Case report: Complex evaluation of coagulation, fibrinolysis and inflammatory cytokines in a SARS-CoV-2 infected pregnant woman with fetal loss.

Background: SARS-CoV-2 infection during pregnancy increases the risk of severe obstetrical complications. Detailed evaluation of COVID-19-associated coagulopathy in a pregnancy with stillbirth hasn't been described so far. Besides knowledge gaps in the pathomechanism leading to stillbirth in COVID-19 pregnancies, currently, no prognostic biomarker is available to identify pregnant patients who are at imminent risk of COVID-19-associated maternal and fetal complications, requiring immediate medical attention. Case: Here we report the case of a 28-year-old SARS-CoV-2 infected pregnant patient, admitted to our hospital at 28 weeks of gestation with intrauterine fetal loss. The presence of SARS-CoV-2 placentitis was confirmed by immunohistological evaluation of the placenta. She had only mild upper respiratory symptoms and her vital signs were within reference throughout labor and postpartum. The stillborn infant was delivered per vias naturales. Fibrinogen concentrate was administered before and after labor due to markedly decreased fibrinogen levels (1.49 g/l) at admission and excessive bleeding during and after delivery. Although coagulation screening tests were not alarming at admission, the balance of hemostasis was strikingly distorted in the patient. As compared to healthy age- and gestational age-matched pregnant controls, increased D-dimer, low FVIII activity, low FXIII level, marked hypocoagulability as demonstrated by the thrombin generation assay, together with shortened clot lysis and decreased levels of fibrinolytic proteins were observed. These alterations most likely have contributed to the increased bleeding observed during labor and in the early postpartum period. Interestingly, at the same time, only moderately altered inflammatory cytokine levels were found at admission. Serum ACE2 activity did not differ in the patient from that of age- and gestational age-matched healthy controls, suggesting that despite previous speculations in the literature, ACE2 may not be used as a potential biomarker for the prediction of COVID-19 placentitis and threatening fetal loss in SARS-CoV-2-infected pregnancies. Conclusions: Although based on this case report no prognostic biomarker could be identified for use in pregnant patients with imminent risk of fetal loss associated with COVID-19 placentitis, the above-described hemostasis alterations warrant awareness of postpartum hemorrhagic complications and could be helpful to identify patients requiring intensified medical attention.

Impact of Endocrine Disorders on IVF Outcomes: Results from a Large, Single-Centre, Prospective Study.

Endocrine disorders negatively influence the ovarian function, and increasing incidence of endocrine diseases with age may have further negative effects on pregnancy rate. Prospective cohort study of 231 consecutively enrolled patients underwent IVF treatment. In patients with known endocrine disorders, the laboratory parameters were corrected before IVF treatment. One hundred sixty one patients (69.7%) had at least one known and treated endocrine disorder (study group), and 70 patients were endocrine negative (control group). Endocrine disorders diagnosed were thyroid disorders (32.5%), diminished ovarian reserve (23.8%), insulin resistance (22.5%), PCOS (15.2%), hyperprolactinaemia (13.4%), obesity (12.1%), hypogonadotropic hypogonadism (0.8%) and congenital adrenal hyperplasia (0.2%). Before the IVF treatment, systematic endocrine laboratory examinations were performed in all patients. Higher age, BMI and FSH were found in the study group, while AMH level was lower. There were no differences in LH, E2, prolactin, TSH, FT3, FT4, TT, DHEAS, androstendione, 17-OHP and SHBG level between the study and control groups. The study group had higher baseline glucose, baseline insulin, 120-min glucose and 120-min insulin level after oral glucose tolerance test. With no difference in the IVF cycles performed, pregnancy rate was lower in the study group (61.43% vs. 34.16%; p = 0.003), and this difference (p = 0.0151) remained in age-corrected rates, as well. The analyses were also performed in individual endocrinology groups. The prevalence of endocrine disorders is high in females participating in IVF programs, and they are often accompanying each other. Even after proper correction, the presence of the endocrine disorder negatively influences the pregnancy rate in IVF treatment.

Prevalence and association of endocrine disorders in women participating in an in vitro fertilization program / Endokrin kórképek elofordulása és társulása in vitro fertilizációs programban részt vevo nok körében

Introduction: Ovulatory dysfunction associated with endocrine diseases is a common leading or associated cause of female infertility, but at optimal reproductive age, causal or ovulation-induction treatment can usually settle fertility. The leading indications for in vitro fertilization (IVF) treatments are currently andrological and originated from age related ovarian infertility, but other accompanying endocrine dysfunctions affect treatment outcomes. Objective: To investigate the incidence of endocrine diseases in female members of couples participating in IVF program. Method: During aptitude tests prior to the IVF program, from the leading indication independently, a detailed endocrinological examination was performed in 231 women (mean age: 34 years). The studies of hypothalamic and ovarian function, thyroid function and thyroid autoimmunity, adrenal function, carbohydrate metabolism and insulin resistance were covered. In addition to the incidence of each endocrine disease, the frequency of their association was analyzed. Results: The distribution of IVF lead indications was in line with the international trends, it was endocrine nature in 87 cases (37.6%; decreased ovarian reserve in 55 cases and chronic anovulation in 32 cases). Associated endocrine abnormalities were found in 141 cases, and a total of 161 women was affected by endocrine dysfunction (69.7%; mean age: 35 years). Endocrine dysfunction incidences in order of frequency were thyroid dysfunction (32.5%), diminished ovarian reserve (23.8%), thyroid autoimmunity (22.5%), polycystic ovarian syndrome (15.6%), insulin resistance (22.5%), obesity (23.8%), hyperprolactinemia (13.4%). The endocrine disease associations were found in all of the cases above. Hypogonadotropic hypogonadism occurred in 2 cases, congenital adrenal hyperplasia occurred in 1 case. No endocrine abnormalities were found in 70 cases (30.3%). Conclusion: Our study confirms the cumulative appearance of endocrine dysfunctions and frequent association in IVF participants with any lead indication. The detailed endocrine examination and proficiency/skill in reproductive endocrinology of IVF practitioners may contribute to IVF treatment success.

The role of bile acid measurement in the management of intrahepatic cholestasis of pregnancy / Az epesavmérés szerepe a súlyos terhességi cholestasis szülészeti ellátásában

Introduction: Intrahepatic cholestasis of pregnancy complicates 1% of pregnancies. It increases the risk of severe fetal complications significantly, including preterm delivery and stillbirth. Objective: To summarize our experience with serum total bile acid level measurement that has recently become available for clinical routine in Hungary, and to present the way of gestational cholestasis care at our university. Patients and method: In a retrospective case series, we analyse the data of 12 patients suffering from severe cholestasis of pregnancy treated between September 2020 and September 2021 at the Department of Obstetrics and Gynecology, University of Debrecen. We also determine the statistical correlation between bile acid, transaminase and bilirubin levels in severe cholestasis. Results: 1258 serum samples of 758 patients were measured. 5 of them (0.7% of all cases, 6.4% of cholestasis cases) had severe (total bile acid 40-99 mu mol/L), 7 (0.9% of all cases and 9.0% of cholestasis cases) had very severe (total bile acid >= 100 mu mol/L) disease. The average age of the 12 cases was 30.6 (21-43) years, 7 of them were primigravid. 5 of the patients had a predisposing disease in their history. 6/12 patients received ursodeoxycholic acid treatment, resulting in significant decrease in the bile acid concentrations. Bile acid and GOT (R-2 = 0,14) and bile acid and GPT (R-2 = 0,17) correlations were found to be week in severe cholestasis (n = 45). Postpartum bile acid levels showed rapid improvement. So far, 11 of the patients have delivered and 13 neonates were born, 2/12 were multiple pregnancies. Average gestational age at delivery was 37 (33-40) weeks. 3/11 (27%) were preterm deliveries. 7/8 (88%) of term deliveries were induced. Elective cesarean delivery was not indicated in any of the cases, and in only 2/11 (18%) of the cases did emergency cesarean sections become necessary during labour. No stillbirth occurred. Conclusion: Serum total bile acid measurement is an effective tool in the diagnosis and follow-up of intrahepatic cholestasis of pregnancy, and is inevitable for the protocoll-based obstetrical management of patients. We also present the local protocol of our Department for the management of obstetrical cholestasis.

How the cesarean delivery rate decreased at the Department of Obstetrics and Gynecology, University of Debrecen during the COVID-19 pandemic / Hogyan csökkent a császármetszések aránya a debreceni Szülészeti Klinikán a koronavírus-pandémia alatt?

Összefoglaló. Bevezetés: Az új koronavírus (SARS-CoV-2) okozta pandémia számos változást eredményezett életünk minden területén, így a debreceni Szülészeti és Nogyógyászati Klinikán is. Célkituzések: A koronavírus-járvány többek között a terminus körüli elektív szülésindukciók gyakorlatának megváltoztatását igényelte. A bevezetett új szakmai eljárásrendeknek, járványügyi intézkedéseknek, a megyei kórházi funkciót ellátó debreceni Kenézy Kórház Szülészeti Osztálya és a Szülészeti Klinika összevonásának, illetve a megváltozott jogi környezetnek a szülészeti ellátásra kifejtett együttes hatásait elemezzük. Módszerek: Helyi protokollokat és részletes eljárásrendeket készítettünk és vezettünk be. 1. Szülésindukció. 2. Szülésindukció cervixérlelést igénylo esetekben. 3. A szülés módjának megválasztása elozményi császármetszés után. 4. A császármetszés utáni hüvelyi szülést támogató, terminus körüli gondozási protokoll. A protokollok bevezetését követo elso 9 hónap szülészeti mutatóit (szülésszám, császármetszések aránya, perinatalis kimenetel, szülésindukciók aránya és sikeressége) vizsgáltuk és hasonlítottuk össze a megelozo idoszak debreceni adataival, illetve az országos szülészeti mutatókkal. Eredmények: Klinikánkon a császármetszés aránya 2020-ban 33,5%-ra csökkent, a protokollok bevezetése óta pedig 30,7%, miközben a 2020. évi magyarországi arány 40,3%. Az összes szülés 20%-a volt 2020-ban szülésindukció, melyek közül 74% végzodött hüvelyi szüléssel, míg ugyanez 2019-ben 11% indukcióból 47%-nak adódott. A havi szülésszám 2020. január és 2021. január között folyamatosan emelkedett (250-rol 450-re), a havi császármetszési arány pedig 41%-ról 25%-ra csökkent. Mindezen változások mellett 2019-rol 2020-ra csökkent mind a perinatalis mortalitás (6,3‰-rol 4,2‰-re), mind a szülés után a Neonatalis Intenzív Centrumba történo felvételek aránya (14,8%-ról 13,5%-ra). Következtetések: A bemutatott tényezok együttes hatásaként - elsodlegesen a megfelelo és következetesen betartott protokolloknak köszönhetoen - a szülésindukciók aránya és sikeressége jelentosen növekedett, a császármetszések aránya szignifikánsan csökkent, javuló perinatalis morbiditási és mortalitási mutatók mellett. Orv Hetil. 2021; 162(21): 811-823. INTRODUCTION: The pandemic caused by the new coronavirus (SARS-CoV-2) has catalized several changes in many fields of our lives, and also at the Department of Obstetrics and Gynecology of the University of Debrecen, Hungary. OBJECTIVES: We wanted to analyse the compound effect of our new local protocols regarding elective labour inductions at term, the coronavirus pandemic and the resulting infection control measures, the merging of the Obstetrics and Gynecology Ward of the Kenézy County Hospital of Debrecen and the University Department of Obstetrics and Gynecology, and also the change of the legal environment. METHODS: Local protocols were introduced: 1. Labour induction. 2. Cervical ripening in labour induction. 3. Choosing the route of delivery after cesarean. 4. Management of pregnancy around term in the case of planned trial of labour after cesarean. We compared the obstetrical data (number of deliveries, cesarean section rate, perinatal outcome and the rate and success rate of labour inductions) before and after the implementation of the protocols. The results were also compared to the Hungarian national database. RESULTS: The annual cesarean rate at our department dropped to 33.5% in 2020. In the first 9-month period, after the introduction of the new reforms, the cesarean rate decreased to 30.7%, whereas the Hungarian national rate was 40.3% in 2020. At our department, 20% of all the deliveries were induced and 74% of them led to vaginal deliveries in 2020, while in 2019 only 11% of deliveries were labour inductions, and 47% of these cases were vaginal deliveries. The monthly number of deliveries was rising constantly between January 2020 (250 deliveries) and January 2021 (450 deliveries), and the monthly cesarean rate decreased from 41% to 25%. Comparing the data of 2019 and 2020, the annual perinatal mortality rate dropped from 6.3‰ in 2019 to 4.2‰ in 2020. Neonatal morbidity, as measured by admissions to the neonatal intensive care unit, also decreased (14.8% in 2019 and 13.5% in 2020). CONCLUSIONS: As a compound result of the described factors, but mainly due to the new protocols, both the rate and the success rate of labour inductions increased significantly, while the cesarean rate decreased with improving perinatal mortality and morbidity. Orv Hetil. 2021; 162(21): 811-823.

Unusual onset of thyroid associated orbitopathy during pregnancy: case report and review of literature.

BACKGROUND: Thyroid associated orbitopathy (TAO) is the most common extrathyroidal complication of Graves' disease. The disease course ranges from mild, where symptomatic therapy is sufficient, to severe, where high dose steroid administration or orbital decompression surgery is required. Women of their reproductive age are more likely to be affected. Although pregnancy is a state of enhanced immune tolerance, TAO may develop or worsen in 0.2-0.4% of pregnant women. CASE PRESENTATION: We present the case of a 19-year-old woman who has developed hyperthyroidism and progressive TAO during the second trimester of her third pregnancy, which has improved postpartum. The possible mechanisms and the importance of follow up in pregnancy is discussed. CONCLUSIONS: Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

Obstetrical aspects of the National Blood Donation and Blood Saving Program / A Nemzeti Véradó és Vérmento Program szülészeti vonatkozásai.

The aims of the National Blood Donation and Blood Saving Program are to support the rational and judicious utilization of blood products and abolish irrational transfusion policy to improve patient safety. In addition to the general principles, this program has got some special obstetrical aspects. Obstetrical, especially the postpartum haemorrhages belong to the leading causes of maternal mortality worldwide. In developed countries, a trend in increasing incidence can be observed. Preparing for delivery includes some important elements such as optimization of hemoglobin level, routinely applied prophylactic or therapeutic iron supplementation and early screening and comprehensive care of patients with high risk of obstetrical bleeding. The main causes of peripartum bleeding are abruptio placentae, placenta praevia, uterine atony, retained tissue in the uterus, trauma during delivery, and haemostatic disorders or their combinations. To prevent postpartum bleeding, it is important to use the active management of the third stage of labour including prophylactic utilization of uterotonics as an essential element. Utilization of blood salvage techniques with adequate indications may be considered in cases of cesarean section or postpartum haemorhage. In cases of obstetrical haemorrhage, management of surgical bleeding has the main priority by the obstetrician. Secondary coagulopathy associated with massive bleeding should be managed by viscoelastic test-guided, individualized and factor concentrate-based algorithm, however, pregnancy-specific reference and target ranges must be used that are different from the non-pregnancy values. Obstetrical bleedings belong to the potentially preventable causes of death. Hopefully, the implementation of the National Blood Donation and Blood Saving Program in the field of obstetrics can decrease the associated morbidity and mortality further. Orv Hetil. 2020; 161(37): 1588-1598.

Hormone Replacement Therapy in Cancer Survivors - Review of the Literature.

Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as a side effect of their oncotherapy, experience the cessation of gonadal function, leading to premature ovarian insufficiency, with disturbing vasomotor symtoms and long-term negative cardiovascular and skeletal effects. Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women's Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude definitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Therefore, the denial of HRT also needs to be supported by evidence and should be weighed againts the risks of HRT. Yet, the oncologic risk of HRT is extremely difficult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies, regarding HRT in survivors of gynecologic and non-gynecologic cancers. Based on our literature research, we group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: 'HRT is advanageous' (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); 'HRT is neutral' (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); 'HRT is relatively contraindicated' for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); 'HRT is diasadvantageous and thus contraindicated' (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).

Revision of the subterranean genus Spelaeodiscus Brusina, 1886 (Gastropoda, Pulmonata, Spelaeodiscidae).

The Balkan genus Spelaeodiscus Brusina, 1886 is revised based on museum collections and newly collected samples from Montenegro and Albania. The following species and subspecies are introduced as new to science: Spelaeodiscus albanicus edentatus Páll-Gergely & P. L. Reischütz, ssp. n. (southern Montenegro and northern Albania), Spelaeodiscus densecostatus Páll-Gergely & A. Reischütz, sp. n., Spelaeodiscus hunyadii Páll-Gergely & Deli, sp. n., Spelaeodiscus latecostatus Páll-Gergely & Eross, sp. n. (all three from southern Montenegro), Spelaeodiscus unidentatus acutus Páll-Gergely & Fehér, ssp. n., and Spelaeodiscus virpazarioides Páll-Gergely & Fehér, sp. n. (both from northern Albania). For all species and subspecies diagnoses and suggestions for conservation status assessments according to IUCN criteria are provided. An overview is given regarding the habitat preference of Spelaeodiscus species, and the "scratch and flotate" method to collect subterranean gastropods.

Reconstructed historical distribution and phylogeography unravels non-steppic origin of Caucasotachea vindobonensis (Gastropoda: Helicidae).

Existing data on the phylogeography of European taxa of steppic provenance suggests that species were widely distributed during glacial periods but underwent range contraction and fragmentation during interglacials into "warm-stage refugia." Among the steppe-related invertebrates that have been examined, the majority has been insects, but data on the phylogeography of snails is wholly missing. To begin to fill this gap, phylogeographic and niche modeling studies on the presumed steppic snail Caucasotachea vindobonensis were conducted. Surprisingly, reconstruction of ancestral areas suggests that extant C. vindobonensis probably originated in the Balkans and survived there during the Late Pleistocene glaciations, with a more recent colonization of the Carpatho-Pannonian and the Ponto-Caspian regions. In the Holocene, C. vindobonensis colonized between the Sudetes and the Carpathians to the north, where its recent and current distribution may have been facilitated by anthropogenic translocations. Together, these data suggest a possible non-steppic origin of C. vindobonensis. Further investigation may reveal the extent to which the steppic snail assemblages consist partly of Holocene newcomers.

[Body image and quality of life in women with polycystic ovary syndrome]. / A testkép és életminoség vizsgálata polycystás ovarium szindrómában.

INTRODUCTION: Polycystic ovary syndrome is the most common endocrine disease in women. Psychic consequences are significant; patients have difficulties to be pregnant and the disease disturbs the quality of life. Due to complications associated with polycystic ovary syndrome, studies on psychological state and disease perception of patients appear to be important. AIM: The aim of the authors was to assess how the disease influences quality of life and changes in body image. METHOD: The authors used the Illness Intrusiveness Ratings Scale, Health-Related-Quality-of-Life Questionnaire for Women with Polycystic Ovary Syndrome and their own body image questionnaire. 121 women took part in the study. RESULTS: There was a negative correlation between illness intrusiveness and quality of life (r = -0.353) and a positive correlation between body image and quality of life (r = 0.614). A significant difference was observed in body satisfaction between patients who had visible body changes and those who had metabolic disturbances (p<0.05). Overweight patients who lost weight with lifestyle changes had significantly better quality of life (p<0.05). CONCLUSIONS: These results appear to be convincing in that in addition to gynecological care, psychotherapy could be offered to patients with polycystic ovary syndrome.

Subgeneric division of the genus Orcula Held 1837 with remarks on Romanian orculid data (Gastropoda, Pulmonata, Orculidae).

The genital anatomy of Orcula jetschini (Romania), Orcula zilchi (Bulgaria), and Orcula wagneri (Albania) is described. Based on anatomical features (morphology of the penial caecum) shell characters (sculpture and shape) and unpublished molecular data the genus Orcula is subdivided into three subgenera. Orcula zilchi was classified within the monotypic subgenus Orcula (Hausdorfia) subgen. n.; Orcula jetschini, Orcula wagneri, and Orcula schmidtii were classified to Orcula (Illyriobanatica) subgen. n. (type species: Pupa schmidtii) whereas the other Orcula species remain in the nominotypical subgenus. Orcula (Hausdorfia) is known from South-Eastern Bulgaria and North-Western Turkey, Orcula (Illyriobanatica) inhabits Western Romania, North-Western Greece, Albania, Macedonia, Kosovo, and Montenegro. The nine species of Orcula (Orcula) are known mainly from the Alps and the Western Carpathians (from Eastern France to Eastern Hungary and Slovakia). The occurrence of only one Orcula species namely Orcula jetschini is verified from Romania. Available information suggests that data on the Romanian occurrence of Orcula dolium and Orcula gularis were based on wrongly identified specimens. Sphyradium dobrogicum (=Orcula dobrogica) is considered as a synonym of Sphyradium doliolum.

[Pena-Shokeir syndrome type I--combination of polyhydramnios and pulmonary hypoplasia in fetal akinesia]. / Pena-Shokeir-szindróma (I-es típus) - polyhydramnion és tüdohypoplasia együttes elofordulása magzati akinesiában.

We present the case of an 18-year-old woman with her second pregnancy, whose first pregnancy was complicated by polyhydramnios. At week 30, the dysmorph fetus died in utero and was delivered via cesarean section due to placental abruption, but the exact diagnosis was not recognized at that time. During the patient's second pregnancy, increasing polyhydramnios was detected from the 19th gestational week. Ultrasound signs of fetal malformation also appeared later: abnormal position of limbs, narrow chest, oedema around the skull, and absence of stomach content. At week 34, decompression amniocentesis became necessary. Chromosome analysis was also carried out and a normal karyotype was obtained. At 39th gestational week, amnioscopy proved meconium staining of the amniotic fluid, thus labour was induced. Following amniotomy, sustained fetal bradycardia commenced and an emergency caesarean section was performed. Despite complex resuscitation, the 3000 gram male newborn died 2.5 hours after delivery, due to respiratory failure. Autopsy and histopathologic examination revealed a large, oedematous head, micrognathia, macroglossia, laryngeal oedema, narrow chest with pulmonary hypoplasia, gracile limbs with muscle atrophy, gracile and bent fingers, and a short umbilical cord. Based on the medical history, the course of the disease and the phenotype of the newborn, Pena-Shokeir syndrome type I was diagnosed. In the second part of the article, we review the etiology, pathogenesis, prenatal diagnosis and differential diagnosis of this syndrome, as well as some aspects of genetic counseling in such cases. To our knowledge, this is the first reported case of Pena-Shokeir syndrome in Hungary.

[Fetal pain and intrauterine analgesia/anesthesia--long-term pathologic effects, causes and alleviation of intrauterine pain]. / Magzati fájdalom es intrauterin fájdalomcsillapítás--az intrauterin fájdalom hosszú távú káros hatásai, okai es csillapítása.

The human fetus can suffer several presumably painful interventions perinatally and even before, during its intrauterine life. In the past years, scientific dispute concerning the existence of fetal pain and the need for its relief has expanded, and a heated social, political, religious, moral and philosophical debate has arisen, focusing mainly on the suffering experienced by the fetus during artificial abortion. In our two connected papers, medical scientific knowledge regarding fetal pain in the literature is reviewed. In the first article published in Orvosi Hetilap volume 150, issue 11, we defined pain and the neuroanatomical structures participating in subjective pain perception, as well as the development of these structures. Then, the objective indicators of intrauterine stress response (such as fetal neuroendocrine, cardiovascular, reflex and behavioral reactions) evoked by noxious stimuli were discussed. The present second article gathers the evidence of long-term pathologic effects caused by early-experienced pain and stress in animal models and humans. Finally, the potentially pain-evoking pre- and perinatal interventions are evaluated, as well as the analgetic/anesthetic methods that can be applied to intrauterine fetuses in everyday obstetrical practice.

[Fetal pain and intrauterine analgesia/anesthesia: neuroanatomy, ontogenesis and physiology of pain perception]. / A magzati fájdalom és intrauterin fájdalomcsillapítás - a fájdalom neuroanatómiája, ontogenezise és fiziológiája.

The human fetus can suffer several presumably painful interventions perinatally and even before, during its intrauterine life. In recent years, a scientific dispute has expanded, concerning the existence of fetal pain and the need for its relief, and a heated social, political, religious, moral and philosophical debate has arisen, focusing mainly on the suffering experienced by the fetus during artificial abortion. We review the medical scientific knowledge regarding fetal pain in the literature. The definition of pain and the neuroanatomical structures participating in subjective pain perception, followed by the development of the latter in the course of ontogeny is presented. The objective indicators of intrauterine stress response (such as fetal neuroendocrine, cardiovascular, reflex and behavioral reactions) evoked by noxious stimuli are discussed.

Altered sarcoplasmic reticulum calcium transport in the presence of the heavy metal chelator TPEN.

TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine) is a membrane-permeable heavy-metal ion chelator with a dissociation constant for Ca2+ comparable to the Ca2+ concentration ([Ca2+]) within the intracellular Ca2+ stores. It has been used as modulator of intracellular heavy metals and of free intraluminal [Ca2+], without influencing the cytosolic [Ca2+] that falls in the nanomolar range. In our previous studies, we gave evidence that TPEN modifies the Ca2+ homeostasis of striated muscle independent of this buffering ability. Here we describe the direct interaction of TPEN with the ryanodine receptor (RyR) Ca2+ release channel and the sarcoplasmic reticulum (SR) Ca2+ pump (SERCA). In lipid bilayers, at negative potentials and low [Ca2+], TPEN increased the open probability of RyR, while at positive potentials it inhibited channel activity. On permeabilized skeletal muscle fibers of the frog, but not of the rat, 50 microM TPEN increased the number of spontaneous Ca2+ sparks and induced propagating events with a velocity of 273 +/- 7 microm/s. Determining the hydrolytic activity of the SR revealed that TPEN inhibits the SERCA pump, with an IC(50) = 692 +/- 62 microM and a Hill coefficient of 0.88 +/- 0.10. These findings provide experimental evidence that TPEN directly modifies both the release of Ca2+ from and its reuptake into the SR.

Extracellular ATP and cancer: an overview with special reference to P2 purinergic receptors.

Purinergic signal transduction mechanisms have been appreciated as a complex intercellular signalling network that plays an important regulatory role in both short- and long-term processes in practically every living cell. One of the most intriguing aspects of the field is the participation of ATP and other purine nucleotides in the determination of cell fate and the way they direct cells towards proliferation, differentiation or apoptosis, thereby possibly taking part in promoting or preventing malignant transformation. In this review, following a very brief introduction to the historical aspects of purinergic signalling and a concise overview of the structure of and signal transduction pathways coupled to P2 purinergic receptors, the current theories concerning the possible ways how extracellular ATP can alter the function of tumour cells and the effectiveness of anticancer therapies are discussed, including pharmacological, nutritional, vasoactive and 'anti-antioxidant' actions of the nucleotide. The effects of ATP on animals inoculated with human tumours and on patients with cancer are looked over next, and then an overview of the literature regarding the expression and presumed functions of P2 purinoceptors on tumour cells in vitro is presented, sorted out according to the relevant special clinical fields. The article is closed by reviewing the latest developments in the diagnostic use of P2 purinergic receptors as tumour markers and prognostic factors, while discussing some of the difficulties and pitfalls of the therapeutic use of ATP analogues.

Functional genomics of calcium channels in human melanoma cells.

Ca(2+)-signaling of human melanoma is in the focus of intensive research since the identification of the role of WNT-signaling in melanomagenesis. Genomic and functional studies pointed to the important role of various Ca(2+) channels in melanoma, but these data were contradictory. In the present study we clearly demonstrate, in a number of different ways including microarray analysis, DNA sequencing and immunocytochemistry, that various human melanoma cell lines and melanoma tissues overexpress ryanodine receptor type 2 (RyR2) and express P2X(7) channel proteins as compared to melanocytes. These channels, although retain some of their usual characteristics and pharmacological properties, display unique features in melanoma cells, including a functional interaction between the two molecules. Unlike P2X(7), RyR2 does not function as a calcium channel. On the other hand, the P2X(7) receptor has an antiapoptotic function in melanoma cells, since ATP-activation suppresses induced apoptosis, while knock down of the gene expression significantly enhances that.

Effect of TPEN on the calcium release of cultured C2C12 mouse myotubes.

N,N,N',N'-tetrakis(2-pyridylmethyl)-ethilenediamine (TPEN) is a membrane permeable heavy metal chelator that has been used to study intracellular calcium homeostasis but its exact mode of action is still unresolved. Here we examine the effects of TPEN on the Ca(2+) release from and the Ca(2+) uptake into the sarcoplasmic reticulum (SR) of cultured C2C12 skeletal muscle cells. Low concentrations (50 microM) of the drug evoked Ca(2+) transients in approximately 60% of C2C12 myotubes, while at high concentrations (500 microM) it significantly reduced the size of both depolarization-and caffeine-induced Ca(2+) transients, decreased the rate constant of decay and the calculated pump activity but failed to induce Ca(2+) transients. Experiments at low extracellular [Ca(2+)] revealed that it is the total rather than free TPEN concentration that is responsible for the observed effects. TPEN does not modify Ca(2+) release by Zn(2+) chelation, as evidenced by the unaltered effect seen after the removal of Zn(2+) from the extracellular space of the cells by chelating with EDPA. These findings provide experimental evidence that TPEN directly modifies both the release of Ca(2+) from the SR and its removal from the myoplasm.