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Background Discoid meniscus (DM) is a rare variant of regular knee anatomy. Compared to standard meniscus it is thicker and abnormal in shape; these characteristics make it more prone to tear. It is a congenital defect whose correct etiology is still debated and far from being clarified. The purpose of this systematic review is to evaluate evidences of DM in human fetuses in order to assess whether embryological development may have a role. Methods A systematic review was performed on PubMed, Scopus, and Embase with different combinations of the keywords “discoid meniscus”, “embryology”, “fetus”, “neonatal”. Search yielded 1013 studies, on which we performed a primary evaluation. Results Seven studies were considered including a total of 1378 fetal menisci specimens, from 396 different fetuses. Discoid shape was not found represented as a normal stage of prenatal development. From 782 lateral menisci analyzed, only 86 (10.86%) were discoid (13 complete, 73 incomplete type). None of medial menisci was found to be discoid. Lateral meniscus was observed to cover a larger surface of tibial plateau than medial one until 28th gestational week. Conclusion Lateral meniscus seems to be more prone to discoid shape for its natural tendency of covering a larger surface of the tibial plateau during fetal stages. However the fact that a discoid shape was not found in the majority of fetuses suggests that it is not a normal stage of fetal development. To support a single etiological factor it will be appropriate to have further morphological and morphometric studies.

Purpose of review Fetal central nervous system malformations are among the most common congenital anomalies. Whereas simple axial views are sufficient for basic fetal brain examination, other important views are essential for a more detailed examination, which are sometimes challenging to obtain. Three-dimensional ultrasound can be helpful in obtaining standardized and reproducible images of many difficult fetal brain views. The aim of the present review is to explore the most recent evidence on the utility and technique of three-dimensional ultrasound in the examination of the fetal brain, with particular emphasis on the brain views that benefit from three-dimensional ultrasound. Recent findings The article describes the various techniques of acquisition and analyses of three-dimensional ultrasound volumes of the fetal brain and their usefulness in the assessment of normal and abnormal fetal brain anatomy. Three-dimensional ultrasound has also permitted the application of many new technologies, such as artificial intelligence and deep machine learning. Recently, thanks to high-quality three-dimensional ultrasound, fetal cortical development can be assessed quantitatively and reliably. Summary Three dimensional ultrasound can help as a complementary tool to two-dimensional ultrasound in the assessment of the fetal brain development and malformations. In addition, it paves the way for the application of promising technologies in the evaluation of fetal brain. Video abstract A video summarizing the findings of the article. The video illustrates the various approaches and techniques applied for the examination of the fetal brain using three-dimensional ultrasound. Furthermore, the advantages and future perspectives of the application of three-dimensional ultrasound in the examination of the fetal brain are discussed, http://links.lww.com/COOG/A74.

Background Congenital malformations of the central nervous system (CNS) consist of a wide range of birth defects of multifactorial origin. Methods Concentrations of 44 metals were determined by Inductively Coupled Plasma Mass Spectrometry in serum of 111 mothers in the second trimester of pregnancy who carried a malformed fetus and compared them with serum concentrations of the same metals in 90 mothers with a normally developed fetus at the same week of pregnancy. Data are reported as means ± standard deviations. Results We found a direct relationship between congenital defects of the CNS and maternal serum concentration of aluminum: it was statistically higher in women carrying a fetus with this class of malformation, compared both to mothers carrying a fetus with another class of malformation (6.45 ± 15.15 μg/L Vs 1.44 ± 4.21 μg/L, p Conclusion CAluminum may play a role in the onset of central nervous system malformations, although the exact Aluminum species and related specific type of malformation needs further elucidation.

Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has been observed. All these effects are dependent on sex, being observable only in female rat fetuses. In conclusion, this work demonstrates that maternal exposure to BPA compromises hepatic lipid metabolism in female offspring, and it also reveals the perspective impact of BPA on human health at doses currently considered safe.

Objective To assess the differential diagnostic significance of a series of quantitative and qualitative variables of the cerebellar vermis in fetuses with posterior fossa cystic malformation, including Dandy-Walker malformation (DWM), vermian hypoplasia (VH) and Blake's pouch cyst (BPC). Methods This was a retrospective study of confirmed cases of DWM, VH and BPC, diagnosed at the Fetal Medicine and Surgery Unit of the Federico II University between January 2005 and June 2013 or the Fetal Medicine and Surgery Unit of G. Gaslini Hospital between July 2013 and September 2017. All included cases had good-quality three-dimensional (3D) volume datasets of the posterior fossa, acquired by transvaginal ultrasound through the posterior fontanelle. The midsagittal view of the posterior fossa was the reference view for the study. We assessed brainstem-tentorium angle and brainstem-vermis angle (BVA), as well as craniocaudal (CCVD) and anteroposterior (APVD) vermian diameters and vermian area (VA), which were normalized by biparietal diameter (BPD) to take into account gestational age (CCVD/BPD × 100, APVD/BPD × 100 and VA/BPD × 100, respectively). Finally, the position of the fourth ventricular choroid plexus (4VCP) was defined as normal ('up') or abnormal ('down'), relative to the roof/cyst inlet of the fourth ventricle. Results We analyzed 67 fetuses with posterior fossa malformations (24 cases of DWM, 13 of VH and 30 of BPC). The mean gestational age at diagnosis was 23.6 weeks. Regardless of gestational age, the BVA differed significantly between the three groups, and the VA/BPD was able to differentiate between VH and BPC. In differentiating between VH and BPC, the greatest areas under the receiver-operating characteristics curve were those for VA/BPD ratio. The 4VCP position was down in all cases of DWM and VH, while it was up in all cases of BPC. Conclusions Our data support the concept that VA/BPD ratio and 4VCP position may be used to differentiate between DWM, VH and BPC in the fetus. In our series, the position of the 4VCP had the highest accuracy, but a larger number of VH cases should be evaluated to confirm that an up position of the 4VCP indicates BPC while a down position indicates DWM or VH. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Background: Occiput posterior position is the most frequent cephalic malposition, and its persistence at delivery is associated with a higher risk of maternal and perinatal morbidity. Diagnosis and management of occiput posterior position remain a clinical challenge. This is partly caused by our inability to predict fetuses who will spontaneously rotate into occiput anterior from those who will have persistent occiput posterior position. The angle of progression, measured with transperineal ultrasound, represents a reliable tool for the evaluation of fetal head station during labor. The relationship between the persistence of occiput posterior position and fetal head station in the second stage of labor has not been previously assessed. Objective: This study aimed to evaluate the role of fetal head station, as measured by the angle of progression, in the prediction of persistent occiput posterior position and the mode of delivery in the second stage of labor. Study Design: We recruited a nonconsecutive series of women with posterior occiput position diagnosed by transabdominal ultrasound in the second stage of labor. For each woman, a transperineal ultrasound was performed to measure the angle of progression at rest. We compared the angle of progression between women who delivered fetuses in occiput anterior position and those with persistent occiput posterior position at delivery. Receiver operating characteristics curves were performed to evaluate the accuracy of the angle of progression in the prediction of persistent occiput posterior position. Finally, we performed a multivariate logistic regression to determine independent predictors of persistent occiput posterior position. Results: Overall, 63 women were included in the analysis. Among these, 39 women (62%) delivered in occiput anterior position, whereas 24 (38%) delivered in occiput posterior position (persistent occiput posterior position). The angle of progression was significantly narrower in the persistent occiput posterior position group than in women who delivered fetuses in occiput anterior position (118.3°±12.2° vs 127.5°±10.5°; P=.003). The area under the receiver operating characteristics curve was 0.731 (95% confidence interval, 0.594–0.869) with an estimated best cutoff range of 121.5° (sensitivity of 72% and specificity of 67%). On logistic regression analysis, the angle of progression was found to be independently associated with persistence of occiput posterior position (odds ratio, 0.942; 95% confidence interval, 0.889–0.998; P=.04). Finally, women who underwent cesarean delivery had significantly narrower angle of progression than women who had a vaginal delivery (113.5°±8.1 vs 128.0°±10.7; P

Background: Pregnant women are usually more susceptible to infection due to typical physiological and mechanical changes, such as increased heart rate, stroke volume and pulmonary residual capacity. The aim of this study was to evaluate an innovative anesthesiologic opioid-free management protocol in symptomatic pregnant women, with COVID-19 and with oxygen therapy, undergoing cesarean delivery with spinal anesthesia. Methods: With the patient in the sitting position, spinal anesthesia was performed at the L1-L2 level. Vertebral level has been identified starting from the sacrum, we counted the laminae in the caudal-to-cephalad direction, which was then marked with a surgical pen. The technique was performed in asepsis, in the subarachnoid space after vision of clear Cephalo-Spinal Fluid (CSF) in the spinal needle 27 Gauge, without letting out the CSF, bupivacaine 0.5% 10 mg, dexmedetomidine 10 μg and dexamethasone 4 mg was injected. Results: During the study period, 40 pregnant women with one or more symptoms and supplemental oxygen (FiO2 35-40%) who underwent cesarean delivery were included in the study. All pregnant women had pain visual analog scale (VAS)

Objective: To assess the feasibility and reliability of transperineal ultrasound in the assessment of fetal breech descent in the birth canal, by measuring the breech progression angle (BPA). Methods: Women with a singleton pregnancy with the fetus in breech presentation between 34 and 41 weeks' gestation were recruited. Transperineal ultrasound images were acquired in the midsagittal view for each woman, twice by one operator and once by another. Each operator measured the BPA after anonymization of the transperineal ultrasound images. BPA was defined as the angle between a line running along the long axis of the pubic symphysis and another line extending from the most inferior portion of the pubic symphysis tangentially to the lowest recognizable fetal part in the maternal pelvis. Each operator was blinded to all other measurements performed for each woman. Intra- and interobserver reproducibility of BPA measurement was evaluated using the intraclass correlation coefficient (ICC). To investigate the presence of any bias, intra- and interobserver agreement was also analyzed using Bland–Altman analysis. Student's t-test and Levene's W0 test were used to investigate whether a number of different clinical factors had an effect on systematic differences and homogeneity, respectively, between BPA measurements. Results: Overall, 44 women were included in the analysis. BPA was measured successfully by both operators on all images. Both intra- and interobserver agreement analyses showed excellent reproducibility in BPA measurement, with ICCs of 0.88 (95% CI, 0.80–0.93) and 0.83 (95% CI, 0.71–0.90), respectively. The mean difference between measurements was 0.4° (95% CI, −1.4 to 2.2°) for intraobserver repeatability and −0.4° (95% CI, −2.6 to 1.8°) for interobserver repeatability. The upper limits of agreement were 12.0° (95% CI, 8.9–15.1°) and 13.6° (95% CI, 9.9–17.3°) for intra- and interobserver repeatability, respectively. The lower limits of agreement were −11.2° (95% CI, −14.3 to −8.1°) and −14.4° (95% CI, −18.2 to −10.7°) for intra- and interobserver repeatability, respectively. No systematic difference between BPA measurements was found on either intra- or interobserver agreement analysis. None of the clinical factors examined (maternal body mass index, maternal age, gestational age at the ultrasound scan and parity) showed a statistically significant effect on intra- or interobserver reliability. Conclusions: BPA represents a new feasible and highly reproducible measurement for the evaluation of fetal breech descent in the birth canal. Future studies assessing its usefulness in the prediction of successful external cephalic version and breech vaginal delivery are needed. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: Abnormal sulcation of the brain is frequently associated with severe malformations, but the prenatal diagnosis is challenging, especially in early pregnancy. OBJECTIVE: Our study aimed to investigate the value of Sylvian fossa sonographic biometry in the diagnosis of cerebral malformation in the second trimester of gestation. STUDY DESIGN: We prospectively established the normal values of the Sylvian fossa depth in a cohort of nonconsecutive patients, with singleton pregnancies and normal fetuses between 18+0 and 23+0 weeks’ gestation. For each patient, a coronal view of the fetal brain, with a clear visualization of the anterior complex and the Sylvian fissure, was acquired by 1 sonologist, who also measured the depth of the fossa. Reproducibility for each parameter was assessed by a second sonologist using stored images. We also retrospectively acquired the same measurements in second trimester fetuses with central nervous system anomalies. RESULTS: In 103 fetuses with a normal sonogram, the mean depth of the Sylvian fossa was 3.9±0.8 mm Interobserver reproducibility analysis demonstrated good results. Notably, 11 of 31 fetuses with cerebral malformations had a Sylvian fossa depth of

Objective To assess the performance of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses diagnosed with isolated corpus callosal (CC) anomaly on multiplanar ultrasound evaluation of the fetal brain (neurosonography). Methods This was a multicenter, retrospective cohort study involving 14 fetal medicine centers in Italy, UK, Portugal, Canada, Austria and Spain. Inclusion criteria were fetuses with an apparently isolated CC anomaly, defined as an anomaly of the CC and no other additional central nervous system (CNS) or extra-CNS abnormality detected on expert ultrasound, including multiplanar neurosonography; normal karyotype; maternal age >= 18 years; and gestational age at diagnosis >= 18 weeks. The primary outcome was the rate of additional CNS abnormalities detected exclusively on fetal MRI within 2 weeks following neurosonography. The secondary outcomes were the rate of additional abnormalities according to the type of CC abnormality (complete (cACC) or partial (pACC) agenesis of the CC) and the rate of additional anomalies detected only on postnatal imaging or at postmortem examination. Results A total of 269 fetuses with a sonographic prenatal diagnosis of apparently isolated CC anomalies (207 with cACC and 62 with pACC) were included in the analysis. Additional structural anomalies of the CNS were detected exclusively on prenatal MRI in 11.2% (30/269) of cases, with malformations of cortical development representing the most common type of anomaly. When stratifying the analysis according to the type of CC anomaly, the rate of associated anomalies detected exclusively on MRI was 11.6% (24/207) in cACC cases and 9.7% (6/62) in pACC cases. On multivariate logistic regression analysis, only maternal body mass index was associated independently with the likelihood of detecting associated anomalies on MRI (odds ratio, 1.07 (95% CI, 1.01-1.14); P = 0.03). Associated anomalies were detected exclusively after delivery and were missed on both types of prenatal imaging in 3.9% (8/205) of fetuses with prenatal diagnosis of isolated anomaly of the CC. Conclusion In fetuses with isolated anomaly of the CC diagnosed on antenatal neurosonography, MRI can identify a small proportion of additional anomalies, mainly malformations of cortical development, which are not detected on ultrasound. (c) 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Fertility in mammals is controlled by hypothalamic neurons that secrete gonadotropin-releasing hormone (GnRH). These neurons differentiate in the olfactory placodes during embryogenesis and migrate from the nose to the hypothalamus before birth. Information regarding this process in humans is sparse. Here, we adapted new tissue-clearing and whole-mount immunohistochemical techniques to entire human embryos/fetuses to meticulously study this system during the first trimester of gestation in the largest series of human fetuses examined to date. Combining these cutting-edge techniques with conventional immunohistochemistry, we provide the first chronological and quantitative analysis of GnRH neuron origins, differentiation and migration, as well as a 3D atlas of their distribution in the fetal brain. We reveal not only that the number of GnRH-immunoreactive neurons in humans is significantly higher than previously thought, but that GnRH cells migrate into several extrahypothalamic brain regions in addition to the hypothalamus. Their presence in these areas raises the possibility that GnRH has non-reproductive roles, creating new avenues for research on GnRH functions in cognitive, behavioral and physiological processes.

Objectives: The aims of this study were to review systematically literature on and describe the sonographic features and associated anomalies of total (TAPVC) and partial (PAPVC) anomalous pulmonary venous connection and scimitar syndrome (SS). Methods: A retrospective cohort study was carried out of cases of TAPVC, PAPVC and SS that underwent comprehensive ultrasound examination, seen over a 20-year period at two tertiary referral centers. Assessed variables included TAPVC subtype, gestational age at diagnosis, area behind the left atrium, ventricular disproportion, vertical vein, pulmonary venous obstruction, mode of diagnosis, association with cardiac and extracardiac conditions, and pregnancy and fetoneonatal outcomes. The outcome was considered favorable if the individual was alive and well (no functional impairment from surgery or cardiac or extracardiac conditions). Cases associated with right isomerism were excluded from the analysis, as TAPVC in these cases was only one of several major cardiac anomalies affecting sonographic signs. A systematic review was performed in order to obtain a synthesis of characteristics associated with TAPVC, PAPVC and SS. The literature search of PubMed and EMBASE (1970–2016) included reviews, case series and case reports. A meta-analysis was conducted only for TAPVC. Random-effects models were used to obtain pooled estimates of the frequencies of clinical characteristics and sonographic features. Results: For TAPVC, a total of 15 studies involving 71 patients (including 13 from the current cohort study) were included in the systematic review and meta-analysis. The pooled estimate for the association of TAPVC with congenital heart disease was 28.3% (95% CI, 18.1–41.3%) and with extracardiac anomalies it was 18.5% (95% CI, 10.5–30.6%). Of TAPVC cases, obstructed venous return was observed in 34.1% (95% CI, 22.7–47.7%), a favorable outcome in 43.8% (95% CI, 24.0–65.8%), ventricular disproportion in 59.2% (95% CI, 45.1–72.0%), increased area behind the left atrium in 58.1% (95% CI, 41.1–73.5%) and a vertical vein in 59.3% (95% CI, 41.1–75.3%). Diagnosis was established by using color or power Doppler in 84.9% (95% CI, 67.3–93.9%) of cases. For SS, there were only three studies describing eight cases, to which the current study added another five. Ventricular disproportion was present in three out of nine SS cases for which data were available, but for two of these, there was a concurrent heart anomaly. Color Doppler was used for all SS diagnoses, and four-dimensional echocardiography was useful in two out of six cases in which it was used. Outcome for SS cases was generally good. For PAPVC, there were only five studies describing five cases, to which the current study added another two. Major cardiac anomalies were associated in four out of seven of these cases, and extracardiac anomalies in three out of six cases for which data were available. Conclusions: TAPVC can be associated with other cardiac and extracardiac anomalies in a significant percentage of cases. Leading sonographic signs are ventricular disproportion, increased area behind the left atrium and the finding of a vertical vein. Color/power Doppler is the key mode for diagnosis of TAPVC. Obstructed venous return can be expected in roughly one-third of cases of TAPVC and outcome is favorable in less than half of cases. Data for SS and PAPVC are too few to synthesize. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVES To compare the efficiency of electronic spatiotemporal image correlation (eSTIC) with that of conventional STIC to acquire four-dimensional (4D) fetal cardiac volumes of diagnostic quality. METHODS This was a randomized controlled trial of 100 patients in mid-gestation with normal sonograms. In half of the cases, STIC volumes of the fetal heart were obtained with a conventional mechanical 4D probe and in the remaining cases eSTIC volumes were obtained with an electronic 4D probe. Examinations were kept within the timeframe allotted for a standard examination of fetal anatomy, and a maximum of two attempts were made at obtaining a 4D cardiac volume. Datasets were stored on a computer and subsequently analyzed and categorized as being of optimal, satisfactory or inadequate quality, depending on whether or not it was possible to perform an extended basic cardiac examination, including obtaining a three vessels and trachea view, as well as a clear reconstruction of both the aortic and ductal arches in the sagittal plane. RESULTS The eSTIC volume datasets were more frequently of optimal or satisfactory diagnostic quality compared with conventional STIC (94% vs 76%, P < 0.0001). Failure to obtain an eSTIC volume of adequate quality was in all cases the consequence of an unfavorable position of the fetus. CONCLUSIONS Compared with a standard mechanical probe, the electronic 4D probe facilitates acquisition of sonographic cardiac volumes in mid-trimester fetuses. In our hands, eSTIC volumes of optimal or satisfactory diagnostic quality, allowing a detailed offline evaluation of the fetal heart, were obtained in more than 90% of cases within the time frame of a standard examination of fetal anatomy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell-restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.

Purpose: The aim of our study was to evaluate the postmortem micro-CT anatomy of early fetal human fetal brains, either in situ or isolated. Methods: We studied 12 ex vivo specimens, 9 whole human fetuses (9–18 GW), and 3 isolated samples (16–26 GW). Specimens were fixed in formalin, then immersed in Lugol solution. Images were evaluated by two neuroradiologists. The depiction of CNS structures was defined based on the comparison between micro-CT images and a reference histologic anatomical Atlas of human brain development. Results: Micro-CT provided informative high-resolution brain images in all cases, with the exception of one case (9weeks) due to advanced maceration. All major CNS structures (i.e., brain hemispheres, layering, ventricles, germinal neuroepithelium, basal ganglia, corpus callosum, major cranial nerves, and structures of the head and neck) were recognizable. Conclusions: Micro-CT imaging of the early fetal brain is feasible and provides high-quality images that correlate with the histological Atlas of the human brain, offering multiplanar and volumetric images that can be stored and shared for clinical, teaching, and research purposes.

Objective: To evaluate whether changes in the cerebroplacental Doppler and birth weight (BW) suggestive of chronic fetal hypoxemia, precede the development of late-onset placental abruption (PA) after 32 weeks. Methods: In a multicenter retrospective study, the Doppler examinations of the fetal umbilical artery (UA) and middle cerebral artery (MCA) recorded after 32 weeks were collected in pregnancies subsequently developing PA. The BW centiles were calculated and the MCA pulsatility indices (PI), and UA PI were converted into multiples of the median (MoM). Afterwards, a comparison was made with a group of fetuses, which did not develop PA. Logistic regression was used to adjust for potential confounders and evaluate the feasibility of the prediction model. Results: Pregnancies complicated by late-onset PA (n = 31) presented lower MCA PI (p = 0.015) and were smaller (p < 0.001) than those who did not (n = 1294). Logistic regression analysis indicated that cerebral vasodilation was more important than umbilical flow in the explanation of PA (MCA PI OR = 0.106, p = 0.014 and UA PI OR 1.901, p = 0.32). In addition, the influence of BW exerted was residual (BW centile OR = 0.989, p = 0.15). Conclusions: Fetuses developing late-onset PA demonstrate significant cerebral vasodilation with scarce placental dysfunction, suggesting the existence of some kind of chronic hypoxemia that follows the late-onset pattern.

Zinc is a key element for growth and development. In this narrative review, we focus on the role of dietary zinc in early life (including embryo, fetus and preterm neonate), analyzing consequences of zinc deficiency and adequacy of current recommendations on dietary zinc. We performed a systematic search of articles on the role of zinc in early life. We selected and analyzed 81 studies. Results of this analysis showed that preservation of zinc balance is of critical importance for the avoidance of possible consequences of low zinc levels on pre- and post-natal life. Insufficient quantities of zinc during embryogenesis may influence the final phenotype of all organs. Maternal zinc restriction during pregnancy influences fetal growth, while adequate zinc supplementation during pregnancy may result in a reduction of the risk of preterm birth. Preterm neonates are at particular risk to develop zinc deficiency due to a combination of different factors: (i) low body stores due to reduced time for placental transfer of zinc; (ii) increased endogenous losses; and (iii) marginal intake. Early diagnosis of zinc deficiency, through the measurement of serum zinc concentrations, may be essential to avoid severe prenatal and postnatal consequences in these patients. Typical clinical manifestations of zinc deficiency are growth impairment and dermatitis. Increasing data suggest that moderate zinc deficiency may have significant subclinical effects, increasing the risk of several complications typical of preterm neonates (i.e., necrotizing enterocolitis, chronic lung disease, and retinopathy), and that current recommended intakes should be revised to meet zinc requirements of extremely preterm neonates. Future studies evaluating the adequacy of current recommendations are advocated.

Aims: Many authors do not recommend hypoglycemic treatment during pregnancy in women affected by monogenic diabetes due to heterozygous glucokinase (GCK) mutations (MODY 2) in case of affected fetus, because maternal hyperglycemia would be necessary to achieve a normal birthweight. We aimed to evaluate differences in birthweight between MODY 2 affected children according to the parent who carried the mutation. Methods: We retrospectively studied 48 MODY 2 affected children, whose mothers did not receive hypoglycemic treatment during pregnancy, divided into two groups according to the presence of the mutation in the mother (group A) or in the father (group B). Data were extracted from the database of the Regional Centre of Pediatric Diabetology of the University of Campania, Naples, collected from 1996 to 2016. We analyzed birthweight and centile birthweight. Results: Percentage of small for gestational age was significantly higher in group B than in group A. We found three large for gestational age in the group that inherited the deficit from the mother, all with the same novel GCK mutation (p.Lys458-Cys461del). Conclusions: We hypothesize that not all MODY 2 affected fetuses need the same levels of hyperglycemia to have an appropriate growth, maybe because different kinds of GCK mutations may result in different phenotypes. Consequently, a “tailored therapy” of maternal hyperglycemia, based on fetal growth frequently monitored through ultrasounds, is essential in MODY 2 pregnancies.

Objectives: To assess the feasibility and reliability of an automated technique for the assessment of the angle of progression (AoP) in labor by using three-dimensional (3D) ultrasound. Methods: AoP was assessed by using 3D transperineal ultrasound by two operators in 52 women in active labor to evaluate intra- and interobserver reproducibility. Furthermore, intermethod agreement between automated and manual techniques on 3D images, and between automated technique on 3D vs 2D images were evaluated. Results: Automated measurements were feasible in all cases. Automated measurements were considered acceptable in 141 (90.4%) out of the 156 on the first assessments and in all 156 after repeating measurements for unacceptable evaluations. The automated technique on 3D images demonstrated good intra- and interobserver reproducibility. The 3D-automated technique showed a very good agreement with the 3D manual technique. Notably, AoP calculated with the 3D automated technique were significantly wider in comparison with those measured manually on 3D images (133 ± 17° vs 118 ± 21°, p = 0.013). Conclusions: The assessment of the angle of progression through 3D ultrasound is highly reproducible. However, automated software leads to a systematic overestimation of AoP in comparison with the standard manual technique thus hindering its use in clinical practice in its present form.

In the last decades, technological development has led to an increasing use of devices and systems based on microwave radiation. The increased employment of these devices has elicited questions about the potential long-term health consequences associated with microwave radiation exposure. From this perspective, biological effects of microwave radiation have been the focus of many studies, but the reported scientific data are unclear and contradictory. The aim of this study is to evaluate the potential genotoxic and cellular effects associated with in vitro exposure of human fetal and adult fibroblasts to microwave radiation at the frequency of 25 GHz. For this purpose, several genetic and biological end points were evaluated. Results obtained from comet assay, phosphorylation of H2AX histone, and antikinetochore antibody (CREST)-negative micronuclei frequency excluded direct DNA damage to human fetal and adult fibroblasts exposed to microwaves. No induction of apoptosis or changes in prosurvival signalling proteins were detected. Moreover, CREST analysis showed for both the cell lines an increase in the total number of micronuclei and centromere positive micronuclei in exposed samples, indicating aneuploidy induction due to chromosome loss.

The aim of this article was to compare plasma estrone sulfate (E1SO4), clinical biochemistry, and milk yield of dairy cows carrying a female fetus from a bull (BULL) or from its clone (CLONE), evaluating also the relationship between the former variables and the birth weight of the newborn. Sixteen recipient dairy Friesian heifers (10 BULL and 7 CLONE) received a female embryo, obtained by in vitro embryo production and sexing by polymerase chain reaction with the semen of the BULL or the CLONE. Blood samples on all cows were obtained before feed distribution in the morning from jugular vein from 4 weeks before to 4 weeks after calving, to be analyzed for metabolic profile. The samples from late gestation were also analyzed for E1SO4 concentration. To separately assess the effect of calf birth weight (CBW), data were categorized as follows: low (46 kg; BWT-C). The plasma concentrations of β-hydroxybutyric acid (BHB, P=0.019), Na (P=0.002), Cl (P=0.026), strong cation-anion balance (P=0.020), total bilirubin (P=0.054), and α1-globulin (P=0.044) were higher in prepartum BULL recipients than those in CLONE, whereas BHB (P=0.021) and Mg (P=0.090) were higher in postpartum BULL recipients, while no differences were recorded in the remaining postpartum parameters. The CBW class had significant interaction with week of gestation on antepartum plasma estrone sulfate (P=0.021), whereas CBW per se affected antepartum plasma BHB (P=0.021), and nonesterified fatty acids (NEFA; P=0.011) being higher in BWT-C which also had the lower NEFA concentration during postpartum. Milk yield was unaffected by the sire used, both for quantitative and qualitative aspects. Cows carrying heavier fetus (BWT-C) had a different lactation affected by month compared with the other 2 CBW groups. From these results, there were no differences between BULL and CLONE recipients. Estrone sulfate, BHB, and NEFA may be used to predict CBW and provide different nutritional management during gestation.

Objective: A systematic review and pooled analysis was carried out to estimate whether the increase in the quantity of cell-free fetal DNA (cffDNA) before the onset of pre-eclampsia (PE) can predict the disease using real-time polymerase chain reaction (PCR). Method: A comprehensive literature search of the PubMed, Scopus, and Web of Knowledge databases was conducted to identify relevant studies that included evaluated cffDNA levels in pregnant women before the clinical onset of PE. A simulation model was generated to calculate the detection rate (DR) of cffDNA for PE, and a random variable was generated using the same number of cases and same statistical measurements of central tendency and dispersion as those reported in the papers considered for the analysis. Simulation of the receiver operating characteristic (ROC) curves was also carried out. Results: Four studies (82 cases and 1315 controls) evaluated cffDNA in early-onset PE, with DRs of 18 and 68.8% at 11–13 and 17–28 weeks, respectively, at a false positive rate of 10%. Nine studies (including two considered for early-onset PE) encompassing 376 cases and 1270 controls were available for the evaluation of ‘any PE’. At 11–14 weeks no significant DR was found, while at 15–28 weeks the DR was 37%. Conclusion: CffDNA quantification is a marker for predicting the development of both early-onset PE and ‘any PE’; however, it can probably only be used from the beginning of the second trimester, otherwise its predictive value is burdened with a DR that is too low or not significant. Due to the heterogeneity and difficulty in interpreting the published data, no conclusion regarding the statistical and clinical relevance, especially for screening ‘any PE’, can be made at present.

OBJECTIVE: To evaluate the accuracy of sonographic measurements of fetal soft tissue in the prediction of macrosomia. METHODS: Electronic databases were searched from their inception until September 2015 with no limit for language. We included only studies assessing the accuracy of sonographic measurements of fetal soft tissue in the abdomen or thigh in the prediction of macrosomia ≥34 weeks of gestation. The primary outcome was the accuracy of sonographic measurements of fetal soft tissue in the prediction of macrosomia. We generated the forest plot for the pooled sensitivity and specificity with 95% confidence interval (CI). Additionally, summary receiver-operating characteristics (ROC) curves were plotted and the area under the curve (AUC) was also computed to evaluate the overall performance of the diagnostic test accuracy. RESULTS: Three studies, including 287 singleton gestations, were analyzed. The pooled sensitivity of sonographic measurements of abdominal or thigh fetal soft tissue in the prediction of macrosomia was 80% (95% CI: 66-89%) and the pooled specificity was 95% (95% CI: 91-97%). The AUC for diagnostic accuracy of sonographic measurements of fetal soft tissue in the prediction of macrosomia was 0.92 and suggested high diagnostic accuracy. CONCLUSIONS: Third-trimester sonographic measurements of fetal soft tissue after 34 weeks may help to detect macrosomia with a high degree of accuracy. The pooled detection rate was 80%. A standardization of measurements criteria, reproducibility, building reference charts of fetal subcutaneous tissue and large studies to assess the optimal cutoff of fetal adipose thickness are necessary before the introduction of fetal soft-tissue markers in the clinical practice.

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B over expression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in JMML.

The aetiology of endometriosis, a gynaecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity, is still open to debate. Research has recently found evidence for endometriosis in human female fetuses at different gestational ages. This paper reports a new case of fetal endometriosis in a 25-week female fetus, deceased due to placental pathology, from a series of 13 female fetuses analysed at autopsy. The exact anatomical localization of this misplaced endometrium, as well as its histopathological and immunohistochemical characteristics are illustrated. The case suggests that endometriosis can be caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Fetal heart rate (FHR) sampling rate used on the bedside is equal or less than 4 Hz. Current FHR analysis methods fail to detect incipient fetal acidemia. In a fetal sheep model of human labour we showed that FHR sampling rates near 1000 Hz are needed to detect fetal acidemia. Trans-abdominal fetal ECG (t-a fECG) sampling FHR at 900 Hz combined with a complex signals bioinformatics approach showed promise in a human cohort. Here we validate this finding in a retrospective human cohort study by comparing the performance of the same bioinformatics approach to predict pH and BE at birth in the cohorts with FHR sampled either at 4 Hz or at 900 Hz.The 4 Hz FHR recording data sets consisted of the open access intrapartum CTG data base with n = 552 subjects used to develop the predictive model and another cohort of prospectively recruited n = 11 labouring women to then validate it. 900 Hz FHR data set comprised two prospectively recruited t-a fECG cohorts of n = 60 and n = 23 subjects. Recruitment criteria were similar across the cohorts. We have determined the goodness of fit (R(2)) and root mean square error (RMSE) as the performance indicators of the model on each cohort.The clinical characteristics of all cohorts were similar (gestational age 280 ± 8 d; gender 50% male; birth body weight 3.5 ± 0.5 kg; pH and BE at birth 7.25 ± 0.1 and -5.7 ± 3.4 mmol L( - 1), respectively; 1' and 5' Apgar scores at birth 8.5 ± 1.4 and 9.4 ± 0.6, respectively). The 4 Hz FHR cohort rendered-for pH and BE-R(2) = 0.26 and 0.2 and RMSE = 0.087 and 3.44, respectively. This could not be confirmed in the validation cohort for neither pH nor BE prediction. The 900 Hz FHR cohort rendered-for pH and BE-R(2) = 0.9 and 0.77 and RMSE = 0.03 and 1.70, respectively, and the pH prediction was validated.In our model, lower FHR sampling rate increased the predicted error range ~3-4 fold. We show that increasing FHR sampling rate to 900 Hz improves prediction of fetal pH and BE at birth. This should improve early identification of babies at risk of brain injury.

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2+ (also known as Tek) cellular pathway generating Csf1r+ erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.

Fetal monitoring during labour currently fails to accurately detect acidemia. We developed a method to assess the multidimensional properties of fetal heart rate variability (fHRV) from trans-abdominal fetal electrocardiogram (fECG) during labour. We aimed to assess this novel bioinformatics approach for correlation between fHRV and neonatal pH or base excess (BE) at birth.We enrolled a prospective pilot cohort of uncomplicated singleton pregnancies at 38-42 weeks' gestation in Milan, Italy, and Liverpool, UK. Fetal monitoring was performed by standard cardiotocography. Simultaneously, with fECG (high sampling frequency) was recorded. To ensure clinician blinding, fECG information was not displayed. Data from the last 60 min preceding onset of second-stage labour were analyzed using clinically validated continuous individualized multiorgan variability analysis (CIMVA) software in 5 min overlapping windows. CIMVA allows simultaneous calculation of 101 fHRV measures across five fHRV signal analysis domains. We validated our mathematical prediction model internally with 80:20 cross-validation split, comparing results to cord pH and BE at birth.The cohort consisted of 60 women with neonatal pH values at birth ranging from 7.44 to 6.99 and BE from -0.3 to -18.7 mmol L(-1). Our model predicted pH from 30 fHRV measures (R(2) = 0.90, P < 0.001) and BE from 21 fHRV measures (R(2) = 0.77, P < 0.001).Novel bioinformatics approach (CIMVA) applied to fHRV derived from trans-abdominal fECG during labor correlated well with acid-base balance at birth. Further refinement and validation in larger cohorts are needed. These new measurements of fHRV might offer a new opportunity to predict fetal acid-base balance at birth.

To investigate the immunohistochemical expression of Dyskerin, a biomarker involved in ribosome production and telomeres maintenance, in human fetal, adult and neoplastic bile ducts, as well as the possible correlations with cholangiocarcinoma aggressiveness.Sixty consecutive intrahepatic cholangiocarcinomas were collected and used for a tissue micro-array construction (total 176 cores); clinical data and follow-up were collected. Five fetal and 10 normal livers were included as controls. Automatic immunohistochemistry for Dyskerin, p53 and Ki67, and nucleolar silver-staining were performed. In normal livers, Dyskerin was negative in smaller bile ducts (mean 44.8 μm) and positive in the bile ducts with larger diameter (mean 116.1 μm; P

Establishment and maintenance of pregnancy represents a challenge for the maternal immune system since it has to defend against pathogens and tolerate paternal alloantigens expressed in fetal tissues. Regulatory T (Treg) cells, a subset of suppressor CD4(+) T cells, play a dominant role in the maintenance of immunological self-tolerance by preventing immune and autoimmune responses against self-antigens. Although localized mechanisms contribute to fetal evasion from immune attack, in the last few years it has been observed that Treg cells are essential in promoting fetal survival avoiding the recognition of paternal semi-allogeneic tissues by maternal immune system. Several functional studies have shown that unexplained infertility, miscarriage and pre-clampsia are often associated with deficit in Treg cell number and function while normal pregnancy selectively stimulates the accumulation of maternal forkhead-box-P3(+) (FoxP3(+)) CD4(+) Treg cells with fetal specificity. Some papers have been reported that the number of Treg cells persists at elevated levels long after delivery developing an immune regulatory memory against father's antigens, moreover these memory Treg cells rapidly proliferate during subsequent pregnancies, however, on the other hand, there are several evidence suggesting a clear decline of Treg cells number after delivery. Different factors such as cytokines, adipokines, pregnancy hormones and seminal fluid have immunoregulatory activity and influence the success of pregnancy by increasing Treg cell number and activity. The development of strategies capable of modulating immune responses toward fetal antigens through Treg cell manipulation, could have an impact on the induction of tolerance against fetal antigens during immune-mediated recurrent abortion.

The determination of fetal head position can be useful in labor to predict the success of labor management, especially in case of malpositions. Malpositions are abnormal positions of the vertex of the fetal head and account for the large part of indication for cesarean sections for dystocic labor. The occiput posterior position occurs in 15-25% of patients before labor at term and, however, most occiput posterior presentations rotate during labor, so that the incidence of occiput posterior at vaginal birth is approximately 5-7%. Persistence of the occiput posterior position is associated with higher rate of interventions and with maternal and neonatal complications and the knowledge of the exact position of the fetal head is of paramount importance prior to any operative vaginal delivery, for both the safe positioning of the instrument that may be used (i.e. forceps versus vacuum) and for its successful outcome. Ultrasound (US) diagnosed occiput posterior position during labor can predict occiput posterior position at birth. By these evidences, the time requested for fetal head descent and the position in the birth canal, had an impact on the diagnosis of labor progression or arrested labor. To try to reduce this pitfalls, authors developed a new algorithm, applied to intrapartum US and based on suitable US pictures, that sets out, in detail, the quantitative evaluation, in degrees, of the occiput posterior position of the fetal head in the pelvis and the birth canal, respectively, in the first and second stage of labor. Authors tested this computer system in a settle of patients in labor.

A conjoined twin is a rarity. It occurs 1 in 50,000 to 1 in 2,00,000 fetuses. Forty percent of the conjoined twins are stillborn and an additional one-third die within 24 h of birth. They result from late twinning events about 14th day after fertilization. We report a case of stillborn conjoined twins sent for autopsy. The bodies of the fetuses were fused from the thorax to the pelvis. There were two heads, three upper limbs and two lower limbs, with fusion of the thoracic, abdominal and pelvic regions. On systemic examination, some organs were fused and some were separate. A multilocular cyst with milky fluid was seen in the pelvic region. This case is reported in view of its rarity.

The aim of this study was to improve knowledge about transplacental transfer of an environmentally relevant PCB mixture by evaluating congener levels in livers and brains of rat dams and fetuses after maternal exposure, and correlating them to the levels of CYP450 and P-glycoprotein, involved in biotransformation and xenobiotics export, respectively. Pregnant dams were injected daily from gestation day (GD) 15 to 19 with 10 mg kg-1 of a reconstituted mixture (RM) composed of PCB138, 153, 180 and 126. Our data indicate that at GD20 RM is partitioned among maternal tissues, and that fetuses are not excluded from this distribution, evidencing a placental transfer of PCBs. Considering the ratio of maternal and fetal PCB concentrations based on lipid-weight, the amounts of congeners were 7-fold lower in fetal livers than in maternal livers and 25-30-fold higher in fetal brains than in maternal ones. Moreover, in dams the congeners were able to induce hepatic CYP450 response (total CYP450, CYP1A and CYP2B), but failed to increase P-170 expression, while in fetuses the constitutive expression of CYP450 and P-170 was not induced by treatment. Pearson Product-Moment Correlation applied to treated group data suggests that PCB accumulation in fetal livers, but not in brains, depended principally on their mothers' intoxication pattern. On the whole, these results emphasize the maternal liver and the fetal brain as depot organs for PCB sequestration and their susceptibility towards PCB toxicological risk. Moreover they highlight the lack of a coordinated response between the investigated defence mechanism. © 2009 Elsevier Ltd. All rights reserved.

OBJECTIVE: We sought to evaluate the association between fetal cerebroplacental ratio (CPR) and intrapartum fetal compromise and admission to the neonatal unit (NNU) in term pregnancies. STUDY DESIGN: This was a retrospective cohort study in a single tertiary referral center over a 14-year period from 2000 through 2013. The umbilical artery pulsatility index, middle cerebral artery pulsatility index, and CPR were recorded within 2 weeks of delivery. The birth-weight (BW) values were converted into centiles and Doppler parameters converted into multiples of median (MoM), adjusting for gestational age using reference ranges. Logistic regression analysis was performed to identify, and adjust for, potential confounders. RESULTS: The study cohort included 9772 singleton pregnancies. The rates of operative delivery for presumed fetal compromise and neonatal admission were 17.2% and 3.9%, respectively. Doppler CPR MoM was significantly lower in pregnancies requiring operative delivery or admission to NNU for presumed fetal compromise (P < .01). On multivariate logistic regression, both CPR MoM and BW centile were independently associated with the risk of operative delivery for presumed fetal compromise (adjusted odds ratio [OR], 0.67; 95% confidence interval [CI], 0.52-0.87; P = .003 and adjusted OR, 0.994; 95% CI, 0.992-0.997; P < .001, respectively). The latter associations persisted even after exclusion of small-for-gestational-age cases from the cohort. Multivariate logistic regression also demonstrated that CPR MoM was an independent predictor for NNU admission at term (adjusted OR, 0.55; 95% CI, 0.33-0.92; P = .021), while BW centile was not (adjusted OR, 1.00; 95% CI, 0.99-1.00; P = .794). The rates of operative delivery for presumed fetal compromise were significantly higher for appropriate-for-gestational-age fetuses with low CPR MoM (22.3%) compared to small-for-gestational-age fetuses with normal CPR MoM (17.3%). CONCLUSION: Lower fetal CPR, regardless of the fetal size, was independently associated with the need for operative delivery for presumed fetal compromise and with NNU admission at term. The extent to which fetal hemodynamic status could be used to predict perinatal morbidity and optimize the mode of delivery merits further investigation.

Aim: To assess whether a very high number of prenatal ultrasonographies affects birthweight. Population and methods: We studied 1203 consecutive women who delivered in Siena Hospital. Exclusion criteria were the following: twin pregnancy, maternal smoke or alcohol ingestion in pregnancy, gestational diabetes, placenta or umbilical cord defects, gestational age at birth < 37 weeks, and major malformations. We analysed birthweights in relation to the number of ultrasound examinations. 120 women had undergone a minimum number (three or less-base group) and 167 a maximum number (nine or more-intensive group) of fetal US scans. We compared the birthweight of the children born in these two groups and the correlation between number of Us scans and birthweight in the whole population. Results: Mean birthweights of the base and the intensive groups were 3389.5 ± 434 g and 3268 ± 438 g, respectively (p = 0.0206). Nevertheless, the regression study did not show a significant correlation between birthweight and number of US scans. The mean age of the base group was 30.1 ± 5.3 years and that of the intensive group was 32.09 ± 4.99 years (p = 0.0018). Eighteen women of base group underwent amniocenteses vs. 71 in the intensive group (p < 0.001). In the base group 57.5% of the mothers had low school level vs. 24.4% in the intensive group (p < 0.01). Conclusion: More studies are needed to confirm or exclude any relationship between an intensive use of prenatal ultrasounds and birthweight, and to exclude other effects of ultrasounds on children's health. Moreover, our study shows an excess of prenatal diagnostic procedures, the causes of which should be investigated © 2005 Elsevier Ireland Ltd. All rights reserved.

We identified zonulin, a novel human protein analogue to the Vibrio cholerae derived Zonula occludens toxin, which induces tight junction disassembly and a subsequent increase in intestinal permeability in non-human primate intestinal epithelia. Zonulin expression was raised in intestinal tissues during the acute phase of coeliac disease, a clinical condition in which tight junctions are opened and permeability is increased.

The 10.1.2 MoAb reacts with a novel alpha chain that associates with the beta 1 integrin chain and is widely distributed among epithelial and endothelial cells of human adult and fetal tissues. In the epidermis and in other squamous epithelia, alpha 10.1.2 chains are expressed exclusively in the basal cell layer. Here we describe the immunohistochemical localization of alpha 10.1.2 in human epidermis, in other squamous epithelia, as well as in cultured keratinocytes. alpha 10.1.2 chain localization has also been investigated in a variety of non-neoplastic and neoplastic lesions of the skin, the uterine cervix, and the lung. We show that alpha 10.1.2 chains retain their basal keratinocyte localization in hyperplastic skin diseases and in benign tumors of the epidermis and that they are strongly expressed in basal cell carcinomas. In contrast, alpha 10.1.2 expression is decreased in keratinocytes that differentiate in vitro and is lost in epidermal dysplastic conditions, in the invading front of squamous cell carcinomas of the epidermis, in microinvasive cervical cancers, and in well-differentiated squamous lung tumors. These findings indicate that alpha 10.1.2 beta 1 integrin is downregulated during keratinocyte differentiation in vitro and in vivo. Moreover, lack of alpha 10.1.2 expression in basal cells of squamous epithelia is associated with early dysplastic changes and with the acquisition of invasive capacity.