Low placental angiotensin-converting enzyme expression is related to fetal small for gestational age but not to metabolic control in type 1 diabetic pregnancies.

The maternal renin-angiotensin system is involved in blood pressure control and plays a crucial role in fetoplacental nutrition. Pre-gestational type 1 diabetes (PGDM) leads to serious pregnancy complications. We thus performed a longitudinal study to analyse the association of maternal angiotensin-converting enzyme (ACE) serum levels and placental mRNA expression with fetal newborns gestational weight in type 1 diabetes mellitus (T1DM) women. We recruited 65 singleton pregnant women with T1DM. Placental mRNA ACE gene expression was examined using quantitative real-time PCR. Serum ACE levels were measured in the first, second and third trimesters of pregnancy by ELISA commercial kits. Placental expression of ACE mRNA was significantly lower in small for gestational age (SGA) than appropriate for gestational age (AGA) and large for gestational age (LGA) mothers (0.55±0.06 vs 0.78±0.06 and 0.85±0.07 respectively, p=0.003). In the SGA group, the mRNA expression of ACE positively correlated with maternal body mass index (BMI) in the third trimester (r=0.49; p=0.04). In all study groups maternal ACE level was significantly higher in the third trimester (mean 139.91±SD 69.64) compared to the first and second trimesters of pregnancy (13.57±4.32 and 15.69±15.92 respectively). Our data suggest that lower placental ACE gene mRNA expression may have a vital role in the etiology of SGA babies.

The role of genetic factors in the pathogenesis of neonatal intraventricular hemorrhage.

Intraventricular hemorrhage (IVH) affects 15-20% of babies born before 32 weeks of pregnancy. Besides gestational age (below 32 weeks) there are a number of IVH risk factors. Increasing attention is being paid to genetic factors in the development of IVH. The authors discuss genetic factors (mutations of coagulation factors, gene polymorphisms in pro-inflammatory cytokines, mutation of type IV collagen gene, polymorphisms of genes responsible for the regulation of systemic blood pressure and cerebral blood flows) whose involvement in IVH pathogenesis has been confirmed in the highest number of reports and for which being a carrier plays an important role in their pathophysiology. The role of genetic factors in IVH remains unclear. Further analysis of the role of genetic factors in the pathophysiology of IVH will make it possible to determine the group of newborns who are specifically at risk of developing IVH in the perinatal period.

Placental vascular endothelial growth factor expression in pregnancies complicated by type 1 diabetes.

UNLABELLED: Type 1 diabetes mellitus (T1DM) is still associated with increased risk of severe maternal and foetal complications but their pathomechanism remains unclear. OBJECTIVES: we investigated the possible role of placental vascular endothelial growth factor (VEGF) and VEGF single nucleotide polymorphisms (SNP) in foetal development in T1DM pregnancies. Sixty seven pregnant women with T1DM and singleton pregnancy were enrolled into the study. Results demonstrated higher expression of placental VEGF in women who delivered neonates with birth weight (NBW)>4000g. No such correlation was found in the overall T1DM group and in women who delivered appropriate for gestational age (AGA) and small for gestational age (SGA) newborns. We also demonstrated a significant correlation between 3(rd) trimester mean blood glucose, HbA1C and placental VEGF. No such correlation was found for the 1(st) and 2(nd) trimesters. Top placental VEGF expression and placental mass were found in women who delivered large for gestational age (LGA) newborns. We also found a statistically significant difference in homozygous and heterozygous frequency variants of VEGF SNPs in study groups. We conclude that the increased placental VEGF together with impaired metabolic control may have a role in stimulating foetal overgrowth in T1DM pregnancy.

The effect of standardized Echinacea purpurea extract on rat cytochrome P450 expression level.

It is claimed that application of botanical supplements or herbal medicinal products with synthetic drugs that are cytochrome P450 enzymes substrates may induce significant herb-drug interactions and may alter pharmacotherapy. Echinacea preparations are one of the best selling products in the Europe and their medicinal use is still increasing but data about interactions of Echinacea extract with CYP enzymes are limited. In this study, we have investigated potential influence of standardized Echinacea purpurea extract containing 3.7% polyphenolic compounds on the mRNA expression level of major CYP450 enzymes using animal model. Total RNA was isolated from the rat liver tissue according to the manufacturer's protocol. Complementary DNA was synthesized from a mature mRNA template using reverse transcription. The level of mRNA expression in liver was analyzed by real-time quantitative PCR using specific target primers for CYP450 genes. In this study, it was demonstrated a significant increase of rat CYP2D1 and CYP1A1 expression level by 40% (p = 0.007) and 80% (p = 0.01), respectively. A weak inductory effect of the extract was observed for CYP1A2 by 16% (p > 0.05) compared with the control group. The levels of rat CYP3A1 and CYP3A2 mRNA were reduced by 41% (p < 0.05) and 25% (p = 0.001), respectively. A weak inhibitory effect was observed for CYP2D2 by 15% (p = 0.008) and CYP2C6 by 18% (p = 0.004) after long application of the Echinacea ethanolic extract. CYP2D2 and CYP2C6 activities were also inhibited by extract but in a lesser degree than CYP3A1 activity. Moreover, very little or no inhibition was noted for CYP2E1 both after 3 and 10 days of treatment. Our in vivo data indicate that the Echinacea ethanolic extract can potently inhibit the expression of CYP3A1/2 and can also induce of CYP1A1, CYP2D1. These findings suggest that Echinacea extract may influence the P450-mediated metabolism of different drugs and may initiate chemical carcinogenesis by activation of some compounds to their carcinogenic metabolites.

Leptin gene, leptin gene polymorphisms and body weight in pregnant women with diabetes mellitus type I.

UNLABELLED: There have been several genetic causes of obesity discussed by past authors, among others leptin, that have provided information regarding signaling pathways in energy expenditure in humans. Genetic variants of the leptin gene and its receptor may influence body weight. AIM: To investigate the role of the leptin gene's polymorphism promotion region (2548 G/A) and the leptin gene receptor polymorphism (668 A/G) and its associations with body weight in pregnant women with type 1 diabetes (PGDM-1). METHODS: 78 PGDM-1 were qualified to the study group (SG) which was divided into normal and over-weight individuals according to BMI criteria. The control group (CG) consisted of first trimester healthy pregnant women with normal body weight. Genetic variants of the leptin gene and its receptor were analyzed using PCR-RFLP assays. Within the SG, the following metabolic parameters were estimated: MBG, HbA1C, insulin dose, LDL, HDL, T-CHOL, creatinine, creatinine clearance and blood pressure. RESULTS: There was a trend found among the majority of homozygous A and G variants in LEP -2548 G/A and LEPR 668 A/G in over-weight and obese individuals in comparison to normal-weight subjects (CG). There were no specific differences found in selected first trimester metabolic parameters in relation to patients' genotypes.

The significance of C3435T point mutation of the MDR1 gene in endometrial cancer.

The P-glycoprotein (P-gp) plays an important role in carcinogen distribution and is connected with cell differentiation and apoptotic processes leading to carcinogenesis. Interindividual differences in P-gp activity could modulate susceptibility to cancer development. The MDR1 gene, coding for P-gp, is highly polymorphic and some mutations modulate P-gp activity. Recently, association between the MDR1 C3435T polymorphism and the cancer susceptibility was shown. We have hypothesized that MDR1 polymorphism could influence endometrial cancer susceptibility. We have matched 198 women with endometrial cancer and 198 controls. An additional group of 488 healthy volunteers was investigated. The MDR1 C3435T polymorphism was tested by LightCycler assay. The distribution of MDR1 3435 genotypes was significantly different between cases and controls (P = 0.006). Genotypes containing at least one 3435T allele were statistically significant more frequent in the endometrial cancer group (86.8% vs 75.2%, OR 2.18, P = 0.004). Our observation suggests that MDR1 C3435T polymorphism is correlated with endometrial cancer susceptibility.

Glucose evaluation trial for remission (GETREM) in type 1 diabetes: a European multicentre study.

OBJECTIVE: Strict metabolic control during the 1st year of type 1 diabetes is thought to be a key factor for achieving clinical remission. The aims of this study were two-fold: (i) to evaluate the frequency and duration of spontaneous remission (defined according to the parameters issued by the International Diabetic Immunotherapy Group (IDIG)) in a European population of consecutive recent onset type 1 diabetes patients (aged 5-35 years), followed-up for a period of 36 months with a common protocol of intensive insulin therapy and without adjunct immune-intervention; and (ii) to identify the predictive factors for clinical remission. RESEARCH DESIGN AND METHOD: A total of 189 consecutive patients with newly diagnosed type 1 diabetes according to ADA criteria were recruited in participating centres (Belgium, Czech Republic, Estonia, France, Germany, Hungary, Italy, Poland, Romania, Sweden and Turkey) and followed-up for a period of up to 36 months. In all patients, intensive insulin therapy was implemented consisting of three or four injections of regular insulin daily with NPH insulin at bedtime. Adjustment of insulin dose was made according to a common protocol. Various clinical characteristics (age, gender, severity of presentation, etc.), history (presence of diabetic siblings in the family, etc.) and integrated parameters of metabolic control (HbA(1c), blood glucose, the total insulin dose at hospital discharge adjusted for body weight) were collected. RESULTS: Twenty-two patients (11.6%) experienced remission. The median duration of remission was 9.6 months and the range was 31 months. There was a wide variation among centres. Logistic regression analysis focused on the centre as the main variable in achieving remission. CONCLUSION: Remission was shown to be very heterogeneous between centres depending on 'other factors' such as patient care and family awareness of the disease rather than on 'measurable factors' such as sex, age, HbA(1c) and severity of presentation at diagnosis. Using intensive insulin therapy and optimisation of metabolic control, remission occurred in nearly one out of eight patients.

[Polymorphism of gene angiotensin converting enzyme in pregnancy induced hypertension]. / Polimorfizm genu kodujacego konwertaze angiotensyny i w nadcisnieniu indukowanym ciaza.

In the recent years genetic background of pregnancy induced hypertension (PIH) are intensively investigated. Genetically determined differences in activity of renin-angiotensin system (RAS) are of importance to hypertension susceptibility. The insertion/deletion (I/D) polymorphism of angiotensin I converting enzyme (ACE) was suggested to play an important role in the aetiology of idiopathic hypertension. We have tested if this polymorphism could be associated with PIH. ACE polymorphism was investigated in 87 pregnant women with PIH and in 110 healthy pregnant women (control group). Investigation was performed by polymerase chain reaction (PCR). We have amplified genomic DNA excteracted by phenol-chloroform method from blood leucocytes. We have detected overrepresentation of the I allele in the PIH group (47.2% and 41.4% in PIH and controls, respectively). ACE genotype frequency in control group was in agreement with expected values, according to Hardy-Weinberg law, but in the PIH group the obtained values were different from expected. This observation confirmed the possible role of I allele in aetiology of PIH, and we believe that continuation of this investigation is necessary.

[Analysis of interleukin-6 serum concentration in trophoblastic tumors prognosis]. / Wartosc kliniczna analizy stezen interleukiny-6 u kobiet chorych na rozrosty i nowotwory trofoblastu.

OBJECTIVES: Our purpose was to estimate the prognosis based on Il-6 concentration in cases of trophoblastic tumors. MATERIALS AND METHODS: The study population was 65 women suffering from hydatiform mola or choriocarcinoma. We divided them into two groups: 30 patients who required only operative management and 35 patients who required operative procedures and additional chemotherapy. The observation period was 6 months. Blood samples were collected every 4 weeks. Concentration of Il-6 was measured in ELISA assay. RESULTS: The serum Il-6 concentration was significantly higher in cases of trophoblastic diseases than in the group of healthy women and higher in patients who required chemotherapy after operation (451.0 +/- 88.5 pg/ml), than in patients treated only surgically (257.1 +/- 77.1 pg/ml). CONCLUSIONS: Patients with hydatiform mola and choriocarcinoma reveal higher concentration of Il-6 than healthy women. It is associated with disease prognosis and allows to determine at the time of establishing a diagnosis, whether a patient can be treated only surgically or requires an additional chemotherapy.

[Gestational hypertension (GH) and a1166c polymorphism of angiotensin II type 1 receptor]. / Nadcisnienie ciazowe (GH) a polimorfizm A1166C receptora typu 1 angiotensyny II (AT1).

INTRODUCTION: Recent studies have suggested an association between genetic background of renin-angiotensin system (RAS) and the pathogenesis of pregnancy induced hypertension (PIH). However, the role of the gene coding for angiotensin II receptor (AT1) polymorphism in PIH is not fully understood, thus the aim of the present study was to determine the frequency of A1166C mutation in women with gestational hypertension (GH) and to establish the role of this polymorphism on the susceptibility to the PIH development. PATIENTS & METHODS: We have analysed 88 women with PIH and 113 healthy pregnant women as a controls. Genomic DNA was extracted from leucocytes using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). RESULTS: We have detected overrepresentation of mutated homozygous genotypes in the PIH group (11.4% in the PIH versus 2.7% in the controls). Homozygous wild-type genotypes were underrepresented in the PIH group (48.9% in PIH and 56.6% in controls). The frequency of heterozygotes was similar in both groups. Statistically significant overrepresentation of allele with mutation in the PIH group (31.3% in the women with PIH, and 23.0% in the controls) (O.R. = 1.5, p = 0.04) was observed. CONCLUSION: We suggest that presence of A1166C mutation is a risk factor for the development of PIH.

[Cesarean section for the second twin during the course of delivering twins]. / Ciecie cesarskie na drugim plodzie w przebiegu porodu ciazy blizniaczej.

We have analysed 6 cases of twin pregnancies with vertex presentation of the first foetus. In this cases after delivery of the first twin by vaginal route caesarean, section was made. Caesarean section of the second twin was made because of: transversal presentation with fetal distress syndrom (four cases), umbilical cord drop (one case), and premature placenta ablation (one case). We have determined acid base balance and Apgar score. We have noted worse results for the second twin, independently too of the time between deliveries both twins. Caesarean section of the second twin is the rarely clinical situation, but in motivated situation is accepted and reasonable solution.

[Triplet gestation--analysis of pregnancy course, delivery and neonatal outcome, based on personal material]. / Ciaza trojacza--analiza przebiegu ciazy, porodu, stanu noworodków, na podstawie materialu wlasnego.

UNLABELLED: Triplet gestation appears in 0.1-0.3% of all pregnancies and it is high risk pregnancy for mother and foetus. It appears more frequently in Afroamerican women, rarely in Japan women. In multifetal pregnancy early prenatal diagnosis and management are very important. AIM: Analysing course of pregnancy, way of delivery, condition of newborns, influence of environmental factors, and concomitant diseases in triplets gestation. MATERIAL: 30 women treated between 1989-1998, in Division of Perinatology, University of Medical Sciences in Poznan, Poland. RESULTS: 21 pregnancies were ended by caesarean section, 9 by vaginal delivery. Apgar score for II and III foetus decreases significantly. pH value of umbilical artery was without significant differences. CONCLUSIONS: Almost all triplets have ended preterm. Route of delivery of triplets have to be considered individually. Environment factors could play an important role in multifetal pregnancy.

Microvascular protective activity of flavonoid glucuronides fraction from Tulipa gesneriana.

A mixture of flavonoid glucuronides, consisting of 7-O-glucuronides of kaempferol and quercetin 3-O-rutinosides, 3-O-gentiobiosides and 3-O-glucosides, was isolated from the perianths of Tulipa gesneriana L. var. 'Paradae'. It showed protective activity against the increased (both chloroform and histamine) skin vascular permeability in rabbits. The protective effect, measured as the reduction in leakage of Evans blue, was 59.8% after peritoneal treatment at a dose of 25 mg/kg, while that of troxerutin was 45.5%.

Intense acute phase response in ischemic patients.

The aim of this study was to estimate the qualitative and quantitative changes of acute phase proteins in patients suffering from coronary heart disease. The study was carried out on 74 patients and 12 healthy volunteers. The patients were divided into three groups as follows: patients with myocardial infarction (n=37), Group I--without heart failure, Group II--with heart failure (II-III NYHA), Group III--patients with unstable angina pectoris (n=35); controls-healthy volunteers (n=12). The immunological measurements were performed at the beginning of hospitalisation (point 0), after 4, 8, 12 and 72 h, and after 6, 9 and 12 days of hospitalisation. The concentrations of C-reactive protein (CRP), alpha1-acid glycoprotein (AGP) and alpha1-antichymotrypsin (ACT) were measured using rocket immunoelectrophoresis according to Laurell. Glycosylation profiles of AGP and ACT were determined using crossed affinity immunoelectrophoresis with Con A as ligand according to Bøg-Hansen. Between Groups I and II statistically significant differences were observed for all investigated parameters. Highest concentration values were observed for Groups II and III; for Group II they appeared earlier than for Group III. The maximal values for reactivity coefficients (AGP-RC and ACT-RC) were observed earlier than the respective maximal values of concentrations. Continuous activation occurring in unstable angina leads to a more rapid increase in the concentrations of acute phase proteins and more marked alterations in their glycosylation profiles. In a way these patients seem to be 'primed' with constant stimulation, so that they respond dramatically to the stimulus of ischemia.

Mutations in the human paraoxonase 1 gene: frequencies, allelic linkages, and association with coronary artery disease.

Oxidative damage is a major cause of atherosclerosis. Since human paraoxonase has been postulated as a factor which plays a role in protection from low density lipoprotein oxidation, recent studies have dealt with the impact of hereditary PON1 gene polymorphisms as risk factors for coronary artery disease (CAD). The results from these studies are conflicting. In a case-control study, 1000 Caucasian patients with angiographically confirmed CAD were recruited and matched by age and gender to 1000 control individuals. PON1 mutations in codons 55 and 192 were evaluated by polymerase chain reaction-restriction fragment length polymorphism and allocated to defined haplotypes *1 (55L/192Q), *2 (55L/192R), and *3 (55M/192Q). Frequency of PON1 genotypes without any mutation (PON1*1/*1, wild-type) in CAD cases was 16.9% versus 17.1% in control individuals. PON1*2/*2 showed a frequency of 6.6% versus 7.3% (P = 0.68 compared to wild-type), and PON1*3/3 occurred in 11.8% in CAD cases versus 10.3% among control individuals (P = 0.40). There was also no difference in the distribution of carriers heterozygous for *2 or *3 among cases and control individuals. A haplotype containing both mutations 55M and 192R was not observed. None of the investigated genotypes demonstrated association with early manifestation, severity of disease, acute coronary syndromes, or myocardial infarction. Logistic regression analysis with adjustment for age, gender, diabetes, hypertension, hypercholesterolemia and smoking revealed no evidence of increased coronary risk associated with PON1 genotypes. These results suggest that PON1 polymorphisms are not major genetic determinants of CAD.

Endogenous drug-like factors.

The discovery of opioid receptors and endogenous substances capable of specific binding to these receptors, i.e. endorphin and enkephalin, is one of the most spectacular indications suggesting that the presence of a receptor for a certain drug in the organism authenticates searching for an endogenous substances with high affinity at this receptor. Later, further studies were undertaken to detect other endogenous drug-like factors. Some experiments led to the discovery of digoxin-like factor in blood which could bind to a specific receptor on Na+, K(+)-ATPase subunit, showing also the affinity for cardiac glucosides. Digoxin-like factor was detected in blood of healthy people who did not receive any drug treatments. It has been estimated to be present in 15% of the population but in some diseases this value is much higher, e.g. digoxin-like factor was detected in 90% of patients with IDDM, and it can be used as a risk factor of the occurrence of vascular complications. In cases with NIDDM, the digoxin-like factor was detected in patients with insulin-resistance. The presence of digoxin-like factor was ascertained in patients with heart failure who did not take digitalis preparations. Endogenous digoxin-like factor can contribute to the detection of falsely increased digoxin blood concentrations during the monitoring of drug level in the course of the therapy. In our studies we ascertained the presence of the quinidine-, cyclosporin-, theophylline- and phenytoin-like substances in the blood of the healthy people who did not receive any drugs. It seems that these endogenous substances resembling drugs are synthesized in human organism when they are needed for maintaining the physiological equilibrium. We can suggest that stimulation of the production of drug-like factors in the organism can be used in the future in the therapy of some diseases.

The acetylation and oxidation phenotypes in insulin-dependent diabetes mellitus.

Polymorphism of the acetylation and oxidation phenotypes in patients with IDDM was evaluated. A greater statistically significant number of fast acetylators in IDDM was found.

Blood levels of alloxan in children with insulin-dependent diabetes mellitus.

Alloxan is a well-known and universally used agent for evoking experimental diabetes through its toxic effect on the B cells of the Langerhans islets. In our study, blood levels of alloxan in children with insulin-dependent diabetes mellitus were investigated. The observations were made in 68 children aged 6-15 years and in a control group of 44 healthy children in the same age range. Alloxan levels were estimated spectrophotometrically. The mean level of alloxan in blood from children with insulin-dependent diabetes mellitus was 8.76 +/- 9.64 micrograms/ml and in blood from healthy children was 1.53 +/- 1.10 micrograms/ml. The difference was statistically significant (P < 0.05). The metabolism of alloxan leads to the production of free superoxide radicals which, as is well known, injure cells and cause conditions conducive to the occurrence of diseases from autoimmunity. The results obtained suggest therefore that higher levels of alloxan in diabetic children are of significance in the onset of insulin-dependent diabetes mellitus.

Endogenous drug-like factors in a Polish population.

In two hundred and twenty-five healthy volunteers not receiving any treatment the occurrence of drug-like factors in blood serum was studied. The examinations were carried out with the use of the fluorescence-polarization-immunoassay (FPIA)-TDx Abbott. The presence of endogenous phenytoin-like, theophylline-like and cyclosporin-like factors has been demonstrated.