Human decidual gamma/delta T cells possess unique effector and TCR repertoire profiles during pregnancy.

Human γδ T cells are enriched at the maternal-fetal interface (MFI, decidua basalis) showing a highly differentiated phenotype. However, their functional potential is not well-known and it is not clear whether this decidua-enrichment is associated with specific γδ T cell receptors (TCR) as is observed in mice. Here we addressed these open questions by investigating decidual γδ T cells during early and late gestation, in comparison with paired blood samples, with flow cytometry (cytotoxic mediators, cytokines) and TCR high-throughput sequencing. While decidual γδ T cells expressed less perforin than their counterparts in the blood, they expressed significant more granulysin during early pregnancy. Strikingly, this high granulysin expression was limited to early pregnancy, as it was reduced at term pregnancy. In contrast to this granulysin expression pattern, decidual γδ T cells produced reduced levels of IFNγ and TNFα (compared to paired blood) in early pregnancy that then increased by term pregnancy. TCR repertoire analysis indicated that human decidual γδ T cells are not generated early in life as in the mouse. Despite this, a specific enrichment of the Vγ2 chain in the decidua in early pregnancy was observed that disappeared later onwards, reflecting dynamic changes in the decidual γδ TCR repertoire during human gestation. In conclusion, our data indicate that decidual γδ T cells express a specific and dynamic pattern of cytotoxic mediators, Th1 cytokines and TCR repertoire suggesting an important role for these unconventional T cells in assuring a healthy pregnancy in human.

Some comments on Bitcoin market (in)efficiency.

In this paper, we explore the (in)efficiency of the continuum Bitcoin-USD market in the period ranging from mid 2010 to early 2019. To deal with, we dynamically analyse the evolution of the self-similarity exponent of Bitcoin-USD daily returns via accurate FD4 approach by a 512 day sliding window with overlapping data. Further, we define the memory indicator by the difference between the self-similarity exponent of Bitcoin-USD series and the self-similarity index of its shuffled series. We also carry out additional analyses via FD4 approach by sliding windows of sizes equal to 64, 128, 256, and 1024 days, and also via FD algorithm for values of q equal to 1 and 2 (and sliding windows equal to 512 days). Moreover, we explored the evolution of the self-similarity exponent of actual S&P500 series via FD4 algorithm by sliding windows of sizes equal to 256 and 512 days. In all the cases, the obtained results were found to be similar to our first analysis. We conclude that the self-similarity exponent of the BTC-USD (resp., S&P500) series stands above 0.5. However, this is not due to the presence of significant memory in the series but to its underlying distribution. In fact, it holds that the self-similarity exponent of BTC-USD (resp., S&P500) series is similar or lower than the self-similarity index of a random series with the same distribution. As such, several periods with significant antipersistent memory in BTC-USD (resp., S&P500) series are distinguished.

Doppler-guided transanal hemorrhoidal dearterilization versus conventional hemorrhoidectomy for treatment of hemorrhoids - early and long-term postoperative results.

BACKGROUND: A variety of effective methods for treatment of hemorrhoids has been proposed. In recent years, there has been an increasing number of studies comparing transanal hemorrhoidal dearterilization (THD) and conventional hemorrhoidectomy (CH), but the focus of most studies has been about the early postoperative results. The data about long-term outcomes is still limited. We aimed to compare Doppler-guided THD and CH with regard to early and long-term postoperative results. METHODS: The conducted prospective research included 287 patients who underwent CH (167 cases) or Doppler-guided THD with mycopexy (120 patients) between November 2010 and December 2015. Information on hemorrhoidal stage, demographic data, presenting symptoms, complications, duration of hospital stay, postoperative pain, patients' satisfaction and follow-up were obtained. Statistical tests were performed by SPSS 19.0. RESULTS: There was no significant difference between the studied groups according to gender, mean age, preoperative prolapse, pain and pruritus, hemorrhoidal stage and postoperative complications. Preoperative bleeding was more frequent in THD group (p = 0,002). The mean visual analog scale (VAS) pain scores in CH and THD groups on days 1, 2 and 7 were 7.01 vs 5.03, 5.07 vs 2.98, 2.39 vs 0,57 (p = 0,000). Practically, there was no difference in VAS on day 30 and patients' satisfaction at the 18th month. Mean hospital stay was 5,13 (CH) and 3,38 days (THD), p = 0,000. The postoperative follow-up was between 18 and 78 months (mean 46 ± 16 months). During this stage, 5 patients (2,99%) in CH group required surgery for recurrence. In THD group, 3 patients (2,5%), all with 4th-degree hemorrhoids underwent additional procedures (p 0,802). CONCLUSIONS: Doppler-guided THD seems to be an efficient and safe option for treatment of hemorrhoids, related to lower postoperative pain and excellent, similar long-term outcomes compared to CH. For advanced grades of hemorrhoids, Doppler-guided THD could be a valuable alternative, but there is a need for patients' selection. TRIAL REGISTRATION: (retrospectively registered) researchregistry 3090 .

Mother-to-newborn transmission of mycobacterial L-forms and Vδ2 T-cell response in placentobiome of BCG-vaccinated pregnant women.

The ability of bacteria to exist as a population of self-replicating forms with defective or entirely missing cell wall (L-forms) is an adaptive mechanism for their survival and reproduction under unfavorable conditions. Bacterial mother-to-fetus transfer is a universal phenomenon in the animal kingdom. However, data about vertical transfer of L bacterial forms are extremely scarce. Bacille Calmette-Guérin is an attenuated strain of M. bovis and the only licensed vaccine used for tuberculosis prevention. We already have shown that filterable L-forms of BCG exist freely in the vaccine and are able to reproduce and to form colonies. The present study was focused on the placental microbiome in the context of mother's BCG vaccination. Here we report an isolation of filterable mycobacterial L-form cultures from gestational tissues and blood of healthy newborns delivered by healthy BCG-vaccinated mothers after normal pregnancy. Of note, vertically transmitted mycobacterial L-forms as a part of placentobiome of the pregnant women didn't influence the number of resident pathogen-reactive Vδ2 cells. Placenta colonization with mycobacterial L-forms occurs by maternal blood-to-decidua transfer very early in gestation. Together, these data showed that BCG L-forms have the capacity to pass trans-placental barrier and that maternal BCG vaccination affects the placentobiome.

[ANTITHROMBOTIC MEDICATION IN PREGNANT WOMEN WITH PREVIOUS INTRAUTERINE GROWTH RESTRICTION].

AIM: To analyze pregnancy outcome in patients who were on antithrombotic medication (AM) because of previous pregnancy with fetal intrauterine growth restriction (IUGR). MATERIALS AND METHODS: The studied group (SG) included 21 pregnancies in 15 women with history of previous IUGR. The patients were on low dose aspirin (LDA) and/or low molecular weight heparin (LMWH). Pregnancy outcome was compared to the one in two more groups: 1) primary group (PG) including the previous 15 pregnancies with IUGR of the same women; 2) control group (CG) including 45 pregnancies of women matched for parity with the ones in the SG, with no history of IUGR and without medication. The SG, PG and CG were compared for the following: mean gestational age (g.a.) at birth, mean birth weight (BW), proportion of cases with early preeclampsia (PE), IUGR (total, moderate, and severe), intrauterine fetal death (IUFD), neonatal death (NND), admission to NICU, cesarean section (CS) because of chronic or acute fetal distress (FD) related to IUGR, PE or placental abruption. Student's t-test was applied to assess differences between the groups. P values < 0.05 were considered statistically significant. RESULTS: The differences between the SG and the PG regarding mean g. a. at delivery (33.7 and 29.8 w.g. respectively) and the proportion of babies admitted to NICU (66.7% vs. 71.4%) were not statistically significant. The mean BW in the SG (2114,7 g.) was significantly higher than in the PG (1090.8 g.). In the SG compared with the PG there were significantly less cases of IUFD (14.3% and 53.3% respectively), early PE (9.5% vs. 46.7%) moderate and severe IUGR (10.5% and 36.8% vs. 41.7% and 58.3%). Neonatal mortality in the SG (5.6%) was significantly lower than in the PG (57.1%), The proportion of CS for FD was not significantly different--53.3% in the SG and 57.1% in the PG. On the other hand, comparison between the SG and the CG demonstrated significantly lower g.a. at delivery in the SG (33.7 vs. 38 w.g.) an lower BW (2114 vs. 3094 g). There were significantly more cases with IUGR in the SG compared to the CG--total, moderate and severe (47.4 %, 10.5% and 36.8% in the SG vs. 8.9%, 6.7% and 2.2% in the CG) and NICU admissions (66.7% vs. 4.4%). There were no cases in the control group with severe PE (9.5% in the SG), IUFD (14.3% in the SG), and CS for FD (53.3% in the SG). The proportion of pregnancies without complication in the SG (23.8%) was significantly lower than in the CG (86.7%). CONCLUSIONS: The outcome of pregnancies with AM because of previous fetal IUGR is improved compared to the index ones. However, it is less favorable compared to the outcome in matched cases with no history of IUGR in previous pregnancies.

HEMORRHOIDAL DISEASE - CONTEMPORARY ASPECTS OF THE PATHOGENESIS, CLINICAL COURSE, DIAGNOSIS AND TREATMENT.

The hemorrhoidal disease affects mainly individuals in their active age, as the reported incidence is much lower than the actual number, due to the nature of the complaints and the "subjective feeling of discomfort" when contacting a healthcare professional. Although in a large part of the cases the disease is successfully treated by non-surgical methods, the persisting symptoms greatly lower patients' quality of life, and the development of complications is related to a high morbidity rate. The defining, diagnosis and determining of the stages of the disease do not pose any difficulties to the modern medical practice, which - however - is not the case with the selection of the optimal and most efficient treatment method. There are a great number of treatment procedures, including surgical, for the treatment of the hemorrhoidal disease. Although there are certain recommended schemes and algorithms for therapeutic behavior, the selection of the method, ensuring individualized and optimal therapy, depends on the judgment of the surgeon.

[INDICATIONS FOR ANTITHROMBOTIC MEDICATION DURING PREGNANCY--ANALYSIS OF CURRENT PRACTICES IN BULGARIA].

AIM: To analyze current practices in Bulgaria regarding antithrombotic medication (AM) during pregnancy, and to compare them with the ones recommended in literature. MATERIALS AND METHODS: In 84 pregnant women who were low dose aspirin (LDA) or/and low molecular weight heparin (LMWH) or unfractionated heparin (UH), data about AM were collected and analyzed. A descriptive analysis was performed of the indications for AM, its type, the applied doses and therapeutic regimens. RESULTS: 39/84 pregnant women (46.4%) had indications for AM. In 18/84 cases (21.4%) the type of AM was precisely selected according to the indications. Of them 12 were on LDA alone (8--history of early preeclampsia/IUGR, 2--diabetes, 1--autoimmune disease, 1--chronic hypertension), 4--on LMWH/UF alone (2--venous thromboembolism, 2--essential thrombocytemia) and 2 received both LMH and LDA (1--antiphospholipid syndrome, 1--phlebothrombosis and stillbirth). Another 21/84 cases (25%) had indications for AM but its type was not appropriately selected. This subgroup included cases with high risk inherited thrombophylia (IT), history of placental mediated disease (PMD) in previous pregnancies and/or accompanying medical disorders. These patients had indications for either LDA or LMA administration, but were on combined medication. In 45/84 cases (53.6%) with uneventful past obstetric history or early pregnancy losses (before 10 w.g.) but no PMD there were no indications for AM. Among them, 17/84 (20.2%) had low risk IT in 18/84 (21.4%) IT was ruled out and 10/84 (12%) were not tested for IT at all. In total, 64/84 patients (76.2%) were on LDA--alone (25/84 - 29.8%), or in combination with LMWH (39/84 - 46.4%). Treatment with LDA was indicated in 45/64 (70.3%) cases--12/25 (48%) of the ones who were on LDA alone and 23/39 (59%) of those on LDA and LMW In 19/64 cases (29.7%) LDA administration was not indicated. 59/84 (70.2%) of the patients were on LMW/UH- alone (20/84 - 23.8%) orin combination with LDA (39/84 - 46.4%). This therapy was indicated in only 6/59 cases (10.2%), treated with LMWH/UH - 4/20 (20%) of the ones on LMWH/UH alone and 2/39 (5.2%) of the ones on LDA plus LMWH. In 53/59 cases (89.8%) the administration of LMWH was not indicated. LDA was started preconceptionally, in the Ist or in the lind trimester in 12/64 (18.7%), 32/64 (50%) and 6/64 (9.4%) of the cases respectively. LMWN/UH was started preconceptionally, in the Ist orin the lind trimester in 5/59 (8.6%), 33/59 (56.9%) and 5/59 (8.6%) of the cases respectively. The information when AM was started was not reliable in 14/64 (21.9%) cases on LDA and in 16/59 (27.1%) - on LMWH. In 12/84 cases (14.3%) LDA and LMWH were administered every other day. This referred to 5/64 (7.8%) cases on LDA and to 7/58 (12.1%) - on LMWH. LDA and LMWH were administered in PAI 4G/4G polymorphism despite the fact that in'these cases fibrinolysis but not coagulation was affected. CONCLUSIONS: AM was administered according to strict indications and with appropriately selected preparations in only 21.4% of the studied cases. In another 25% there were indications for AM, but its type was not precisely selected. 53.6% of the patients had no indications for AM. LDA administration (alone or in combination with LMWH) was indicated in 70.9% of the cases; the same referred to only 10.2% of the ones who were on LMWH. Application/administration of AM every other day was inappropriate given the pharmacokinetics of the preparations. AM was also applied in IT with decreased fibrinolysis but not increased coagulability.

[BRONCHOPULMONARY DYSPLASIA IN VERY LOW BIRTH WEIGHT INFANTS--THE OLD NEW PROBLEM].

BACKGROUND: The advances in perinatal intensive care have increased the survival rate of extremely low birthweight (ELBW) and gestational age infants. Among them the risk of developing bronchopulmonary dysplasia (BPD) remains high. AIM: To evaluate the frequency of BPD by birthweight and gestational age, to identify the main postnatal risk factors and the associated comorbidities. METHODS: 683 VLBW infants (< 1500g) were admitted in NICU from 2008 to 2010. 597 survived more than 28 days and were included in this study. BPD was diagnosed if supplemental O2 for the first 28 days was necessary; the severity was assessed by the need of O2 and/or ventilator support at 36 gestational weeks (gw). RESULTS: 27.6% (n = 164) infants were with supplemental O2 at 28d of life (BPD-group), 10.9% (n = 65) were with moderate, 3.9% (n = 23) with severe BPD (FiO2 > 30% and/or ventilator support). Infants with BPD were with significantly higher CRIB (9.9 ± 3.1) compared with those without BPD (4.0 ± 3.0), p < 0.0001. The frequency decreased progressively from almost 100% at 23gw or birthweight < 600g to single cases after 31gw and bitthweight > 1200g. Logistic regression analysis showed that each gestational week decreased the odds of BPD by 60%; each CRIB point increased the odds by 62%. Each point increment in 1/5 min Apgar-scores reduced the risk by 40%/50% respectively The need for ventilator support increased from 1.4 ± 2.7 days (no-BPD group) to 52.8 ± 5.1 days (severe-BPD infants), p < 0.05. Postnatal complications significantly increasing the odds for BPD were found to be: PDA - 19.7, Pneumothorax - 12.1 times. There was a significant correlation between BPD, severe brain injury and ROP (p < 0.000 1). CONCLUSION: The frequency of BPD strongly correlates with gestational age and birthweight and CRIB. Additional risk factors are low A pgar scores, PDA and air leak syndrome. Associated comorbidities as severe brain injury and ROP further worsen the long term prognosis.

[PROLONGED RETAINED PLACENTA ACCRETA IN THE UTERUS AFTER VAGINAL DELIVERY (A CASE REPORT AND REVIEW OF LITERATURE)].

A case of prolonged retention in the uterus of placenta accreta after vaginal delivery is reported in the paper. The patient was 20 years old G3, P0 with two pregnancy terminations on request. She was admitted to the obstetric department of a regional hospital one day after the EDD with irregular contractions and non reassuring CTG. A few hours later intrauterine fetal demise occurred. Spontaneous labor commenced and a stillborn growth retarded fetus was delivered. Methergin was administered during the third stage of labor, but the placenta was not separated even after repeated Crede maneuvers, the last one under anesthesia. Since cervical spasm was present, the attempts for manual or instrumental separation of the placenta were unsuccessful. There was no genital bleeding, so further conservative approach was followed including continuous IV infusion of uterotonics, combined antibiotic therapy, close observation of the vital signs and the laboratory indicators. Three days after delivery the patient was transferred to a University Hospital because of subfebrile temperature. Her general condition on admission, although subfebrile, was good, there was no genital bleeding, the cervix was closed. The subfebrile temperatrure persisted despite antibiotic treatment; CRP was elevated (51,9 mg/l.). Because of suspicion for endomyometritis, on day 8th after delivery instrumental extraction of the placenta was undertaken with preparedness for hysterectomy in case of need. Although the procedure was difficult, with the placenta being extracted in parts, bleeding was scarce. The post operative period was uneventful and the patient was discharged from hospital five days after the intervention. A review of literature on the obstetric management of cases with retained placenta accreta after vaginal delivery is presented. The existing therapeutic options are discussed including their advantages and complications.

Targeting the PI3K/AKT/mTOR signaling pathway in medulloblastoma.

Medulloblastoma is the most common malignant childhood brain tumor and is associated with a poor outcome. There is an urgent need to develop novel targeted therapeutic approaches for medulloblastoma, which will arise from an enhanced understanding of the disease at the molecular level. Medulloblastoma has been recognized to be a heterogeneous disease, and no recurrent cancer gene mutations have been found, although many of the mutations described so far affect key intracellular signaling pathways, such as sonic hedgehog (SHH) and Wnt/ß-catenin. The PI3K/AKT/mTOR (PAM) signaling pathway controls key cellular responses, such as cell growth and proliferation, survival, migration and metabolism. Over the last decades, it has been recognized that this intracellular signaling pathway is frequently activated by genetic and epigenetic alterations in malignant brain tumors, including medulloblastoma. Clinical trials have started to evaluate the safety and efficacy of agents targeting this pathway in malignant brain tumors. Due to the complexity of the PAM signaling pathway, there remain significant difficulties in the development of novel therapeutic approaches. The future challenges in developing effective treatments for cancer patients include the development of predictive biomarkers and combinatorial approaches to effectively target multiple signal transduction pathways. In this review article, we will summarize the current knowledge about the role of PAM signaling in medulloblastoma and discuss the strategies that are currently being evaluated with targeted agents against this pathway.

TRENDS AND ALTERNATIVES IN TREATMENT OF MALIGNANT TUMORS OF EXTRAHEPATIC BILE DUCTS.

Neoplasms of extrahepatic bile ducts are rare and represent about 2% of all malignant diseases. Their clinical manifestation is delayed, when they are in advanced stage and the opportunities for radical treatment are limited. The resectability rate of the tumors of the middle and distal part of the bile ducts is higher than the percentage of the neoplasms with perihilar localization. Improved methods for preoperative diagnostic and staging as well as the individualized therapeutic approach, including biliary drainage, use of contemporary surgical techniques and methods, selective embolization of portal vein, partial hepatectomy, resection of caudal lobe, lead to increased rate of radical operations and improved long-term results.

[Pregnant women's attitudes towards the acceptable age limits for conceiving and giving birth to a child].

AIM: To assess whether there are socially determined permissible and desirable age limits for conceiving and childbirth among pregnant women in Bulgaria and their relation to age, general and obstetrical medical history, method of conception, level of education and whether pregnancy has been postponed or not. MATERIALS AND METHODS: 388 patients from the Fetal Medicine Clinic of the State University Hospital "Maichin Dom" in Sofia were provided with anonymous questionnaires, containing 38 questions. Two of the questions were essensial: 1) "What is the maximal permissible age for a woman to become pregnant and give birth to a child?". 2) "What is the maximal desirable age for a woman to become pregnant and deliver the planned numberof children?". The questionnaire contained also 23 questions related to the demographic characteristics of the participants and to their general and obstetric medical history. Data were processed with SPSS 13.0 statistical package. Descriptive and comparative analysis was performed after grouping according to one or mare chracteristics. P values < 0.05 were considered statistically significant. RESULTS: 54.2% (208/388) of the respondents determined a limit of the maximal permissible age for woman to conceive and give birth to a child. 53.4% (111/208) of them set the age limit of 40 years (28.9% of all patients). 63.6% (245/388) of the interrogated set a desirable age limit for conception and giving birth. Among then 82.9% (203/245) have set the limit at 40 years. The factors that influenced significantly the attitude towards the permissible age forconception/giving birth were the mode of conception, age and the level of education. Patients who had conceived spontaneously and had higher educational level were more confident when assessing the permissible age for conception/giving birth. Patients who had conceived by IVF/ICSI were significantly less confident answering the questions about age limits. The understanding for the permissible age for conception was not influenced by past obstetric history, deliberate postponemend of reproductive plans and the presence of chronic medical disorders. The understanding that pregnancy is always permissible (irrespective of age) was not influenced significantly by any of the factors. The understanding about the desirable age for conceiving/giving birth was influenced significantly only by the educational level--patients with higher degree of education were more confident in setting a desirable age limit.

Liver hemangiomas--surgical point of view.

UNLABELLED: Most of the liver hemangiomas do not change substantially their size for years. In some of the cases they grow, which may correlate to complaints and a risk of complications. Due to the rarity and the benign nature of the pathology, the surgical tactics and the technical methods have not been fully clarified. The goal of the present study is to present the experience of the Department of General and Liver-pancreatic Surgery in the surgical treatment of liver hemangiomas against data of the specialized literature. MATERIALS AND METHODS: In the January 1995-March 2013 period, 101 patients were subjected to liver hemangioma surgery at the Department of General and Liver-pancreatic Surgery, UH "Alexandrovska" Sofia. Main demographic, clinical, diagnostic and surgical procedures have been analyzed. RESULTS: Of 101 operated patients, 27 (26.7%) were male and 74 (73.3%)--female, aged 25- 77, mean age--50.7. The focal lesion was successfully diagnosed with diagnostic imaging methods: 96.9% with US, 98.3% with CT and 100 % with MRI. We established diagnostic specificity of 60.3%, 55.0% and 85.7%, respectively. The following interventions were performed: 14 large liver resections of three and more segments, 35 left-side lobectomies, 35 enucleations and enucleoresections and 30 mono- and bisegmentectomies. Post-operative complications were observed with 6 (5.9%) patients. None of the patients died. CONCLUSION: The combination of modern non-invasive imaging methods reaches diagnostic sensitivity and specificity sufficient to identify the liver hemangioma and take a decision on the therapeutic conduct. The possibilities for surgical treatment is limited and is applied upon strict indications. Liver resections in different volume and enucleations should be applied after correct selection of patients, so as to ensure minimum risk of morbidity and mortality.

Clinical case of a patient diagnosed with sinister inguinal hernia and disembriogenesis of the inguinal canal.

Hernia (lat. - rupture, burst) or protrusion represents the act of escape of tissue, organ or an organ constituent through an innate or acquired fault of the muscle or the connective tissue membrane. The inguinal hernia, also known as groin hernia, rates one of the most frequent surgical conditions. It is manifested by all ages, however is more common in males. The inguinal hernia exhibits by the protrusion of abdominal organs or their segments, for instance portions of the small or large intestine, into the inguinal canal. The groin hernias classify into two subtypes--direct and indirect, and also acquired and inherited. Two kind of anomalies exist--anomalies connected with the obliteration of processus vaginalis peritonei and anomalies connected with the embryogenessis of the inguinal canal. We present a clinical case of a 59-years-old male presenting with emerged arch-like protuberance in the sinister groin region, enlarging during physical effort and strain, accompanied by a strong, harsh pain. Intraoperatively it was discovered a disembryogenessis of the inguinal canal, a total lack of the front wall of the canal itself, a lack of formed superficial inguinal opening and inobliterated processus vaginalis peritonei.

Clinical case of neuroendocrine malignant tumor with unusual localization in the adrenal cortex.

The authors present unusual clinical case with atypical diagnostic work-up and histological result of adrenal neuroendocrine carcinoma.

[Pregnancy and delivery in women above the age of 35].

During the past decades there is a tendency among women in developed countries for postponing their reproductive plans for later age. This results from the substantial change of women's role in society and the development and availability of assisted reproduction technologies. The latter made possible women to become pregnant after the end of their reproductive years. In the present review, data from the literature, published in the recent 15 years and related to pregnancy course and outcome in women above the age of 35, are analyzed. Decreased fertility, higher incidence of early pregnancy complications including spontaneous abortions and ectopic pregnancy, and of congenital anomalies (chromosomal, structural, genetic syndromes) are discussed. Advanced maternal age is characterized with more frequent late pregnancy complication such as hypertension and diabetes. Problems of placentation, perinatal and maternal mortality are more frequent in these patients.. Data at present suggest higher risk for maternal and fetal pregnancy complications as maternal age advances. On the other hand, some positive aspects of postponing pregnancy have to be considered--financial, emotional, and the overall low absolute number of complications. With adequate antenatal care it is possible for women of advanced maternal age to have successful pregnancies with overall favorable outcome comparable to that in young women.

[Mode of conception, acompanying medical disorders and complications in the second half of pregnancy in women over the age of 35].

AIM: To assess the impact of maternal age on the mode of conception, the incidence of accompanying medical disorders and past surgical procedures (gynecological and non-gynecological) and the complications in the second half of pregnancy (preeclampsia, placenta praevia, placental abruption, preterm delivery) in women ≥ 35 years, followed prospectively. MATERIALS AND METHODS: Between 02/2012 - 02/2014 495 pregnant women of ≥ 12 weeks of gestation were enrolled in the study. The patients were admitted for different indications at the Fetal Medicine Clinic of the State University Hospital "Maichin Dom". They were divided in 3 age groups according to age: ≤ 34, 35-39 and ≥ 40 years. The information about pregnancy course and outcome was retrieved from the hospital records or obtained from the patents themselves by phone interviews. The following complications in the second half of pregnancy were analyzed: preeclampsia, placenta praevia, placental abruption, preterm delivery. The data were processed with SPSS 13.0. statistical package. Descriptive and comparative analysis was performed after grouping according to one or more characteristics; p values < 0.05 were considered as evidence of statistical significance for tested effects. RESULTS: The number of patients ≤ 34 years of age was 131/495 (26.5%), between 35-39 years--54/495 (51,.%) and >≥40 years --10/495 (22,.%). Conception by ART was significantly more frequent in women aged >3 5. Pregnancy occurred afterA RTi n 1,.% (2/131) of the women <3 4, in 8,.% (22/254) of those between 35-39 and in 10,.% (12/110) of those >≥ 0 years of age (p= O 0.08). The incidence of accompanying medical disorders (intemrnl, tumors, of the female genital system) was significantly higher in women of more advanced age (p< O 0.01). It was 36,.% (48/131) in those <3 4, 53,1% (135/254) --n the ones between 35-39 and 68,.% (75/110) --mong those >≥ 0 years of age. The increased incidence was mainly due to more frequent intemrnl (p= 0 ,.218) and female reproductive system (p=0,0027) disorders. The incidence of past surgical procedures was increased significantly with advancing maternal age; this was attributed mainly to non-gynecological surgical procedures (p= O 0.04). Among women <3 4 years 41,.% (54/131) reported past surgery, while in the age groups between 35-39 and >≥ 0 years the figures were 57,.% (146/254) and 59, 1% (65/110) respectively .The increase of maternal age was related to significantly more frequent complications in the second half of pregnancy --reeclampsia, placenta praevia, placental abruption and preterm delivery. The incidence of preeclampsia increased from 1,.3% (2/131) in the age group <3 4, to 3,.3% (10/254) for those aged 35-39 and to 7,.7% (8/110) --or the ones _≥ 0 (p= O 0.5). The combined incidence of placenta praevia and placental abruption was also significantly higher in women of more advanced age (p= 0 ,.056). In the age group <3 4 no such cases were registered while in women aged 35-39 the incidence of these complications was 3, 14% (8/254) and for the age group >≥ 0 it was 8,.8% (9/110). The combined incidence of placenta previa and placental abruption was considered because of the small number of cases. The complications cited above were significantly more frequent in women with accompanying medical disorders (p = 0,001). The incidence of preterm deliveries increased significantly with maternal age --rom 10,.% (14/131) for women <3 4 to 25,.% (52/208) --or those between 35-39 and 21,.% (20/93) --or those _≥ 0 years of age (p= 0 ,.13). The combined preterm delivery rate was considered in the study (spontaneous and induced). CONCLUSION: In our study maternal age >≥ 5 years was related to significantly more frequent conception by ART history of accompanying medical disorders, past surgery (non-gynecological) and complications in the second half of pregnancy (preeclampsia, placenta praevia, placental abruption and preterm delivery).

EPIDEMIOLOGICAL REGISTRY OF NEUROENDOCRINE TUMORS IN BULGARIA--A PILOT SURVEY.

The National registry of patients with neuroendocrine tumors (NET) in Bulgaria was established in 2013 as a joint initiative of the Bulgarian Surgical Society and the Institute for Rare Diseases. The register aims to explore the epidemiology of NET in Bulgaria, as well as the different diagnostic and treatment approaches for the disease throughout the country. This the first of its kind retrospective study of NET in the country is covering the period January 2012 - January 2013. A total of 127 patients with NET were identified. At the time of the survey the average age of patients with NET was 58.61 ± 15.59 years. The data show almost equal distribution between the genders with a slight predominance of women. The largest relative part of NET is those of NET located in the gastrointestinal tract (54.10 ± 4.51%), followed by those located in the pancreas (12.30 ± 2.97%) and in the lungs (10.66 ± 2.79%). In 72.44 ± 3.96% of the patients a immunohistochemical diagnosis was performed. The study confirmed the leading role of the surgery method of the NET management. In 65.83 ± 4.33% of the patients a radical removal of the tumor was conducted, while the relative part of the undertaken partial resection was 7.50 ± 2.40%. A statistically significant association between the type of surgical treatment and during the follow-up of patients was found. An update of the information in the register will allow a more precise determining of the distribution and management of NET in Bulgaria.

[Case of intrauterine retardation and fetal death during labor].

The case concerns to a 37 years old pregnant woman with a history of three miscarriages. Ultrasound biometry in early pregnancy corresponds to the term calculated according the last menstrual period (LMP). At 37 week of gestation was determined retardation of 5 weeks. Doppler velocimetry and quantity of amniotic fluid were in normal ranges and the pregnant refused hospitalization. She was admitted to the hospital three days after the appointed term without uterine contractions. The fetal ultrasound biometry meets 33 weeks and the Doppler examination of a. umbilicalis found resistance index (RI) of the upper limit of normal. The cardiotocography record shows: baseline fetal heart rate--143 beats/min, good variability and reactivity. There was one deceleration for 3 minutes, and then the recording returns to normal. Re-monitoring after 30 minutes establishes of a periodic decelerations and a tendency to bradycardia with reserved variability. At the start of the emergency Cesarean Section fetal heart beats are single. The delivered babe was with Apgar O. The reanimation was not successful and the fetus died. From the autopsy signs of severe asphyxia. In conclusion, it can be assumed that in strongly retarded fetuses, cardiotocography recording and Doppler velosimetry are not sufficiently reliable methods for continued monitoring. In late-onset and severe intrauterine growth retardation (IUGR) desirable delivery time is after reaching biological maturity at 36-37 week.

[Pregnancy outcome in women over the age of 35].

AIM: To assess pregnancy outcome in women aged > or =35, followed prospectively, and the relation between maternal age and the incidence of abortions after 12 gw (spontaneous and medical), preterm delivery, mode of delivery and congenital anomalies. MATERIALS AND METHODS: 495 women from the Fetal Medicine Clinic of the State University Hospital "Maichin Dom" in Sofia were enrolled in the study between 02/2012 and 02/2014 with gestational age > or =12 completed weeks. The patients were devided in 3 groups according to age-- < or =34, between 35 and 39 and > or = 40 years of age. Pregnancy outcome was veirified from hospital records and phone intenrviews with the patients themselves. Data were processed with SPSS 13.0 statistical package. Descriptive and comparative analysis was performed after grouping according to one or more characteristics; p values <0.05 were considered as evidence of statistical significance for tested effects. RESULTS: 131/495 (26.5%) of the patients were < or =34 years of age, 254/495 (51.3%) were between 35 and 39 and 110/495 (22.2%) were > or =40 years of age. Maternal age > or =35 was associated with statistically significant increase of the total late abortion rate (spontaneous and medical abortions)--from 6.9% for those < or =34 yars of age to 11.3%--for the ones between 35-39 and 11.4%--for the ones > or =40 years. There was also statistically significant increase in the incidence of late medical abortions in the group > or =40 years of age (p=0.011). It was 2/124 (1.6%) for the group aged < or =34, 7/230 (3%)--in the group aged 35-39 and 9/100 (9.0%)--in the group > or =40 years of age. The difference in late spontaneous abortions rate was not statistically significant among the groups. There was statistically significant increase in the incidence of preterm deliveries (spontaneous and induced)--14/131 (10.7%) in the group aged < or =34, 52/208 (25.0%)--in the group between 35-39 and 20/93 (21.5%)--in the group > or =40 years of age (p=0.013). There was also a significant increase in Cesarean section rate with age--from 44/131 (33.6%) in the group < or =34, to 139/254 (54.7%)--in the group between 35-39, and 69/110 (62.7%)--in the group > or =40 years (p=0.0001). There is a tendency for increased operative vaginal delivery rate with age; however the difference is not statistically significant, probably due to the small number of cases (p=O. 113). There was also statistically significant increase in the proportion of newborns with congenital anomalies in women > or =40 years of age (p=0.005)--from 1/131 (0.8%) in patients < or =34, to 2/254 (1.0%) for those between 35 and 39, and 6/110 (5.5%)--for those > or =40 years. Part of the congenital anomalies was prenatally diagnosed chromosomal defects without termination of pregnancy CONCLUSIONS: Maternal age > or =35 years is associated with statistically significant increase in late medical abortions, preterm delivery and Cesarean section rate and congenital fetal anomalies.