Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.

The merger that led to the formation of the Milky Way's inner stellar halo and thick disk.

The assembly of our Galaxy can be reconstructed using the motions and chemistry of individual stars1,2. Chemo-dynamical studies of the stellar halo near the Sun have indicated the presence of multiple components3, such as streams4 and clumps5, as well as correlations between the stars' chemical abundances and orbital parameters6-8. Recently, analyses of two large stellar surveys9,10 revealed the presence of a well populated elemental abundance sequence7,11, two distinct sequences in the colour-magnitude diagram12 and a prominent, slightly retrograde kinematic structure13,14 in the halo near the Sun, which may trace an important accretion event experienced by the Galaxy15. However, the link between these observations and their implications for Galactic history is not well understood. Here we report an analysis of the kinematics, chemistry, age and spatial distribution of stars that are mainly linked to two major Galactic components: the thick disk and the stellar halo. We demonstrate that the inner halo is dominated by debris from an object that at infall was slightly more massive than the Small Magellanic Cloud, and which we refer to as Gaia-Enceladus. The stars that originate in Gaia-Enceladus cover nearly the full sky, and their motions reveal the presence of streams and slightly retrograde and elongated trajectories. With an estimated mass ratio of four to one, the merger of the Milky Way with Gaia-Enceladus must have led to the dynamical heating of the precursor of the Galactic thick disk, thus contributing to the formation of this component approximately ten billion years ago. These findings are in line with the results of galaxy formation simulations, which predict that the inner stellar halo should be dominated by debris from only a few massive progenitors2,16.

[Management of postpartum hemorrhage (PPH): algorithm of the interdisciplinary D-A-CH consensus group PPH (Germany - Austria - Switzerland)]. / Management der postpartalen Blutung (PPH): Algorithmus der Interdisziplinären D-A-CH-Konsensusgruppe PPH (Deutschland - Österreich - Schweiz).

Postpartum hemorrhage (PPH) is one of the main causes of maternal deaths even in industrialized countries. It represents an emergency situation which necessitates a rapid decision and in particular an exact diagnosis and root cause analysis in order to initiate the correct therapeutic measures in an interdisciplinary cooperation. In addition to established guidelines, the benefits of standardized therapy algorithms have been demonstrated. A therapy algorithm for the obstetric emergency of postpartum hemorrhage in the German language is not yet available. The establishment of an international (Germany, Austria and Switzerland D-A-CH) "treatment algorithm for postpartum hemorrhage" was an interdisciplinary project based on the guidelines of the corresponding specialist societies (anesthesia and intensive care medicine and obstetrics) in the three countries as well as comparable international algorithms for therapy of PPH.The obstetrics and anesthesiology personnel must possess sufficient expertise for emergency situations despite lower case numbers. The rarity of occurrence for individual patients and the life-threatening situation necessitate a structured approach according to predetermined treatment algorithms. This can then be carried out according to the established algorithm. Furthermore, this algorithm presents the opportunity to train for emergency situations in an interdisciplinary team.

Preterm neonates display altered plasmacytoid dendritic cell function and morphology.

Bacterial and viral infections cause high rates of morbidity and mortality in premature newborns. In the setting of viral infection, pDCs play a key role as strong producers of IFN-α upon TLR9 activation. We analyzed pDC frequency, phenotype, morphology, and function in CB of preterm and term newborns in comparison with adults. Whereas all age groups show similar pDC numbers, BDCA-2, CD123, and TLR9 levels, the expression of BDCA-4 and capacity to produce IFN-α upon TLR9 challenge were decreased significantly in preterm neonates. Furthermore, we show by means of electron microscopy that pDCs from preterm newborns exhibit a distinct, "immature" morphology. Taken together, these findings suggest decreased functionality of pDCs in the premature newborn. The reduced capacity to produce IFN-α is likely to render such infants more susceptible to viral infections.

Guidelines for the management of third and fourth degree perineal tears after vaginal birth from the Austrian Urogynecology Working Group.

The purpose of this guideline is to provide a decision aid for diagnosis, treatment, and follow-up of patients with major perineal tears and thus minimize the risk of persistent symptoms. In 2007, the "Guideline for the management of third and fourth degree perineal tears after vaginal birth" was established by members of the Austrian Urogynecologic Working Group (AUB). The guideline was updated in 2011, including literature published up to 30 November 2011. The DELPHI method was used to reach consensus. Evidence-based and consensus-based statements were defined for epidemiology, risk factors, classification, diagnosis, surgery, and follow-up of major perineal lacerations at vaginal birth.

Safety concerns for the use of calcium channel blockers in pregnancy for the treatment of spontaneous preterm labour and hypertension: a systematic review and meta-regression analysis.

BACKGROUND: Calcium channel blockers (CCBs) are not licensed for use in pregnancy but are used without robust surveillance to treat hypertension in pregnancy and preterm labour. The objective of this study was to evaluate the fetomaternal safety of CCB in pregnancy by a quantitative systematic review. METHODS: Medline (1996-2005), EMBASE (1996-2003), BIOSIS (1993-2003), Current contents (1995-2003), DERWENT DRUGFILE (1983-2003) and Cochrane Library (2005: issue 3). The number of women reporting an adverse event was used to compute a percentage of the total number of women in whom the occurrence of that event or confirmation of its absence was reported. Meta-regression with generalised estimation equations modelling explored reasons for heterogeneity, seeking factors that increased the rates of the most commonly reported adverse events. FINDINGS: Of 269 relevant reports, including 5607 women, adverse fetomaternal events varied according to the total dose of nifedipine and study design. Adverse events were highest amongst women given more than 60 mg total dose of nifedipine [odds ratio (OR) 3.78, 95% confidence interval (CI) 1.27-11.2, p = 0.017] and in reports from case series compared to controlled studies (OR 2.45, 95% CI 1.17-5.15, p = 0.018). INTERPRETATION: Adverse event rates generated from this study provide an evidence base for clinical guidelines and informed patient consent for CCB use in pregnancy.

Effects of different human chorionic gonadotrophin preparations on trophoblast differentiation.

Recent evidence from the literature suggested that hCG preparations purified from urine of pregnant women, which are widely used in in vitro studies and IVF programs, may contain contaminants such as EGF. To determine the putative biological effects of the contaminating growth factor, we here investigated distinct trophoblast differentiation processes in the presence of various hCG compounds. Western blot analyses indicated that treatment of trophoblastic SGHPL-5 cells and purified term trophoblasts with potentially EGF-contaminated hCG (hCG-A) resulted in auto-phosphorylation of the EGF receptor at tyrosine 1173 whereas supplementation of another urine-purified hCG preparation (hCG-B), recombinant holo-hCG or recombinant alphahCG had no effects. Phosphorylation was specifically blocked by the EGF receptor inhibitor PD153035. Urinary hCG-A was most effective in promoting invasion of SGHPL-5 cells through Matrigel-coated transwells, but increased invasiveness was also observed in the presence of hCG-B or recombinant holo-hCG. Similarly, the extent of syncytialisation of term trophoblasts, quantitated by nuclei in desmoplakin-negative areas, was highest upon addition of hCG-A or recombinant EGF as a control. PD153035 reduced invasion and fusion of trophoblasts supplemented with hCG-A, but did not diminish the effects provoked by hCG-B. In conclusion, the data suggest that the EGF contamination of hCG considerably affects trophoblast function. Experiments using EGF-free hCG preparations demonstrate that the hormone increases trophoblast invasion and syncytialisation.

[Fetal lung development on MRT. Normal course and impairment due to premature rupture of membranes]. / Fetale Lungenentwicklung in der MRT. Normaler Verlauf und Beeinträchtigung durch vorzeitigen Blasensprung.

A well-organized interplay between many molecular factors as well as mechanical forces influence fetal lung development. At the end of this complex process a sufficiently sized and structurally mature organ should ensure the postnatal survival of the newborn. Besides prenatal ultrasonography, magnetic resonance imaging (MRI) can now be used to investigate normal and pathological human lung growth in utero. Oligohydramnios, due to premature rupture of membranes (PROM), is an important risk factor for compromised fetal lung growth. In these situations MR volumetry can be used to measure the size of the fetal lung quite accurately. Together with the evaluation of lung signal intensities on T2-weighted sequences, fetuses with pulmonary hypoplasia can be readily detected.

Continuing challenges in treating preterm labour: preterm prelabour rupture of the membranes.

Preterm prelabour rupture of the membranes (PPROM) is defined as prelabour rupture of the membranes prior to 37 weeks of gestation. It occurs in approximately 3% of pregnancies and is responsible for one-third of all preterm births. Effective treatment relies on accurate diagnosis, and it is gestational age dependent because the potential complications change with gestational age. Diagnosis itself is made by clinical suspicion, patient history and simple testing. Studies have shown that if a combination of patient history, nitrazine testing and ferning was used, the accuracy of at least two positive tests was 93.1%. PPROM is associated with significant maternal and neonatal morbidity and mortality from infection, umbilical cord compression, placental abruption and preterm birth. Subclinical uterine infection has been implicated as a major aetiological factor in the pathogenesis and subsequent morbidity associated with PPROM and antenatal antibiotics, together with corticosteroid therapies, have clear benefits and should be offered to all women without contraindications. Women with PPROM after 32 weeks should be considered for delivery, and after 34 weeks of gestation the benefits of elective delivery appear to outweigh the risks. Here, two cases are discussed that were experienced in our unit.

Clinical practice evaluation of atosiban in preterm labour management in six European countries.

OBJECTIVE: To evaluate the efficacy and safety of early administration compared with standard administration of atosiban, when predefined eligibility criteria were met. DESIGN: A prospective, open-label, randomised clinical trial. Women were randomised to receive atosiban either immediately (early) or when specified criteria, in terms of duration/frequency of uterine contraction or status of cervical dilation/effacement, were fulfilled (standard). SETTING: Carried out at 105 centres in six European countries. POPULATION: Pregnant women admitted to hospital in threatened preterm labour between 24 and 34 weeks of gestation, comprising a subgroup of women enrolled in the Tractocile Efficacy Assessment Survey in Europe (TREASURE) clinical experience review. MAIN OUTCOME MEASURES: Efficacy was defined as the successful delay of delivery with no alternative tocolytic agent for 48 hours. RESULTS: More women in the early group remained undelivered at 48 hours with no alternative tocolytic agent compared with those who received atosiban when specified criteria were fulfilled (88.9 versus 76.1%; P = 0.03). Safety was comparable between the groups. There were no statistical differences in maternal, fetal or neonatal adverse events between the early and standard atosiban arms. CONCLUSIONS: The use of atosiban was effective for the delay of preterm labour and presented no safety concerns irrespective of the time it was administered.

A newly discovered function of palatine tonsils in immune defence: the expression of defensins.

The palatine tonsils have an undoubted role in the immune defence system. After antigen contact an effective adaptive immune response by B- and T-cell lymphocytes will be released. In addition the palatine tonsils seem to exert influence to the defence by the innate immune system. Therefore, we studied the ability of palatine tonsils to express different alpha and beta defensins and to find out any distinctions in chronic inflamed tonsils. Total RNA of 49 specimens of hyperplastic tonsils and chronic tonsillitis with pathological provided evidence of Actinomyces israelii was isolated using TRIzol protocol, reverse transcribed and the HNP-1, HNP-4, HBD-1 and HBD-2 gene expression densitometric determined, standardised in relation to glycerinaldehyd-3-phosphatdehydrogenase gene expression, after a semiquantitative polymerase chain reaction was performed. mRNA of HNP-1, HNP-4, HBD-1 and HBD-2 was detected in tissue samples, but their amount differed within the two defensin families and tissue of origins. HBD-1 was detected in all 49 tissues of hyperplastic tonsils and chronic tonsillitis. Only in chronic inflamed tonsils the amount of HBD-2 mRNA expression was significant increased. In these specimens also mean relative expression rate of all defensins was observed to be manifestly increased. Palatine tonsils express mRNA for different alpha and beta defensins and this expression suggest a newly supposed function in immune defence: the participation in the innate, non-adaptive immune system. Thus, palatine tonsils have a potentially influence in the growth and control of the physiological mouth bacteria by their bactericidal activity.

Promoter elements and transcription factors involved in differentiation-dependent human chorionic gonadotrophin-alpha messenger ribonucleic acid expression of term villous trophoblasts.

Differentiation of primary villous cytotrophoblasts into syncytia is associated with increasing production of alpha and beta human CG subunits, which is predominantly governed at the level of messenger RNA expression. Here, we present a detailed study on the mechanisms involved in the differentiation-dependent regulation of the trophoblast-specific CGalpha gene promoter. Site-directed mutations in each of the five DNA-elements of the composite enhancer were performed to investigate the contribution of the individual regulatory sequences to the overall transcriptional activity of the promoter at two different stages of trophoblast in vitro differentiation. We show that deletion of one cyclic AMP response element (CRE) did not affect CGalpha promoter activity in cytotrophoblasts; however, it reduced transcription by 33% in differentiating cultures. Removal of both CREs almost abolished transcription at early and later stages of in vitro differentiation. Upon mutation the enhancer elements alphaACT, JRE, and CCAAT significantly decreased luciferase reporter transcription; however their contribution to the total promoter activity did not change during in vitro differentiation. Contrary to that, mutated TSE diminished promoter activity by 19% during 12 and 48 h of cultivation but reduced luciferase expression by 78% between 48 and 84 h of differentiation. In electrophoretic mobility shift assay, the TSE interacted with activating protein (AP)-2alpha in both primary trophoblasts and choriocarcinoma cells. While CRE-interacting proteins were detectable 12 h after isolation, the TSE-binding complex did not appear before 36 h of in vitro differentiation. During syncytium formation increasing protein expression of activating transcription factor (ATF)-1, cAMP response element-binding protein (CREB)-1, and AP-2alpha was observed on Western blots. Moreover, phosphorylated CREB-1 and ATF-1 accumulated between 24 and 78 h of trophoblast cultivation. By fluorescence immunohistochemistry, we show that CREB-1 was predominantly expressed in syncytiotrophoblasts, whereas ATF-1 and AP-2alpha localized to the syncytium and some cytototrophoblasts as well as to stromal and endothelial cells of the placental villus. Phosphorylated CREB-1/ATF-1 and the coactivator protein CBP were primarily detected in syncytial nuclei, suggesting the presence of functional, cAMP-dependent transcriptional complexes in the differentiated tissue. In agreement to the in vivo situation, phosphorylated CREB-1/ATF-1 were observed in nuclei of the differentiated trophoblast cultures. The activity of the CGalpha promoter as well as CREB-1/ATF-1 phosphorylation increased upon elevation of cAMP levels and overexpression of the catalytic subunit of protein kinase A. Additionally, we demonstrate that overproduction of the enzyme enhanced protein expression and binding of AP-2alpha to the TSE. We conclude that differentiation-dependent transcription of the CGalpha gene in villous trophoblasts is mainly governed by increasing expression of AP-2alpha and PKA-dependent phosphorylation of CREB-1 and ATF-1.

Oxytocin and vasopressin 1a receptor gene expression in the cycling or pregnant human uterus.

OBJECTIVE: Our purpose was to compare concentrations of messenger ribonucleic acid specific for the oxytocin receptor and for the vasopressin 1a receptor in myometrial and endometrial tissues of pregnant and nonpregnant women. STUDY DESIGN: Tissues from pregnant uteri were obtained from 95 women who were undergoing cesarean delivery between 26 and 42 weeks' gestation. Tissues from nonpregnant uteri were obtained from 7 cycling women who were undergoing hysterectomy. The competitive reverse-transcription polymerase chain reaction method was used to determine messenger ribonucleic acid concentrations. RESULTS: A significant increase in oxytocin receptor messenger ribonucleic acid was found during the first half of pregnancy. Oxytocin receptor messenger ribonucleic acid concentrations were lower in tissues with spontaneous contractions than in quiescent tissues and were decreased in patients with advanced labor. Vasopressin 1a receptor messenger ribonucleic acid concentrations were high in tissues from both cycling and pregnant uteri but remained unchanged throughout gestation. CONCLUSION: The increase in oxytocin receptor protein concentrations seen in pregnancy is only partially controlled by messenger ribonucleic acid abundance. High concentrations of vasopressin 1a receptor messenger ribonucleic acid confirm the biologically active role of this receptor in both the cycling and the pregnant uterus.

Comparison of Burch and lyodura sling procedures for repair of unsuccessful incontinence surgery.

OBJECTIVE: To assess the effectiveness and late postoperative morbidity of the Burch procedure and the sling procedure for the treatment of recurrent urinary stress incontinence after vaginal hysterectomy and anterior repair. METHODS: Clinical, urodynamic, and sonographic examinations were done on 77 women suffering with recurrent urinary stress incontinence. The women were randomized to two groups, modified Burch colposuspension and lyophilized dura mater sling surgery; 72 women were reexamined 32-48 months after these procedures. RESULTS: The cure rate at 32-48 months' follow-up was 86% for the Burch procedure and 92% for the sling. Women who had had the sling procedure demonstrated a clear decrease in maximal bladder capacity, from 330 to 240 mL (P < .05). In both groups, stress profiles demonstrated a shift of maximal pressure point toward the proximal urethra and a significant improvement in pressure transmission (P < .05). The post-operative patients who had persistent incontinence were found to have insufficient elevation of the bladder neck (less than 10 mm). The uroflow examination showed an increase of urination time in both groups. The incidence of bladder problems was 10% with the Burch procedure and 29% with the sling procedure; however, 13% of the Burch group developed rectoceles. CONCLUSION: Both procedures offer a high rate of success. We believe that the sling surgery should be used only in certain special cases because of its higher rate of complications, but that posterior vaginal repair should be considered after modified Burch colposuspension because of the possibility of rectocele and enterocele.

HER-2 oncogene is not amplified in primary carcinoma of the fallopian tube. Austrian Cooperative Study Group for Fallopian Tube Carcinoma.

73 women suffering from primary carcinoma of the fallopian tube underwent surgical excision of their tubes. The tissue was embedded in paraffin and investigated for HER-2 oncogene amplification with a quantitative polymerase chain reaction method. DNA could be extracted and successfully prepared in 65/73 samples. None of the tissue samples exhibited amplified the HER-2 oncogene. Data suggest that the HER-2 oncogene does not play a role in tumor transformation and progression in fallopian tube carcinomas. This contrasts with observations in ovarian carcinomas, with which fallopian tube carcinomas share many clinical, histological and biochemical similarities.