efficacy of prodrug is limited by its cancer-targeting ability. Here this group reports an engineered commensal Lactobacillus plantarum strain with anticancer prodrugs loading on the surface for nasopharyngeal carcinoma cell-targeting and growth inhibition. [ABSTRACT FROM AUTHOR]

Asthma presents special challenges to both the athletes who have it and to their health care providers. This article briefly reviews the problem of asthma--especially exercise-induced asthma--in the competitive athlete, and then describes treatments that are effective in controlling asthma. Drug-doping regulations are explained, as is the worldwide impact of drug doping on competitive athletes who have asthma. This review concludes with recommendations for competitive athletes and their health care providers regarding how to deal with asthma in this patient population.

Background: Exercise is a common trigger of asthma symptoms in patients with persistent asthma., Objective: To evaluate the protective effect of fluticasone/salmeterol against exercise-induced bronchospasm., Methods: Multicenter, randomized, double-blind, parallel-group trial of 192 asthma patients who used moderate-dose inhaled corticosteroids. Patients (aged 12-50 years; mean forced expiratory volume in 1 second [FEV1], 78% of predicted at baseline) were randomized to receive fluticasone/salmeterol (250/50 microg twice daily) or fluticasone alone (250 microg twice daily) via Diskus for 4 weeks. Exercise challenge tests were performed 1 and 8.5 hours after administration of the first (day 1) and last (week 4) doses of blinded study medication., Results: On day 1 and at week 4, mean +/- SEM values for the maximal percentage decline in FEV1 1 hour after drug administration were 11.4% +/- 1.5% and 10.9% +/- 1.5% for fluticasone/salmeterol compared with 20.0% +/- 1.7% and 18.4% +/- 1.8% for fluticasone (P < .001). At 8.5 hours, mean +/- SEM values on day 1 and at week 4 were 11.6% +/- 1.4% and 8.9% +/1.1%, respectively, for fluticasone/salmeterol and 12.6% +/- 1.6% and 12.9% +/- 1.4%, respectively, for fluticasone (P = .01 at week 4). More fluticasone-treated patients did not complete the 8.5-hour exercise challenges (36% on day 1 and 33% at week 4) compared with the fluticasone/salmeterol group (18% each) (P < or = .01). Improvements in peak expiratory flow rate and albuterol rescue-free days were significantly greater with fluticasone/salmeterol vs fluticasone over weeks 1 to 4 (P < or = .03)., Conclusions: Consistent with the improvements in other measures of asthma control, long-term fluticasone/salmeterol therapy also provided protection against exercise-induced bronchospasm in patients with persistent asthma.

Glycosylation, an important post-translation modification, could alter biological activity or influence the clearance rates of glycoproteins. We report here the first example of a heterozygous protein deficiency leading to metabolic alteration of N-glycan structures in residual secreted protein. Analysis of C1 esterase inhibitor (C1INH) glycans from normal individuals and patients with hereditary deficiency of C1INH demonstrated identical O-glycan structures but the N-glycans of patients with a heterozygous genetic deficiency were small, highly charged and lacked sialidase releasable N-acetylneuraminic acid. Structural studies indicate that the charge character of these aberrant N-glycan structures may result from the presence of mannose-6-phosphate residues. These residues might facilitate secretion of C1INH through an alternate lysosomal pathway, possibly serving as a compensatory mechanism to enhance plasma levels of C1INH in these deficient patients.

The use of estrogen for protection against vascular dysfunction is limited due to its effects on the reproductive system, particularly in males. We postulated that daidzein, an isoflavone with estrogen-like effects on the systemic vasculature but not the reproductive system, might enhance nitric oxide (NO)-mediated cerebral vasodilatation. Male rats were administered vehicle, 17beta-estradiol (0.1 mg/kg s.c.), or daidzein (0.2 mg/kg s.c.) daily for 7 days. Basal and acetylcholine-stimulated NO release was assessed in vitro via carotid arterial rings or in vivo by measuring changes in basilar artery diameter. Levels of protein expression of endothelial NO synthase (eNOS), caveolin-1, and calmodulin were assessed in carotid arteries using Western analysis. Plasma NO levels were doubled by daidzein or 17beta-estradiol. NO production and endothelium-dependent contraction in response to the NOS inhibitor NG-nitro-L-arginine (L-NNA; 100 microM) was enhanced by 50 to 100% in carotid arteries from rats treated with daidzein or 17beta-estradiol. Acetylcholine-induced relaxation was selectively enhanced in carotid arteries from rats treated with daidzein. Similarly, constrictor responses of the basilar artery to L-NNA in vivo were selectively augmented by approximately 100% by 17beta-estradiol treatment and tended to be approximately 50% greater in daidzein-treated rats. Expression of caveolin-1 was decreased, and calmodulin was increased, in vessels from daidzein- or 17beta-estradiol-treated rats. eNOS expression was unaffected by the treatments. These data suggest that short-term administration of daidzein or 17beta-estradiol modulates cerebral artery reactivity in males by enhancing synthesis and release of endothelium-derived NO. Isoflavone therapy may therefore be a feasible approach to protect against cerebrovascular disease and stroke.

Background: Accuracy and reliability of diary data collected in allergic rhinitis trials depends on how and when the information is recorded by the subjects., Objective: To compare diary data collected by using paper (optical mark readable) and electronic [telephone, interactive voice response system (IVRS)] tools., Methods: There was a randomized, 3-week, 3-way, crossover trial, in 87 adults with allergic rhinitis recording diary data at home. Outcome measures were (1) comparison of symptom data during weeks when both or only 1 instrument was used; (2) missing data: and (3) ease of use and participant preference., Results: More than 40,000 symptom data elements were recorded by 72 protocol-correct subjects. Symptoms recorded during the week that both instruments were used and when the 2 instruments were used alone were indistinguishable. Overall, 0.45% of paper and 4.12% of IVRS symptom data were missing. Of 10,080 paired data collected on paper and IVRS diaries during the week in which subjects used both, 94.44% were identical. Using IVRS, 63.2% of protocol-correct data were entered within the designated time and 87.6% within 1 half-day of the time specified; 85% of subjects preferred the paper instrument, 4% preferred IVRS, and 11% had no preference., Conclusions: A paper-based instrument can capture data indistinguishable from data captured from an electronic product. Processes to collect diary data should be evaluated for each study rather than simply to use the "latest" technology. Another interpretation is that frequency of recording diary data does not have a significant impact on outcomes.

Background: Allergic rhinitis afflicts more than 40 million people in the United States and is a leading cause of reduced productivity at work and in school. Patients with allergic rhinitis have a wide range of symptoms that are often treated with oral combination products that contain antihistamines, decongestants, and analgesics., Objective: To evaluate the onset of action and the extent of efficacy and safety of a combination (CPA) of clemastine (0.68 mg), pseudoephedrine (60 mg), and acetaminophen (1,000 mg) versus a combination (PA) of pseudoephedrine and acetaminophen versus placebo in the treatment of seasonal allergic rhinitis (SAR). The primary goal was to evaluate the benefit of adding clemastine to the PA combination product to treat the symptoms of SAR., Method: A 1-day, multicenter, double-blind, double-dummy, randomized, parallel-group park study was organized, and medication was given at 9:00 AM and 3:00 PM., Results: A total of 298 subjects participated at two outdoor facilities. The primary efficacy outcome was the major symptom complex score averaged over the period of 2 to 5 hours after each dose. Mean absolute and percentage reduction in major symptom complex averaged over the period of 2 to 5 hours in the CPA group was significantly superior to those of either the PA (P < 0.01) or placebo (P < 0.03) groups. Somnolence, fatigue, and nausea were the most common volunteered adverse events; only somnolence was significantly greater after CPA than after either PA or placebo., Conclusions: Treatment with CPA was safe and highly effective in reducing symptoms associated with SAR. It was more effective than either PA or placebo over most of the postdose observation period.

Background: Hereditary angioedema (HAE) is a rare disorder characterized by episodes of angioedema of the skin, mucous membranes, and gastrointestinal tract resulting from a defect in the gene that produces C1 esterase inhibitor. Although in vitro laboratory data and past reports suggested that heparin might be efficacious in preventing HAE attacks, no controlled study has been reported to examine heparin's efficacy in this regard., Objectives: We sought to determine the safety and efficacy of inhaled and subcutaneous heparin versus that of placebo in the prevention of HAE attacks., Methods: We performed a double-blind, double-dummy, saline placebo-controlled, randomized, 3-way crossover study with 11 visits., Results: The study was designed to enroll 24 patients. Twenty-two patients were randomized and received the study drug. Patients did not have a significant decrease in average flare intensity after they received injected or inhaled heparin compared with that seen after placebo, the primary endpoint. However, when patients received injected heparin, they had a statistically significant decrease in average flare intensity compared with that seen with inhaled heparin after a normalizing transformation was applied. When the means are back transformed, this translates into median flare intensities of 9.2, 8.0, and 5.1 in the patients treated with inhaled heparin, placebo, and injected heparin, respectively. There were no significant differences when individual symptoms were examined, when total numbers of flares over a 6-week observation period were examined, or when global evaluations by the patients and investigators were evaluated. Adverse event severity was fairly uniform across treatments, with the majority of events classified as moderate and the remainder split between mild and severe. Injected heparin treatment was associated with higher rates of relatedness than other treatments, which was partially explained by 17 adverse events specifically related to the injection process itself (tenderness, bruising, redness, pain, and itching at the injection site). The injection treatment was also associated with a larger overall number of reported adverse events (70 vs 48 in the placebo treatment). Tenderness and bruising at the injection site were entirely confined to the injected heparin treatment., Conclusions: Injected and inhaled heparin failed to attenuate average flare intensity, the primary endpoint, compared with placebo. Interestingly, after patients injected heparin, they had a significant decrease in average flare intensity compared with that seen after inhalation of heparin. There were no differences among groups in other efficacy parameters. Taken together, these data indicate that commercial heparin was ineffective in preventing exacerbations of HAE.

First-generation antihistamines are well-known to cause subjective drowsiness. A myriad of studies has also been published that suggest a clear relationship between the use of these drugs and objective performance impairment. Although not all of the tests used in these studies have been validated, the data are fairly consistent, and suggest a difference between earlier (first-generation) sedating antihistamines and the newer (second-generation) nonsedating antihistamines.

Background: Acetaminophen hypersensitivity is rare and, when seen, is usually in association with sensitivity to nonsteroidal anti-inflammatory drugs., Methods: This is a case report of an immediate reaction to acetaminophen, confirmed by a drug challenge, in a subject who tolerated ibuprofen., Results: After an oral challenge with 50 mg of acetaminophen, the subject had generalized pruritus, urticaria, and dyspnea., Conclusions: This patient demonstrates a rare but potentially severe reaction to acetaminophen that may occur in patients who are not otherwise sensitive to other nonsteroidal anti-inflammatory drugs.

C1 esterase inhibitor (C1INH) is an important regulator of the classical complement pathway. Hereditary deficiency of C1INH causes angioedema of the skin, gut, and respiratory tissues that may be fatal. C1INH replacement therapy may be lifesaving for patients with this disorder. The objective of this study was to evaluate the use of the baculovirus expression vector system for mass producing biologically active human recombinant (rC1INH). A recombinant baculovirus was constructed coding the human native (nC1INH) sequence under control of the polyhedrin promoter. Spodoptera frugiperda Sf-9 insect cells were infected with this recombinant baculovirus in a medium-scale (10-L) bioreactor to produce rC1INH with a specific activity of 45 U/mg. Purification of rC1INH from the culture harvested at 60 h postinfection yielded 5.9 microg rC1INH/mL supernatant of a 75-kDa product with a specific activity of 31,000 U/mg purified rC1INH compared to 71,000 U/mg purified nC1INH from human serum using the same procedure. This rC1INH was about 25 kDa smaller than nC1INH, suggesting that Sf-9 cells express underglycosylated rC1INH. Glycan analysis showed that both N-glycan and O-glycan chains were present in rC1INH. The N-glycan chains, released using PNGaseF and fluorescently labeled, were analyzed using exoglycosidase treatment and capillary electrophoresis. Their high-mannose structure was consistent with the known failure of the insect cell glycosylation pathway to afford the fully elaborated biantennary structures found on human native nC1INH., (Copyright 2001 Academic Press.)

Vitronectin is a 70-kDa protein that is found in both the extracellular matrix as well as serum. Vitronectin is one of the few proteins that regulates both the complement and the coagulation systems. Heparin is known to bind to vitronectin. Review of the literature reveals apparently conflicting outcomes of the interaction of heparin, vitronectin, and the complement system. Previous studies demonstrated that heparin diminishes vitronectin inhibition of complement activity. Numerous studies have also demonstrated that heparin exerts a net inhibitory effect on complement. We used two dimensional affinity resolution electrophoresis (2DARE) to examine this apparent paradox. 2DARE allowed simultaneous determination of binding affinity of heparin for vitronectin as well as the M(r) of the heparin species. In the 2DARE experiment, the interaction of heparin with vitronectin caused retardation of the movement of the heparin through the tube gel in the first dimension. The degree of the retardation of movement was used to calculate the approximate K(d) of that interaction. The heparin from the tube gel was then subjected to a second dimension electrophoresis to determine the M(r) of the heparin. 2DARE analysis of the interaction of heparin with vitronectin clearly demonstrated that a sub-population of heparin chains with M(r) > 8000 bound vitronectin with high affinity whereas most high M(r) chains and all lower M(r) chains showed little to no affinity for vitronectin. Our findings are consistent with the hypothesis that a unique binding domain exists in certain heparin chains for vitronectin., (Copyright 2001 Academic Press.)

C1 esterase inhibitor (C1INH) is an important regulatory protein of the classical pathway of complement. Mutations in the gene for this protein cause the autosomal dominant disorder hereditary angioedema (HAE). Approximately 85% of patients with HAE have a Type I defect, characterized by a diminished level of antigenic and functional C1INH. Patients with Type II defects have sufficient protein, but one allele produces dysfunctional protein. We have sequenced the DNA from HAE patients and have discovered four previously unreported mutations. The first mutation is a splice site error at nucleotide 8721, which changes the 3' acceptor splice site AG to GG at the end of intron 5 at nucleotide 8721-8722. The second mutation is a single base insertion in exon 3 between nucleotides 2467 and 2468. The third mutation is a missense error present in the eighth exon of the C1INH; at nucleotide 16867 (amino acid 470), a T to A mutation transforms a Met to a Lys. The fourth mutation closely resembles the third mutation in that it is a missense error occurring in exon 8 in the distal hinge region; a T16827C substitution changes the Phe at amino acid 457 to Leu. This report compiles a list of 97 distinct defects in the C1INH gene that cause hereditary angioedema., (Copyright 2000 Academic Press.)

Background: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document., Methods: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work., Results: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost., Conclusion: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: About one of every 5 athletes who participated in the 1996 Summer Olympic Games in Atlanta had a past history of asthma, had symptoms that suggested asthma, or took asthma medications. No previous study has determined the prevalence of asthma in all US athletes who participated in an Olympic Winter Games., Objectives: We sought to determine how many US athletes who participated in the 1998 Olympic Winter Games had a past history of asthma, had symptoms that suggested asthma, or indicated taking a medication used to treat asthma., Methods: We evaluated responses to questions that asked about allergic and respiratory diseases in the United States Olympic Committee Medical History Questionnaire that was completed by all 196 athletes who represented the United States at the 1998 Olympic Winter Games in Nagano, Japan., Results: Forty-three (21.9%) of the 196 athletes had a previous diagnosis of asthma, and 36 (18. 4%) recorded use of an asthma medication at some time in the past. Forty-four (22.4%) reported use of an asthma medication, a diagnosis of asthma, or both (our basis for the diagnosis of asthma). Thirty-four (17.4%) of the athletes were currently taking an asthma medication at the time that they completed the questionnaire or indicated that they took these medications on a permanent or semipermanent basis and were considered to have active asthma. Athletes who participated in Nordic combined, cross-country, and short track events had the highest prevalence of having been told that they had asthma or had taken an asthma medication in the past (60.7%) in contrast with only one (2.8%) of the 36 athletes who participated in bobsled, biathlon, luge, and ski jumping. Eighteen (24%) of 75 athletes who participated in alpine, long track, figure skating, snow boarding, and curling had a previous diagnosis of asthma or recorded use of an asthma medication., Conclusions: We conclude that asthma appeared to have been more common in athletes who participated in the 1998 Winter Games than in athletes who participated in either the 1996 or 1984 Summer Games. Clearly, asthma rates vary widely among sports. This suggests that the environment in which exercise is performed is important in leading to a decrease in the amount of exercise required to trigger asthma and perhaps in causing injury to the airways.

18 amino acid peptides from the C-terminal region of IGFBP-3, -5 (P3, P5), increased the incorporation of(35)SO(4)into proteoglycans in endothelial cells with greater stimulation in large vessel than microvessel cells. The homologous region of IGFBP-6 (P6) also stimulated sulfate uptake, but less potently than P3 and P5. P6 variants were synthesized with one or two amino acids changed to the basic amino acid in the equivalent position of P3. The P6 variants with one additional basic amino acid behaved similarly to P6. The P6 mutant with two altered amino acids was equipotent to P3. P3F, a scrambled version of P3 was less effective than P3. P3, P5, P6, P3F and all P6 variants all stimulated glucose uptake, which occurred only in microvessel cells. P1, P2, P4, and equimolar intact IGFBP-3 stimulated neither glucose uptake nor sulfate incorporation. Thus, C-terminal basic portions of IGFBP-3, -5 and -6 alter two specific functions of endothelial cells with sufficient differences to suggest mediation by distinct mechanisms., (Copyright 2000 Harcourt Publishers Ltd.)