The role of glycogen synthase kinase 3 (GSK3) in cancer with emphasis on ovarian cancer development and progression: A comprehensive review.

Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3ß, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.

[THE INCIDENCE OF PERIPARTUM HYSTERECTOMY IN FIVE CROATIAN HOSPITALS DURING A SIXTEEN-YEAR PERIOD]. / UCESTALOST PERIPARTALNIH HISTEREKTOMIJA U PET HRVATSKIH BOLNICA TIJEKOM SESNAESTOGODISNJEG RAZDOBLJA.

INTRODUCTION: Peripartal hysterectomy (PPH) is a life saving surgical procedure that is performed when conservative measures fail to control bleeding. According to literature data there is an increase in incidence among developed countries. AIM: To define the rate of PPH during two eight-year periods in five Croatian hospitals in respect to mode of delivery. METHODS: Patients data were collected retrospectively from the medical records of the five Croatian hospitals. We analyzed data from 1998 to 2013, and divided them in two eight-year periods. RESULTS: In 70 cases out of 153,302 deliveries urgent PPH was performed. PPH after vaginal deliveries was found in 0.21%o and 0.16%o and PPH after caesarean section was 1.91 %o and 2.04%o in the first and second period, respectively. DISCUSSION AND CONCLUSION: There is no increase of PPH rate in the two analyzed periods, although there is a statistically significant increase of caesarean section rate. Caesarean section presents higher risk for PPH.

Glycosylation pattern and axin expression in normal and IUGR placentae.

OBJECTIVE: The aim of this study was to investigate the protein glycosylation pattern and AXIN1 protein expression in human placentae of normal pregnancies and compare them with placentae of pregnancies complicated with intrauterine growth restriction (IUGR). METHODS: A total of 38 placentae (17 placentae of IUGR fetuses from singleton pregnancies and gestational age-matched 21 control placentae from normal singleton pregnancies) were collected from the Clinical Hospital Sveti Duh, Department of Gynecology and Obstetrics, Zagreb, Croatia. Gestational age was determined according to the last menstrual period (LMP) and by ultrasound measurements. Expression of glycoproteins was measured by Western blotting with SNA, UEA-I, PHA-E and DBA lectins as probes whereas expression of AXIN1 was determined by immunohistochemistry. RESULTS: Comparison of detected sugars revealed differences in protein glycosylation between normal and IUGR placentae. Higher expression of AXIN1 protein located mostly in the cytoplasm of syncytiotrophoblast and to a lesser extent in its nuclei was found in IUGR placentae. CONCLUSION: Results of our study suggest that changes in glycoprotein content may contribute to restricted placenta growth and development. Higher expression of AXIN1 protein in IUGR placentae indicates a role of Wnt/ß-catenin signaling pathway in pathology of placental development.

Prenatal diagnosis of sex chromosome aneuploidies and disorders of sex development--a retrospective analysis of 11-year data.

OBJECTIVE: Analysis of prenatally diagnosed sex chromosome aneuploidies and disorders of sex development (DSDs). METHODS: This study includes a retrospective data analysis of 46 prenatally detected sex chromosome aneuploidies and one case of 46,XY DSD diagnosed during an 11-year period (2002-2012) at our department. RESULTS: Of the 46 sex chromosome aneuploidies, 29 cases (63.0%) were in the group of a selected population of women according to abnormal first-/second-trimester ultrasound and 17 (37.0%) cases in an unselected population of women who underwent fetal karyotyping because of advanced maternal age. The most common aneuploidy was Turner syndrome in full and mosaic form (50%). Complete androgen insensitivity syndrome was diagnosed in the case of 46,XY DSD. CONCLUSIONS: Sex chromosome aneuploidies must be taken into consideration if, in the first or second trimester, abnormalities are revealed on ultrasound, mainly Turner syndrome in full or mosaic form and 47,XYY.

Diagnosis and counseling of thanatophoric dysplasia with four-dimensional ultrasound.

Thanatophoric dysplasia is a severe skeletal disorder with estimated frequency of 0.2-0.5 per 10,000 births. Affected infants die shortly after birth. The diagnosis of thanatophoric dysplasia can be made by two-dimensional ultrasound but the perception of these images is very difficult for the patients. The use of four-dimensional real time ultrasound gives the physician the possibility to discuss and counsel the patients with images that are more understandable to the general public.

[Acute abdomen two days after vaginal birth after cesarean section]. / Akutni abdomen dva dana nakon rodnickog porodaja poslije prethodnoga carskog reza.

A case is presented of puerperal acute abdomen with diffuse peritonitis and paralytic ileus two days after unnoticed complete uterine rupture after VBAC (vaginal birth after cesarean section) and uterine cavity obstetric examination. Explorative laparotomy, intestinal adhesiolysis, uterine revision and sutures, abdominal lavage and drainage were performed. The operation was followed by successful recovery and intact fertility. Medical and forensic aspects are discussed.

Intrauterine growth restriction and cerebral palsy.

Intrauterine growth restriction (IUGR) can be described as condition in which fetus fails to reach his potential growth. It is common diagnosis in obstetrics, and carries an increased risk of perinatal mortality and morbidity. Moreover, IUGR has lifelong implications on health, especially on neurological outcome. There is a need for additional neurological assessment during monitoring of fetal well-being, in order to better predict antenatally which fetuses are at risk for adverse neurological outcome. Studies have revealed that the behavior of the fetus reflects the maturational processes of the central nervous system (CNS). Hence, ultrasound investigation of the fetal behavior can give us insight into the integrity and functioning of the fetal CNS. Furthermore, investigations carried out using modern method, four-dimensional (4D) sonography, have produced invaluable details of fetal behavior and its development, opening the door to a better understanding of the prenatal functional development of the CNS. Based on previous observations and several years of investigation, our reaserch group has proposed a new scoring system for the assessment of fetal neurological status by 4D sonography named Kurjak antenatal neurodevelopmental test (KANET). The value of KANET in distinguishing fetal brain and neurodevelopmental alterations due to the early brain impairment in utero is yet to be assessed in large population studies. However, preliminary results are very encouraging.

Neurobehavioral continuity from fetus to neonate.

Neurobehavior represents development of the central nervous system (CNS). Fetuses and newborns exhibit a large number of endogenously generated motor patterns, among which general movements are often investigated pre- and post-natally. Spontaneous activity is probably a more sensitive indicator of brain dysfunction than reactivity to sensory stimuli while testing reflexes. Nutritional stress at critical times during fetal development can have persistent and potentially irreversible effects particularly on brain growth and function. Unfavorable intrauterine environment can affect adversely brain growth. All endogenously generated movement patterns from un-stimulated CNS might be observed as early as from the seven to eight weeks' gestation, with a rich repertoire of movements within the next two or three weeks, continuing for five to six months postnatally. It is still uncertain whether a new scoring system for prenatal neurological assessment will be adequate for the distinction between normal and abnormal fetuses in low-risk pregnancies. The continuity of behavioral patterns from prenatal to postnatal life might answer these intriguing questions.

Modification of conservative treatment of heterotopic cervical pregnancy by Foley catheter balloon fixation with cerclage sutures at the level of the external cervical os: a case report.

INTRODUCTION: Conservative treatment of a heterotopic cervical pregnancy was performed with a modification of the fixation of a Foley catheter at the level of the external cervical os, followed by the ligature of the descending cervical branches of the uterine arteries and systemic methotrexate application. CASE PRESENTATION: A 34-year-old Caucasian woman was diagnosed with double gestation after 6 weeks of in vitro fertilization treatment. A gynecological examination and color Doppler ultrasound scan revealed intra-uterine and cervical gestational sacs both containing live fetuses. A Foley catheter balloon was inserted into the cervical canal, inflated and fixed by a cerclage suture at the level of the external cervical os, followed by ligation of the descending cervical branches of the uterine arteries. Systemic methotrexate was applied. Three days after removal of the Foley catheter, an evacuation of the intra-uterine gestational sac was performed. Hemorrhage from the implantation site was controlled immediately and a pregnancy termination was successfully performed. The procedure was uneventful and our patient was discharged with a preserved uterus. CONCLUSIONS: Conservative treatment of cervical pregnancy using a Foley catheter balloon is more efficacious if the Foley catheter balloon is attached in the correct position with a cerclage suture at the level of the external os, followed by ligation of the descending cervical branches of the uterine arteries, thereby exerting maximal pressure on the bleeding vessels.

Is hyperthyroidism underestimated in pregnancy and misdiagnosed as hyperemesis gravidarum?

Thyroid changes are considered to be normal events that happen as a large maternal multiorganic adjustment to pregnancy. However, hyperthyroidism occurs in pregnancy with clinical presentation similar to hyperemesis gravidarum (HG) and pregnancy itself. Moreover, 10% of women with HG will continue to have symptoms throughout the pregnancy suggesting that the underlying cause might not be elevation of human chorionic gonadotropin in the first trimester. Variable frequency of both hyperthyroidism and HG worldwide might suggest the puzzlement of inclusion criteria for both diagnoses enhanced by the alternation of thyroid hormone levels assessed in normal pregnancy. Increased number of hyperthyroidism among women population without the expected rise in gestational hyperthyroidism encouraged us for creating the hypotheses that hyperthyroidism could be underestimated in normal pregnancy and even misdiagnosed as HG. This hypothesis, if confirmed, might have beneficial clinical implications, such as better detection of hyperthyroidism in pregnancies, application of therapy when needed with the reduction of maternal or fetal consequences.

The comparison of fetal behavior in high risk and normal pregnancies assessed by four dimensional ultrasound.

OBJECTIVE: We compared fetal behavior (FB) in high risk and normal pregnancies using four dimensional ultrasound (4DUS). METHODS: For assessment of FB in high risk and normal pregnancies, we used a scoring system of Kurjak's antenatal neurological test (KANET). The newborns were assessed by a postnatal neurological test, Amiel-Tison neurological assessment at term (ATNAT). The scores of KANET in high risk (N=116) and in normal pregnancies (N=110) were compared. After delivery, the results of KANET from both groups were compared with ATNAT test. RESULTS: There was a statistically significant difference between group of high risk and normal pregnancies, for 8 out of 10 parameters in KANET: isolated anteflection of the head, eye blinking, facial expressions, mouth movements, isolated hand movement, hand to face movement, fist and finger movements, general movements. There was no difference for cranial sutures and isolated leg movements. Comparison of KANET and ATNAT showed statistically significant, moderate correlation between the two tests, which means that the neuropediatric exam (ATNAT) confirmed the prenatal 4DUS finding (KANET). CONCLUSION: The difference of FB between the high risk and normal pregnancies was evident. These preliminary results are promising but further studies have to be done before the test could be recommended for wider clinical practice.

The potential of 4D sonography in the assessment of fetal neurobehavior--multicentric study in high-risk pregnancies.

OBJECTIVE: An evolving challenge for obstetrician is to better define normal and abnormal fetal neurological function in utero in order to better predict antenatally which fetuses are at risk for adverse neurological outcome. PATIENTS AND METHODS: Prenatal neurological assessment in high-risk fetuses using four-dimensional ultrasound applying the recently developed Kurjak antenatal neurodevelopmental test (KANET). Postnatal neurological assessment was performed using Amiel Tison's neurological assessment at term (ATNAT) for all live-borns and general movement (GM) assessment for those with borderline and abnormal ATNAT. RESULTS: Inclusion criteria were met by 288 pregnant women in four centers of whom 266 gave birth to a live-born baby. It was revealed that 234 fetuses were neurologically normal, 7 abnormal and 25 borderline. Out of 7 abnormal fetuses ATNAT was borderline in 5 and abnormal in 2, whereas GM assessment was abnormal in 5 and definitely abnormal in 2. Out of 25 KANET borderline fetuses, ATNAT was normal in 7, borderline in 17 and abnormal in 1, whereas the GM assessment was as follows: normal optimal in 4, normal suboptimal in 20, and abnormal in 1. In summary, out of 32 borderline and abnormal fetuses ATNAT was normal in 7, borderline in 22 and abnormal in 3; GM assessment was normal optimal in 4, normal suboptimal in 20, abnormal in 6 and definitely abnormal in 2. CONCLUSION: The sonographic test requires further studies before being recommended for wider clinical practice.

The assessment of fetal neurobehavior by three-dimensional and four-dimensional ultrasound.

The development of three-dimensional (3D) and four-dimensional ultrasound (4D) has provided new opportunities to study fetal and even embryonic behavior. These techniques enable simultaneous spatial imaging of the entire fetus and its movements. Recently, multicenter studies of fetal brain function have been carried out, the aim of which is to establish the standards of embryonic and fetal peripheral and body movements and facial expression as additional diagnostic criteria for prenatal brain development. Additional studies have been conducted in order to provide more information on specific movement patterns and quality of movement in the high-risk fetus. The purpose of this paper is to review and analyze the published literature on the use of 3D and 4D ultrasound in the assessment of fetal behavior.

Association of angiotensin-converting enzyme insertion-deletion polymorphism with preeclampsia.

The aim of this study was to determine if insertion-deletion polymorphism of angiotensin-converting enzyme is a risk factor for the development of preeclampsia. Sixty women with preeclampsia and 50 normotensive pregnant women were included in this study. Preeclampsia was defined as blood pressure >140/90 mmHg in a previously normotensive women with proteinuria >300 mg/L in a 24-hours. Twelve women also had preeclampsia in previous pregnancy. The genotyping of polymorphism in the intron 16 of the angiotensin-converting enzyme was performed by the polymerase chain reaction followed by the agarose electrophoresis. The patients were divided into three groups according to the presence (I) or absence (D) of insertional polymorphism (II, ID, and DD). Genotype distribution and allele frequencies were compared by Mantel-Haenszel chi2 testing. The frequency of DD genotype was not significantly higher in women with preeclampsia (26/60) than in the control group (14/50, p=0.096). The D allele frequency was significantly higher in 17 women with preeclampsias who required delivery before 34 weeks of pregnancy (0.735), than in 43 women in whom obstetric complications took place after 34 weeks of pregnancy (0.56, p=0.036). The D allele frequency was 0.83 in women having recurrent preeclampsia, i.e. significantly higher compared with women, who were for the first time, experienced preeclampsia (0.57, p=0.013). This study showed a significantly positive association between D allele frequency and risk of recurrent preeclampsia and preterm delivery before 34 weeks of pregnancy. The deletion genotype could be an important contributing factor for an early onset and recurrent preeclampsia.

[Prenatal genotyping of the RhD locus by polymerase chain reaction in fetus at risk of hemolytic disease]. / Prenatalna genotipizacija RhD-lokusa s pomocu lancane reakcije polimerazom u fetusa s rizikom od hemoliticke bolesti.

Modern management of Rh alloimmunization includes early diagnosis of fetal RhD genotype, precise assessment of the severity of fetal anemia and the use of minimal number of invasive diagnostic and therapeutic procedures. The severity of fetal anemia can be assessed by Doppler ultrasound, while fetal RhD genotype is determined from the amniotic cells or fetal DNA extracted from the mother's serum by polymerase chain reaction (PCR). Although prenatal RhD genotype diagnostic techniques have been used in developed countries more than 10 years, they have not been available in Croatia until recently. As a consequence of unavailability of these techniques in Croatia there has been inadequate approach to the patient, in whom inappropriate and unnecessary visits, amniocentesis, cordocentesis and laboratory tests were performed. Therefore, we describe the first case of successful prenatal diagnosis of fetal RhD genotype by PCR analysis of DNA extracted from amniotic fluid cells.

New scoring system for fetal neurobehavior assessed by three- and four-dimensional sonography.

AIM: To produce a new scoring system for fetal neurobehavior based on prenatal assessment by 3D/4D sonography. We identified severely brain damaged infants and those with optimal neurological findings and compared fetal with neonatal findings. RESULTS: The new scoring system was retrospectively applied in a group of 100 low-risk pregnancies. After delivery, postnatal neurological assessment was performed, and all neonates assessed as normal reached a score between 14 and 20, which we assumed to be a score of optimal neurological development. Subsequently, the same scoring system was applied in the group of 120 high-risk pregnancies in which, based on postnatal neurological findings, three subgroups of newborns were found: normal, mildly or moderately abnormal, and abnormal. Normal neonates had a prenatal score between 14 and 20, mildly or moderately abnormal neonates had a prenatal score of 5-13, whereas those infants who were assigned as neurologically abnormal had a prenatal score from 0-5. CONCLUSION: A new scoring system for the assessment of neurological status for antenatal application is proposed, similar to the neonatal optimality test of Amiel-Tison. This preliminary work may help in detecting fetal brain and neurodevelopmental alterations due to in utero brain impairment.

How useful is 3D and 4D ultrasound in perinatal medicine?

AIM: The purpose of this paper is to review and analyze the published literature on the use of three-dimensional (3DUS) and four-dimensional (4DUS) ultrasound in perinatal medicine. METHODS: We systematically searched Medline through PubMED (January 2000-January 2006), including EMBASE/Excerpta Medica database as well as the Cochrane Database of Systematic Reviews. The search terms used to identify clinical application of 3DUS and 4DUS studies in perinatal medicine were technical development, special features, and recommendation for fetal imaging, research on 3DUS or 4DUS, and the usage of invasive 3DUS or 4DUS procedures. The reference bibliographies of relevant books were also manually searched for supplementary citations. Inclusion criteria were as follows: (1) studies related to the use of 3DUS or 4DUS in perinatal medicine; (2) full text were available in English; (3) publication format of original scientific articles, case reports, editorials or literature reviews and chapters in the books. RESULTS: Five hundred and seventy-five articles were identified, and among those, 438 were relevant to this review. CONCLUSIONS: 3DUS and 4DUS provided additional information for the diagnosis of facial anomalies, evaluation of neural tube defects, and skeletal malformations. Additional research is needed to determine the clinical utility of 3DUS and 4DUS for the diagnosis of congenital heart disease, central nervous system (CNS) anomalies and detection of fetal neurodevelopmental impairment assessed by abnormal behavior in high-risk fetuses.

Diagnosis and management of Rh alloimmunization.

OBJECTIVE: To assess the current problem of alloimmunization in a tertiary referral center in Croatia. The results obtained were compared to data published worldwide. METHODS: Retrospective case analysis included women with Rhesus (Rh) alloimmunization treated in our department from January 1997 to January 2003. Data of interest included the incidence, prevention, diagnosis and treatment, with the final point being perinatal mortality and morbidity. RESULTS: 23 pregnant women with alloimmunization were identified. The incidence was 0.138% of deliveries in the same time period. The median gestational age at diagnosis/referral was 22 (range 9-37) weeks. Anti-D antigen, alone or in combination with the other antigens, was responsible for more than 90% of the alloimmunization cases included. A defined protocol for prevention of Rh D immunization after previous delivery was not followed properly in 9/19 cases. A particular problem was prophylaxis after previous pregnancy termination (TOP), whereby only 1/14 woman received adequate prophylaxis and only after 2 of 5 TOPs. Regarding fetal treatment, 9/23 women had a total of 24 intrauterine intravascular blood transfusions. Overall, perinatal mortality was 13%, and the median gestational age at delivery was 34 (range 31-40) weeks. In all there were 31 fetal exchange transfusions after delivery performed in 14/20 newborns. CONCLUSION: Despite precise diagnostic criteria and modern therapeutic options, alloimmunization remains a problem in Croatia. It is still related with a high perinatal mortality and morbidity. The main problem is inadequate prevention.