Prediction of the pre-eclampsia in the first trimester - pilot study.

AIM OF STUDY: Aim of study was to find out the possibility of prediction of pre-eclampsia in the first trimester among patients with risk factors. TYPE OF STUDY: Prospective study. Name and seat of workplace: 1st Department of Gynecology and Obstetrics, Comenius University in Bratislava, the University Hospital of Bratislava. METHODS: Study included 77 women, who were examined in first trimester between 11+0 and 13+6 weeks of gestation from 1. 6. 2016 to 1. 6. 2017 in 1st Department of Gynecology and Obstetric in the Comenius University Hospital in the Bratislava and enlisted patients delivered until 31. 2. 2018. The study was approved by Hospital Ethics Committee and all patients signed consent form. We included patients, who ran at least one risk factor for developing pre-eclampsia, nulliparous, pregnancy after assisted reproduction technology, body mass index 25 in the beginning of pregnancy, age of patients and multiple gestation pregnancy. In addition, an ultrasound scans were performed in the first trimester. Doppler ultrasound pulsality index of uterine artery, pregnancy-associated plasma protein and mean arterial pressure were used for prediction of the pre-eclampsia. Sensitivity and specificity of test were calculated. We assessed pre-eclampsia according to diagnostic criteria of the American College Obstetricians and Gynecologists. In the last part, we compared perinatal and maternal outcomes in the pre-eclampsia group and in the control group. STATISTICAL ANALYSIS: Statistical analysis was realized by the IBM SPSS Statistics 25 Software. Risk factors were analysed by using Fisher exact test and Odds ratio. Mann-Whitney test and a one way analysis of variance were used for comparison the pre-eclampsia group and the control group. RESULTS: Patients, whose had got conceived after assisted reproduction technology, had significant higher probability of pre-eclampsia (Odds ratio = 7.7, p = 0.028). Patients with multiple gestation pregnancy had also significant higher risk of pre-eclampsia (Odds ratio = 16.5, p = 0.031). Mean arterial pressure was only significant as predictive test in 12th weeks of gestation. Adverse perinatal outcomes and higher rate of cesarean section were in the preeclampsia group. CONCLUSION: Mean arterial pressure is easy to use and cost-effective predictor, but sensitivity was only 66.6% and specificity 49%.

The effect of long term testosterone replacement therapy on bone mineral density.

OBJECTIVE: Long-term results of testosterone replacement therapy (TRT) on bone mineral density (BMD) in literature are still missing. MATERIALS AND METHODS: Totally, 45 males with testosterone deficiency syndrome (TDS) underwent TRT. The mean age was 57.84 years and the follow-up period was 94.62 months. Males were treated with three-month intramuscular injections of 1000 mg testosterone undecanoate. BMD was check at beginning of treatment, after two years and after 5 years. For a statistic evaluation, nonparametric Wilcoxon test was used. RESULTS: Mean BMD of lumbar spine was 1.067 at beginning, 1.122 after two years and 1.667 and after 5 years. The results after two and also 5 years showed a significant improvement (p < 0.001). CONCLUSION: Authors proved a positive effect of long-term TRT on BMD of the lumbar spine. Densitometry of the whole hip showed also an improvement, but only after 5 years. Densitometry of the femoral neck was relatively stable. Important is that despite the fact that males became older, BMD values of the lumbar spine were improved (Fig. 6, Ref. 18).

Results of long term testosterone replacement therapy in men with abdominal obesity, erectile dysfunction and testosterone deficiency.

INTRODUCTION: In this article, the authors evaluate subjective and objective results of long testosterone replacement therapy (TRT) and possible risk. METHODS: In a single center study, the authors treated 69 men with testosterone deficiency syndrome (TDS). The average age was 57.84 years and the follow-up period was 94.62 months. All men had at beginning a complete urological and internal examination. All the men were treated with three-month i.m. injections of 1000 mg testosterone undecanoate. The men were regularly checked according to the EAU guidelines. RESULTS: All of the men on treatment felt much better. Weight and waist circumference during monitoring showed a mild improvement. Excellent results were on red blood cells. Glucose, HDL cholesterol, triglycerides had stable values. PSA slightly increased and testosterone was within the normal range. In two men during treatment, we found a prostate cancer (low risk). Bone mineral density (BMD) of lumbar spine revealed a significant improvement. CONCLUSION: TRT had multiple positive effect on affected men with TDS. Our long-term results showed a long mild improvement during the time. Authors concluded that long term treatment had multiple benefit for affected men (Fig. 11, Ref. 13).

Single umbilical artery and reproduction losses in Slovak population: relation to karyotype and fetal anomalies.

AIM: The purpose of this study was to monitor the association between single umbilical artery (SUA), chromosomal abnormalities and associated anomalies during the routine examination of spontaneous or induced miscarriages and premature births. METHODS: During 1992-2015 we morphologically and cytogenetically examined a series of 4098 samples. For 1330 cases the number of umbilical cord vessels could be reported. RESULTS: The presence of single umbilical artery was identified in 67 fetuses of 1330 pregnancies (5.04 %); 36 of the 67 fetuses (53.7 %) had additional congenital malformations. The cultures were unsuccessful in 29 of 67 cases (43.3 %). 38 cases (56.7 %) were successfully karyotyped; 20 out of them had a normal karyotype and 18 had chromosomal anomalies including trisomy 18 (n = 4), trisomy 13 (n = 3), trisomy 21 (n = 2), trisomy 11 (n = 1), triploidy (n = 3), monosomy X (n = 3) and structural chromosomal aberrations (n = 2). CONCLUSION: Isolated SUA is not at increased risk of chromosomal abnormalities and generally does not endanger pregnancy. All chromosomally abnormal embryos and fetuses had associated congenital anomalies. The most frequently associated congenital anomalies were in the musculoskeletal system, central nervous system and genitourinary tract (Tab. 4, Ref. 44).

Testosterone replacement therapy (TRT) and its effect on bone marrow. How serious is it and is there a true polyglobulia?

INTRODUCTION: TRT in men with testosterone deficiency syndrome (TDS) had multiple positive effects and restore a quality of life of affected men. Polyglobulia is the most common dose-limiting adverse effect of TRT, but the mechanisms of TRT-mediated erythropoesis remain unclear. In this study, we evaluated long term haematological side effects of TRT: polyglobulia, elevated hemoglobin (Hb) and haematocrit (Ht). METHODS: In a cross-sectional descriptive study, the authors treated 69 men with TDS and the average age 59 years and the follow-up period 81.32 months. The men were treated with three-month i.m. injections of 1000 mg testosterone undecanoate. The elevated values were: Hb above 176 g/l, Ht above 0.52 and erythrocytes (Ery) above 6.0 mil/mcl. RESULTS: 21 out of 69 patients (30.43 %) had an increased Hb, Ht or Ery during treatment. The interesting fact was that only five men (7.24 %) had increased the number of Ery (true polyglobulia). No men with elevated level of Hb, Ht or Ery had other side effects (like thrombosis). CONCLUSION: It is still not clear, why in some men on TRT the feedback does not work and bone marrow production of red blood cells continues even if the upper limit is reached. Authors expect that only 7% of men had true polyglobulia, other men had elevated Hb or Ht. Based on our own experience we recommend a regular check of men on TRT on order to avoid possible serious side-effects (Tab. 1, Fig. 2, Ref. 25).

Distribution of the most common polymorphisms in TYMS gene in Slavic population of central Europe.

Thymidylate synthetase (TS) plays a critical role in the de novo synthesis of dTMP inside the cell. Therefore, TS is a suitable target for cytotoxic drugs such as fluoropyrimidines. Drug efficacy and toxicity depend on the intracellular level of TS, which is significantly influenced by the polymorphisms in the 5'UTR (TSER - rs45445694, TSER*3G>C - rs2853542) and 3'UTR (1494del TTAAAG - rs151264360) of TYMS gene. Polymorphic variants of TYMS gene affect TS activity via gene expression and transcript stability. Patients who undergo fluoropyrimidine therapy may benefit from genetic testing prior to the administration of chemotherapy. At the 5' terminus of TYMS, there is a polymorphic region represented by a variable number of 28bp long tandem repeats (2-9 tandems) with the G or C nucleotide variant (SNP G>C). The 3'end of TYMS gene may decrease the stability of mRNA in the case of 6 base deletion (1494del6, D). In our study, we have focused on testing of TYMS gene polymorphisms, determination of TYMS variant frequencies in Western Slavic population and comparison of Slovak population with other populations.We performed identification of 5'UTR (rs45445694 - TSER*2 or TSER*3; rs2853542 - TSER*3G>C; TSER*3+ins6) and 3'UTR (rs151264360/1494del6/D) polymorphic regions of TYMS gene among 96 volunteers by PCR-RFLP and fragment analysis. Slovak frequencies of selected polymorphisms were established as follows: the frequency of TSER*2, TSER*3, TSER*3G>C, 1494del6/D and I to be 41%, 59%, 34%, 37.5% and 62.5% respectively. The high resolution of the capillary electrophoresis technique allowed among TSER*3 group identification of a subgroup of four individuals with rare 6bp insertion in 3R allele, id est 2.1% TSER*3+ins6 allele frequency. In our study, we have revealed individuals with rare G>C substitution in the first 28bp tandem repeat of TSER*2 promoter enhancer region (rs183205964) as well, the overall frequency of this polymorphic allele in Slovak population was 2.1%. Our results proved that Slovak population is in Hardy-Weinberg equilibrium and proportion of TYMS polymorphisms is in accordance with other published data.

Expression of ezrin and moesin in primary breast carcinoma and matched lymph node metastases.

Ezrin, radixin, moesin (ERM) are important membrane-cytoskeletal crosslinkers and are suggested to play important role in cancer progression and metastasis. Even though ERM proteins were generally considered to be functionally redundant and the most studied was ezrin, recent studies highlight their distinct roles in metastatic process. Little information is available regarding the role of individual ERM proteins and their phosphorylated forms in human breast cancer. Our study is the first to examine expression of ezrin, moesin and their phosphorylated forms in primary breast tumors and matched lymph node metastases (LNMs) and their correlation with clinicopathological variables. A total of 88 primary breast cancer, 91 LNMs, 54 intraductal carcinoma and 26 normal adjacent breast tissue samples from tissue microarrays were studied. Expression was determined by immunohistochemistry, the intensity and number of positive cells was scored. Statistical analysis of protein expression and patients' age, tumor grade and hormonal status was performed. No statistical significant difference was found in ezrin, moesin, p-ezrinTyr353 and pan-p-ezrinThr567/radixinThr564/moesinThr558 expression between primary tumors and LNMs. Even though it was not significant, moesin expression varied between primary tumors, intraductal carcinoma, normal breast adjacent tissue and LNMs. A significant positive correlation between moesin and tumor grade has been proven. Even though primary tumors and matched LNMs did not show different expression patterns, moesin correlated significantly with higher tumor grade. Its positivity in intraductal carcinoma and normal breast tissue adjacent to cancer might indicate its role in tumor intiation/progression.

Trend and challenge in mother-to-child transmission of syphilis.

OBJECTIVE: The aim of the study was to evaluate the epidemiological trends in the incidence rates of mother-to-child transmission of syphilis, syphilis in women of reproductive age and pregnant women in the antenatal care program over the period 1991-2014, in order to find a basis for preventive measures. MATERIAL AND METHOD: Case series data of confirmed syphilis was used to evaluate the incidence rates over the period 1991-2014 in Slovakia. RESULTS: During the monitored period, 101 cases of mother-to-child transmitted syphilis were detected. The rate increased in 1996, corresponding to 33.3 per 100,000 live births and discovered discordance in antenatal care program. The rates of syphilis in women of reproductive age showed increased rate in 2001, corresponding to 10.44 per 100 000 population. Pregnant women reported the highest rate in 2000, corresponding to 3.24 per 1,000 pregnant women population. Syphilis notification rates in all three groups showed increased trend in the first decade following with decreased trend in the second decade. The high decrease in rate notification among pregnant women in 2011 (0.37) decreasing up to 0.11 in 2014 was followed with decreasing of mother-to-child transmission. CONCLUSION: Mother-to-child transmission of syphilis poses a public health problem and requires comprehensive surveillance in all countries. These data result in the requirement of effective improvement of antenatal care program in pregnant women. The last years 2011-2014 showed improvement in antenatal care program corresponding with decrease rate of mother-to-child transmission of syphilis.

Paraoxonase activity in sera of patients with non-alcoholic fatty liver disease.

The results of our study showed significantly decreased levels of PON1 in patients with chronic liver diseases (controls 185 ± 14 U/l, NAFLD 160 ± 15 U/l, chronic hepatitis 99 ± 18 U/l, cirrhosis 52 ± 11 U/l). There were significant correlations of PON activities with standard liver function tests (Tab. 1, Ref. 5).

Can we predict orofacial cleft in future pregnancy?

AIM: The aim of this thesis was not only to define the frequency of all orofacial clefts and their particular types, but also to determine the sex of an embryo or fetus and detect associated developmental and chromosomal abnormalities. Approximately one third of orofacial clefts are a part of chromosomal syndromes. MATERIALS AND METHODS: Retrospective morphological and cytogenetic study of 43 cases of different types of orofacial clefts between 1992-2014 from miscarriages (spontaneous abortions) and premature births. RESULTS: Associated abnormalities were found in 34 cases. Most of the anomalies were skeletal anomalies (29), NTD (24) and anomalies of the abdominal wall (9). Most associated anomalies were found in the R III group (93.3 %). Eleven of the successfully cultivated cases (26 %) had a normal karyotype and in 14 of the cases (32 %), numerical or unbalanced structural chromosomal aberrations were found. CONCLUSION: Our data did not show that isolated clefts were not associated with a higher risk of chromosomal aberrations. Higher percentage of chromosomal aberrations found in isolated clefts in our pool can be explained by the age of the embryos and fetuses - usually between day 43 and week 12. It is nearly impossible to diagnose some associated congenital defects at such an early age. Thanks to the morphological and cytogenetic analysis of embryos and fetuses with orofacial cleft, it is possible to estimate if not determine the etiologic factor which influenced the miscarriage. Additionally, in the case of birth defects, the prognosis for future pregnancy can be offered, which is important information for gynecologist and clinical geneticist (Tab. 5, Fig. 5, Ref. 31).

Increasing trend in syphilis.

OBJECTIVES: The aim of this study was to evaluate the epidemiological situation of syphilis in the Slovak Republic in the period of the past two decades. BACKGROUND: In last decade, the incidence of syphilis has decreased in European countries by 13%. However, several countries reported an increase in the trend of syphilis. METHODS: Cases of syphilis reported to the National Health Information Center in the Slovak Republic were statistically evaluated. RESULTS: In the first decade syphilis possessed an increase rate 262.5% and 127.6% in five subsequent year intervals, and then the rate fluctuated and showed minimal decrease in the last three years. The highest rate 7.3 per 100,000 population documented in 2009. The peak in the Bratislava region reached 36.36 in 2000. Epidemic was documented in marginalized group in East region. Early syphilis was the most frequent stage observed in both decades but late and no specified cases increased in the last period. The M/F rate was up to 1.7, the most frequently recorded age category was 15-24 years. CONCLUSION: These results indicate a requirement for developing a comprehensive control and educational program in the overall population, particularly in marginalized groups, and improving case management by health providers (Fig. 3, Ref. 20).

Polycystic ovary syndrome - a risk factor of pre-eclampsia after in vitro fertilisation.

AIM: Taking into account an increasing number of pregnancies after the assisted reproduction, we tried to evaluate the risk of pre-eclampsia for mono-foetal pregnancy after IVF and to determine the degree of risk factors. MATERIAL AND METHODS: The study included 16,400 patients, while 15,874 of them were after spontaneous conception and 526 after conception using assisted reproductive technologies. For the basic statistical analysis, we used frequency tables and basic statistical characteristics for numeric and ordinary variables. To verify the statistical dependence, we used contingency tables, Fisher exact test and the odds ratio. RESULTS: In the group of women after in vitro fertilisation, a higher incidence of pre-eclampsia was recorded than in the group of women after spontaneous conception. Conception via in vitro fertilisation represents the 3.4-fold risk of pre-eclampsia development (OR 3.404 95% CI 2.407-4.8). CONCLUSION: The major causes of a higher incidence of pre-eclampsia in case of assisted reproduction include: polycystic ovary syndrome, insulin resistance, subfertility, age and obesity of patients. Assisted reproductive technologies are not the cause of a higher incidence of pre-eclampsia in case of the assisted reproduction (Tab. 4, Fig. 2, Ref. 22).

Frequencies of polymorphisms in CYP2C9 and VKORC1 genes influencing warfarin metabolism in Slovak population: implication for clinical practice.

OBJECTIVES: The study was aimed at establishing an effective molecular-genetic method for detecting polymorphisms in genes CYP2C9 and VKORC1, which affect the pharmacogenetics of warfarin, and at determining their prevalence in Slovak population. BACKGROUND: Warfarin, derivative of coumarin, belongs to the most commonly prescribed oral anticoagulants with narrow therapeutic index. An insufficient dose of warfarin can result in failure to produce the antithrombotic effect, whereas an overdose increases the risk of bleeding. It was proven that genetic variability in two genes, CYP2C9 a VKORC1, has a significant influence on the individual's response to the dosage of warfarin. METHODS: In a control group of 112 randomly selected individuals, we tested the frequency of selected single nucleotide polymorphisms including CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), VKORC1*2 (1173C>T) by allele-specific Real-Time PCR and VKORC1*2 (-1639G>A) by using PCR-RFLP. RESULTS: Due to the combination of frequent alleles CYP2C9*2, CYP2C9*3 and VKORC1*2 in Slovak population we determine that 25% of population need a standard 5-mg daily dose of warfarin, while 44%, 23%, and 8% need 4 mg, 3 mg and 2 mg of warfarin per day. CONCLUSION: Slovak population is in Hardy-Weinberg equilibrium and frequencies of SNPs were in accordance with other published results in European populations (Tab. 5. Fig. 3, Ref. 51).

Thymic tumours associated with Myasthenia gravis: a long term observation study of operated patients.

Primary tumours of thymus, thymoma and thymic carcinoma, are very rare, they represent less than 1 % of all neoplasms. The most common manifestation of thymoma with appearance of 40 to 50 % of the neuromuscular autoimmune disease is myasthenia gravis (MG). The performance of a complete resection is the most predictive indicator for long-term survival of patients with thymic tumour, also important prognostic factors are the histological type of thymic tumour and its invasiveness. The aim of our study is to study the long-term survival of patients after the resection of the tumour, as well as enhanced efficiency of radical thymectomy in the complex treatment of myasthenia gravis. From 1989 to 2010 we operated on 369 patients with MG. Out of 49 patients (13.7 %) 38 cases (76.6 %) were thymomas and 11 cases (23.4 %) thymic carcinomas. Complete removal of tumours (stage I, II, and III) were performed in 45 (92 %) cases. Of the 41 living patients (83.7 %), three (7.3 %) were diagnosed with metastatic thymic carcinoma or thymoma, and treated with adjuvant therapy. In one case, the patient died due to generalization of the thymic carcinoma. Statistical analysis with Kaplan-Meier method showed better overall survival of patients with thymoma than patients with thymic carcinoma. The difference in survival curves was not significant. (Mantel-Cox p = 0.479, Generalized Wilcoxon p = 0.326). In terms of treatment of Myasthenia gravis associated with thymoma, we achieved 70 % successful clinical and pharmacological remission. On the other hand, paraneoplastic MGAT has the worst prognosis of all the other forms of MG. The difference between MGAT to every other form of MG was statistically significant (Tab. 6, Fig. 1,Ref. 28).

Metabolic syndrome and its effect on aortic stiffness in premenopausal women.

BACKGROUND: Metabolic syndrome (MS) is a cluster of proatherogenic risk factors (RF) (abdominal obesity, atherogenic dyslipidemia, impaired fasting glucose or type 2 diabetes mellitus, higher blood pressure or antihypertensive therapy) that move patients into a higher risk for development of cardiovascular disease (CVD) and type 2 diabetes. The preclinical (subclinical) target organ diseases (SOD) are early signs of atherosclerosis. An increased aortic stiffness characterised by an increased pulse wave velocity in aorta (PWV Ao) is one of SOD.The aim of the present study was to assess the impact of metabolic syndrome (MS) on aortic wall stiffness and the risk profile in premenopausal women. METHODS: The aortic stiffness was measured using Arteriograph-Tensiomed, based on oscillometric measurement and analysis of the shape of brachial pulse wave, giving the PWV Ao. The results of measurements characterise a global aortic stiffness. RESULTS: We examined 81 premenopausal women (without history of CVD). The MS (according to the 2009 "harmonizing" definition) was present in 31 women (mean age 41.5 y), in the control group, there were 50 women (39 y). The most frequent components of MS were abdominal obesity (93 % vs 42%), arterial hypertension (68 % vs 10 %) and dyslipidemia (29 % vs 8 %). The PWV Ao was significantly higher in women with MS (9.26 m/s) compared to the control group (7.44 m/s). CONCLUSION: The aortic stiffness in women with MS compared to controls was significantly higher despite a presumed general protective hormonal effect on cardiovascular system in women with child-bearing potential (Tab. 4, Ref. 25).