Three mechanisms in the pathogenesis of pre-eclampsia suggested by over-represented transcription factor-binding sites detected with comparative promoter analysis

Microarray studies generating lists of genes with altered expression in placentas from pregnancies complicated with pre-eclampsia (PE) have so far been published in several different studies. Working under the assumption that altered gene expression in PE may be the result of altered expression of regulatory transcription factors (TFs), we looked for over-represented TF-binding sites (TFBSs)-which indicate the involvement of TFs in gene regulatory networks-in lists of genes (n = 143) compiled in these studies. We compared the prevalence of TFBSs in the promoter regions of 68 genes with the background prevalence of TFBSs in promoters of the human genome. The prevalence of the E47, sterol regulatory element binding protein (SREBP) and NFKB-p50 TFBSs was higher (P < 0.005) in the promoter sequences of the PE gene lists than in the background model. Each of these TFBSs could be implicated in the development of PE. The E47 protein is an E-protein or basic helix-loop-helix (bHLH) TF. Data support the role of bHLHs in the differentiation of placental tissue. SREBP-1, a lipid-sensing sterol regulatory element-binding protein, is a critical regulator of fatty acid homeostasis in the placenta. The target genes of NFKB-p50 determine inflammatory response, and aberrant cytokine homeostasis is a further sign of PE. These TFs may provide an insight into the pathogenesis of the disease

Citokin-gén polimorfizmusok kapcsolata koraszülöttek perinatális szövődményeivel = The association of cytokine genetic polymorphisms with perinatal complications of premature infants

Vizsgálatsorozatunk kapcsán több mint 300 kis súlyú koraszülött bevonásával 32 különböző genetikai polimorfizmus (SNP) hordozás kapcsolatát elemeztük a perinatális szövődményekkel. Több olyan elemre sikerült rámutatni, amelynek jelentősége lehet egy adott szövődmény kialakulásában. Ilyen az ösztrogén-receptorral szembeni érzékenységet befolyásoló SNP, illetve a renin-angiotenzin rendszer polimorfizmusok összefüggése a perinatalis adaptációs zavarokkal, a VEGF SNP-k perinatalis szövődményekkel való kapcsolata, a TNF-alfa és az IFN-gamma, valamint az IL-12 SNP-k lélegeztetés iránti igénnyel való kapcsolata. Vizsgálataink a gyógyszerfejlesztés, valamint a terápia optimálása szempontjából végzett klinikai vizsgálatok számára kiindulási alapot jelenthetnek. Az eredmények másik hasznosítási területe a szövődmény-predikció lehet. Azt, hogy a genotípus-mintázat ismerete a megszületéskor mennyire segíti ezt a célt, egy új statisztikai eljárással (random forest technikával) elemeztük. Ezzel a módszerrel meghatároztuk, hogy az egyes SNP-k milyen mértékben segítik önmagukban a predikciót, illetve olyan SNP-mintázatokat állítottunk össze, amelyekkel megszületéskor a szövődmény-predikció pontossága fokozható. | During our studies we enrolled more than 300 preterm infants and determined the association between carrier status of 32 different genetic polymorphisms with the risk of perinatal complications. Several SNPs with a possible involvement in the investigated complications were identified. These include the association of perinatal adaptational disturaűbances with an SNP with an impact on estrogen sensitivity and with genetic polymorphisms of renin-angiotensin system; the association between VEGF SNPs and some perinatal complications; the link between TNF-alpha, IFN-gamma and IL-12 SNPs and need for ventilatory support. These results may for a basis for studies aiming drug developemnt and optimization of therapy. Another psosible field for the use of these results is complication prediction. We applied a new statistical approach (random forest technique) to determine, whether the information about genotype patterns at birth may improve complication prediction. For this purpose we established the importance score values of individual SNPs and created optimized SNP patterns with the highest predictive value

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

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

Immune phenotype in children with therapy-naïve remitted and relapsed Crohn’s disease

AIM To characterize the prevalence of subpopulations of CD4+ cells along with that of major inhibitor or stimulator cell types in therapy naive childhood Crohn s disease (CD) and to test whether abnormalities of immune phenotype are normalized with the improvement of clinical signs and symptoms of disease METHODS We enrolled 26 pediatric patients with CD 14 therapy naive CD children, of those, 10 children remitted on conventional therapy and formed the re mission group We also tested another group of 12 children who relapsed with conventional therapy and were given infliximab, and 15 healthy children who served as controls The prevalence of Th1 and Th2, naive and memory, activated and regulatory T cells, along with the members of innate immunity such as natural killer (NK), NK T, myeloid and plasmocytoid dendritic cells (DCs), monocytes and Toll like receptor (TLR) 2 and TLR 4 expression were determined in peripheral blood samples RESULTS Children with therapy naive CD and those in relapse showed a decrease in Th1 cell prevalence Simultaneously, an increased prevalence of memory and activated lymphocytes along with that of DCs and monocytes was observed In addition, the ratio of myeloid/plasmocytoid DCs and the prevalence of TLR2 or TLR4 positive DCs and monocytes were also higher in therapy naive CD than in controls The majority of alterations diminished in remitted CD irrespective of whether remission was obtained by conventional or biological therapy CONCLUSION The finding that immune phenotype is normalized in remission suggests a link between immune phenotype and disease activity in childhood CD Our observations support the involvement of members of the adaptive and innate immune systems in childhood CD (C) 2010 Baishideng All rights reserve

Genetic polymorphisms for vascular endothelial growth factor in perinatal complications

Low birth weight (LBW) infants have increased susceptibility to perinatal complications. An immature and impaired vascular system may possibly participate in these complications. There is evidence that supports the notion that vascular endothelial growth factor (VEGF), which is an essential regulator of embryonic angiogenesis, plays a central role in the pathogenesis of perinatal complications. We aimed to test whether functional genetic polymorphisms of VEGF are associated with the risk of preterm birth or perinatal morbidity. We enrolled 128 LBW infants (<= 1500 grams). VEGF T-460C, VEGF C-2578A and VEGF G+405C polymorphisms were determined by real-time PCR or PCR-RFLP, respectively. Their genotypes were compared with VEGF genotypes of 200 healthy, term neonates. The prevalence of the VEGF+405 C allele was higher in LBW infants than in healthy, term neonates (OR [95% CI]: 1.29 [1.01-1.65]). Carrier state for the VEGF -2578A allele was an independent risk factor for enterocolitis necrotisans (NEC) (adjusted OR [95% CI]: 2.77 [1.00-7.65]). The carrier state for the VEGF -2578AA genotype was associated with a decreased risk of acute renal failure (ARF) (adjusted OR [95% CI]: 0.2 [0.05-0.78]). These results suggest that VEGF G+405C polymorphism might be associated with a higher risk of preterm birth and that VEGF C-2578A polymorphism may participate in the development of perinatal complications such as NEC and ARF

Use of vitamin K antagonists for secondary stroke prevention depends on the treating healthcare provider in Germany – results from the German AFNET registry

Background Anticoagulation using vitamin K antagonists (VKAs) significantly reduces the risk of recurrent stroke in stroke patients with atrial fibrillation (AF) and is recommended by guidelines. Methods The German Competence NETwork on Atrial Fibrillation established a nationwide prospective registry including 9,574 AF patients, providing the opportunity to analyse AF management according to German healthcare providers. Results On enrolment, 896 (9.4 %) patients reported a prior ischaemic stroke or transient ischaemic attack. Stroke patients were significantly older, more likely to be female, had a higher rate of cardiovascular risk factors, and more frequently received anticoagulation (almost exclusively VKA) than patients without prior stroke history. Following enrolment, 76.4 % of all stroke patients without VKA contraindications received anticoagulation, which inversely associated with age (OR 0.95 per year; 95 % CI 0.92–0.97). General practitioners/internists (OR 0.40; 95 % CI 0.21–0.77) and physicians working in regional hospitals (OR 0.47; 95 % CI 0.29–0.77) prescribed anticoagulation for secondary stroke prevention less frequently than physicians working at university hospitals (reference) and office-based cardiologists (OR 1.40; 95 % CI 0.76–2.60). The impact of the treating healthcare provider was less evident in registry patients without prior stroke. Conclusions In the AFNET registry, anticoagulation for secondary stroke prevention was prescribed in roughly three-quarters of AF patients, a significantly higher rate than in primary prevention. We identified two factors associated with withholding oral anticoagulation in stroke survivors, namely higher age and—most prominently—treatment by a general practitioner/internist or physicians working at regional hospitals

Psychosocial factors and major adverse cardiac and cerebrovascular events after cardiac surgery

Our aim was to prospectively examine the association of psychosocial factors with adverse outcome after cardiac surgery. One hundred and eighty cardiac surgery patients were enrolled and contacted annually by mail. Depression [Beck depression inventory (BDI)], anxiety [state anxiety subscale in Spielberger State-Trait Anxiety Inventory (STAI-S) and trait anxiety subscale in Spielberger State-Trait Anxiety Inventory (STAI-T)] were investigated annually, social support, negative affectivity, social inhibition (SI), illness intrusiveness, self-rated health and sleeping disorders were investigated by standardized tests at the second and fifth year. The end-point was the major adverse cardiac and cerebrovascular event (MACCE) including death. Twenty-eight (15.5%) patients died by the end of the fifth year. At the end of the second and fifth years, 146 (81.1%) and 118 (65.5%) patients fulfilled the tests, respectively. At the end of the second year after adjustment for medical and perioperative factors worse self-rated health [adjusted hazard ratio (AHR): 0.67, P=0.006], sleeping disorders (AHR: 1.14, P=0.001), higher illness intrusiveness (AHR: 1.03, P=0.018), higher BDI (AHR: 1.12, P=0.001), STAI-S (AHR: 1.09, P=0.001) and higher STAI-T scores (AHR: 1.08, P=0.002) showed higher risk for MACCE. Significant individual elevation in scores of sleeping disorders, illness intrusiveness and SI were observed over the three-year period in the MACCE group. Assessment of psychosocial factors could help in identifying patients at high-risk for MACCE after cardiac surgery