Expression of lymphocyte activation markers of preterm neonates is associated with perinatal complications

BACKGROUND: Inappropriate activation of T lymphocytes plays an important role in perinatal complications. However, data on T lymphocyte activation markers of preterm infants is scarce. We investigated the association between gender, gestational and postnatal age, preeclampsia (PE), premature rupture of membranes (PROM) as well as prenatal steroid treatment (PS) and the frequency of activated T lymphocyte subsets (HLA-DR+, CD69+, CD25+, CD62L+) and major T lymphocyte subpopulations (CD4, CD8, Th1, Th2, naive, memory) in peripheral blood during the first postnatal week in preterm infants. RESULTS: Cord blood and peripheral blood samples were collected from 43 preterm infants on the 1st, 3rd, and 7th days of life. We assessed the frequency of the above T lymphocyte subsets using flow cytometry. The 'mixed effect model' was used to analyze the effects of clinical parameters on T lymphocyte markers. The frequency of CD25+ T lymphocytes was higher in PROM. The frequency of CD4+ and CD8+ cells and the CD4+/CD8+ cell ratio was decreased in PE. The frequency of CD62L+ T lymphocytes was higher in male compared with female infants. PS did not affect the frequency of the investigated markers. CD4+ CD25+ cells had a lower frequency at birth than on day 7. Th2 lymphocytes had a lower frequency on postnatal days 1 and 3 when compared to day 7. CONCLUSIONS: Our observations indicate that alterations affecting the expression of T lymphocyte activation markers are associated with the above factors and may play a role in the development of perinatal complications

Koraszülöttek perinatális szövődményeinek előrejelzése: limfocita-aktiváció és biomarkerek = Prediction of perinatal complications in preterm infants: lymphocyte activation and biomarkers

Koraszülötteken elért eredményeink jelzik, hogy a veleszületett és szerzett immunitást számos, a koraszülöttséggel járó tényező befolyásolja. A citokinválaszt befolyásoló legfontosabb tényező a magzati korban fennálló gyulladás (chorioamnionitis, CA). CA hiányában a citokinek jellegzetes módon fluktuálnak; ezt a jelenséget figyelembe kell venni akkor, ha a perinatalis citokinszintekkel kapcsolatosan vizsgálatokra kerül sor. A fluktuáció CA jelenlétében teljes mértékben megszűnik. A citokinektől eltérően az adaptív immunválasz szabályozásában kulcsszerepet játszó CD4 és CD8 sejtek számát a CA nem befolyásolja. Ezzel szemben a mellékvese működése, valamint a postnatalis és a gesztációs kor egyaránt alapvető hatást gyakorol ezekre a sejtekre. A veleszületett immunitásért felelős sejtek esetében a postnatalis kor a fő meghatározó. Érdekes módon a vizsgált tényezők közül a magzatnál a tüdő érés érdekében adott anyai szteroidkezelés nem hatott az immunrendszerre. A pályázat időtartama alatt több új módszert vezettünk be az immunsejtek működésének a vizsgálatára. Ezek segítségével egyéb, az immunrendszer működési zavarával járó betegségek kutatásában is fontos eredményeket értünk el. | These results obtained in preterm neonates clearly indicate that the investigated elements of adaptive and innate immunity including cytokines and cellular players are influenced by a number of factors inherent with the premature birth. The major factor having a large impact on cytokine response is chorioamnionitis (CA). In the neonates without CA the measured cytokines presented a characteristic fluctuation. One should emphasize that there is some ’physiologic’ kinetics of postnatal cytokine expression in the preterm neonate that is masked in the presence of CA. This ’physiologic’ kinetics should be taken into account when any investigation on perinatal inflammation is performed. In contrast with cytokines CD4 and CD8 cells governing the adaptive immune responses of the neonates are not affected by CA. Instead, the prevalence of some subpopulations of CD4 and CD8 cells correlated with neonatal cortisol levels, and with postnatal and gestational age. The major determinant of the prevalence of innate immune cells is the postnatal age emphasizing that that the timing of postnatal blood sampling is essential when the innate immune response of a neonate is analyzed. Interestingly, maternal steroid therapy has no effect the neonate’s immune system. During the proposal we also made several achievements in different conditions where the immune dysregulation is dominantly present

Súlyos keringési elégtelenséggel járó neonatalis hyperthyreosis = Severe circulatory insufficiency in a patient with neonatal hyperthyroidism

A szerzők egy Basedow–Graves-kór miatt korábban thyreoidectomián átesett, kezeletlen anya koraszülöttjének esetét ismertetik. Gondozatlan terhességből magzati tachycardia, fenyegető intrauterin asphyxia miatt sürgős császármetszéssel született a 33. hétnek megfelelő érettségű, 1350 gramm súlyú, dysmaturus (testsúlypercentil 180/perc), cardialis decompensatio miatt béta-blokkoló, digoxin- és dobutaminterápiát igényelt. Kivizsgálása során cardiomegalia, pericardialis folyadékgyülem, súlyos tüdőhypoplasia, mitralis és tricuspidalis insufficientia, hepatosplenomegalia igazolódott. A pajzsmirigy-szabadhormonok szintje többszörösen meghaladta a referenciaértéket (fT4: > 6 ng/dl, fT3: > 30 pg/ml), a TSH-szint ugyanakkor 0 volt. Légzéstámogatást 7, keringéstámogatást 10 napig igényelt, propranolol- mellett K-jodid-kezelésben részesült. Tachycardiája mérséklődött, a béta-blokkoló kezelést csökkentett adagban kapta tovább, pajzsmirigyhormonszintjei fokozatosan a normális tartományba kerültek. A szerzők felhívják a figyelmet arra, hogy a Basedow–Graves-kórban szenvedő anya újszülöttjénél jelentős súlybeli, növekedésbeli elmaradás, súlyos keringési elégtelenség, thyreotoxicosis tünetei alakulhatnak ki, és hangsúlyozzák az anyai hormon-, valamint antitestszintek nyomon követésének jelentőségét. | Authors describe a case of a premature infant whose mother had a history of thyroidectomy due to Graves’ disease and her hormonal status was not controlled during pregnancy. She did not receive prenatal care and on 33rd week the premature infant was delivered by emergency cesarean section because of fetal tachycardia and imminent intrauterine asphyxia. The infant with a weight of 1350 gram (percentile 180/min) and cardiac decompensation. Further examinations proved cardiomegaly, pericardial fluid, severe pulmonary hypoplasia, mitral- and tricuspid insufficiency and hepatosplenomegaly. The level of free thyroid hormones was several times higher than normal (fT4: > 6 ng/dl, fT3 > 30 pg/ml), while TSH level was 0. Respiratory support was required for 7 days, inotropic support for 10 days; at the same time propranolol and K-iodide were administered. Eventually, the tachycardia settled and beta-blocker therapy was continued with reduced doses. Finally, the thyroid hormone levels became normal. Authors emphasize that newborns of women suffering from Graves’ disease can significantly lag behind in weight increase, may have severe circulatory insufficiency and symptoms of thyrotoxicosis. We also emphasize the importance of the monitoring maternal hormone levels and antibody titers

Cantrell-pentalógia: a praenatalis felismerés lehetőségei hat saját eset kapcsán = Pentalogy of Cantrell: six new cases

A praenatalis ultrahangvizsgálatok elterjedése óta számos próbálkozás történt a ritka Cantrell-pentalógia (elülső hasfali defektus, sternumdefektus, elülső diaphragmahernia, pericardiumhiány és szívfejlődési rendellenesség) intrauterin felismerésére. Célkitűzés és módszerek: Intézetünkben 1991. január és 2009. június között diagnosztizált Cantrell-pentalógiás magzatok praenatalis ultrahangvizsgálati eredményeit hasonlítottuk össze a boncolás során leírt fejlődési rendellenességeikkel. Saját és a nemzetközi szakirodalomban található Cantrell-pentalógiás magzatok prae- és postnatalis leletei alapján vizsgáltuk a pentalógia részét képező malformatiók és ectopia cordis előfordulási gyakoriságát, és ezek praenatalis felismerési arányát. Eredmények: A fenti időszakban 6 Cantrell-pentalógiás magzatot diagnosztizáltunk. Praenatalisan 3 esetben multiplex, 3 esetben izolált malformatiót észleltünk. A boncolás sternumdefektust minden magzatban igazolt. Összesen 49 Cantrell-pentalógiás eset adatainak elemzése azt mutatja, hogy a praenatalisan leggyakrabban felismert ectopia cordis (91%, 31/34) és hasfali defektus (83%, 38/46) mellett (prevalenciájuk 69%, 34/49 és 94%, 46/49) a pentalógiás magzatok jelentős részében sternumdefektus (80%, 39/49) és elülső diaphragmahernia (73%, 36/49) is megtalálható. Következtetések: A Cantrell-pentalógia részét képező, de izoláltnak vélt malformatio praenatalis észlelésekor érdemes keresni a tünetegyüttes további összetevőit a pontos diagnózis intrauterin felállítása érdekében. | Cantrell’s pentalogy is a rare multiple malformation syndrome consisting of supraumbilical abdominal wall defect, sternal defect, pericardial defect, anterior diaphragmatic defect and heart malformation. Aims and methods: Prenatal ultrasound findings and malformations described during autopsy of the Cantrell’s pentalogy cases diagnosed between January 1991 and June 2009 in our institute were reviewed. A literature research was conducted to analyze the prevalence and prenatal detection rate of the five previously described malformations and ectopia cordis in the Cantrell’s pentalogy cases. Results: Six cases of Cantrell’s pentalogy were diagnosed during the study period in our department. Sonography detected multiple malformations in 3 cases, and isolated malformation in 3 cases. Analyzing the data of 49 Cantrell’s pentalogy cases altogether showed that, beside abdominal wall defect and ectopia cordis which had the highest prenatal detection rate (83% and 91% with a prevalence of 94% and 69%, respectively), sternal defect and anterior diaphragmatic hernia were also present in a large number of the cases (80% and 73% respectively). Conclusion: Sonographic identification of the sternal defect or diaphragmatic hernia may help to differentiate Cantrell’s pentalogy from malformations part of the syndrome but occurring as isolated defects

Search for new phenomena in events with high jet multiplicity and low missing transverse momentum in proton–proton collisions at

A dedicated search is presented for new phenomena in inclusive 8- and 10-jet final states with low missing transverse momentum, with and without identification of jets originating from b quarks. The analysis is based on data from proton–proton collisions corresponding to an integrated luminosity of 19.7 fb−1 collected with the CMS detector at the LHC at √s = 8 TeV. The dominant multijet background expectations are obtained from low jet multiplicity control samples. Data agree well with the standard model background predictions, and limits are set in several benchmark models. Colorons (axigluons) with masses between 0.6 and 0.75 (up to 1.15) TeV are excluded at 95% confidence level. Similar exclusion limits for gluinos in R-parity violating supersymmetric scenarios are from 0.6 up to 1.1 TeV. These results comprise the first experimental probe of the coloron and axigluon models in multijet final states. © 2017 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY licenseL

Design and selection of novel C1s inhibitors by in silico and in vitro approaches

The complement system is associated with various diseases such as inflammation or autoimmune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively. © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Studies of dijet pseudorapidity distributions and transverse momentum balance in pPb collisions at √sNN=5.02 TeV

Dijet production has been measured in pPb collisions at a nucleon-nucleon centre-of- mass energy of 5.02 TeV. A data sample corresponding to an integrated luminosity of 35 nb−1 was collected using the Compact Muon Solenoid detector at the Large Hadron Collider. The dijet transverse momentum balance, azimuthal angle corre- lations, and pseudorapidity distributions are studied as a function of the transverse energy in the forward calorimeters (E4<|η|<5.2 T ). For pPb collisions, the dijet transverse momentum ratio and the width of the distribution of dijet azimuthal angle differ- ence are comparable to the same quantities obtained from a simulated pp reference and insensitive to E4<|η|<5.2 T . In contrast, the mean value of the dijet pseudorapidity is found to change monotonically with increasing E4<|η|<5.2 T , indicating a correlation between the energy emitted at large pseudorapidity and the longitudinal motion of the dijet frame. The pseudorapidity distribution of the dijet system in minimum bias pPb collisions is compared with next-to-leading-order perturbative QCD predictions obtained from both nucleon and nuclear parton distribution functions, and the data more closely match the latter