Csaba Demendi

Gene expression patterns of the 11β-hydroxysteroid dehydrogenase 2 enzyme in human placenta from intrauterine growth restriction: the role of impaired feto-maternal glucocorticoid metabolism

OBJECTIVE To assess 11-β-hydroxysteroid dehydrogenase 2 (11β-HSD2) gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. STUDY DESIGN We compared 11-β-HSD2 gene expression in placental samples from all IUGR pregnancies treated in our clinic between January 1, 2010 and January 1, 2011 vs. 140 normal pregnancy samples from the same study period. Clinical characteristics were also assessed and compared between the IUGR and normal pregnancy groups. RESULTS Mean gestational weight gain in the IUGR group was significantly lower than in the control group. Similarly, change in body mass index (BMI) was lower. Impending intrauterine fetal asphyxia was significantly more common in the IUGR group. The 11β-HSD2 gene was underexpressed compared to controls, but this underexpression was only observed after the 33rd gestational week. Within the IUGR group, in cases of impending intrauterine fetal asphyxia the 11β-HSD2 gene was underexpressed compared to both impending asphyxia in non-IUGR cases, or IUGR without impending asphyxia. CONCLUSION Low gestational weight gain appears to predict IUGR. The 11β-HSD2 gene in IUGR is underexpressed and may result in an impaired placental barrier, decreasing protection against maternal glucocorticoids, which are thought to be prominent in fetal programming. Maternal glucocorticoid exposure resulting from an impaired placental barrier may increase the risk for cardiovascular and metobolic disorders later in adult life. In IUGR, before the 33rd gestational week, the expression of the 11β-HSD2 gene remains physiological. The underexpression of this gene after the 33rd week in impending intrauterine fetal asphyxia in IUGR points to an increased sensitivity to hypoxia when impending asphyxia is present in the late phase of IUGR pregnancies.

Gene expression patterns of insulin-like growth factor 1, 2 (IGF-1, IGF-2) and insulin-like growth factor binding protein 3 (IGFBP-3) in human placenta from preterm deliveries: influence of additional factors

OBJECTIVE To compare patterns of human placental gene expression of IGF from pregnancies that ended with preterm delivery vs. full term pregnancies as controls. STUDY DESIGN Real-time PCR was used to assess gene expression of IGF in human placental samples from 104 preterm and 140 full term pregnancies. RESULTS In the preterm delivery group, the proportion of smokers was significantly higher than in the control group. A history of preterm delivery was more common in the preterm delivery group compared to the control group. In the preterm delivery group, placental samples showed an underexpression of the IGF-1 gene compared to controls. In cases of male fetal gender an overexpression of both the IGF-2 and the IGFBP-3 genes was observed. CONCLUSION Among environmental factors influencing preterm delivery, smoking was the most significant in our study. In the majority of cases, preterm delivery was induced by intrauterine infection leading to a decreased activity of the IGF system. This mechanism may also play a role in the development of neurological sequelae and in decreased tolerance to fetal distress. The overexpression of the IGF-2 gene observed in the placenta with male fetal gender can be explained by its physiological role in the development of the male phenotype.

The regulation of apoptosis in intrauterine growth restriction: a study of Bcl-2 and Bax gene expression in human placenta.

Objective: In this study, we assessed Bcl-2 and Bax gene expression patterns in human placental samples from intrauterine growth restriction (IUGR) pregnancies using normal pregnancy as control. Methods: We compared Bcl-2 and Bax gene expression in placental samples from all IUGR pregnancies treated in our clinic between 1 January 2010–1 January 2011 vs. 140 normal pregnancy samples from the same study period. We also assessed clinical parameters such as maternal age, gestational weight gain, gestational body mass index (BMI) change, and maternal birth weight. Results: In IUGR, the Bcl-2 gene was underexpressed compared to normal pregnancy. There was no difference in the Bax gene activity in the two groups. The degree of growth restriction within the IUGR group did not correlate with Bcl-2 or Bax gene activity. Conclusions: Our study revealed that it is the reduced inhibitory activity of the Bcl-2 gene rather than an enhanced stimulatory activity of the Bax gene in the background of the increased apoptosis observed in IUGR. IUGR appears to be more common with maternal age around 20 years and above 35 years. Gestational weight gain and gestational BMI change also predict the risk for IUGR.

Abnormal fetomaternal glucocorticoid metabolism in the background of premature delivery: placental expression patterns of the 11β-hydroxysteroid dehydrogenase 2 gene.

OBJECTIVE During pregnancy, 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is involved in the development of the placental barrier, and its main function is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids. We compared human placental gene expression patterns of 11β-HSD2 from pregnancies that ended with preterm delivery versus full term pregnancies as controls. STUDY DESIGN We used real-time PCR to assess the placental gene expression patterns of 11β-HSD2 in 104 preterm and 140 full term pregnancies (control group) at the time of delivery. RESULTS In the preterm delivery group, the proportion of smokers was 26.9%, significantly higher than in the control group. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. The 11β-HSD2 gene was underexpressed in the preterm delivery group compared to normal pregnancy between 28 and 36 gestational weeks, but unchanged between 24 and 28 weeks. There was no fetal gender effect on 11β-HSD2 gene expression. CONCLUSION The reduced activity of the 11β-HSD2 gene seen in the preterm delivery group may impair fetal defences against maternal glucocorticoid exposure. In cases of impending premature delivery, glucocorticoid effects, potentially including postnatal neurological abnormalities and growth restriction, may be worsened by prophylactic steroids given to accelerate fetal lung maturity. The impairment in fetal defences against maternal glucocorticoids due to reduced 11β-HSD2 enzyme activity appears to begin after gestational week 28.

Placental gene expression patterns of epidermal growth factor in intrauterine growth restriction

OBJECTIVE In this study, we compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control. STUDY DESIGN Gene expression of EGF was determined from human placental samples collected from all pregnancies presenting with IUGR at our institution during the study period January 1, 2010-January 1, 2011. Multiple clinical variables were also assessed including maternal age, gestational weight gain, increase of BMI during pregnancy and fetal gender. RESULTS A total of 241 samples were obtained (101 in the IUGR pregnancy group, 140 in the normal pregnancy group). EGF was found to be underexpressed in the IUGR group compared to normal pregnancy (Ln2(α): -1.54; p<0.04). Within the IUGR group no fetal gender-dependent difference was seen in EGF gene expression (Ln2(α): 0.44; p<0.06). Similarly, no significant difference in EGF expression was noted in cases with more vs. less severe forms of IUGR (Ln2(α): -0.08; p=0.05). IUGR pregnancies were significantly more common in the maternal age group 35-44 years compared to other age groups. Gestational weight gain and gestational BMI increase were significantly lower in IUGR pregnancies compared to controls. CONCLUSIONS Placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy.

Placental gene expression of the placental growth factor (PlGF) in intrauterine growth restriction.

Abstract Objective: We analyzed changes in gene expression of placental growth factor (PIGF) in human placental samples obtained postpartum from pregnancies with IUGR. Methods: During a twelve-month study period representing the calendar year of 2012 placental samples from 101 pregnancies with IUGR and from 140 normal pregnancies were obtained for analysis of a potential difference in PIGF gene expression. Results: There was no significant difference in gene activity of the PIGF gene between the IUGR versus normal pregnancy groups (Ln2α: 0.92; p < 0.06). Within the IUGR group, no fetal gender-dependent differences were seen in placental PIGF gene expression (Ln2α: 0.72; p = 0.05). Placental PIGF gene activity was significantly lower in fetuses with more severe IUGR versus less severe cases (Ln2α: −1.49; p < 0.03). Conclusion: We found no difference in gene expression of PIGF in placental samples obtained from IUGR pregnancies versus normal pregnancy suggesting the absence of a direct role of PIGF gene activity in the development of defective angiogenesis in IUGR during the later stages of gestation. However, in more severe cases of intrauterine growth restriction PIGF expression does show a significant decrease indicating its potential role in the profound defect in angiogenesis in these cases.

Current concepts in the genetic diagnostics of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown etiology. HLA-DRB1 and PTPN22 1858T gene variants are risk factors of RA, clinical manifestations and rate of progression of joint destruction in this autoimmune disease. Currently, several immunopathogenetic models of other genes (CTLA4, MIF, PADI4 and SLC22A4) are under debate. The clinical influence of some of the gene polymorphisms associated with RA and the principles of pharmacogenetics applied to different therapies, such as classical disease-modifying anti-rheumatic drugs and new biological agents. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patient’s genetic profile.

Gene expression patterns of the Bcl-2 and Bax genes in preterm birth.

Objective. The apoptotic genes Bax and Bcl‐2 are both involved in the pathogenesis of preterm delivery in conjunction with additional factors. We characterized gene expression patterns of these apoptotic regulatory genes as well as relevant environmental factors. Design. A gene expression study with evaluation of clinical data. Setting. Semmelweis University, Budapest, Hungary. Sample. Human placental samples from 104 preterm and 140 full‐term pregnancies. Methods. Gene tests were performed using real‐time PCR to assess gene expression patterns of Bax and Bcl‐2 in human placental samples. Clinical data were collected from our computerized database. Main outcome measures. Apoptotic gene expression pattern and clinical information against the background of preterm delivery. Results. In placental samples from preterm delivery pregnancies, expression of the Bcl‐2 gene was unchanged, whereas the Bax gene was overexpressed. Placental gene expression of Bax in preterm delivery was dependent on gestational age with gestational weeks 28–32 and 32–36 associated with overexpression, and no overexpression in gestational weeks 24–28. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. Conclusions. The Bax gene was overexpressed in preterm delivery, whereas expression of the Bcl‐2 gene remained unchanged. After the 28th gestational week, apoptosis appears to be a key factor in the pathogenesis of preterm delivery.

Successful operative management of an intact second trimester abdominal pregnancy with additional preoperative selective catheter embolization and postoperative methotrexate therapy

Summary Background Abdominal pregnancy is a rare condition that may lead to severe complications. Case Report The authors report the case of a 17-week intact abdominal pregnancy diagnosed in the course of an investigation of lower abdominal pain. Ultrasonography and MR examination revealed an intact abdominal pregnancy. Subsequent angiography was performed to occlude the supportive artery of the pregnancy by selective embolization. The pregnancy was terminated safely by laparotomy a day later. The placenta was left in the abdominal cavity because of the high risk of massive and often uncontrollable bleeding, and treatment with methotrexate was applied postoperatively. Conclusions Preoperative embolization and the postoperative methotrexate therapy facilitate the safe surgical treatment of abdominal pregnancy.

Placental gene expression of transforming growth factor beta 1 (TGF-β1) in small for gestational age newborns.

Abstract Objective: The gene expression of transforming growth factor beta-1 (TGF-β1) in human placental samples obtained from pregnancies with small for gestational age fetuses (SGA) was compared to those of normal pregnancies. Methods: In 2011 placental samples from 101 pregnancies with SGA and from 140 normal pregnancies were obtained for analysis of TGF-β1 gene expression. Several clinical parameters were also assessed for correlation between genetic and clinical parameters. Results: There were no significant differences in gene activity of the TGF-β1 gene between the SGA versus normal pregnancy groups (Ln2α: 0.16; p = 0.07). Within the SGA group, no fetal gender-dependent differences were seen in TGF-β1 gene expression (Ln2α: −0.11; p = 0.05). Similarly, no significant differences in gene activity were observed by the degree of severity of SGA as assessed by percentile fetal birth-weight (Ln2α: 0.32; p = 0.06). Conclusion: We found no change in gene expression of TGF-β1 in placental samples obtained from SGA pregnancies versus normal pregnancy suggesting an absence of a direct role of the TGF-β1 gene in the development of SGA. However, the absence of increased gene expression of TGF-β1 in SGA can be conceptualized as a failure to mount a compensatory response in the SGA environment.