Institut fĂŒr Klinische Chemie und Laboratoriumsmedizin
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Objective
This study provides a comprehensive overview of the associations of five adipokines (adiponectin, chemerin, galectinâ3, leptin, and resistin) with fat deposits, behavioral risk factors, and metabolic phenotypes.
Methods
Using multivariable linear and logistic regression models, crossâsectional data from 4,116 participants of the populationâbased Study of Health in Pomerania were analyzed.
Results
Participants with obesity showed higher chemerin, galectinâ3, and leptin but showed lower adiponectin concentrations. Independently of other fat compounds, liver fat content, visceral adipose tissue, and subcutaneous adipose tissue (SAT) were inversely associated with adiponectin. Independent positive associations of liver fat content and SAT with chemerin as well as of SAT with galectinâ3 and leptin were observed. Physically inactive participants had higher chemerin and leptin concentrations. Smokers had higher chemerin and galectinâ3 as well as lower leptin. Alcohol consumption was associated with adiponectin (positive) and resistin (inverse). All adipokines were associated with at least one lipid marker. Associations with glucose metabolism were seen for adiponectin, chemerin, galectinâ3, and leptin.
Conclusions
High adiponectin concentrations were related to favorable metabolic conditions, whereas high chemerin, galectinâ3, and leptin were associated with an unfavorable metabolic profile. High leptin seems to be primarily indicative of obesity, whereas high adiponectin and chemerin are associated with a broader range of metabolic phenotypes.
Adipositas und Osteoporose stellen immer gröĂer werdende Herausforderungen fĂŒr
das Gesundheitssystem dar. Beide Erkrankungen gehen mit erheblichen negativen
Auswirkungen fĂŒr die Betroffenen einher. Ăbergewicht ist mit der Entstehung von
Diabetes mellitus, sowie einer Erhöhung des Blutdrucks und dem Auftreten eines
inflammatorischen PhÀnotyps assoziiert. Wiederrum ist die Plasmakonzentration des
Adipokins Chemerin bei ĂŒbergewichtigen oder adipösen Patienten erhöht. Kleinere
Beobachtungsstudien zeigen, dass erhöhtes Plasmachemerin zudem mit einem
Verlust an Knochensubstanz in Verbindung steht. Die Ergebnisse vorheriger Studien
zu diesem Thema waren jedoch durch ihre kleine Teilnehmerzahl, ihr Studiendesign
oder ihre ausschlieĂlich weibliche Kohorte nicht auf die Allgemeinbevölkerung
ĂŒbertragbar. Dies ist daher die erste populationsbasierte Studie, die den potentiellen
Zusammenhang zwischen Chemerin und der KnochenqualitÀt in der
Allgemeinbevölkerung untersucht hat. Zudem wurde der Einfluss des Body-MassIndex (BMI) auf den genannten Zusammenhang berĂŒcksichtigt.
FĂŒr diese Arbeit wurden Daten von 3583 Teilnehmern der Study of Health in
Pomerania (SHIP)âTrend untersucht. Die Probanden wurden nach Geschlecht und
BMI-Gruppen in normalgewichtig (BMI<25 kg/mÂČ), ĂŒbergewichtig (BMI 25-29 kg/mÂČ)
und adipös (â„30 kg/mÂČ) eingeteilt. Die Plasmachemerinkonzentration wurde im EDTAPlasma der Probanden bestimmt. Die Messung der KnochenqualitĂ€t erfolgte mittels
quantitativen Ultraschalls (QUS) an der Ferse.
Die statistischen Analysen (lineare und logistische Regressionsmodelle) zeigten bei
adipösen Probanden einen signifikanten inversen Zusammenhang zwischen
Chemerin und der Knochenfestigkeit (BreitbandultraschallabschwÀchung bei
MÀnnern, Schallgeschwindigkeit und Steifigkeitsindex bei Frauen) sowie eine erhöhte
Chance fĂŒr ein mittleres oder hohes QUS-basiertes Frakturrisiko. Bei normal- und
ĂŒbergewichtigen Probanden gab es keinen Hinweis auf signifikante Assoziationen
zwischen den untersuchten Parametern. Chemerin hat somit bei adipösen MÀnnern
und Frauen einen negativen Einfluss auf die Knochenfestigkeit.
Zusammenfassend lÀsst sich festhalten, dass dies die erste Studie ist, die an einem
groĂen Studienkollektiv den Zusammenhang zwischen Plasmachemerin und der
KnochenqualitĂ€t in AbhĂ€ngigkeit vom BMI statistisch umfassend geprĂŒft hat. Es
wurden verschiedene Hypothesen zum pathophysiologischen Zusammenhang
zwischen Chemerin und den QUS-Parametern diskutiert. Eine abschlieĂende
ErklÀrung kann mit den vorhandenen Daten aber nicht geliefert werden. Um den
klinischen und therapeutischen Nutzen fĂŒr den Patienten genauer herauszuarbeiten
als auch zur Findung neuer Therapie- und Diagnosekonzepte, sollten weitere Studien
folgen.
Abstract
Metabolomics studies now approach large sample sizes and the health characterization of the study population often include complete blood count (CBC) results. Upon careful interpretation the CBC aids diagnosis and provides insight into the health status of the patient within a clinical setting. Uncovering metabolic signatures associated with parameters of the CBC in apparently healthy individuals may facilitate interpretation of metabolomics studies in general and related to diseases. For this purpose 879 subjects from the populationâbased Study of Health in Pomerania (SHIP)âTREND were included. Using metabolomics data resulting from massâspectrometry based measurements in plasma samples associations of specific CBC parameters with metabolites were determined by linear regression models. In total, 118 metabolites significantly associated with at least one of the CBC parameters. Strongest associations were observed with metabolites of heme degradation and energy production/consumption. Inverse association seen with mean corpuscular volume and mean corpuscular haemoglobin comprised metabolites potentially related to kidney function. The presently identified metabolic signatures are likely derived from the general function and formation/elimination of blood cells. The wealth of associated metabolites strongly argues to consider CBC in the interpretation of metabolomics studies, in particular if mutual effects on those parameters by the disease of interest are known.
Abstract
Aim
The aim of this study was to evaluate the effect of nonâsurgical periodontal therapy on circulating levels of the systemic inflammationâassociated biomarkers orosomucoid (ORM), highâsensitivity Câreactive protein (hsCRP), chemerin, and retinolâbinding protein 4 (RBP4) in overweight or normalâweight patients with periodontitis at 27.5Â months after therapy.
Materials and methods
This exploratory subanalysis includes patients from the ABPAROâtrial (ClinicalTrials.gov NCT00707369). The perâprotocol collective provided untreated periodontitis patients with high (â„28 kg/m2) or moderate (21â24 kg/m2) BMI. Out of the perâprotocol collective, 80 patients were randomly selected and stratified for BMI group, sex, and treatment group (antibiotics/placebo), resulting in 40 overweight and normalâweight patients. Patients received nonâsurgical periodontal therapy and maintenance at 3âmonth intervals. Plasma samples from baseline and 27.5 months following initial treatment were used to measure the concentrations of ORM, hsCRP, chemerin, and RBP4.
Results
At the 27.5âmonth examination, ORM and hsCRP decreased noticeably in the overweight group (ORM: p = .001, hsCRP: p = .004) and normalâweight patients (ORM: p = .007, hsCRP: p < .001). Chemerin decreased in the overweight group (p = .048), and RBP4 concentrations remained stable.
Conclusion
Nonâsurgical periodontal therapy reduced systemically elevated inflammationâassociated biomarkers in periodontitis patients. These improvements were more pronounced in overweight patients than in normalâweight patients.
In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000â100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-BlowNK+ SCID, one case of atypical Tlow BlowNK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe.
Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.
Ziel der vorliegenden Arbeit war es, Assoziationen von Sexualhormonen und anthropometrischen Parametern bei Frauen und MaÌnnern aus der AllgemeinbevoÌlkerung zu untersuchen.
Studiendesign und Methodik
Es wurden Querschnittsdaten von 957 Frauen und MaÌnnern aus der bevoÌlkerungsbasierten Gesundheitsstudie in Pommern âStudy of Health in Pomeraniaâ (SHIP) verwendet. Assoziationen von Sexualhormonen mit physischen, laborchemischen und bildgebenden Parametern der Anthropometrie wurden in multivariablen Regressionsmodellen fuÌr die gesamte Stichprobe analysiert und nach Geschlecht stratifiziert. Sexualhormonmessungen umfassten Gesamttestosteron (TT), freies Testosteron (fT), Estron und Estradiol, Androstendion (ASD), Dehydroepiandrosteronsulfat (DHEAS) und Sexualhormon-bindendes Globulin (SHBG). Zu den anthropometrischen Parametern zaÌhlten Body-Mass-Index (BMI), Taillenumfang, HuÌftumfang, Taille-zu-HoÌhe-VerhaÌltnis und Taillen-HuÌft-VerhaÌltnis (WHR). Zu den Magnetresonanztomographie basierten MessgroÌĂen zaÌhlten viszerales Fettgewebe und subkutanes Fettgewebe. Zu den laborchemisch bestimmten Fettgewebshormonen zaÌhlten Leptin und Vaspin.
Ergebnisse
Bei MaÌnnern wurden inverse Assoziationen zwischen allen beruÌcksichtigten anthropometrischen Parametern mit TT gefunden: BMI (ÎČ-Koeffizient, Standardfehler (SE): -0,159, 0,037), Taillenumfang (ÎČ-Koeffizient, SE: -0,892, 0,292), subkutan Fettgewebe (ÎČ-Koeffizient, SE: -0,156, 0,023) und Leptin (ÎČ-Koeffizient, SE: -0,046, 0,009). Bei Frauen waren TT (ÎČ-Koeffizient, SE: 1,356, 0,615) und Estron (ÎČ-Koeffizient, SE: 0,014, 0,005) positiv mit dem BMI assoziiert. In Varianzanalysen waren BMI und Leptin bei MaÌnnern invers mit TT, ASD und DHEAS assoziiert, jedoch positiv mit Estron. Bei Frauen waren BMI und Leptin mit allen Sexualhormonen positiv assoziiert.
Schlussfolgerung
Zusammenfassend bestaÌtigte und erweiterte die vorliegende Arbeit die zuvor beschriebenen geschlechtsspezifischen Assoziationen zwischen Sexualhormonen und verschiedenen anthropometrischen Parametern fuÌr UÌbergewicht und Adipositas.
Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources.
Background: Fetal growth failure has been associated with an increased risk of hypertension, cardiovascular disease and diabetes in adulthood. Exploring the mechanisms underlying this association should improve our understanding of these common adult diseases. Patients and Methods: We investigated 225 SNPs in 10 genes involved in growth and glucose metabolism (GH1, GHR, IGF1, IGF1R, STAT5A, STAT5B, MAPK1, MAPK3, PPARÎł and INS) in 1,437 children from the multinational NESTEGG consortium: 345 patients born small for gestational age who remained short (SGA-S), 288 who showed catch-up growth (SGA-Cu), 410 idiopathic short stature (ISS) and 394 controls. We related genotype to pre- and/or postnatal growth parameters, response to growth hormone (if applicable) and blood pressure. Results: We found several clinical associations for GH1, GHR, IGF1, IGF1R, PPARÎł and MAPK1. One SNP remained significant after Bonferroni's correction: IGF1R SNP rs4966035's minor allele A was significantly more prevalent among SGA and associated with smaller birth length (p = 0.000378) and birth weight (weaker association), independent of gestational age. Conclusion:IGF1R SNP rs4966035 is significantly associated with birth length, independent of gestational age. This and other associations suggest that polymorphisms in these genes might partly explain the phenotype of short children born SGA and children with ISS.
In aktuellen Studien aus den letzten Jahren mehren sich die Hinweise auf metabolische EinflĂŒsse
von Osteocalcin. Neben dem Skelettsystem scheint besonders der Energiestoffwechsel,
speziell auf der Ebene der Distribution und des Verbrauchs von Glucose mit Osteocalcin
zu interagieren. In der vorliegenden Studie wurden Blutplasma- und Urinproben von 931
gesunden Probanden mittels Massenspektrometrie (Tandem-Massenspektroskopie mit vorgeschalteter
FlĂŒssigkeitschromatographie) auf niedermolekulare Substanzen untersucht, um
dann auf systemische Effekte von Osteocalcin zu schlieĂen. Diese Methodik erlaubt eine
breite Untersuchung von Wirkungen von Osteocalcin in allen Organsystemen, auch in jenen,
fĂŒr die bisher noch keine Interaktionen mit Osteocalcin bekannt sind. Die Berechnung eines
ersten Modells zeigte viele ZusammenhÀnge. Diese waren jedoch stark durch die Nierenfunktion
beeinflusst. Nach Adjustierung fĂŒr die Nierenfunktion blieben insgesamt 29 signifikante
Ergebnisse erhalten. Zu diesen Ergebnissen zÀhlten zuvorderst Zwischenprodukte des
Kollagenstoffwechsels, besonders Prolinderivate, was die Bedeutung von Osteocalcin im
Knochenstoffwechsel unterstreicht. Die weiteren Ergebnisse umfassten eine Assoziation mit
Kynurenin, ein Hinweis auf die Möglichkeit, dass EntzĂŒndungen EinflĂŒsse auf zirkulierendes
Osteocalcin haben könnten. Weitere Hinweise auf die bereits bekannte VerknĂŒpfung zwischen
dem Energiestoffwechsel und Osteocalcin bietet die vorliegende Studie durch die Detektion
einer Assoziation zwischen Osteocalcin und Abbauprodukten von verzweigtkettigen
AminosÀuren. Auch scheint Osteocalcin vom Lebensstil, wie beispielsweise dem Tabakrauchen,
beeinflusst zu werden. Zusammenfassend bietet die vorliegende Studie einen umfassenden
Ăberblick ĂŒber die metabolischen EinflĂŒsse von Osteocalcin. Darin war eine Vielzahl
von Assoziationen nachweisbar, die jedoch insgesamt fĂŒr eine eher geringe Rolle von Osteocalcin
im menschlichen Stoffwechsel sprechen.