Prevalence of asthma and COPD and blood eosinophil count in a middle-aged Belgian population

Various phenotypes exist in asthma and Chronic Obstructive Pulmonary Disease (COPD). These are important to identify in order to guide treatment decisions. We aim to investigate the prevalence and clinical characteristics of obstructive airway diseases in the middle-aged population. We estimated the prevalence of COPD and/or asthma in the Asklepios cohort study (Belgium), using information from the third European Community Respiratory Health Survey (ECRHS3), medical records, and spirometry. Respiratory symptoms, respiratory medication, and current disease status distinguished clinical from sub-clinical cases. In addition, we compared the blood eosinophil count/mu L (median [IQR]) between cases and controls. Of the 2221 participants (mean age 56.1 +/- 5.9 years; 48.7% males), 138 (6.2%) participants had clinical current asthma, 22 (1.0%) participants had sub-clinical ever asthma, 102 (4.6%) had sub-clinical spirometry-defined COPD, 104 (4.6%) participants had clinical spirometry-confirmed COPD, and 11 (0.5%) had asthma and COPD overlap (ACO). Clinical current asthma (160.0 [110.0-250.0]), sub-clinical ever asthma (170.0 [110.0-230.0]), and clinical COPD (160.0 [110.0-220.0])-but less sub-clinical COPD (140.0 [90.0-210.0])-had higher eosinophil counts, compared to controls (130.0 [80.0-200.0]). We conclude that obstructive airway diseases are prevalent in the middle-aged Asklepios cohort. Moreover, the systemic eosinophil count is increased in clinical COPD cases, and in asthma cases regardless of clinical remission

Поняття та ознаки юридичної колізії

Розглядаються основні теоретичні підходи до визначення поняття юридичної колізії. В статті акцентується увага на необхідності розуміння колізії саме як про­тиріччя норм права, а не нормативних актів. Наведено авторське визначення поняття юридичної колізії.Рассматриваются оснорвные теоретические подходы к определению понятия юридической коллизии. В статье акцентируется внимание на необходимости понима­ния коллизии именно как противоречия норм права, а не нормативних актов. Приво­диться авторское определение понятия юридической коллизии.The author analyzed modern theoretical approaches to definition of conflict of laws and analyzed conflict of laws in legislation of Ukraine. The author substantiates the conclusion that conflicts of law is a conflict between legal rules, not between statutes. The author’s defi­nition of conflict of laws is given

Echocardiography during submaximal isometric exercise in children with repaired coarctation of the aorta compared with controls

Objective Patients with repaired coarctation (RCoA) remain at higher risk of cardiac dysfunction, initially often only detected during exercise. In this study, haemodynamics of isometric handgrip (HG) and bicycle ergometry (BE) were compared in patients with RCoA and matched controls (MCs). Methods Case-control study of 19 children with RCoA (mean age 12.9 +/- 2.3 years; mean age of repair 7 months) compared with 20 MC. HG with echocardiography followed by BE was performed in both groups. Results During HG (blood pressure) BP increased from 114 +/- 11/64 +/- 4 mm Hg to 132 +/- 14/79 +/- 7 mm Hg, without significant differences. During HG as well as BE, HR increased less in patients with RCoA. There were no significant differences in (left ventricle) LV dimensions or LV mass. The RCoA group had diastolic dysfunction: both at rest and during HG they had significantly higher transmitral E and A velocities and lower tissue Doppler E' and A' velocities. E/E' was higher, reaching statistical significance during HG (p<0001). Conventional parameters of systolic function (FS and EF) were similar at rest and HG. More sensitive tissue Doppler S' was significantly lower at rest in CoA subjects (5.1 +/- 1.5 cm/s vs 6.5 +/- 1 +/- 1 cm/s; p<0.01), decreasing further during HG by 5% in the CoA group (NS) while unchanged in controls. Conclusions We provide first evidence that HG with echocardiography is feasible, easy and patient-friendly. A decreased systolic (tissue Doppler) and impaired diastolic LV function was measured in the RCoA group, a difference that tended to increase during HG

Thyroid hormone levels within reference range are associated with heart rate, cardiac structure, and function in middle-aged men and women

Background: Triiodothyronine (T3) has many effects on the heart, and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure. Methods: Subjects were selected from the Asklepios study (n=2524), a population-representative random sample of patients aged between 35 and 55 years, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having antithyroperoxidase antibody levels above clinical cut-off or thyrotropin (TSH) levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence. Results: Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27-4.2 μU/L) and in narrow TSH range (0.5-2.5 μU/L; p<0.0001). FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness. Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling. Conclusion: We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest a smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction, and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation in thyroid hormone levels, even within the reference range, exerts effects on the heart

Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects

Background: We previously showed that in healthy young men a less favorable body composition is associated with higher FT3 levels within the euthyroid range. Besides, a higher FT3-to-FT4 ratio has been related to a less favorable metabolic phenotype and more placental growth in pregnant women. In the present study, we therefore investigated whether serum TSH, thyroid hormone levels and the FT3-to-FT4 ratio are associated with metabolic and adiposity-related cardiovascular risk markers in a healthy population of middle-aged euthyroid men and women. Methods: Thyroid parameters were measured in 2524 generally healthy subjects from the Asklepios study (35-55yrs, mean age 46 years). Analyses were restricted to 2315 subjects (1138 women and 1177 men), not using thyroid medication, not having anti-TPO levels above clinical cut-off values nor TSH levels outside the reference range (0.27-4.2 mU/L). Twenty-seven percent of the women and 47.5% of the men were overweight, while 13% of women and 17% of men were obese. Twenty percent of the subjects were active smokers. Serum thyroid function parameters were determined by electrochemiluminescence. Results: (F) T3 and the FT3-to-FT4 ratio were positively related to BMI, waist circumference and components of the metabolic syndrome, i.e. triglycerides, systolic and diastolic blood pressure and fasting plasma glucose, and negatively with HDL-cholesterol levels, whereas FT4 was negatively associated to BMI, waist circumference and triglycerides (all p-values <0.001). TSH related positively to total cholesterol levels (p<0.01), triglycerides and to systolic and diastolic blood pressure (all p<0.001). The FT3-to-FT4 ratio was further positively associated to the adiposity-related inflammation markers interleukin-6 (IL6) and high-sensitive CRP (hs-CRP) and to pulse wave velocity. All associations were adjusted for sex, age, height and smoking and most associations persisted after additional adjustment for weight or waist circumference. Conclusion: In healthy euthyroid middle-aged men and women, higher (F) T3 levels, lower FT4 levels and thus a higher FT3-to-FT4 ratio are consistently associated with various markers of unfavorable metabolic profile and cardiovascular risk

Leader-Member Exchange (LMX) and Innovation:A Test of Competing Hypotheses

In this paper, we address the relation between Leader‐Member Exchange (LMX; the quality of the relationship between leader and subordinate), employee creativity (the generation of novel and useful ideas), and employee innovation (the promotion and implementation of these ideas). In the current set of studies, we test the competing hypotheses that LMX will either have a direct effect on employee innovation, or an indirect effect through employee creativity. In a field study of leader–subordinate dyads (N = 118), we found that LMX had no direct effect on employee innovation, and that employee creativity fully mediated the relationship between LMX and innovation. In a follow‐up two‐wave field study of employees (N = 398), we found that the LMX dimension professional respect predicted innovation through creativity, while the other dimensions did not. The results of this work indicate that research on LMX and innovation requires a multidimensional perspective, and that it may be valuable to differentiate between creativity and innovation

Assessment of model based (input) impedance, pulse wave velocity, and wave reflection in the Asklepios Cohort

Objectives : Arterial stiffness and wave reflection parameters assessed from both invasive and non-invasive pressure and flow readings are used as surrogates for ventricular and vascular load. They have been reported to predict adverse cardiovascular events, but clinical assessment is laborious and may limit widespread use. This study aims to investigate measures of arterial stiffness and central hemodynamics provided by arterial tonometry alone and in combination with aortic root flows derived by echocardiography against surrogates derived by a mathematical pressure and flow model in a healthy middle-aged cohort. Methods : Measurements of carotid artery tonometry and echocardiography were performed on 2226 ASKLEPIOS study participants and parameters of systemic hemodynamics, arterial stiffness and wave reflection based on pressure and flow were measured. In a second step, the analysis was repeated but echocardiography derived flows were substituted by flows provided by a novel mathematical model. This was followed by a quantitative method comparison. Results : All investigated parameters showed a significant association between the methods. Overall agreement was acceptable for all parameters (mean differences: -0.0102 (0.033 SD) mmHg*s/ml for characteristic impedance, 0.36 (4.21 SD) mmHg for forward pressure amplitude, 2.26 (3.51 SD) mmHg for backward pressure amplitude and 0.717 (1.25 SD) m/s for pulse wave velocity). Conclusion : The results indicate that the use of model-based surrogates in a healthy middle aged cohort is feasible and deserves further attention

Rolle des mitochondrialen Carriers Rim2 und des Transkriptionsfaktors Yap5 im Eisenmetabolismus von Saccharomyces cerevisiae

Eisen ist ein essentielles Spurenelement mit entscheidenden Funktionen in einer Vielzahl an metabolischen Prozessen wie der mitochondrialen Atmung, Aminosäure- und Nukleotid-Synthese, Ribosomen-Assemblierung, DNA-Replikation und DNA-Reparatur. Jedoch sind erhöhte zelluläre Eisenkonzentrationen toxisch für die Zelle. Daher ist eine exakte Regulation des intrazellulären Transports und der Erfassung des Eisenstatus erforderlich, um sowohl Eisenmangel als auch Eisenüberschuss zu vermeiden. Die vorliegende Arbeit widmet sich deshalb dem Mechanismus der mitochondrialen Eisenaufnahme und der Adaption an erhöhte Eisenmengen. Mitochondrien sind essentielle Organellen, die unter anderem eine entscheidende Rolle in der Eisen-Schwefel-(Fe/S)-Cluster- und in der Häm-Biogenese spielen. Aufgrund dieser Stoffwechselleistungen konsumieren Mitochondrien den größten Anteil des in die Zelle aufgenommenen Eisens. Frühere Studien konnten die mitochondrialen Carrier-Proteine Mrs3 und Mrs4 als mitochondriale Eisentransporter charakterisieren. Allerdings ist die simultane Deletion beider Gene für die Hefezellen nicht letal. Da die Fe/S-Cluster Biogenese essentiell ist, lässt dies auf einen weiteren Carrier schließen, der ebenfalls in der Lage ist, Eisenionen zu transportieren. Ein vielversprechender Kandidat ist der mitochondriale Carrier Rim2. Auch wenn dieser ursprünglich als Pyrimidintransporter charakterisiert wurde, häufen sich die Hinweise auf eine zusätzliche Funktion in der Eisenaufnahme. Dabei stellt sich die Frage, inwiefern sich die gut dokumentierte Transportfunktion für Pyrimidine mit einer möglichen Rolle im Eisentransport vereinen ließe. Im ersten Teil dieser Arbeit konnte gezeigt werden, dass die zusätzliche Deletion von RIM2 die in mrs3/4Δ Zellen vorhandene Defekte im Wachstum und in der Biosynthese von Eisen-abhängigen Proteinen verstärkt. Dagegen rettet die Überexpression von RIM2 in mrs3/4Δ Zellen die Maturierung der Fe/S-Proteine und der Häm-Synthese auf Wildtypniveau. Demzufolge sind hohe Konzentrationen von Rim2 ausreichend, um die mitochondriale Eisenversorgung in mrs3/4Δ Zellen wiederherzustellen. Der direkte biochemische Nachweis für eine Transportfunktion von Rim2 wurde durch in vitro Transportexperimente mit sog. submitochondrialen Partikeln in Zusammenarbeit mit der Arbeitsgruppe Dr. Wiesenberger (Wien) geliefert. Zusammengenommen zeigen die in vivo, in organello und in vitro Experimente, dass Rim2 als mitochondrialer Carrier den obligatorischen Co-Transport von Pyrimidinen und divalenten Metallionen einschließlich Fe2+ vermittelt. Diese Modelvorstel-lung erklärt, wie die mitochondriale Eisenaufnahme in mrs3/4Δ Zellen gesichert werden kann und wie Rim2 als „high copy suppressor“ von mrs3/4Δ Zellen fungiert. Eine Funktion des Rim2 in der mitochondrialen Eisenhomöostase unter normalen physiologischen Bedingungen, d.h. in Anwesenheit von Mrs3 und Mrs4, ist jedoch vernachlässigbar. Der zweite Teil dieser Arbeit konzentrierte sich auf die Charakterisierung des Sensors für hohe Eisenkonzentrationen, Yap5, der eine zentrale Rolle bei der Anpassung an toxische Eisenmengen in S. cerevisiae spielt. Bei Eisenüberschuss aktiviert der Transkriptionsfaktor Yap5 die Expression von CCC1, dem einzigen bekannten vakuolären Eisenimporter, was zur Speicherung von Eisen in der Vakuole und damit zur Vermeidung einer toxischen Eisenakkumulation im Cytosol führt. Wie Yap5 biochemisch den Eisenstatus der Zelle erfasst, ist allerdings unklar. Zunächst konnte die direkte Bindung von radioaktivem Eisen (55Fe) an die Aktivator-Domäne von Yap5 (tYap5) in vivo nachgewiesen werden. Zirkular-dichroismus-, Elektronenspinresonanz- und Mößbauer-Spektroskopie des rekombinanten tYap5 belegten die Bindung eines [2Fe-2S]-Clusters an tYap5 nach chemischer Rekonsti-tution. Dieser [2Fe-2S]-Cluster wird durch die N-terminale Cystein-reiche-Domäne (n-CRD) in der Aktivator-Domäne koordiniert und ist entscheidend für die transkriptionelle Aktivität. Des Weiteren induziert die Fe/S-Cluster-Bindung an tYap5 eine Konformationsänderung, die möglicherweise geeignet ist, die Transkriptionsaktivität von Yap5 zu modulieren. Zusätzlich bindet Yap5 in vitro einen zweiten Fe/S-Cofaktor an der C-terminalen CRD, der nicht an der Regulation der transkriptionellen Aktivität von Yap5 in vivo beteiligt ist. Dagegen ist das Fe/S-Cluster-Bindungsmotiv innerhalb der regulatorischen n-CRD von Yap5 in mehreren Pilzarten konserviert, u.a. auch im Aspergillus Transkriptionsfaktor HapX. Daher könnte dieses Motiv als konservierte Bindungsstelle für einen sensorischen Fe/S-Cluster in der eukaryotischen Stressantwort fungieren. Zusammengefasst hat diese Arbeit an Yap5 grundlegende neue Einblicke in den transkriptionellen Mechanismus der Erfassung und Regulation des Eisenstatus in Pilzen geliefert. Yap5 konnte somit als erster eukaryotischer Transkriptionsfaktor, der einen Fe/S-Cluster als Sensor für intrazelluläre Eisenkonzentrationen nutzt, charakterisiert werden