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Objective: To evaluate the performance of ultrasound for antenatal identification of invasive placentation in women with placenta previa in the setting of prior cesarean delivery., Study Design: This was a multicenter, retrospective, cohort study. Singleton pregnancies at risk of placenta accreta because of persistent placenta previa in the setting of prior cesarean delivery who delivered at four centers, from January 2010 to May 2020, were included in the study. For this study, pregnancies with diagnosis of accreta, increta, or percreta were considered under the umbrella term of placenta accreta. All women with placenta previa identified in the second trimester had a follow-up ultrasound at 32-34 weeks. Only those with prior cesarean delivery were considered at risk of placenta accreta. Women were considered with suspected accreta in case of suspected prenatal ultrasound. Women with suspected placenta accreta had delivery planned via cesarean hysterectomy at 34+0 - 35+6 weeks, without any attempt to remove the placenta. The primary endpoint of the study was the performance of ultrasound for antenatal identification of invasive placentation. The following ultrasound signs were evaluated: placenta lacunae; loss of clear space; increased vascularity between myometrium and placenta; intracervical lake; rail sign; uterovesical hypervascularity; increased vascularity in the inferior part of the lower uterine segment potentially extending into the parametrial region; and disruption of bladder-myometrial interface., Results: 180 singleton pregnancies with placenta previa in the setting of prior cesarean delivery were identified. Of them, 155 (86.1%) had antenatal suspected placenta accreta based on ultrasound, having at least one sign of invasive placentation. Of the 155 suspected cases, 99 had confirmed placenta accreta at the time of delivery. Among the 99 cases of confirmed placenta accreta, all of them had at least one sign of invasive placentation at ultrasound. Among the 81 cases with placenta previa, prior cesarean delivery, without placenta accreta, 25/81 (30.9%) had ultrasound scan negative for sign of invasive placentation, and 56/81 (69.1%) had at least one sign of invasive placentation). In particular, 12/81 (14.8%) had placenta lacunae, 16/81 (19.8%) had loss of clear space, 20/81 (24.7%) had increased vascularity between myometrium and placenta, 9/81 (11.1%) had intracervical lake, 14/81 (17.3%) had rail sign, 14 (17.3%) had uterovesical hypervascularity, 5/81 (6.2%) had increased vascularity in the inferior part of the lower uterine segment potentially extending into the parametrial region, 8/81 (9.9%) had disruption of bladder-myometrial interface. In the group of women with confirmed placenta accreta, the most common sign recorded was the disruption of bladder-myometrial interface, being recorded in 88/99 women. Disruption of bladder-myometrial interface had the highest sensitivity in detection placenta accreta. Women with disruption of bladder-myometrial interface at ultrasound had 73-fold increase in the risk of placenta accreta compared to those who did not., Conclusion: Prenatal ultrasound has an excellent diagnostic accuracy in identifying invasive placentation in women with placenta previa and prior cesarean delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The rheological behavior of human semen is overlooked and essentially unexplored in the scientific literature. Here, we provide the first quantitative experimental evidence that post-liquafaction normospermic human semen behaves as a viscoelastic fluid and the shear moduli can be scaled according to the weak-gel model.

Objective: To evaluate whether in fetuses with open spina bifida (OSB) the tentorium can be seen to be displaced downwards and vertically oriented by the time of the 11-13-week scan and whether this is reflected in an alteration of the brainstem-tentorium (BST) angle., Methods: The study population was recruited between 2015 and 2020 from three fetal medicine referral centers and comprised a control group and a study group of pregnancies with OSB. The control group was recruited prospectively and included singleton pregnancies with a normal sonographic examination after first-trimester combined screening for chromosomal abnormalities and normal outcome. The study group was selected retrospectively and included all cases with OSB between 2015 and 2020. All cases underwent detailed ultrasound assessment at 11 + 0 to 13 + 6 weeks' gestation. The position of the torcular Herophili (TH) was identified in the midsagittal view of the fetal brain with the use of color Doppler and was considered as a proxy for the insertion of the tentorium on the fetal skull. The BST angle was calculated in the same view and was compared between the two groups., Results: Sixty normal fetuses were included in the control group and 22 fetuses with OSB in the study group. In both groups, the BST angle was found to be independent of gestational age or crown-rump length (P = 0.8815, R 2  = 0.0003861 in the controls, and P = 0.2665, R 2  = 0.00978 in the OSB group). The mean BST angle was 48.7 ± 7.8° in controls and 88.1 ± 1.18°, i.e. close to 90°, in fetuses with OSB. Comparison of BST-angle measurements between the control group and cases with OSB showed a statistically significant difference (P = 0.0153). In all fetuses with OSB, the downward displacement of the TH and tentorium was clearly visible at the 11-13-week scan., Conclusions: In fetuses with OSB, the BST angle is significantly larger than in normal controls, with the tentorium being almost perpendicular to the brainstem. This sign confirms the inferior displacement of the tentorium cerebelli with respect to its normal insertion on the occipital clivus as early as the first trimester of pregnancy and is useful in the diagnosis of Chiari-II malformation at this early stage. In fetuses with OSB, the low position of the tentorium and TH is clearly visible, even subjectively, at the 11-13-week scan. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To describe the sonographic appearance and position of the choroid plexus of the fourth ventricle (4V-CP) between 12 and 21 weeks' gestation in normal fetuses and in fetuses with Dandy-Walker malformation (DWM) or Blake's pouch cyst (BPC)., Methods: The study population comprised 90 prospectively recruited normal singleton pregnancies and 41 pregnancies identified retrospectively from our institutional database that had a suspected posterior fossa anomaly at 12-13 weeks' gestation based on the ultrasound finding of abnormal hindbrain spaces. In all cases the final diagnosis was confirmed by prenatal and/or postnatal magnetic resonance imaging or postmortem examination. All pregnancies underwent a detailed ultrasound assessment, including a dedicated examination of the posterior fossa, at 12-13 weeks, 15-16 weeks and 20-21 weeks of gestation. Two-dimensional ultrasound images of the midsagittal and coronal views of the brain through the posterior fontanelle and three-dimensional volume datasets were obtained. Multiplanar orthogonal image correlation with volume contrast imaging was used as the reference visualization mode. Two independent operators, blinded to the fetal outcome, were asked to classify the 4V-CP as visible or not visible in both normal and abnormal cases, and to assess if the 4V-CP was positioned inside or outside the cyst in fetuses with DWM and BPC., Results: Of the 41 fetuses with apparently isolated cystic posterior fossa anomaly in the first trimester, eight were diagnosed with DWM, 29 were diagnosed with BPC and four were found to be normal in the second trimester. The position of the 4V-CP differed between DWM, BPC and normal cases in the first- and second-trimester ultrasound examinations. In particular, in normal fetuses, no cyst was present and, in the midsagittal and coronal planes of the posterior fossa, the 4V-CP appeared as an echogenic oval-shaped structure located inside the 4V apparently attached to the cerebellar vermis. In fetuses with DWM, the 4V-CP was not visible in the midsagittal view because it was displaced inferolaterally by the cyst. In contrast, in the coronal view of the posterior brain, the 4V-CP was visualized in all cases with DWM at 12-13 weeks, with a moderate decrease in the visualization rate at 15-16 weeks (87.5%) and at 20-21 weeks (75%). In the coronal view, the 4V-CP was classified as being outside the cyst in all DWM cases at 12-13 weeks and in 87.5% and 75% of cases at 15-16 and 20-21 weeks, respectively. In fetuses with BPC, the 4V-CP was visualized in all cases in both the midsagittal and coronal views at 12-13 weeks and in 100% and 96.6% of cases, respectively, at 15-16 weeks. In the coronal view, the 4V-CP was classified as being inside the cyst in 28 (96.6%), 27 (93.1%) and 25 (86.2%) cases at 12-13, 15-16 and 20-21 weeks, respectively. The medial segment of the 4V-CP was visualized near the inferior part of the vermis., Conclusions: Our study shows that longitudinal ultrasound assessment of the 4V-CP and its temporal changes from 12 to 21 weeks is feasible. The 4V-CP is located inside the cyst, just below the vermis, in BPC and outside the cyst, inferolaterally displaced and distant from the vermian margin, in DWM, consistent with the pathogenesis of the two conditions. The position of the 4V-CP is a useful sonographic marker that can help differentiate between DWM and BPC as early as in the first trimester of pregnancy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1 . Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.

Introduction: The objective of the study was to provide more detailed data about fetal isolated upward rotation of the cerebellar vermis rotation (Blake's pouch cyst) in particular regarding pregnancy outcome., Methods: This is a retrospective study of all cases of fetal isolated upward rotation of the cerebellar vermis (URCV) diagnosed in 3 referral centers in Italy from January 2009 to November 2019. Whenever possible, prenatal magnetic resonance imaging (MRI) was performed and a fetal karyotype was obtained. A detailed follow-up was obtained by consultation of medical records, interview with the parents, and the pediatricians., Results: Our study population included 111 patients with a prenatal diagnosis of isolated URCV made at a median gestational age of 21 weeks +3 days (interquartile range (IQR) 21 + 0-22 + 2). The median brain stem-vermis (BV) angle was 27° (IQR 24-29°). In 37.9% of the cases, a regression of the finding with restoration of normal anatomy was noted at a follow-up scan or at postnatal checks. A BV angle of 25° or less predicted regression with a probability in excess of 90%. MRI was performed in utero or at birth in 101 patients and always confirmed sonographic diagnosis. Fetal CGH array and/or karyotype was available in 97 cases and was always normal, but in 1 case. A postnatal follow-up was available in 102 infants (mean 7 months, range 0-10 years of age) and documented a normal neurologic development in all the cases., Conclusions: Isolated URCV is most likely a normal variant of fetal anatomy without clinical consequences, at least at an early follow-up. A BV angle of 25° or less predicts intrauterine regression of the finding, but the outcome is good in all the cases. When a confident sonographic diagnosis is made, MRI is not mandatory. The risk of a chromosomal anomaly in these cases is probably low., (© 2021 S. Karger AG, Basel.)

Background: The role of the first-trimester scan has expanded from aneuploidy screening to the diagnosis of fetal malformations. Abnormal appearance of the posterior brain at 11-14 weeks gestation is a marker of cerebral anomalies; in fact an increased amount of fluid, particularly when the choroid plexus of the fourth ventricle is not visible and only 2 brain spaces instead of 3 are seen, may indicate the presence of cystic or cyst-like posterior fossa anomalies, such as Blake's pouch cyst or Dandy-Walker malformation., Objective: The purpose of this study was to assess the role of ultrasound scanning in the identification of cystic posterior fossa anomalies at 11-14 weeks gestation., Study Design: A prospective cohort study of fetuses with cystic appearance of the posterior fossa at 11-14 weeks gestation was performed. In all cases and in a control group of 40 normal fetuses, the brainstem-tentorium angle was also measured. The presence or absence of cystic posterior anomalies was determined at birth or at postmortem evaluation., Results: In the period 2014-2018, 32 fetuses with an increased brainstem-occipital bone distance and/or failure to visualize the choroid plexus of fourth ventricle (2 brain spaces) were seen. Of these, 18 fetuses were terminated in the first trimester because of associated anomalies and were excluded from the study because of unavailable autoptic findings. The remaining 14 fetuses eventually were found to have a Dandy-Walker malformation in 4 cases, a Blake's pouch cyst in 8 cases, and normal brain anatomy in 2 cases. Two brain spaces were seen in all cases with Dandy-Walker malformation and in 2 of 8 cases with Blake's pouch cyst. Both brainstem-occipital bone measurement and brainstem-tentorium angle were significantly different in fetuses with Dandy-Walker malformation, Blake's pouch cyst, and control subjects (P<.0001). The brainstem-occipital bone z-scores of fetuses with Dandy-Walker malformation and Blake's pouch cyst were always +3 or more and +1.7 or more, respectively. The brainstem-tentorium angle z-scores were always -5 or less and -0.1 or less, respectively., Conclusion: Our study confirms that sonography of the posterior brain at 11-14 weeks gestation allows the identification of cystic posterior fossa anomalies. A large brainstem-occipital bone predicts Dandy-Walker malformation or Blake's pouch cyst. The presence of 2 brain spaces and a small brainstem-tentorium angle are correlated significantly with the presence of Dandy-Walker malformation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To evaluate the presence of maxillary gap (MG) and abnormal retronasal triangle (RT) as markers of cleft palate (CP) with and without cleft lip in the first trimester and to assess their association with the type of orofacial cleft (OC)., Methods: The RT and the mid-sagittal view of the face were evaluated retrospectively by two operators in 26 fetuses with OC and in 80 normal controls to detect abnormal RT and/or MG. The agreement between operators was calculated., Results: Amongst the 26 fetuses, there were 15 cases of bilateral, 6 cases of unilateral, and 4 cases of median cleft lip and palate, and 1 case of CP alone. The MG was observed in 18 cases by operator 1 and in 17 cases by operator 2; an abnormal RT was detected in 21 cases by operator 1 and in 22 cases by operator 2. Great agreement between operators was obtained. In controls, MG or abnormal RT was suspected in 6 and 2-4% of cases, respectively., Conclusions: RT seems to be more sensitive compared to MG; however, the latter showed an additional diagnostic ability when the secondary palate was involved. Both approaches in combination could be useful in detecting OC in the first trimester., (© 2019 S. Karger AG, Basel.)

Objectives: To evaluate postmortem ultrasound (PM-US) for minimally invasive autopsy, and to demonstrate its feasibility, sensitivity and specificity, as compared with conventional autopsy, in detecting major congenital abnormalities., Methods: Over a 19-month study period from 1 March 2012 to 30 September 2013, we recruited from a referral hospital 88 consecutive fetuses, at 11-40 weeks' gestation, which had undergone termination, miscarriage or intrauterine fetal death. We performed PM-US using different transducers and compared the data with those from conventional autopsy. The latter was performed, according to the Societé Francaise de Foetopathologie (France) guidelines, by experienced perinatal pathologists who were blinded to the ultrasound data., Results: Complete virtual autopsy by ultrasound was possible in 95.5% of the cases. The sensitivity of PM-US for detecting brain abnormalities was 90.9% (95% CI, 58.7-99.8%) and the specificity was 87.3% (95% CI, 75.5-94.7%). In 20% of cases, a neuropathological examination was not possible due to severe maceration. The sensitivity for detection of thoracic abnormalities was 88.9% (95% CI, 65.3-98.6%) and the specificity was 92.8% (95% CI, 84.1-97.6%), and the sensitivity for detection of abdominal anomalies was 85.7% (95% CI, 57.2-98.2%) and the specificity was 94.6% (95% CI, 86.7-98.5%)., Conclusion: This pilot study confirms the feasibility of PM-US for virtual autopsy as early as 11 weeks' gestation. This new technique shows high sensitivity and specificity in detecting congenital structural abnormalities as compared with conventional autopsy. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the effectiveness of cervical pessary for preventing spontaneous preterm birth (SPTB) in twin pregnancies with an asymptomatic transvaginal ultrasound cervical length (TVU CL) in the second trimester., Methods: We performed a meta-analysis including all randomized clinical trials (RCTs) comparing the use of cervical pessary (i.e. intervention group) with expectant management (i.e. control group). The primary outcome was incidence of SPTB <34 weeks., Results: Three trials, including 481 twin pregnancies with short cervix, were analyzed. Two RCTs defined short cervix as TVU CL ≤25 mm and one as TVU CL ≤38 mm. Pessary was not associated with prevention of SPTB, and the mean gestational age at delivery and the mean latency were similar in the pessary group compared to the control group. Moreover, no benefits were noticed in neonatal outcomes., Conclusions: Use of the Arabin pessary in twin pregnancies with short TVU CL at 16-24 weeks does not prevent SPTB or improve perinatal outcome.

Background: Bloom syndrome is a rare and recessive disorder characterized by loss-of-function mutations of the BLM gene, which encodes a RecQ 3'-5' DNA helicase. Despite its putative tumor suppressor function, the contribution of BLM to human sporadic colorectal cancer (CRC) remains poorly understood., Methods: The transcriptional regulation mechanism underlying BLM and related DNA damage response regulation in independent CRC subsets and a panel of derived cell lines was investigated by bioinformatics analysis, the transcriptomic profile, a CpG island promoter methylation assay, Western blot, and an immunolocalization assay., Results: In silico analysis of gene expression data sets revealed that BLM is overexpressed in poorly differentiated CRC and exhibits a close connection with shorter relapse-free survival even after adjustment for prognostic factors and pathways that respond to DNA damage response through ataxia telangiectasia mutated (ATM) signaling. Functional characterization demonstrated that CpG island promoter hypomethylation increases BLM expression and associates with cytoplasmic BLM mislocalization and increased DNA damage response both in clinical CRC samples and in derived cancer cell lines. The DNA-damaging agent S-adenosylmethionine suppresses BLM expression, leading to the inhibition of cell growth following accumulation of DNA damage. In tumor specimens, cytoplasmic accumulation of BLM correlates with DNA damage and γH2AX and phosphorylated ATM foci and predicts long-term progression-free survival in metastatic patients treated with irinotecan., Conclusions: Taken together, the findings of this study provide the first evidence that cancer-linked DNA hypomethylation and cytosolic BLM mislocalization might reflect compromised levels of DNA-repair activity and enhanced hypersensitivity to DNA-damaging agents in CRC patients.

Currently, the only efficient way to prevent human Cytomegalovirus (HCMV) infection in pregnancy is primary prophylaxis through hygienic measures. So, we evaluated knowledge of HCMV and its prevention in a group of pregnant women. An anonymous questionnaire with multiple-choice answers was administered to all pregnant women who were followed up at the Obstetrics and Gynecology Unit of "Pugliese-Ciaccio Hospital," a third-level hospital in Catanzaro (Southern Italy), from November 2015 to March 2016. Previously prescribed serology results for HCMV were also evaluated. Three hundred and fifty women participated in the study and the results clearly demonstrated that knowledge of pregnant women about HCMV is poor. Moreover, prescribed screening procedures need to be optimized, since one out of three pregnant women has not been tested for HCMV or the screening was not performed adequately. For this reason, it is important to implement informative campaign in both pregnant women and providing physicians.

Pregnant women with urinary schistosomiasis should be treated, but screening is not implemented in migrants. We report herein a case of a migrant diagnosed late into pregnancy, after diagnosis was made in her husband. Praziquantel was safe and effective. Schistosomiasis should be considered in pregnant women from endemic countries., (© International Society of Travel Medicine, 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Cladosporols are secondary metabolites from Cladosporium tenuissimum characterized for their ability to control cell proliferation. We previously showed that cladosporol A inhibits proliferation of human colon cancer cells through a PPARγ-mediated modulation of gene expression. In this work, we investigated cladosporol B, an oxidate form of cladosporol A, and demonstrate that it is more efficient in inhibiting HT-29 cell proliferation due to a robust G0/G1-phase arrest and p21(waf1/cip1) overexpression. Cladosporol B acts as a PPARγ partial agonist with lower affinity and reduced transactivation potential in transient transfections as compared to the full agonists cladosporol A and rosiglitazone. Site-specific PPARγ mutants and surface plasmon resonance (SPR) experiments confirm these conclusions. Cladosporol B in addition displays a sustained proapoptotic activity also validated by p21(waf1/cip1) expression analysis in the presence of the selective PPARγ inhibitor GW9662. In the DMSO/H2O system, cladosporols A and B are unstable and convert to the ring-opened compounds 2A and 2B. Finally, docking experiments provide the structural basis for full and partial PPARγ agonism of 2A and 2B, respectively. In summary, we report here, for the first time, the structural characteristics of the binding of cladosporols, two natural molecules, to PPARγ. The binding of compound 2B is endowed with a lower transactivation potential, higher antiproliferative and proapoptotic activity than the two full agonists as compound 2A and rosiglitazone (RGZ)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Impairment of the immune response and aberrant expression of microRNAs are emerging hallmarks of tumour initiation/progression, in addition to driver gene mutations and epigenetic modifications. We performed a preliminary survey of independent adenoma and colorectal cancer (CRC) miRnoma data sets and, among the most dysregulated miRNAs, we selected miR-27a and disclosed that it is already upregulated in adenoma and further increases during the evolution to adenocarcinoma. To identify novel genes and pathways regulated by this miRNA, we employed a differential 2DE-DIGE proteome analysis. We showed that miR-27a modulates a group of proteins involved in MHC class I cell surface exposure and, mechanistically, demonstrated that calreticulin is a miR-27a direct target responsible for most downstream effects in epistasis experiments. In vitro miR-27a affected cell proliferation and angiogenesis; mouse xenografts of human CRC cell lines expressing different miR-27a levels confirmed the protein variations and recapitulated the cell growth and apoptosis effects. In vivo miR-27a inversely correlated with MHC class I molecules and calreticulin expression, CD8(+) T cells infiltration and cytotoxic activity (LAMP-1 exposure and perforin release). Tumours with high miR-27a, low calreticulin and CD8(+) T cells' infiltration were associated with distant metastasis and poor prognosis. Our data demonstrate that miR-27a acts as an oncomiRNA, represses MHC class I expression through calreticulin downregulation and affects tumour progression. These results may pave the way for better diagnosis, patient stratification and novel therapeutic approaches.

Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined., (Copyright © 2016 the American Physiological Society.)

Objective: There is insufficient research on the mother's early relationship with a child born subsequent to a previous medical termination of pregnancy (TOP). This study explores mother-infant interactions following prior TOP and the impact on the infant's development., Methods: Being an exploratory research comprising 12 mother-infant (6-7 months old) couples, following prior TOP, and five controls, this study uses a descriptive methodology and a qualitative approach. The Greenspan and Lieberman Observation Scale (GLOS) and the Stern's "R"-Interview were employed to investigate the mother-infant relationship. We used the Brunet-Lézine's Revised Scales (BL-R) and the Projective Kit for Early Childhood (PKEC) to assess the infant's development. Grief resolution was taken into account (Perinatal Grief Scale, semi-structured interview)., Results: The later the perinatal loss, the less likely children are to express their emotions and respond contingently (GLOS). Their psychomotor (BL-R) and emotional (PKEC) development remains adequate. Unresolved grief is associated with more pronounced disturbances: no dyadic exchange (GLOS), language disruptions (BL-R), and withdrawal from the environment (PKEC)., Conclusions: This study suggests that mother-infant interactions following a prior late TOP could undergo disturbances, which do not lead systematically to pathogenic effect on the subsequent child. Nevertheless, unresolved grief could lead to adverse effects.

Objective: To describe a new grading method for stomach position (SP) in fetuses with left-sided congenital diaphragmatic hernia (L-CDH) using ultrasound and to correlate SP to liver position and to liver-to-thoracic cavity volume ratio (LiTR) using magnetic resonance imaging., Methods: SP were graded at the level of the 4-chamber view as following: grade 1-to-4 for stomach not visualised, visualised anteriorly at the apex of the heart, stomach showing abdominal structures anteriorly and stomach with its larger part posterior to the level of the atrial-ventricular heart valves, respectively. The LiTR was calculated and correlated to SP using the Mann-Whitney U test., Results: Seventy-four fetuses were included. Median LiTR for grade 1 SP was 0% and was not different from median LiTR for grade 2 SP (0%, p=NS). Median LiTR for grade 3 SP was 14.9% and was significantly higher than for grade 2 SP (p<0.001). Similarly, median LiTR for grade 4 SP was 20.7% and was significantly higher than for grade 3 SP (p<0.05). When SP was grade 1 or 2, liver was intra-abdominal in 21 (84%) out of 25 fetuses while it was always intrathoracic for SP 3 or 4., Conclusion: In L-CDH, SP as described represents a simple indirect measurement of intrathoracic position and quantification of liver.

Multiple lines of evidence indicate that Wnt/β-catenin signaling plays a fundamental role in colorectal cancer (CRC) initiation and progression. Recent genome-wide data have confirmed that in CRC this pathway is one of the most frequently modified by genetic or epigenetic alterations affecting almost 90% of Wnt/β-catenin gene members. A major challenge is thus learning how the corrupted coordination of this pathway is tied to other signalings to enhance cell growth. Peroxisome proliferator activated receptor γ (PPARγ) is emerging as a growth-limiting and differentiation-promoting factor. In tumorigenesis it exerts a tumor suppressor role and is potentially linked with the Wnt/β-catenin pathway. Based on these results, the identification of new selective PPARγ modulators with inhibitory effects on the Wnt/β-catenin pathway is becoming an interesting perspective. Should, in fact, these molecules display such properties, new research avenues would be opened aimed at developing new molecular targeted drugs. Herein, we review the basic principles and present new hypotheses underlying the crosstalk between Wnt/β-catenin and PPARγ signaling. Furthermore, we discuss the advances in our understanding as to how their altered regulation can culminate in colon cancer and the efforts aimed at designing novel PPARγ agonists endowed with Wnt/β-catenin inhibitory effects to be used as therapeutic and/or preventive agents.

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma; in its classical presentation it evolves slowly, but it can have an aggressive course in a subset of patients., Objectives: To investigate the impact of epigenetic mechanisms on the progression of early stage MF., Methods: We analysed DNA methylation at 12 different loci and long interspersed nucleotide elements-1 (LINE-1), as a surrogate marker of global methylation, on tissue samples from 41 patients with stage I MF followed up for at least 12 years or until disease progression. The methylation profiles were also analysed in two T-cell lymphoma cell lines and correlated with gene expression., Results: The selected loci were methylated in a tumour-specific manner; concomitant hypermethylation of at least four loci was more frequent in cases progressing within 1-3 and 3-6 years than in late-progressive or non-progressive cases. LINE-1 methylation was significantly lower in rapidly progressive MF at 3 years (61%, P < 0·001) than in those at 12 years (67%). PPARG, SOCS1 and NEUROG1 methylation showed remarkable differences among the prognostic groups, but only PPARG was a significant predictor of disease progression within 6 years, after adjustment for patients' age or gender. Strikingly, a methylation profile similar to progressive cases was found in highly proliferative Sézary-derived HUT78 cells but not in MF-derived HUT102 cells. Exposure to a DNA demethylating agent restored sensitivity to apoptosis and cell cycle arrest., Conclusions: Epigenetic silencing of specific biomarkers can predict the risk of disease progression in early-stage MF, providing insights into its pathogenesis, prognosis and therapy., (© 2013 British Association of Dermatologists.)

Unlabelled: MicroRNAs (miRNAs) regulate diverse biological processes by inhibiting translation or inducing degradation of target mRNAs. miR-145 is a candidate tumor suppressor in colorectal carcinoma (CRC). Colorectal carcinogenesis involves deregulation of cellular processes controlled by a number of intertwined chief transcription factors, such as PPARγ and SOX9. Since PPAR family members are able to modulate complex miRNAs networks, we hypothesized a role of miRNA-145 in the interaction between PPARγ and SOX9 in colorectal carcinogenesis. To address this issue, we evaluated gene expression in tissue specimens of CRC patients and we took advantage of invitro models represented by CRC derived cell lines (CaCo2, SW480, HCT116, and HT-29), employing PPARγ activation and/or miRNA-145 ectopic overexpression to analyze how their interplay impact the expression of SOX9 and the development of a malignant phenotype., Results: PPARγ regulates the expression of miR-145 by directly binding to a PPAR response element (PPRE) in its promoter at -1207/-1194bp from the transcription start site. The binding is essential for miR-145 upregulation by PPARγ upon rosiglitazone treatment. Ectopic expression of miR-145, in turn, regulates SOX9 expression through the binding to specific seed motifs. The PPARγ-miR-145-SOX9 axis overarches cell cycle progression, invasiveness and differentiation of CRC derived cell lines. Together, these results suggest that miR-145 is a novel target of PPARγ, acts as a tumor suppressor in CRC cell lines and is a key regulator of intestinal cell differentiation by directly targeting SOX9, a marker of undifferentiated progenitors in the colonic crypts., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To assess prospectively the use of four-dimensional (4D) spatiotemporal image correlation (STIC) in the evaluation of the fetal heart at 11-14 weeks' gestation., Methods: The study involved offline analysis of 4D-STIC volumes of the fetal heart acquired at 11-14 weeks' gestation in a population at high risk for congenital heart disease (CHD). Regression analysis was used to investigate the effect of gestational age, maternal body mass index, quality of the 4D-STIC volume, use of a transvaginal vs transabdominal probe and use of color Doppler ultrasonography on the ability to visualize separately different heart structures. The accuracy in diagnosing CHD based on early fetal echocardiography (EFE) using 4D-STIC vs conventional two-dimensional (2D) ultrasound was also evaluated., Results: One hundred and thirty-nine fetuses with a total of 243 STIC volumes were included in this study. Regression analysis showed that the ability to visualize different heart structures was correlated with the quality of the acquired 4D-STIC volumes. Independently, the use of a transvaginal approach improved visualization of the four-chamber view, and the use of Doppler improved visualization of the outflow tracts, aortic arch and interventricular septum. Follow-up was available in 121 of the 139 fetuses, of which 27 had a confirmed CHD. A diagnosis based on EFE using 4D-STIC was possible in 130 (93.5%) of the 139 fetuses. Accuracy in diagnosing CHD using 4D-STIC was 88.7%, and the results of 45% of the cases were fully concordant with those of 2D ultrasound or the final follow-up diagnosis. EFE using 2D ultrasound was possible in all fetuses, and accuracy in diagnosing CHD was 94.2%. Five of the seven false-positive or false-negative cases were minor CHD., Conclusions: In fetuses at 11-14 weeks' gestation, the heart can be evaluated offline using 4D-STIC in a large number of cases, and this evaluation is more successful the higher the quality of the acquired volume. 2D ultrasound remains superior to 4D-STIC at 11-14 weeks, unless volumes of good to high quality can be obtained., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

MicroRNA-130b (miR-130b) is involved in several biologic processes; its role in colorectal tumorigenesis has not been addressed so far. Herein, we demonstrate that miR-130b up-regulation exhibits clinical relevance as it is linked to advanced colorectal cancers (CRCs), poor patients' prognosis, and molecular features of enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. miR-130b high-expressing cells develop large, dedifferentiated, and vascularized tumors in mouse xenografts, features that are reverted by intratumor injection of a specific antisense RNA. In contrast, injection of the corresponding mimic in mouse xenografts from miR-130b low-expressing cells increases tumor growth and angiogenic potential while reduces the epithelial hallmarks. These biologic effects are reproduced in human CRC cell lines. We identify peroxisome proliferator-activated receptor γ (PPARγ) as an miR-130b direct target in CRC in vitro and in vivo. Notably, the effects of PPARγ gain- and loss-of-function phenocopy those due to miR-130b down-regulation or up-regulation, respectively, underscoring their biologic relevance. Furthermore, we provide mechanistic evidences that most of the miR-130b-dependent effects are due to PPARγ suppression that in turn deregulates PTEN, E-cadherin, Snail, and vascular endothelial growth factor, key mediators of cell proliferation, EMT, and angiogenesis. Since higher levels of miR-130b are found in advanced tumor stages (III-IV), we propose a novel role of the miR-130b-PPARγ axis in fostering the progression toward more invasive CRCs. Detection of onco-miR-130b and its association with PPARγ may be useful as a prognostic biomarker. Its targeting in vivo should be evaluated as a novel effective therapeutic tool against CRC.

We describe a novel bioinformatic and translational pathology approach, gene Signature Finder Algorithm (gSFA) to identify biomarkers associated with Colorectal Cancer (CRC) survival. Here a robust set of CRC markers is selected by an ensemble method. By using a dataset of 232 gene expression profiles, gSFA discovers 16 highly significant small gene signatures. Analysis of dichotomies generated by the signatures results in a set of 133 samples stably classified in good prognosis group and 56 samples in poor prognosis group, whereas 43 remain unreliably classified. AKAP12, DCBLD2, NT5E and SPON1 are particularly represented in the signatures and selected for validation in vivo on two independent patients cohorts comprising 140 tumor tissues and 60 matched normal tissues. Their expression and regulatory programs are investigated in vitro. We show that the coupled expression of NT5E and DCBLD2 robustly stratifies our patients in two groups (one of which with 100% survival at five years). We show that NT5E is a target of the TNF-α signaling in vitro; the tumor suppressor PPARγ acts as a novel NT5E antagonist that positively and concomitantly regulates DCBLD2 in a cancer cell context-dependent manner.

Purpose: To evaluate image quality and diagnostic accuracy of high-field post-mortem (PM) magnetic resonance imaging (MRI) on fetuses below 20 weeks of gestation before and after the freeze-thaw process., Materials and Methods: Nine fetuses were scanned with three different scanning procedures: "fresh", just after termination of pregnancy (TOP), "non-fresh short scan" and "non-fresh long scan" after being kept at -20 °C, followed by a conventional autopsy. The brain, thorax except the heart, heart and abdomen were studied. The qualities of the images for the four different fetal regions and for the three different scanning procedures were reported. Regression analysis was used to investigate the effect on image quality of different factors. Additionally, the diagnostic accuracy was also evaluated., Results: Fetuses at 12.0-19.6 weeks were included. Regression analysis showed that better image quality was correlated to advanced gestation at TOP and scan on fresh fetuses. PM-MRI on fresh fetuses was always diagnostic for the brain and in more than half of cases on non-fresh fetuses and was nearly equally diagnostic for thoracic and abdominal structures., Conclusion: High-field PM-MRI seems to offer a quite reliable alternative to the parents declining conventional PM for fetuses before 20 weeks whether these fetuses are freshly scanned or after being frozen.

Background: Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum. The molecular mechanisms underlying RCT pathogenesis remain poorly elucidated. The differential diagnosis is with the malignant rhabdoid tumors of infancy characterized by genetic inactivation of SMARCB1 (INI1) or deletions of chromosome 22q12 locus., Materials and Methods: To shed light on RCT pathogenesis, we investigated genetic and epigenetic alterations in two cases of pure and composite RCT and compared them with the profiles of matched adenomas and normal mucosa. Immunohistochemical analysis, FISH, methylation specific PCR and DNA sequencing analysis were performed on paraffin-embedded tissues., Results: Loss of epithelial markers, (CK20, CDX2 and E-cadherin) and intense vimentin expression was observed in RCTs but neither in the normal mucosa or adenomas. INI1 expression was detected in normal mucosa, adenomas and retained in pure RCT, while it was undetected in composite RCT. Rearrangement of the 22q12 locus was found only in pure RCT. The APC/β-catenin pathway was not altered, while MLH1 immunostaining was negative in RCTs and positive in adenomas and normal mucosa. These expression profiles were associated with V600E BRAF mutation, a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma and RCT., Conclusions: Right-sided RCT could be characterized by epigenetic events and molecular features likely similar to those occurring in the serrated pathway and associated with epithelial-mesenchymal transition. These extremely rare tumors may benefit from the use of new biological molecules specific for colorectal carcinoma., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1641385210804556.

Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

Rationale and Objectives: Little is known about molecular changes in lungs of fetal rabbits with surgically induced diaphragmatic hernia (DH). Therefore, we examined in this model gene expressions of pivotal molecules for the developing lung., Methods: At day 23 of gestation, DH was created in 12 fetuses from 4 does. Both lungs from six live DH fetuses and from six unoperated controls were harvested and weighed at term. Transcription of 15 genes involved in alveolarization, angiogenesis, regulation of vascular tone, or epithelial maturation was investigated by real-time quantitative polymerase chain reaction., Main Results: DH decreased lung-to-body weight ratio (P < 0.001). A bilateral downregulation was seen for genes encoding for tropoelastin (P < 0.01), lysyl oxidase (P < 0.05), fibulin 5 (P < 0.05), and cGMP specific phosphodiesterase 5 (P < 0.05). Lower mRNA levels for endothelial nitric oxide synthase occurred in the ipsilateral lung (P < 0.05)., Conclusions: Experimental DH in fetal rabbits disrupted transcription of genes implicated in lung growth and function. Similarities with the human disease make this model appropriate for investigation of new prenatal therapies., (Copyright © 2012 Wiley Periodicals, Inc.)

Objectives: To compare the diagnostic usefulness of high-field with low-field magnetic resonance imaging (MRI) and stereomicroscopic autopsy for examination of the heart in fetuses at or under 20 weeks' gestation., Methods: Prior to invasive stereomicroscopic autopsy, MRI scans at 9.4, 3.0 and 1.5 T were performed on 24 fetuses between 11 and 20 weeks' gestation, including 10 fetuses with cardiac abnormalities. The ability to visualize different heart structures was evaluated according to the different field strength MRI magnets used and gestational age at examination., Results: On 1.5- and 3.0-T MRI, only the heart situs and four-chamber view could be visualized consistently (in 75% or more of cases) when the fetus was beyond 16 weeks' gestation, but other heart structures could not be visualized for fetuses at any gestational age. In contrast, using high-field MRI at 9.4 T, the heart situs, four-chamber view and the outflow tracts could be visualized in all fetuses irrespective of gestational age. Using high-field MRI, the sensitivity for detecting an abnormality of the four-chamber view was 66.7% (95% CI, 30.1-92.1%) with a specificity of 80.0% (95% CI, 51.9-95.4%). For abnormalities of the outflow tracts, sensitivity was 75.0% (95% CI, 20.3-95.9%) and specificity 100.0% (95% CI, 83.3-100.0%). Eight fetuses out of 10 with congenital heart disease (CHD) were classified as having major CHD. High-field MRI at 9.4 T was able to identify seven out of the eight cases of major CHD., Conclusion: High-field MRI at 9.4 T seems to be an acceptable alternative approach to invasive stereomicroscopic autopsy for fetuses with CHD at or below 20 weeks' gestation., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

The detailed study of the fetal cardiac anatomy in the first trimester of pregnancy by means of ultrasound is feasible whether using a transvaginal or a transabdominal approach. There is nowadays enough evidence that ultrasound in the first trimester of pregnancy is a safe procedure provided thermal and mechanical indices are taken into account. The best timing for successful imaging of the four chambers and great arteries in early gestation appears to be between around 13 to 14 weeks rather than 11 to 12 weeks. In experienced hands, first-trimester fetal echocardiography is quite sensitive for the detection of major structural cardiac abnormalities. Besides the nasal bone, markers for first trimester screening of chromosomal abnormalities such as nuchal translucency thickness, the flow in the ductus venosus and the flow through the tricuspid valve constitute also markers for cardiac abnormalities. The finding of an increased nuchal translucency, an abnormal flow in the ductus venosus or a tricuspid regurgitation constitutes an indication for more detailed fetal cardiac assessment. Other indication for a detailed cardiac assessment is the finding of an aberrant right subclavian artery and vascular anomalies. The emerging importance of these markers has caused renewed interest in the early study of the fetal heart.

Objective: To ascertain whether high-field magnetic resonance imaging (MRI) allows accurate estimation of the weight of various fetal organs at postmortem before 20 weeks' gestation., Methods: From 23 fetuses at 9-20 weeks, following termination of pregnancy or in-utero fetal death (IUFD), 207 assorted fetal organs were evaluated by high-field MRI at 9.4 T prior to conventional autopsy. Fetal organ density was calculated by correlating volume and weight at autopsy using linear regression analysis, and this was used to estimate fetal organ weight by MRI. The relative error in MRI estimation of organ weight was calculated as follows: (|MRI weight - autopsy weight|/autopsy weight) × 100 (%). Multiple regression analysis was used to investigate the effect on the relative error of MRI organ weight estimates of gestational age at TOP or delivery following IUFD, autopsy weight, fetal organ examined, IUFD and fetal maceration., Results: Of the 207 organs evaluated, 133 (64%) were examined for fetal organ density and 155 (75%) for fetal organ weight. Fifty-two organs were excluded from our analysis; 41 of these were from fetuses with IUFD, with 39 organs macerated. In 32 cases, exclusion was due to an inability to assess the organ both on MRI and on conventional autopsy. Volume and weight at autopsy correlated significantly, following the linear equation: autopsy volume = (0.9947 × autopsy weight) - 4.7556, where autopsy volume is in mm(3) and weight is in mg (r = 0.99, P < 0.001). Overall the mean relative error in the MRI estimation of organ weight was 68%. Multiple regression analysis showed that the relative error in the MRI estimation of organ weight was significantly associated with gestational age at TOP or delivery following IUFD and fetal maceration, but not with autopsy weight, fetal organ examined or IUFD. In the subgroup of non-macerated organs and for fetuses above 14 weeks' gestation, the mean relative error in the MRI estimation of organ weight was 34%., Conclusion: In fetuses before 20 weeks' gestation, noninvasive estimation of organ weight is feasible using high-field MRI, but there is a mean overestimation. Limitations of the technique occur mainly in cases of small macerated fetuses before 14 weeks' gestation., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To determine the feasibility of postmortem computed tomographic (pm-CT) angiography for fetal heart evaluation., Methods: Following termination of pregnancy (TOP) or intrauterine fetal death (IUFD) beyond 18 weeks' gestation, 33 fetuses were examined by pm-CT; in eight contrast medium was injected through the umbilical cord and in 25 contrast medium was injected directly into the heart. Logistic regression analysis was used to investigate the effect on the ability to visualize cardiac structures on pm-CT angiography of gestational age at TOP or delivery following IUFD, the time delay between fetal death and examination, the technique used for contrast-medium injection, the presence of cardiac abnormalities and whether or not there was IUFD. The diagnostic accuracy of pm-CT angiography for the evaluation of fetal cardiac structures was also evaluated., Results: Cardiac anatomy including heart situs, the four-chamber view and great vessels could be visualized on pm-CT angiography in 29 out of 33 fetuses (87.9%). Logistic regression analysis showed that the ability to visualize cardiac structures on pm-CT angiography was positively correlated only with contrast medium injected directly into the heart. Twenty-five out of the 33 fetuses underwent conventional autopsy. There were five cases with suspected major cardiac abnormality at prenatal ultrasound and one with a minor cardiac abnormality. In one of these cases, severe leakage into the pleural cavity did not allow for visualization of any heart structure on pm-CT angiography and in another invasive autopsy was declined. In two of the remaining four cases, the findings on pm-CT angiography and invasive autopsy were in agreement, while in two a ventricular septal defect was found on invasive autopsy but not on pm-CT. None of the 27 cases with normal hearts was falsely classified as abnormal using pm-CT angiography., Conclusion: Pm-CT angiography by direct injection into the heart seems to be a feasible method for its evaluation. The extent to which such a technique could be used for the evaluation of congenital heart disease as an alternative to classical postmortem autopsy remains to be determined., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objectives: To compare prospectively maternal acceptance of fetal and neonatal virtuopsy with that of conventional autopsy and to determine the confidence with which magnetic resonance (MR) virtuopsy can be used to diagnose normality/abnormality of various fetal anatomical structures., Methods: MR and/or computed tomography virtuopsy and conventional autopsy were offered to 96 women (102 fetuses/neonates) following termination of pregnancy (TOP), intrauterine fetal death (IUFD) or neonatal death. Multivariable logistic regression analysis was used to investigate the effect on maternal acceptance of virtuopsy and/or conventional autopsy of the age of the mother, gestational age at TOP or delivery after IUFD, order of pregnancy, parity, religion, type of caregiver obtaining consent and reason for death. When parents consented to both MR virtuopsy and conventional autopsy of fetuses ≥ 20 weeks of gestation or neonates, the confidence with which MR virtuopsy could be used to diagnose normality/abnormality of various anatomical structures was determined on a scale in which conventional autopsy was considered gold standard. On autopsy we classified fetuses/neonates as having either 'normal' or 'abnormal' anatomical structures; these groups were analyzed separately. At virtuopsy, we indicated confidence of diagnosis of normality/abnormality of every anatomical structure in each of these two groups defined at autopsy, using a scale from 0 (definitely abnormal) to 100 (definitely normal)., Results: Of the 96 women, 99% (n = 95) consented to virtuopsy and 61.5% (n = 59) to both conventional autopsy and virtuopsy; i.e. 36 (37.5%) consented to virtuopsy alone. Maternal acceptance of conventional autopsy was independently positively related to singleton pregnancy, non-Moslem mother, earlier gestation at TOP or delivery afer IUFD and a maternal-fetal medicine specialist obtaining consent. Thirty-three fetuses ≥ 20 weeks of gestation had both conventional autopsy and MR virtuopsy, of which 19 had a full autopsy including the brain. In fetuses with normal anatomical structures at conventional autopsy, MR virtuopsy was associated with high diagnostic confidence (scores > 80) for the brain, skeleton, thoracic organs except the heart, abdominal organs except the pancreas, ureters, bladder and genitals. In fetuses with abnormal anatomical structures at autopsy, MR virtuopsy detected the anomalies with high confidence (scores < 20) for these same anatomical structures. However, in three cases, virtuopsy diagnosed brain anomalies additional to those observed at conventional autopsy., Conclusion: MR virtuopsy is accepted by nearly all mothers while conventional autopsy is accepted by about two-thirds of mothers, in whom refusal depends mainly on factors over which we have no control. Although conventional autopsy remains the gold standard, the high acceptance of virtuopsy makes it an acceptable alternative when the former is declined., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To evaluate prospectively the feasibility of magnetic resonance imaging (MRI) for assessment of the fetal heart for congenital heart disease (CHD)., Methods: This was a cross-sectional study, including 66 fetuses with a normal heart and 40 with CHD. The fetal heart was examined on MRI using axial steady-state free precession (SSFP) sequences. Regression analysis was used to investigate the effect on the ability to visualize cardiac anatomy of gestational age at examination, maternal body mass index, presence of fetal cardiac abnormality, fetal movements, fetal lie and twinning. The sensitivity and specificity of detecting cardiac defects were calculated., Results: The four-chamber view was visualized in 98.1% of fetuses. The sensitivity of detecting a cardiac defect on the four-chamber view was 88% and the specificity 96%. The ability to visualize the left and right outflow tracts was only influenced by the presence of fetal movements: for the left outflow tract 94.4 vs. 50.0% visualization and for the right outflow tract 92.6 vs. 53.8% visualization without and with fetal movements, respectively. The sensitivity of detecting a cardiac defect of the left outflow tract was 63% and the specificity 100%, while sensitivity and specificity were 59 and 97%, respectively, for the right outflow tract., Conclusions: Despite the use of SSFP sequences, MRI in the fetal heart remains of limited value. It can only be used as a second-line approach for abnormalities of the four-chamber view suspected at prenatal ultrasound., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To prospectively assess the contribution of a high-frequency linear transducer and of moving target indicator (MTI) filtered color flow mapping in the visualization of cardiac fetal anatomy at the routine 11 to 13 + 6-week scan., Methods: This was a cross-sectional prospective study, including 300 singleton fetuses at 11 to 13 + 6 weeks' gestation. Patients were randomized into four groups and a detailed fetal cardiac examination was conducted transabdominally using either a conventional curvilinear transducer, a conventional curvilinear transducer and MTI filtered color flow mapping, a high-frequency linear transducer or a high-frequency linear transducer and MTI filtered color flow mapping. Regression analysis was used to investigate the effect on the ability to visualize different cardiac structures of the following parameters: gestational age at ultrasound examination; fetal crown-rump length (CRL); maternal body mass index (BMI); transducer-heart distance; the technique used at ultrasound; and the position of the placenta., Results: The four-chamber view was visualized in 89.0% of fetuses and regression analysis showed this rate was correlated with CRL and the use of MTI filtered color flow mapping during ultrasonography, and inversely correlated with BMI and transducer-heart distance. Use of a conventional curvilinear transducer and MTI filtered color flow mapping allowed visualization of the four-chamber view in 97.3% of fetuses, while this was only possible in 84.0% of fetuses using a high-frequency linear transducer. The left and right outflow tracts were visualized in 62.3 and 57.7% of fetuses, respectively. Regression analysis showed that the ability to visualize the left or the right outflow tract was correlated with the use of MTI filtered color flow mapping during scanning and was inversely correlated with transducer-heart distance. The use of a conventional curvilinear transducer and MTI filtered color flow mapping allowed visualization of the left and right outflow tracts in 96.0 and 97.3% of fetuses, respectively, while this was only possible in 37.3 and 26.7% of fetuses using a high-frequency linear transducer., Conclusions: During the routine 11 to 13 + 6-week scan, the use of MTI filtered color flow mapping but not of a high-frequency linear transducer, improves visualization of cardiac anatomy., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Tumors of the gastrointestinal tract are among the most frequent human malignancies and account for approximately 30% of cancer-related deaths worldwide. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control diverse cellular functions such as proliferation, differentiation, and cell death. Owing to their involvement in so many processes, they play crucial roles also in the development and physiology of the gastrointestinal tract. Consistently, PPARs deregulation has been implicated in several pathophysiological conditions, including chronic inflammation and cancer development. This paper summarizes the current knowledge on the role that the various PPAR isoforms play in the pathogenesis of the esophageal, gastric, and intestinal cancer. Elucidation of the molecular mechanisms underlying PPARs' signaling pathways will provide insights into their possible use as predictive biomarkers in the initial stages of the process. In addition, this understanding will provide the basis for new molecular targets in cancer therapy and chemoprevention.

Objective: It was the aim of this study to report a case of fetomaternal hemorrhage (FMH) that was successfully treated with fetal intravascular transfusions in which the middle cerebral artery peak systolic velocity (MCA-PSV) detected fetal anemia., Methods: A massive FMH occurred twice in a healthy 33-year-old pregnant woman at 26 and 29 weeks of gestation with no evident cause. Four repeated intravascular transfusions were performed. The MCA-PSV increased in the presence of anemia and decreased following correction of fetal hematocrit., Results: A healthy neonate was delivered at 33 weeks of gestation., Conclusion: MCA-PSV detected fetal anemia both before the first transfusion and following the next intravascular transfusions. In our case, the change in fetal blood viscosity following transfusion with adult blood did not affect the MCA-PSV value for detection of fetal anemia., (Copyright 2009 S. Karger AG, Basel.)

The study objective was to assess the feasibility and the efficacy of bilateral uterine artery embolization (BUAE) for the treatment of cervical pregnancy. The design was a series of 3 cases of viable cervical pregnancy diagnosed by transvaginal ultrasonography and treated by means of BUAE and subsequent uterine curettage. Three women with viable cervical pregnancy underwent BUAE and subsequent uterine curettage in the department of obstetrics and gynecology, High Risk Pregnancy Center, University "Federico II" of Naples. Measurements included surgical outcomes and preservation of fertility. The treatment was effective in all cases. Two patients resumed normal menstruation about 1 month after the procedure, whereas 1 patient underwent a hysterectomy 2 weeks after embolization because of acute ischemic degeneration of a concomitant myoma. The conservative management of cervical pregnancy with angiographic BUAE is a feasible and effective option, even if subsequent hysterectomy may be required. Counseling is necessary.

Objective: To determine whether cervical fetal fibronectin is a reliable predictor of first trimester pregnancy outcome in patients with unexplained recurrent miscarriage., Study Design: A prospective observational study was carried out on 49 pregnant women with a history of unexplained recurrent miscarriage. In all participants the presence of fetal fibronectin in the cervical secretion was determined with a qualitative rapid immunoassay. The outcome of the first trimester pregnancy was recorded a successful outcome was a pregnancy that progressed beyond 12 weeks of gestation; a miscarriage referred to a pregnancy loss in the first 12 weeks., Results: Of the 49 subjects screened, fetal fibronectin was positive in 17 and negative in 32. Overall, 14 pregnancies resulted in fetal loss before the 12th week of gestation. Fetal cervical fibronectin was positive in 6 of the 14 patients who miscarried and in 11 of the 35 in whom outcome was successful. As predictor of first trimester pregnancy outcome the test had a sensitivity and a specificity of 43% and 69% and positive and negative predictive values of 35%, and 75%, respectively. Subgroup analysis by number of previous miscarriages and maternal age gave similar values., Conclusion: This study examines the possible value of cervical fetal fibronectin in predicting first trimester pregnancy outcome. We conclude that the occurrence of positive or negative fetal cervical fibronectin test has only limited predictive value and therefore its use cannot be considered for clinical application.

Background: Fetal fibronectin (FFN) in cervical secretion is one of the most effective markers of pre-term and term delivery. The presence of FFN in cervicovaginal secretions has recently been shown to reflect cervical state and an uncomplicated induction of labor at term. This study was designed to determine whether FFN could be a biochemical marker to predict the response to prostaglandins in early mid-trimester abortion., Methods: The presence of cervical FFN was evaluated by means of qualitative rapid immunoassay in 270 patients, who required second trimester termination of pregnancy at the Department of Gynecology and Obstetrics, University of Naples 'Federico II'. According to the standard protocol of our unit, women received 1.0 mg of gemeprost intravaginally at 3-hr intervals up to a maximum of five suppositories. The induction-to-abortion interval and the percentage of successful abortions within 24 hr in women in the positive FFN group (n=19) were compared with those in the negative FFN group (n=251)., Results: FFN in the cervical secretions was present in seven women (10.2%) at 16-weeks gestation, in seven women (7.5%) at 17-weeks gestation, and in five women (4.5%) at 18-week gestation. Final termination rates were 13 (68.4%) in the fibronectin-positive group and 177 (70.5%) in the fibronectin-negative group. The median abortion interval was similar (14.7 versus 15.1 hr) in both groups., Conclusions: A positive cervical fetal fibronectin test does not predict a successful medical termination of pregnancy in second trimester abortion. In this setting, the role of fetal cervical fibronectin in cervical ripening is, therefore, questionable.

Pentalogy of Cantrell is a rare congenital anomaly consisting of the following features: 1) midline supraumbilical abdominal wall defects; 2) deficiency of the anterior diaphragm; 3) defects in the diaphragmatic pericardium; 4) defects of the lower sternum; 5) congenital intracardiac defects. We report 3 cases of pentalogy of Cantrell diagnosed respectively at 13, 18 and 24 weeks of gestation. In case 1 Cantrell's pentalogy was diagnosed during the 1(st) trimester. Case 2 revealed the coexistence of cystic hygroma. Case 3 showed an association with dysplastic left kidney and mild pyelectasis of the right kidney. Our results confirm the possibility of an early detection of Cantrell's pentalogy and reveal the possibility of associations with other pathological findings.

Maternal hyperglycemia alters placental glucose metabolism and induces placental hypercellularity. In this study we investigated, in JAr cells, the effect of a protein tyrosine phosphatase inhibitor, vanadate, on the insulin receptor substrate 1 (IRS1)-mitogen-activated protein kinase (MAPK) pathway and on cell proliferation in the presence of normal or high glucose concentration. When JAr cells were cultured in the presence of 25 mmol/l glucose, treatment with vanadate completely prevented SHP-2 association with IRS1. However, vanadate treatment reverted the effect of high glucose on basal and insulin-stimulated insulin receptor and IRS1 phosphorylation. Similar effects were observed on MAPK activation. These events determined a related modification in cell proliferation. Indeed, after high glucose and vanadate treatment, thymidine incorporation levels were comparable to those observed in the presence of normal glucose concentration and in the absence of vanadate. Therefore, in JAr cells, vanadate exerts an inhibitory effect on cell proliferation. This action is related to a modulation of the SHP-2 association with IRS1 that in turn might regulate the phosphorylation state of the main substrates involved in mitogenesic signaling of the insulin receptor.

Background: To assess the effect of estriol treatment per vaginam before Burch culposuspension in postmenopausal women with stress urinary incontinence (IUS)., Design: prospective randomised study., Setting: Department of Gynaecology, Obstetrics and Physiopathology of Human Reproduction-Medical School-University of Naples Federico II ., Patients: twenty women in postmenopause at least from five years with a urogenital symptomatology due to IUS., Interventions: women were randomised into one of two groups (treated or control) and they were submitted to an evaluation of vulva and vagina trophism. All the women were submitted to a urodynamic examination and to a transvaginal ultrasonography with evaluation of pubis-bladder neck distance, bladder and proximal urethra position, before treatment, one week before the operation and after six months from the same operation., Evaluations: subjective symptomatology and urodynamic parameters between treated and control groups before and after operation., Results: After 12 weeks of treatment, a significant improvement of subjective symptomatology and a not significant improvement of all the urodynamic parameters in the treated group in comparison with the control group have been demonstrated, while any anatomic alteration compared with the basal hasn t been observed. After six months from the operation in all the women a significant reduction of subjective quantity of urine lost after a strain has been demonstrated and significant variations of urodynamic parameters without significant differences between treated group and control group were also observed., Conclusions: The estriol treatment per vaginam is not so effective on the result of Burch culposuspension in postmenopausal women with IUS.