Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study

BackgroundLarge-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays.Methods and findingsFor this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA₂DS₂-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m², 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation.ConclusionsAge, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF.Trial registrationRegistry IRAS ID 97753 Health Research Authority (HRA), United Kingdom

Winnie Chua and colleagues identify and validate biomarkers for atrial fibrillation     

Association of allergic bronchial asthma with certain air pollutants and weather parameters

Student bronchial asthma at the University of Minnesota was studied in grain sensitive and in control groups to find the influence of air pollutants from nearby grain installations on this problem.Under relatively high dust conditions it was observed that grain sensitive students had a two-fold increase in asthma attacks while the controls showed no significant changes. A combined association of wind direction and relatively high dust conditions with asthma gave a correlation of higher significance in the grain sensitive group. Multiple associations indicated that this relationship is only weakly affected by seasonal and temperature changes. It was also observed that relative humidity conditions may significantly influence the effectiveness of the dust exposure in sensitive students. Weather parameters showed no association with asthma in the control group.

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Zusammenfassung Bronchialasthma bei Studenten der Universität Minnesota wurde bezüglich der Empfindlichkeit gegen Getreidesamen mit Kontrollgruppen untersucht, um den Einfluss der in der Luft befindlichen Pollen durch nahe gelegene Getreidefelder zu finden. Unter verhältnismässig hohen Konzentrationen wurde beobachtet,dass gegen Getreidesamen empfindliche Studenten doppelt so viele Asthmaanfälle hatten, wie die Kontrollgruppe, die keine signifikante Änderung zeigte. Eine Verbindung von Windrichtung und relativ hohen Staubkonzentrationen mit Asthmaanfällen ergab eine Korrelation von höherer Signifikanz in der sensiblen Gruppe. Weitere Zuordnungen zeigten, dass diese Beziehung nur wenig durch Änderungen von Jahreszeit und Temperatur beeinflusst wird. Es wurde auch beobachtet, dass die Relative Feuchte die Empfindlichkeit gegen Pollen bei entsprechend sensibilisierten Studenten beeinflussen kann. In der Kontrollgruppe zeigten Wetterparameter keine Beziehung zum Asthma.

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Resume On a étudié les accès d'asthme bronchial provoqués par les polluants de l'atmosphère provenant d'entreprises travaillant les céréales et situées dans le voisinage du l'Université du Minnesota. Pour ce faire,on s'est servi d'étudiants de la dite Université sensibles aux poussières de céréales d'une part et d'un groupe de contrôle d'autre part. Dans des conditions de poussière relativement forte,on a observé que les étudiants sensibles aux poussières de céréales présentaient une fréquence double d'accès d'asthme alors que le groupe de contrôle n'était pas touché de façon significative. En utilisant une conbinaison des facteurs direction du vent et forte poussière d'une part, accès d'asthme d'autre part,on obtient une corrélation plus significative dans le groupe des gens sensibles.Des combinaisons multiples indiquent que cette corrélation n'est que peu influencée par la saison ou des changements de température. On a aussi remarqué que les conditions d'humidité relative peuvent influencer de façon significative la sensibilité effective aux poussières des étudiants du premier groupe. Quant au groupe de contrôle, on n'a pas trouvé de relation entre les accès d'asthme et les paramètres météorologiques.

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Paper presented during the Fourth International Biometeorological Congress, New Brunswick, N.J., 26 August – 2 September 1966.This work was performed under Air Pollution Grant No. AP 00090-07,Division of Air Pollution, Bureau of State Services, United States Public Health Service.     

Facile preparation and some applications of an affinity matrix with a cleavable connector arm containing a disulfide bond

A versatile affinity matrix in which the ligand of interest is linked to the matrix through a connector arm containing a disulfide bond is described. It can be synthesized from any amino-substituted matrix by successive reaction with 2-imino-thiolane, 5,5'-dithiobis(2-nitrobenzoic acid), and a thiol derivative of the ligand of choice. The repertoire of ligands can be significantly increased by the appropriate use of avidin-biotin bridges. After adsorption of the material to be fractionated, elution can be effected by reducing the disulfide bond in the connector arm with dithiothreitol. Examples of the preparation and use of various affinity matrices based on amino-substituted Sepharose 6MB are given. One involves the immobilization of the Fab' fragment of a monoclonal antibody against Aspergillus oryzae beta-galactosidase and the specific binding of that enzyme to the resulting immunoaffinity matrix. Another involves the immobilization of N-biotinyl-2-thioethylamine followed by complex formation with avidin. The resulting avidin-substituted matrix was used for the selective adsorption and subsequent recovery of mouse hybridoma cells producing anti-avidin antibodies. By further complexing the avidin-substituted matrix with appropriate biotinylated antigens, it should be possible to fractionate cells producing antibodies against a variety of antigens.     

Die feinstruktur der flüigelschuppen einiger Lycaeniden (Insecta,Lepidoptera)

Green, blue and violet colours of Lycaenidae examined by us — with the exception of Rapala arata (Theclinae) — are due to iridescent scales which are arranged before a dark background. The iridescent scales are constructed according to the Urania-type and may be diverted from pigmented scales by laying in equidistant lamellae and little cuticular bars, which maintain the distance between the lamellae. The ribs in the longitudinal axis of the scales contain lamellae and bars only in the Plebejinae, in Lycaeninae and Theclinae they are small and sit on the plain upperside of the scale with a narrow base.

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft     

Marine polyprenylated hydroquinones, quinones, and chromenols with inhibitory effects on leukotriene formation

A series of polyprenylated hydroquinones, quinones, and chromenols were isolated from the extracts of the marine sponge Ircinia spinosula and the brown alga Taonia atomaria, which gave rise to the constituents 1-4 and 5-8, respectively. Compounds 1, 2, 6, and 7 are new natural products, which were fully characterized. Their anti-inflammatory activities in terms of leukotriene formation were evaluated in an in vitro assay with pork leukocytes. The new hydroxylated compound, 2'-[28-hydroxy]heptaprenyl-1',4'-hydroquinone (= 2-[(2E,6E,10E,14E,18Z,22E)-19-(hydroxymethyl)-3,7,11,15,23,27-hexamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]benzene-1,4-diol; 1), the known tetraprenyl benzoquinone sargaquinone (5), and the known polyprenyl chromenols 3 and 4 exhibited the highest anti-inflammatory activities, with IC50 values of 1.9-9.4 microM (Table 3). Potential structure-activity relationships (SAR) are discussed.     

Regulation and structure of aspartokinase in the genusBacillus

The aspartate pathway of amino acid biosynthesis in bacteria serves as paradigm for the evolution of patterns of enzyme regulation in response to specific physiological requirements. InBacillus species, the first step in the pathway is catalyzed by multiple forms of aspartokinase, which differ in their structure and feedback regulation. One form of aspartokinase (V-type) functions primarily during cell growth, another form (S-type) during sporulation. The V-type aspartokinase fromBacillus subtilis andBacillus polymyxa is discussed in some detail on account of its complex pattern of regulation by the pathway endproducts lysine and threonine and its unusual subunit structure. The enzyme is composed of two dissimilar subunits, the smaller of which corresponds to the carboxyl-terminal domain of the larger subunit. The coding sequence for the subunits ofBacillus subtilis aspartokinase has recently been cloned inEscherichia coli. The study of its structure and mode of expression has revealed that the two aspartokinase subunits are encoded by in-phase overlapping genes. These unusual features of aspartokinase suggest that important aspects of the regulation of the aspartate pathway are yet to be discovered.     

Indocyanine green-enhanced multimodal photoacoustic microscopy and optical coherence tomography molecular imaging of choroidal neovascularization

Photoacoustic microscopy (PAM) has great potential for visualization of the microvasculature with high spatial resolution and contrast. Early detection and differentiation of newly developed blood vessels named choroidal neovascularization (CNV) from normal vasculature remains a challenge in ophthalmology. Exogenous contrast agents can assist with improving PAM sensitivity, leading to differentiation of CNV. Here, an FDA-approved indocyanine green (ICG) was utilized as a PAM contrast agent. ICG was conjugated with RGD peptides, allowing the ICG to bind to the integrin expressed in CNV. Molecular PAM imaging showed that ICG-RGD can target CNV for up to 5 days post intravenous administration in living rabbits with a model of CNV. The PAM image sensitivity and image contrast were significantly enhanced by 15-fold at 24 h post-injection. Overall, the presented approach demonstrates the possibility of targeted ICG to be employed in PAM molecular imaging, allowing more precise evaluation of neovascularization.