Synthesis, Biological Evaluation and Docking Studies of 13-Epimeric 10-fluoro- and 10-Chloroestra-1,4-dien-3-ones as Potential Aromatase Inhibitors.

Fluorination of 13-epimeric estrones and their 17-deoxy counterparts was performed with Selectfluor as the reagent. In acetonitrile or trifluoroacetic acid (TFA), 10ß-fluoroestra-1,4-dien-3-ones were formed exclusively. Mechanistic investigations suggest that fluorinations occurred via SET in acetonitrile, but another mechanism was operative in TFA. Simultaneous application of N-chlorosuccinimide (NCS) and Selectfluor in TFA led to a 1.3:1 mixture of 10ß-fluoroestra-1,4-dien-3-one and 10ß-chloroestra-1,4-dien-3-one as the main products. The potential inhibitory action of the 10-fluoro- or 10-chloroestra-1,4-dien-3-one products on human aromatase was investigated via in vitro radiosubstrate incubation. The classical estrane conformation with trans ring anellations and a 13ß-methyl group seems to be crucial for the inhibition of the enzyme, while test compounds bearing the 13ß-methyl group exclusively displayed potent inhibitory action with submicromolar or micromolar IC50 values. Concerning molecular level explanation of biological activity or inactivity, computational simulations were performed. Docking studies reinforced that besides the well-known Met374 H-bond connection, the stereocenter in the 13 position has an important role in the binding affinity. The configuration inversion at C-13 results in weaker binding of 13α-estrone derivatives to the aromatase enzyme.

Learning to imitate individual finger movements by the human neonate.

Imitation in human neonates, unlike imitation in young infants, is still regarded as controversial. Four studies with 203 newborns are presented to examine the imitation of index finger, two- and three-finger movements in human neonates. Results found differential imitations of all three modelled gestures, a left-handed pattern, and a rapid learning mechanism. The lateralized behavioural pattern suggests the involvement of a right lateralized neural network, and the mechanisms described in this study - (i) the accurate imitation of all aspects of the model's movements, (ii) the rapid learning component, and the (iii) the early sensitive period might fulfil the criteria for filial imprinting.

Non-medical determinants of cesarean section in a medically dominated maternity system.

OBJECTIVE: To assess the contribution of non-medical factors to actual mode of delivery in a setting with high cesarean rates. DESIGN: Follow-up survey. SETTING: University department of obstetrics and gynecology. SAMPLE: Women with singleton pregnancies (n = 453) where there was no awareness of medical contradictions to vaginal delivery, attending for routine mid-pregnancy ultrasound examination in November 2011 to March 2012, and delivering between March and August 2012. METHODS: Structured questionnaire completed in gestational weeks 18-22. Information on subsequent delivery was obtained from patient files and through personal contact. MAIN OUTCOME MEASURES: Contribution of childbirth preference, Wijma Delivery Expectancy/Experience Questionnaire A score, socio-demographic characteristics, attitudes toward birth issues and circumstances of pregnancy/delivery to mode of delivery. RESULTS: The majority of respondents (410/453; 90.5%) preferred vaginal delivery; nevertheless, one-third (two-fifths of nulliparas) had a cesarean delivery. Among nulliparous respondents, a longer perceived interval from decision for pregnancy to conception, lower importance assigned to personal control, and the presence of an obstetrician with power to decide about cesarean delivery, were independent contributors to the binary logistic regression model explaining higher maternal cesarean risks. For parous respondents, corresponding factors were younger maternal age, perceived environmental influence towards cesarean section, the respondent's belief that cesarean is more beneficial than vaginal delivery and an older obstetrician attending the delivery. CONCLUSIONS: The results of this questionnaire survey contribute to the already existing evidence that against the background of high cesarean rates, non-medical factors, as much related to the obstetricians as to pregnant women's attitudes, play an important role.

Women's antenatal preferences for delivery route in a setting with high cesarean section rates and a medically dominated maternity system.

OBJECTIVE: To assess birth preferences in a sample of Hungarian pregnant women and identify determinants of ambivalence or clear choices for cesarean section throughout pregnancy. DESIGN: Follow-up two-point questionnaire survey. SETTING: University Department of Obstetrics and Gynecology in Hungary. SAMPLE: A total of 413 women with singleton pregnancies where there was no awareness of medical contradictions to vaginal delivery, attending for routine ultrasound examination in mid-pregnancy from November 2011 to March 2012. METHODS: Questionnaires completed in mid- and late pregnancy (gestational weeks 18-22 and 35-37) including the Wijma Delivery Expectancy/Experience Questionnaire A. MAIN OUTCOME MEASURES: Prevalence of women preferring cesarean section or being uncertain about what delivery route to choose, in case they had the choice; their demographic characteristics, attitudes toward birth issues and their Wijma Delivery Expectancy/Experience Questionnaire A scores, compared with women consistent in their preference for vaginal delivery. RESULTS: Of the 413 respondents, 365 (88.4%) were consistent in their preference for vaginal delivery. In logistic regression models the important contributors to describing preferences for cesarean section or uncertain preferences were previous cesarean section and maternal belief that cesarean section is more beneficial than vaginal delivery. CONCLUSIONS: The majority of pregnant women preferred vaginal delivery to cesarean section. Neither a higher Wijma Delivery Expectancy/Experience Questionnaire A score nor sociodemographic differences were important determinants of a preference for cesarean section or for an uncertain preference. On the other hand, previous cesarean section and certain preconceived maternal attitudes towards delivery were characteristic for these women.

Identification of causes of stillbirth through autopsy and placental examination reports.

The autopsy and placental histopathological examination results following fetal deaths were analyzed retrospectively in an attempt to explain the stillbirths that occurred from 1996 to 2010 at the Department of Obstetrics and Gynecology, University of Szeged. One hundred and forty fetal deaths were recorded in that period, i.e. a rate of 4.69 stillbirths per 1000 deliveries. The postmortem examination provided the exact cause of the fetal death in 57.9% of the cases. The most common causes were a placental insufficiency (46.9%) and an umbilical cord complication (25.9%). In the first half of the third trimester, a placental insufficiency predominated as the cause of stillbirth, whereas mainly umbilical cord complications occurred around term. In spite of the availability of the autopsy and histopathological examination results, the proportion of unexplained stillbirths in our sample was relatively high. A considerable proportion of stillbirth cases could probably be prevented by more effective screening of a placental insufficiency.

[Fetus, small for gestational age]. / A kis súlyú magzat.

A small for gestational age foetus is defined by the foetal weight below the 10th centile for the corresponding gestational age. However, the vast majority of these cases has no apparent underlying abnormality, while in other cases a serious causative pathological condition can be identified. The detection, follow-up and treatment of an intrauterine growth retarded, compromised foetus has great obstetric and neonatologic relevance. In this review, the causes, clinical aspects and screening methods of intrauterine growth retardation are summarized based on the most recent international guidelines. Furthermore, recommendations regarding the monitoring and the optimal timing of the labour induction of pregnancies complicated with intrauterine growth retardation are discussed.

Magnetic resonance vs. sonographic imaging: diagnostics of a large congenital pulmonary airway malformation.

Sonographic scan revealed a homogenously hyperechogenic lesion in the right fetal lung with microcystic pattern by a primigravid women at 22nd weeks of gestation. A large congenital pulmonary airway malformation (CPAM) was suspected with a lesion-to-lung ratio over 90%. The microcystic image of this thoracic anomaly was moderately visible on magnetic resonance imaging (MRI) at that early stage of the pregnancy. Fetopsy confirmed the diagnosis as a pure microcystic CPAM following termination of pregnancy. A controlled prospective study could be performed to compare ultrasound as a diagnostic modality to the MRI, focusing on volumetry, signal characteristics, and follow-up/regression of fetal pulmonary malformations.

[Cesarean delivery on maternal request: survey among obstetricians/gynecologists in south-east Hungary]. / Császármetszés anyai kérésre - ahogyan a délkelet-magyarországi szülész-nogyógyászok látják.

INTRODUCTION: increased frequency of maternal request for cesarean delivery may be a contributing factor to the rising cesarean section rate in Hungary, although there is no formal indication that would allow Hungarian obstetricians to perform this procedure legally. Thus, it is difficult to estimate the role of maternal request in the rising cesarean rate. AIM: The aim of the authors was to assess the attitudes of obstetricians toward this procedure. METHOD: In early 2010 anonymous questionnaires were distributed to each of the 137 obstetricians working in the maternity wards of counties Bács-Kiskun, Békés and Csongrád, with a response rate of 74.5% (n = 102). RESULTS: More than half of the respondents refused the possibility of a legalized indication for this procedure in Hungary; however, in case it was legalized, 81 (79.4%) obstetricians would feel ready to perform it. CONCLUSIONS: The resistance of more than half of the obstetricians to an explicit indication for the procedure is in conflict with the theoretical willingness of the majority of them to perform it.

Can a brief antepartum preventive group intervention help reduce postpartum depressive symptomatology?

BACKGROUND: Psychosocial and psychological interventions are generally effective in reducing depressive symptomatology in the postpartum period. Our aim was to evaluate the effectiveness of a brief preventive group intervention for postpartum depression (PPD) in a naturalistic setting, and study the effect of this on social and psychological risk factors. METHODS: We conducted a randomized controlled trial (n = 1,719) in south-eastern Hungary in 62 antepartum centers. Pregnant women (n = 710) underwent a 4-session preventive group intervention whereas a control group (n = 1,009) attended 4 sessions providing the same information given in usual care. RESULTS: Our intervention appeared to significantly reduce the risk of PPD, as defined by Leverton Questionnaire total scores (OR = 0.69). It resulted in an absolute risk reduction of about 18% in those with antepartum depression and 0.5% in those with no depression at recruitment. A multiple logistic regression analysis revealed a much reduced risk in those with a perceived lack of partner support (OR = 0.4) in the treatment group. Unplanned pregnancy, an irreversible risk factor affecting every fifth woman, also seemed to have a reduced effect on PPD after our group intervention (OR = 0.81). CONCLUSIONS: A brief preventive antepartum group intervention focusing on psychoeducation, stress management, improving coping mechanisms, and the development of social support can be effective in reducing postpartum depressive symptomatology.

Determinants of emergency contraceptive use after unprotected intercourse: who seeks emergency contraception and who seeks abortion?

OBJECTIVE: To compare differences in contraceptive characteristics and the knowledge of emergency contraception (EC) between women who used EC after unprotected intercourse and those who sought abortion. DESIGN: A questionnaire survey. SETTING: A Hungarian university hospital. SAMPLE: Two large clinical groups were enrolled: women who were prescribed EC after unprotected intercourse (n= 952) (EC group) and women who presented for termination of pregnancy who had not taken EC after a contraceptive failure despite being suitable candidates to take EC (n= 577) (control group). METHODS: Questionnaire evaluation. MAIN OUTCOME MEASURES: Knowledge concerning, previous use of, and other factors related to EC use. RESULTS: The EC group experienced a condom failure significantly more often (odds ratio (OR) = 3.07), while the control group reported more failures with the contraceptive pill (OR = 0.69) and with periodic abstinence (OR = 0.09). Use of EC depended on age, education level, place of residence, accurate knowledge of EC (OR = 3.87) and previous EC use (OR = 1.16). Awareness of EC was influenced by information obtained from healthcare providers (OR = 3.63) or by school education (OR = 1.28). CONCLUSIONS: Women who use less reliable contraceptive methods should be targeted for health education that stresses the importance of reliable contraception and provides more detailed knowledge on EC and when it should be used.

Prevalence rates and socioeconomic characteristics of post-partum depression in Hungary.

The rapid socioeconomic transition in post-communist Hungary adversely affected the overall morbidity and mortality rates in the 1990s. Prevalence data on depressive disorders from the region are still scarce, however. This study reports the findings of the first epidemiological survey, using the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory (BDI), on the prevalence of post-partum depression and the associated risk factors in Hungary. A total of 1030 mothers who delivered their babies between May and July 1999 in 16 counties in Hungary were screened for depressive symptoms 3-26 weeks post-partum. The survey found that 10.81% of the sample was above the cut-off score of 13, and the EPDS detected post-partum depressive symptoms with 76% (95% confidence interval (CI)=60.5-87.1) sensitivity and 92% (95% CI=90.5-94.1) specificity. In addition, 24 socio-demographic, socio-psychiatric data and personal and obstetric variables were surveyed. Results of a hierarchical logistic regression analysis showed that depression of the mother during pregnancy was the strongest predictor of depressive symptoms post-partum. Depression before pregnancy, housing conditions, marital relationship status and family history of alcohol problems were also identified as predictors for post-partum depressive symptoms.

Social dynamics of postpartum depression: a population-based screening in South-Eastern Hungary.

PURPOSE: To determine contributing psychosocial factors to postnatal depression (PND) in Hungary in 1996 and in 2006. METHODS: In 1996 and 2006, a total of 2,333 and 1,619 women, respectively, were screened for PND in South-Eastern Hungary, based on a Leverton questionnaire (LQ) score of ≥ 12 at 6-10 weeks after delivery. RESULTS: The LQ scores indicated an increase in PND from 15.0% in 1996 to 17.4% in 2006. The best predictors for PND in a multiple regression analysis were living in an urban environment [adjusted odds ratio (AOR) = 11.26], unstable relationship (AOR = 3.1) and a perceived lack of social support from partner (AOR = 3.65) in 1996, and recent major life events (AOR = 3.38), unstable relationship (AOR = 3.84), self-reported low income (AOR = 1.82), and intention to return to work soon after delivery (AOR = 0.47) in 2006. CONCLUSIONS: A self-defined low socioeconomic status and an intention to return to work have become significant factors in the development of PND. Besides the family factors recognized as salient variables in 1996, economic features came into prominence as newly identified main predictive factors for PND in 2006.

Role of the vascular endothelial growth factor in the inverse relationship between increased nuchal translucency thickness and fetomaternal transfusion.

OBJECTIVE: To elucidate the possible etiological role of the vascular endothelial growth factor (VEGF) in the inverse correlation between nuchal translucency (NT) thickness and fetomaternal transfusion (FMT). METHODS: The level of FMT was determined prospectively in 80 viable, singleton pregnancies in which 10-14-week ultrasonographic scanning, NT thickness measurement; chorionic villus sampling (CVS) for fetal karyotyping and VEGF concentration determination were performed. The grouping procedures were based either on NT thickness (<2 MoM in Group I, and ≥2 MoM in Group II), or on karyotype (euploid in Group A, and aneuploid in Group B). The level of FMT was determined via maternal serum α-fetoprotein levels before and after CVS. The FMT and the VEGF concentration of the chorionic tissue were analysed in comparisons between Groups I and II, and between Groups "A" and "B". RESULTS: The mean level of FMT after CVS was 72.5±21.3 µL and 19.28±5.4 µL in Groups I (n=44) and II (n=36), respectively (P<0.02). The VEGF concentration of the chorionic tissue in Groups I and II was 40.6±16.7 pg/mg protein and 21.1±6.3 pg/mg protein, respectively (P=0.28). The mean level of FMT was 57.9±15.0 µL and 8.1±3.9 µL in Groups A and B, respectively (P<0.003). The VEGF concentration of the chorionic tissue in Groups A and B was 25.9±10.7 pg/mg protein and 21.3±11.3 pg/mg protein, respectively (P=0.77). CONCLUSION: No difference exists in the VEGF concentration in the aspirated chorionic tissue between Groups I and II and between Groups A and B. A higher level of FMT was observed among the aneuploid pregnancies after CVS than among the euploid cases. Chorionic VEGF does not influence the inverse relationship between the pre-CVS NT thickness and FMT.

Transcriptome analysis indicates an enhanced activation of adaptive and innate immunity by chlamydia-infected murine epithelial cells treated with interferon γ.

BACKGROUND: Interferon γ (IFN­Î³) is the major cytokine involved in the elimination of Chlamydia infection. Despite its importance, the combined effect of Chlamydia infection and IFN­Î³ on the gene expression of murine epithelial cells has only partially been described. METHODS: The DNA chip method was used to evaluate the impact of IFN­Î³ and both the human strain Chlamydia trachomatis L2 infection and the murine strain Chlamydia muridarum infection on the transcriptome of murine epithelial cells. RESULTS: The gene expression analysis revealed that IFN­Î³ had an enhancing effect on both the up­regulation and down­regulation of the epithelial gene expression. The influenced gene functional classes included cytokine and chemokine expression, antigen presentation, apoptosis, and genes involved in basic metabolic processes such as fatty acid oxidation. We also detected the up­regulation of various genes that could be directly antichlamydial, such as members of the p47 GTPase family, inducible nitric oxide synthase, and monokine induced by IFN­Î³ (MIG). As a functional validation of DNA chip data, we measured the antichlamydial effect of MIG on the extracellular form of Chlamydia. CONCLUSIONS: Our results show that IFN­Î³ is a key cytokine that primes epithelial cells to activate adaptive and innate immunity and to express antichlamydial effector genes both intracellularly and extracellularly.

[Pregnant women's oral hygiene knowledge and habits after the second millennium in South-East Hungary]. / Terhes nok szájhigiénés ismeretei, szokásai az ezredfordulón Délkelet-Magyarországon.

Among the predisposing agents for inflammatory periodontal lesion dental plaque is the most important, but different local and systemic factors may influence the seriousness or progression of periodontitis. Hormonal changes during pregnancy belong to the systemic aggravating factors. The aim of the present study was to assess pregnant women's oral hygiene knowledge and habits, and if these have a relationship with age, residence, educational level and profession/occupation. Questionnaires were used for the data collection. 275 pregnant women, who underwent prenatal care at the Department of Obstetrics and Gynecology in Szeged, volunteered to answer the questions. The results showed that almost all the women brushed their teeth daily, but only about one third of them used special oral hygiene tools, like dental floss. Many of the women claimed to have gingival bleeding when brushing their teeth. More then 70% visited a dentist during pregnancy. There was a significant relationship between educational level and the use of dental floss (p=0.004) and gingival bleeding (p=0.023) Oral hygiene education, dental and periodontal treatment of pregnant women need more emphasis during prenatal care.

Potentiation of the uterus-relaxing effects of ß-adrenergic agonists with nifedipine: studies on rats and the human myometrium.

OBJECTIVE: We investigated how progesterone and salmeterol modify the effect of nifedipine in an in vivo preterm birth model in rats, and how terbutaline and nifedipine modify the contractions of the isolated human myometrium. DESIGN: Experimental animal and human myometrial studies. SAMPLE: Twenty-four female Sprague-Dawley rats and 13 human uterine tissues sampled from cesarean section. METHODS: Preterm birth was induced in Sprague-Dawley rats with a combination of mifepristone and prostaglandin-E(2). The animals were treated with nifedipine or its combination with salmeterol and progesterone. Additionally, isolated human myometrial strips from cesarean sections were stimulated with oxytocin, and the inhibitory effects of nifedipine and terbutaline were studied. RESULTS: Nifedipine delayed the preterm delivery in the rats, but its effect was tripled by the addition of ß(2)-mimetics, or abolished after progesterone pretreatment. Synergism was observed in the relaxing effects of nifedipine and terbutaline on the isolated human myometrium. CONCLUSION: The action of nifedipine in delaying labor is impeded by progesterone. A combination of nifedipine and ß(2)-agonists should be considered for the treatment or prevention of preterm birth.

[Investigation of uterus-relaxing effects of nifedipine in the presence of terbutaline and K(+)-channel blockers]. / Nifedipin miometrium relaxáló hatásának vizsgálata terbutalin és K(+)-csatorna gátlók jelenlétében in vitro.

UNLABELLED: Tocolysis is one of the greatest challenges in obstetrical practice. It is known that the calcium channel antagonists abolish the intracellular calcium ion transients and myometrial contraction. However there is a growing interest in experimental studies to use different tocolytic combination. The aims of the study were to investigate the effects of nifedipine on potassium chloride (KCl)-evoked rat uterine contractions on the last day of pregnancy (22) in vitro, and the alterations in the effects of nifedipine on combination with BK(Ca-channel blockers paxillin and tetraethyl ammonium chloride in late pregnancy in vitro. An other aim was to investigate the modification of the effect of nifedipine by terbutaline on the contraction of isolated rat and human myometrium. For human myometrial rings rhythmic contractions were evoked with oxytocin in an isolated organ bath. KCl-stimulated uterine contractions were inhibited concentration-dependently by nifedipine. In the presence of the potassium channel blockers, the action of nifedipine was not modified. Synergism was observed in the uterus-relaxing effect of nifedipine and terbutaline, though the extent of potentiation depended on the sequence of the administration of the two compounds. When terbutaline was added first in a single dose, the maximal inhibitory effect of nifedipine was lower. This decrease in the inhibition was suspended by a Ca(2+)-poor buffer, indicating the role of Ca2+ channel activating effect of terbutaline. However, in the isolated organ bath studies the BK(Ca) channel had no effect on the uterus relaxing effect of nifedipine in spite of literature. CONCLUSION: It is concluded that the combination of nifedipine and beta2-agonists should be considered for clinical use. However, the administration of terbutaline can not precede the administration of nifedipine.

Unusual clinical history of a male infant with Edwards syndrome.

Edwards syndrome (trisomy of chromosome 18) is generally characterized by the disorders of central nervous system, as well as the musculoskeletal and genitourinary systems. In majority of the cases with trisomy 18 the following malformations can be found: ventricular septal defect, horseshoe kidneys, oesophageal atresia, omphalocele, facial clefts, diaphragmatic hernias and genital hypoplasia. We report a male patient with Edwards syndrome. The boy had a partial agenesis of corpus callosum, oesophageal atresia with tracheo-oesophageal fistula, renal agenesis, ventricular septal defect, Dandy-Walker cyst and low-set malformed ears. The first three features are unique based on previous literature reports on trisomy 18. This report allows a further delineation of the trisomy 18 syndrome.

Endothelial nitric oxide synthase is up-regulated in the umbilical cord in pregnancies complicated with intrauterine growth retardation.

BACKGROUND: NO and NO synthases (NOS) play an important role in the physiology of the fetomaternal blood circulation, although their expression in pathological conditions is unclear. Intrauterine growth retardation (IUGR) is a disorder most probably caused by abnormality of the fetomaternal bloodflow. MATERIALS AND METHODS: The expression of endothelial NOS (ecNOS) from arteria umbilicalis and the nitrite and peroxynitrite level of umbilical blood were determined. Major consequences of peroxynitrite toxicity are lipid peroxidation and glutathione depletion; these parameters were also measured. Finally, superoxide dismutase (SOD) activity was assayed to evaluate the level of superoxide anions. RESULTS: Elevated expression of ecNOS was found to be coupled with significantly lower SOD activity and glutathione level, and increased lipid peroxidation in IUGR neonates. CONCLUSION: The increased NO indices could represent a compensatory effort to improve placental bloodflow, but in IUGR neonates it is coupled with inadequate antioxidant defence, resulting in significant oxidative stress.

Prevention of preterm delivery with periodontal treatment.

OBJECTIVE: To demonstrate the role of periodontal treatment (PT) in the prevention of preterm delivery (PD). METHODS: A comparative prospective study of two groups of pregnant women with threatening PD was carried out at the Department of Obstetrics and Gynaecology of the University of Szeged: group A (n = 39) comprised patients who were merely examined dentally for periodontitis, and group B (n = 44) consisted of patients who received periodontal treatment during pregnancy. RESULTS: Periodontitis was identified in 19 cases (48.7%) in group A and in 18 cases (40.9%) in group B. The mean birth weight of the newborns was significantly higher in group B (3,009.1 g) than in group A (2,580.8 g; p = 0.007). The rate of premature birth was significantly lower in the group who received PT (p = 0.012, odds ratio = 3.5, 95% confidence interval = 1.38-8.86). CONCLUSIONS: The PT of pregnant women can decrease the rate of premature birth and consequently lead to a better neonatal health outcome.