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Publikacije (107)

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A. Jeyabalan, A. Rajakumar, S. McGonigal, N. Marković, C. Hubel, S. Morris

Meredith Snook Parrott, F. von Versen-Hoeynck, R. Ness, N. Marković, J. Roberts

Using intact villous fragments from normal term placentas, the authors characterize the e fect of reduced amino acid availability on amino acid uptake via the system A amino acid transporter. Villous fragments deprived of amino acids demonstrate increased system A activity compared with those incubated in an amino acid—su ficient medium (P < .05). Similarly, placental villous fragments exposed to media containing only amino acids not specifically transported by system A have a significant increase in system A activity compared with villous fragments incubated in an amino acid—su ficient medium containing only substrates of system A (P < .05). There is a significant trend for increasing system A activity as the concentrations of the system A amino acid substrates are decreased (P < .01). Collectively, these data indicate that normal placentas can increase system A amino acid transporter activity in a substrate-specific and dose-dependent manner as a means to ensure optimal fetal growth in the presence of amino acid limitation.

J. Catov, L. Bodnar, R. Ness, N. Marković, J. Roberts

The authors' objective was to determine the relation between periconceptional multivitamin use and the risk of small-for-gestational-age (SGA: <5th percentile; 5th-<10th percentiles) or preterm (<34 weeks; 34-<37 weeks) births. Women in the Pregnancy Exposures and Preeclampsia Prevention Study (1997-2001) reported at enrollment their regular multivitamin use in the past 6 months (n=1,823). Women were classified as users or nonusers in multinomial logistic models. After adjustment for race, age, education, enrollment gestational age, and household density, periconceptional multivitamin use was associated with a reduced risk of preterm births (<34 weeks) (odds ratio (OR)=0.29, 95% confidence interval (CI): 0.13, 0.64) and spontaneous preterm births (<34 weeks) (OR=0.40, 95% CI: 0.16, 0.99). Risk of SGA (<5th percentile) was marginally lower (OR=0.64, 95% CI: 0.40, 1.03) after adjustment for smoking, education, parity, enrollment gestational age, and body mass index. Prepregnancy body mass index modified this relation. Nonobese users had a reduction (OR=0.54, 95% CI: 0.32, 0.91) in risk of SGA (<5th percentile); there was no effect among obese women. There was no effect of multivitamin use on risk of preterm births (34-<37 weeks) or SGA (5th-<10th percentiles). Sensitivity analysis for unmeasured confounding by folate intake supported these findings. Study results indicate lower rates of severe preterm births and extreme SGA in women who report periconceptional vitamin use, although these should be considered cautiously until replicated.

A. Rajakumar, A. Jeyabalan, N. Marković, R. Ness, C. Gilmour, K. Conrad

Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion are believed to underlie the pregnancy pathologies preeclampsia (PE) and intrauterine growth restric...

C. Hubel, G. Wallukat, M. Wolf, F. Herse, A. Rajakumar, J. Roberts, N. Marković, R. Thadhani et al.

Activating angiotensin II type 1 autoantibodies (AT1-AAs) develop in women with preeclampsia and may contribute to the disorder. Insulin resistance and serum concentrations of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are also increased in women with preeclampsia compared with normal pregnancy. sFlt-1 and insulin resistance decrease substantially after delivery; however, significant group differences persist postpartum. Women who have had preeclampsia are at increased cardiovascular risk later in life. We measured AT1-AAs in groups of women with previous preeclampsia (n=29) and previous normal pregnancies (n=35) 18±9 months after the first completed pregnancy. These women had had sFlt-1, insulin resistance homeostasis model assessment score, and related cardiovascular risk factors measured. Activating antibodies were detected by the chronotropic response of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (losartan and prazosin). AT1-AAs were detected in 17.2% of women with previous preeclampsia versus 2.9% of women with previous uncomplicated pregnancies (P<0.05). In contrast, there was no difference in the prevalence of autoantibodies against the α1-adrenoceptor (10% of previous preeclamptic versus 14% of previous normal pregnant). Women with activating autoantibodies had significantly increased sFlt-1, reduced free vascular endothelial growth factor, and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. These data suggest that, as with sFlt-1 and insulin resistance, the AT1-AA does not regress completely after delivery and, secondarily, that correlations exist among these variables. The impact of AT1-AA after preeclampsia, especially in the context of cardiovascular risk, remains to be determined.

Laura D Jenkins, R. Powers, Mary Adotey, M. Gallaher, N. Marković, R. Ness, J. Roberts

Leptin concentrations were measured in African American women in order to assess leptin's role in the increased frequency and severity of preeclampsia. In addition, leptin concentrations were measured in women who delivered small-for-gestational-age (SGA) infants. A case-control study of African American and Caucasian women with normal pregnancies, preeclampsia, or SGA infants was done. Plasma leptin was quantitated by radio-immunoassay. The previously recognized pattern of increased leptin concentrations in preeclampsia was replicated. Leptin concentrations did not differ by race in any diagnostic category, and concentrations in women with SGA infants were not higher than those in healthy women. Differences in the frequency and severity of preeclampsia in African Americans cannot be explained by higher leptin concentrations.

A. Rajakumar, A. Jeyabalan, N. Marković, R. Ness, C. Gilmour, K. Conrad

Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion are believed to underlie the pregnancy pathologies preeclampsia (PE) and intrauterine growth restriction (IUGR). The main objective of this study was to investigate hypoxia-inducible transcription factor-alpha (HIF-alpha) and downstream genes (VEGF receptor-1) Flt-1 and soluble fms-like tyrosine kinase 1 (sFlt-1) proteins in IUGR placentas. Placentas from normal pregnant (NP; n = 18), PE (n = 18), and IUGR (n = 10) patients were investigated. Normotensive patients with IUGR delivered babies at >or= 37 wk of gestation with birth weights of <10% and asymmetrical growth. HIF-1 alpha, -2 alpha, Flt-1, and sFlt-1 protein, and mRNA were assessed by Western and Northern blot analyses, respectively. The results are expressed as ratios of the densitometric values for each pair of pathologic and normal placentas, a ratio of 1.0 indicating no difference. Comparable to our earlier studies, the PE/NP ratios for HIF-1 alpha, -2 alpha, and Flt proteins were significantly increased by 50-100% (all P < 0.01 vs. 1.0). Unexpectedly, the IUGR/NP ratios for HIF-1 alpha and -2 alpha proteins were 1.03 +/- 0.07 and 0.96 +/- 0.16, respectively, and for Flt and sFlt were 1.14 +/- 0.15 and 0.95 +/- 0.12, respectively (all P = not significant vs. 1.0). Northern blot analysis revealed comparable levels of HIF-alpha mRNA in abnormal and normal placentas. In contrast to PE, HIF-alpha proteins and regulated genes are not increased in placentas from normotensive pregnant women delivering small, asymmetrically grown babies >or= 37 wk of gestation. The absence of an increase in HIF-alpha protein is not due to insufficient HIF-alpha mRNA for protein synthesis. Thus, the placentas from women with PE and late IUGR are fundamentally different at the molecular level.

A. Muratbegović, N. Marković, M. Ganibegovic Selimovic

AIM This was to establish the prevalence of MIH among 12-year-old children in Bosnia and Herzegovina, and to investigate its aetiological background and clinical consequences of MIH in a population with medium caries activity. METHODS MIH prevalence was determined as a part of the first national oral health survey in Bosnia and Herzegovina in 2004, conducted on a gender balanced sample of 560 12-year-old children, in line with recommended criteria for MIH diagnosis and registration. The MIH sub-sample had been selected from the main sample and it included children with MIH and their control pairs. The two groups were matched in terms of gender, age, place of living and birth. The examinees completed questionnaires to determine variables related to development of enamel defects in first permanent molars and permanent incisors. Clinical consequences were analyzed by comparing DMFT and treatment needs. The relationship between the number of affected teeth in maxillas and mandibles and any relationship between right and left side of the jaw was also analyzed. Results were analyzed using: percentages, arithmetic mean value, standard deviation, chi- square test, T-test 2 independent samples, T test for proportion, Pearson correlation, Mann-Whitney U-test, multiple regression analyses. RESULTS The prevalence of MIH among the 12-year-old children was 12.3%. An equal number of male and female were affected. The average number of affected teeth among children with MIH was 5.59 (SD+/-2) out of which 3.16 (SD+/-1) were the first permanent molars. The research revealed demographic predisposition to MIH. The examinees with MIH suffered more often from various diseases, particularly from tonsillitis and illnesses accompanied with high fever. With the exception of tonsillectomy, variables did not appear to be related to MIH. CONCLUSIONS Based on the information about the early childhood illnesses and using multiple regression analyses, it was not possible to make a reliable prediction, whether or not a person would develop MIH. There is a clear need for further studies focused on aetiological factors in order to understand the development of MIH and adopt preventive measures for this clinically demanding condition.

H. Laivuori, M. Gallaher, L. Collura, W. Crombleholme, N. Marković, A. Rajakumar, C. Hubel, J. Roberts et al.

Leptin, an adipocyte hormone involved in energy homeostasis, is important in reproduction and pregnancy. Questions yet to be addressed include the source of higher leptin during pregnancy and its relationship to pregnancy outcome and fetal growth. The objective of this study was to investigate the relationship between placental leptin gene expression, placental leptin protein concentration and maternal plasma leptin concentration among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We also investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), carnitine palmitoyltransferase I (CPT-1B) and lipoprotein lipase (LPL). Placental leptin expression, placental protein and maternal plasma concentration were higher in pre-eclampsia than in controls but not in women with growth-restricted infants. Placental leptin expression and placental protein were higher in the preterm pre-eclamptic subjects, whereas maternal leptin was higher in the term pre-eclamptic subjects. The placental gene expression of CD36, CPT-1B and LPL were not different among the groups. This study suggests that despite similar failed placental bed vascular remodelling in pre-eclampsia and intrauterine growth restriction (IUGR), leptin gene expression is higher only in preterm pre-eclampsia.

P. Luppi, H. Tse, K. Lain, N. Marković, J. Piganelli, J. Deloia

Compelling evidence implicates peripheral immune activation in the pathophysiology of preeclampsia. Polymorphonuclear neutrophils appear to be the cells most strongly affected, with changes in expression of surface markers and release of granule enzymes. Here, we investigated activation in additional leukocyte populations among women with preeclampsia.

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