Antiretroviral therapy (ART) in pregnancy has resulted in a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV. However the safety of in utero ART exposure in newborns remains a concern.A multicenter prospective observational study of HIV-infected mother and their infants was performed in Madrid, Spain, from 2000 to 2009. Children had regular visits with clinical examination according to protocol until the age of 24 months. An abdominal ultrasound and an echocardiogram were scheduled during follow up. Birth defects (BDs) were registered according to European Surveillance of Congenital Anomalies (EUROCAT).A total of 897 live births from 872 mothers were included. Overall the birth defects prevalence observed was 6.9% (95% CI 5.4-9.1).The most commonly reported birth defects types were in genital organs and urinary system  and cardiovascular system . There was no increased risk for infants exposed in the first trimester to ARVs compared with unexposed infants. No significant associations were observed between exposure to any individual antiretroviral agent during pregnancy and birth defectsA higher prevalence of BDs was observed, higher than previously reported. In utero exposure to ART was not proved to be a major risk factor of birth defects in infants. However the relatively small number of patients is a major limitation of this study. Antiretroviral therapy (ART) in pregnancy has a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV . In 1994There are concerns about potential adverse events in newborns exposed to ART during pregnancy, including birth defects. Different prevalences of birth defects (BDs) have been reported in studies with large number of subjects from Europe and United States. While some studies have not detected an overall increase in the prevalences of birth defects (BDs) associated with ART exposure in pregnancy ,7], oth, oth7], Some studies have reported elevated risks with specific exposures. Nucleoside reverse transcriptase inhibitors have a high transplacentary passage -12]. Th. Th12]. Exposure to efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) has been associated with central nervous system defects in monkeys , and casThe continued surveillance of birth defects in newborns exposed to antiretrovirals in utero is required, more even when newer antiretroviral agents become available. The aim of our study was to estimate the prevalence of birth defects in children exposed in utero to ARV drugs and to assess the association between in utero exposure to antirretovirals and birth defects in the Madrid Cohort of HIV-infected mother-infants pairs.The Madrid Cohort of HIV-infected mother-infants pairs is a multicenter prospective observational study of HIV-infected pregnant women and their infants followed up since birth. Beginning in 2000, pregnant women and infants were recruited in 8 hospitals in Madrid, Spain. All participants gave verbal informed consent and the study was approved by the Clinical Research Ethics Committee at Hospital Universitario de Getafe.The baseline characteristics of the cohort and the mother-to-child transmission of HIV data have been provided previously .A collabThe cohort for the current analyses includes pregnancies with a definitive outcome through December 31, 2009.+ lymphocyte counts and percentage were collected at each scheduled visit. Start and stop dates were recorded for each antiretroviral agent used. Maternal viral load less than 50 copies/ml was defined as ‘undetectable’.Women were visited during pregnancy, at delivery and at postpartum. Women with a previous diagnosis of HIV infection were enrolled in the first visit of pregnancy. Women who were diagnosed with HIV infection during pregnancy were enrolled in the first visit after the diagnosis. Information on maternal demographic characteristics was recorded. At each visit, a medical history and a physical examination was performed. Blood count, biochemistry panel, HIV-1 viral load (plasma quantitative HIV-1 RNA level) and CD4Trimesters of pregnancy were defined as follows: first trimester, the first day of the last menstrual period through 13 completed weeks of gestation; second trimester, 14 through 28 completed weeks of gestation; and third trimester, beginning at 29 weeks of gestation until delivery.ART in pregnant women was classified as: none, monotherapy with zidovudine, dual therapy and any combination of 3 or more drugs was categorized as HAART. HAART was further categorized according to whether a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) was included. ART treatment administered during pregnancy was recorded, with the dates when started and stopped. Exposure status for each drug was categorised as unexposed, exposed during first trimester, or exposed since the second or third trimester. Birth defects were studied associated to exposure to each drug in first or since second or third trimester compared to no exposure.A self-report of illicit drug use or a positive urine test result for heroin or opiates, methadone or cocaine was registered. Other variables like cigarette smoking and alcohol use were also self-reported. Diabetes was included as a maternal condition in the analysis. However no other drugs different from ARV were analysed.Stillbirths and termination of pregnancy are not considered in this analysis. Newborn/infant visits occurred at birth, after 2 or 3 and 6 weeks and thereafter 3, 6, 12, 18 and 24 months. Children had regular visits with clinical examination according to protocol until the age of 24 months. Each visit included a medical history and a physical examination. An abdominal ultrasound was also performed in the first month of life, and an echocardiogram during the first 24 months of life by protocol.‘Premature birth’ was defined as children born before 37 weeks of pregnancy. ‘Low birth weight’ was defined as children born weighing from 1.500 to 2.500 g; ‘very low birth weight’ was defined as 1.499 g or less.Birth defect was defined as a structural defect of the body or organ system that may affect viability, quality of life and often requiring surgery .Abnormalities in the fetus/newborn/infant were determined from all available data, including prenatal ultrasound examinations, physical examinations in the newborn period and at each follow-up visit.Abnormalities observed in the active surveillance system including abdominal ultrasound in neonatal period or echocardiograms during follow-up, as scheduled in the follow-up of this cohort, were also included.BDs were recorded and classified according to EUROCAT  , a simpl“Minor” anomalies are excluded, when isolated, because they have lesser medical, functional or cosmetic consequences. We also exclude anomalies which are not always truly congenital in origin, sometimes associated with immaturity at birth.Angiomas, congenital nevi, pre-auricular appendices, sinus nodules, sacral dimples, atresia of the tears ducts, ovarian cysts, hydrocele, hip dislocation not associated to dysplasia, renal pelvis dilatation of less than 10 mm , inguinal and umbilical hernias were not classified as BDs and therefore also not included.These cases have not been reported previously to the Antiretroviral Pregnancy Registry or any other regulatory authorithy.The categorical variables were expressed as frequencies and percentages, while numerical variables were presented as means, medians, standard deviation, and interquartile range. The categorical variables were compared using the chi square, linear tendency chi square or Fisher’s exact test when considered appropriate. Continuous variables were analyzed with ANOVA test, or, in case of non normal distributions, using a non-parametric test. Regression logistic model was used to estimate the strength of association between birth defect and ARV trimester exposure. Results are presented as crude and adjusted odds ratio and 95% confidence intervals (CIs) adjusted for alcohol and illegal drug use during pregnancy. All p values are two-sided p-values and a p value of < 0.05 was considered as statistically significant. The data were analysed with the SPSS  program, version 15.0 for Windows.During the study period 898 children, including 25 twins or triplets, were considered for this analysis.The baseline characteristics of the mothers by antiretroviral exposure  are compared in Table Women had a good immunological condition status at baseline, and there was no significant difference observed in CD4 lymphocyte counts between the three groups.Eighty women (8.9%) did not receive treatment during pregnancy. For those who treatment was known during pregnancy, ten women (1.2%) received monotherapy with zidovudine; 21 women  received dual therapy (zidovudine plus lamivudine or nevirapine) and 709 (86.6%) received HAART. More than a third of infants (36.7%) had early in-utero exposure.Four hundred and seventy one infants (52.9%) were males. The median gestational age was 38 completed weeks [interquartile range (IQR): 37–39 weeks]. One hundred and ninety four infants were premature (22.8%); 221 infants (25.6%) presented low weight at birth. The median time of follow-up of the children was 18 months (interquartile range 12–24 months).Among the study population, major birth defects were recorded in 62 infants, presenting an overall prevalence of 6.9% (95% CI: 5.3-8.7). There were 70 anomalies identified in these 62 infants. Minor defects, classified according EUROCAT, were excluded.The prevalence of birth defects among HIV-infected women with first-trimester antiretroviral exposure was 7.0% (95% CI: 4.5-10.3). No significant differences were found in the BD prevalence of children receiving intrauterine ART during the first trimester of pregnancy compared with those who started later  or those non exposed to antiretroviral treatment during pregnancy .The most commonly reported birth defects were in genital organs and urinary system , cardiovascular system , musculoskeletal  and digestive system   but although there was a slight difference, the association did not reach significance for preterm delivery .The type of treatment received by their mothers  was not associated with BD Table .In analysis there was no significant association with exposure to specific drugs. Table . There wWe observed a high prevalence of defects after atazanavir exposure, even when we broke down this result by trimester of exposure (16.7% in first trimester and 15.8% in second/third trimester). The defect after atazanavir exposure in first trimester was oesophageal atresia, and the defects after atazanavir exposure in second/third trimester were Pierre Robin syndrome, hydronephrosis and atrial septal defect.As we observed differences between baseline characteristics of HIV infected mothers and time of earliest antiretroviral therapy during pregnancy, we analysed the association between birth defect and ARV treatment exposure adjusted for age, alcohol and illegal drug use, but not significant differences were found Table .A major birth defects prevalence of 6.9% was observed in this cohort. This population of infants born to HIV-infected women was similar to other European cohorts in aspects such as the characteristics of the mothers and rates of perinatal HIV transmission. However, the prematurity rates in our cohort are higher than in other cohorts ,5],24],[24]5],5],. The preA difference has to be established between passive surveillance systems  and active surveillance systems, which include ultrasound scans and echocardiogram in all infants with follow-up from birth. Active surveillance systems, usually show higher BD prevalences. In more than thirty thousand of German newborns not exposed to ART, an active vigilance study showed a BD prevalence of 6.9% .We have reported 17 cardiac malformations, including 9 atrial septal defects and 4 ventricular septal defects. Some authors have reported that early screening echocardiography can detect important subclinical malformations and produce prevalences of cardiac defects of 5% to 10% higher than expected ,32]. We. We32]. There are obviously ethnic and environmental factors related to BDs. However we could not show any association between ethnic group and BD in our cohort Table . In prevPreterm birth and birth defects, especially congenital heart defects have been previously associated. Based on these results, it has been suggested that an underlying mechanism or a genetic disorder could explain this association . We coulThe use of illicit drugs during pregnancy  was not associated with BD. Two cases of foetal alcoholic syndrome were documented. Mothers of these two children reported to consume large amounts of alcohol. However, we could not observe an association between alcohol consumption and BD. Alcohol was a self-reported variable, and it was an important limitation for its analysis.We did not detect any significant association between BD prevalence and type or timing of ART in pregnancy. First-trimester antiretroviral exposure was not significantly associated with birth defects. This fact is consistent with most of the reports concerning BD and ART, which do not show an increased risk of teratogenesis in infants exposed to ART in the first trimester of pregnancy. However, others studies have found higher rates of BD associated a specific ARV drugs. Exposure to zidovudine in first trimester have been associated to higher prevalence of hypospadias  but alsoAccording to the type of drug used Table , no signRecently a significant association was found between indinavir and head and neck defects. In our cohort, we observed a higher prevalence of defects in children exposed to indinavir in the first trimester, however, this difference did not reach significance and did not concern head or neck defects.This study has several limitations. In prospective cohorts the confounding factors are not sufficiently controlled and can lead to bias due to the interpretation of the results. We have not consider for analysis stillbirths and termination of pregnancy. Data as smoking or using illicit drugs during pregnancy were self reported. Also no other drugs used during pregnancy were analysed in this report. The major limitation of our study is the small number of children exposed to ARV in first trimester. We have not analysed any association of specific BDs with each ARV drug. For this reason, no conclusion could be assessed when the number of exposures in first trimester is low. Cohort collaborations and long term follow up are required to further analysis.In conclusion, a higher prevalence on BDs in infants born to HIV-infected women was observed in this report. However, in utero exposure to ART was not associated to BD. The relatively small number of patients is a major limitation for further analysis in this study.Hospital Universitario 12 de Octubre: MI González-Tomé, E Muñoz, O Nieto, P Rojo, JM Hernández-García, R Rubio, F Pulido, D Lora, A Gómez de la Cámara, M de Matías, B Fraile, D Blázquez, LI González-Granado, A Navas.Hospital Universitario La Paz: MI de José, JM Peña, M González, MJ Mellado, L Escosa.Hospital General Universitario Gregorio Marañón: ML Navarro, J Saavedra, MDGurbindo, MC Viñuelas, P Miralles.Hospital General de Móstoles: MA Roa, C Garaulet.Hospital Severo Ochoa: I Olabarrieta, MJ Santos, N Martínez, G Alonso.Hospital Príncipe de Asturias: J Beceiro, S Oñate.Hospital Ramón y Cajal: A Holguín, P Rojas, C Fernández.Hospital Universitario de Getafe: JT Ramos, B Soto, A Álvarez, M Fernández Ibieta, S Guillén, E Iglesias, I Cuadrado, I Solis, G Gaspar, L Prieto, I García de Diego.


A 45-year-old caucasian man with progressive dyspnea appeared to have a giant intrathoracic cyst in the anterior mediastinum encasing the heart and compressing both lungs. He underwent succesful removal of the cyst through a median sternotomy. Recovery was uneventful. Gross examination revealed a thin-walled cyst filled with clear fluid. Microscopic histopathologic examination revealed a cyst wall lined by cubic cells and underlying loose connective tissue with remnants of thymic tissue. The definitive diagnosis was an intrathoracic (simple) mesothelial cyst. An intrathoracic mesothelial cyst is a benign, generally asymptomatic tumor that can be located in the anterior cardiophrenic angle, the paravertebral or paratracheal regions, or in the anterior mediastinum. It can become rather large before it becomes symptomatic, at which point surgical removal is generally warranted.The online version of this article (doi:10.1186/s13019-014-0152-2) contains supplementary material, which is available to authorized users. An intrathoracic mesothelial cyst is a congenital abnormality and represents 3-6% of mediastinal tumors ,2]. The. The2]. A 45-year-old caucasian man with no significant past medical history was referred to our institution with progressive dyspnea. A chest X-ray showed a large mass in the anterior mediastinum Figure A,B. TranThe patient chose to have the cyst removed due to its symptomatic nature and he underwent successful removal of the giant cyst through a median sternotomy. Due to the location and size of the cyst and in order to keep the cyst intact during resection, we were required to perform a median sternotomy. The cyst did not involve the pericardium or other surrounding structures. Only mild adhesions were encountered and the cyst was left intact during resection. The cyst was thin-walled and filled with clear fluid Figure E. A postMicroscopic histopathologic examination Figure G showed An intrathoracic mesothelial (or “coelomic”) cyst is a congenital abnormality. Little is known about the exact embryology, but mesothelial cysts are hypothesized to occur as a result of an anomaly in the development of the pericardial coelom . MesotheThe optimal management of intrathoracic mesothelial cysts is unknown. Due to its benign nature most asymptomatic cysts only require serial follow-up imaging . SymptomAn intrathoracic mesothelial cyst is a benign, generally asymptomatic tumor that can be located in the anterior cardiophrenic angle, the paravertebral or paratracheal regions, or in the anterior mediastinum. It can become rather large before it becomes symptomatic, at which point surgical removal is generally warranted.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Supplemental Digital Content is available in the text. P=0.002). This postnatal loss varied according to the vasculogenic capacity of the endothelial cells of the infant at birth . The degree of reduction in both in vitro and postnatal in vivo vascular development was proportional to levels of antiangiogenic factors in the maternal circulation. In conclusion, our data indicate that offspring born to hypertensive pregnancies have reduced vasculogenic capacity at birth that predicts microvessel density loss over the first 3 postnatal months. Degree of postnatal microvessel reduction is proportional to levels of antiangiogenic factors in the maternal circulation at birth.Offspring of hypertensive pregnancies are more likely to have microvascular rarefaction and increased blood pressure in later life. We tested the hypothesis that maternal angiogenic profile during a hypertensive pregnancy is associated with fetal vasculogenic capacity and abnormal postnatal microvascular remodeling. Infants (n=255) born after either hypertensive or normotensive pregnancies were recruited for quantification of postnatal dermal microvascular structure at birth and 3 months of age. Vasculogenic cell potential was assessed in umbilical vein endothelial cells from 55 offspring based on in vitro microvessel tube formation and proliferation assays. Maternal angiogenic profile  was measured from postpartum plasma samples to characterize severity of pregnancy disorder. At birth, offspring born after hypertensive pregnancy had similar microvessel density to those born after a normotensive pregnancy, but during the first 3 postnatal months, they had an almost 2-fold greater reduction in total vessel density (−17.7±16.4% versus −9.9±18.7%;  Alternatively, there may be a more direct association between fetal and fetoplacental vascular development with long-term consequences for later risk of cardiovascular diseases. Consistent with this hypothesis, offspring born to preeclamptic mothers have evidence of altered endothelial cell function from very early in life14 and, in both experimental hypertensive pregnancy models and human studies, display altered microvascular structure.18 However, the timepoint when microvascular structural differences emerge and the degree to which they relate to endothelial cell dysfunction in the offspring or the severity of angiogenic markers in the mother is unclear.Placental dysfunction is thought to be a primary event in a large proportion of women who go on to develop more severe, new-onset hypertension during pregnancy. The ischemic placenta triggers an adverse maternal circulatory milieu, including deranged angiogenic factors, inflammation, and oxidative stress.19 We then determined whether these vascular developmental differences are predicted by angiogenic markers in the maternal circulation.Therefore, we studied whether there is a correlation between fetal vascular cell potential at birth and microvascular development, in particular, during the critical postnatal phase, as the disorderly fetal microvascular plexus remodels into the mature ex utero horizontal papillary loop structure.Between 2011 and 2015, 600 mothers being cared for by Oxford University Hospitals NHS Foundation Trust were identified by their clinical care team and invited to take part in ≥1 of a portfolio of studies coordinated by the Oxford Cardiovascular Clinical Research Facility. These studies investigated associations between pregnancy complications and cardiovascular development during fetal and neonatal life . In addition, we performed in vitro assays using human umbilical vein endothelial cells (HUVECs) provided under ethical approval from the Oxford Cardiovascular Tissue Bioresource . Matched in vivo measures and cell samples were available for a subset of offspring whose mothers had participated in both studies.To study microvascular development, we used maternal blood samples and longitudinal in vivo microvascular measures at birth and 3 months of age in the offspring recruited to the Effect of Prematurity and Hypertensive Disorders of Pregnancy on Offspring Cardiovascular Health (EPOCH) study . A stratified recruitment strategy was used in this study to recruit similar numbers of mother and infant dyads from hypertensive and normotensive pregnancies across a range of gestations and hypertensive pregnancy disorders, including pregnancy-induced hypertension and preeclampsia, defined according to International Society for the Study of Hypertension in Pregnancy guidelineshttps://clinicaltrials.gov (NCT0188870).Mothers with a history of hypertension before pregnancy were excluded, as were infants with evidence of congenital cardiovascular disease, chromosomal abnormalities, or genetic disorders. Those with persistent features of a fetal circulation at birth, ie, a persistent ductus arteriosus or atrial septal defect, were not excluded, but the presence was recorded. All mothers gave written informed consent and assent for involvement of their children, including permission to access maternal and offspring clinical records and link data between studies. Systems for collection of clinical data and characterization of pregnancy complications based on medical records and questionnaire were standardized across studies and performed by the same data collection team . Data collection details are available from online-only Data Supplement]. Blood samples collected from the mothers when the infants had their postnatal assessment were centrifuged and separated within 30 minutes for storage at −80°C pending analysis. Plasma circulating vascular endothelial growth factor A, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor, and soluble endoglin concentrations were quantified with commercial ELISAs according to standard manufacture protocols . To confirm measures at this early postnatal time point reflected levels during late pregnancy, we additionally measured the angiogenic factor sFlt-1 in a group of women who had samples collected at 34 weeks of gestation and 5 days postnatally. A subgroup of them also had measures at 3 months postnatally.At both the birth and 3-month assessments, blood pressure and anthropometry were assessed using standard methodology . Analysis was performed by 1 of the 3 operators  blinded to the clinical background of the clip. Coefficient of variation for intra- and interobserver variability based on 10 sequences was 4.35% (intraobserver) and 6.54% (interobserver) for total vessel density (TVD) and 4.46% (intraobserver) and 6.10% (interobserver) for De Backer (DB) score.Imaging of the axillary small-vessel network was performed with Side Stream Dark Field imaging , as previously reported for neonatesonline-only Data Supplement). Angiogenic capacity was assessed by 2 complementary approaches: tube formation assays, including Matrigel and coculture with human bone marrow stromal mesenchymal stem cells, and CyQUANT NF Cell Proliferation assay (Methods in the online-only Data Supplement).Umbilical cords were collected at birth, and HUVECs were isolated and stored according to standard operating procedures (Methods in the online-only Data Supplement). A sample size of 200 for the clinical study provided 80% power at a significance level of α=0.05 to detect a difference of 0.35 SD between equal-sized groups. For the in vitro tube formation cohort, a sample size of 50 provided 80% power at a significance level of α=0.05 to detect a difference of 0.75 SD between groups.Statistical analysis was performed using SPSS version 22 and GraphPad Prism 6.0 (full details are provided in the Methods in the online-only Data Supplement). Hypertensive and normotensive pregnancy groups were matched for maternal age and smoking, sex ratio, birth order, gestational age and age at birth, and follow-up assessments. Maternal body mass index and blood pressure  were higher in the hypertensive group (P<0.001), and the infants had lower birthweight Z score (P=0.002) with greater incidence of iatrogenic delivery (P=0.02). Microvascular measures at both birth and 3 months were available for 197 infants. Of those initially recruited, one was excluded because of a subsequent diagnosis of Turner syndrome and, of the remainder, both sets of images were not available because of nonattendance at 1 visit or equipment failure (5 visits), unanalyzable images (6 scans), or inability to obtain image (4 scans). There were no differences in the demographic or clinical characteristics of those with or without microvascular images at both timepoints (data not presented).Maternal and offspring demographic and anthropometric characteristics are presented in Tables P=0.002 and DB change, −9.6±17.2 versus −17.3±17.7; P=0.002) so that by 3 months, TVD was significantly lower in the hypertensive pregnancy group  with a borderline difference in the semiquantitative DB score .There were no differences in TVD or DB score between the offspring born to normotensive and hypertensive pregnancies at birth  and systolic and diastolic blood pressures during pregnancy. Samples available for normotensive mothers from the Cardiovascular Tissue Bioresource tended to have been collected at term, and so there were differences in gestational age (P=0.03) and exposure to antenatal steroids (P<0.001) and in higher birth weight Z score (P=0.002) and lower rates of iatrogenic delivery (P<0.001). The hypertensive pregnancy history tended to be more severe in the available tissue samples with a higher incidence of abnormal maternal liver function tests (P<0.001) and edema (P<0.001).Maternal and fetal characteristics of the samples used for microvessel tube Matrigel measures are presented in Tables P<0.001) and branching . These differences were validated in a subgroup (n=14) by coculture tube formation  and branching  compared with cells from normotensive pregnancies. Furthermore, proliferation evaluated by CyQUANT assay in a subset  showed hypertensive pregnancy HUVECs had significantly slower growth, presented as fold change between day 3 versus day 0, than those from normotensive pregnancies .Hypertensive pregnancy HUVECs developed a more fragmented, shorter capillary-like microvascular network in Matrigel compared with HUVECS from normotensive pregnancies Figure C, i withn Figure C, ii, whr=0.56; P=0.004; Figure r=0.55; P=0.006; Figure Umbilical-derived cell samples and in vivo microvascular measures were available in the same individuals for 28 participants (10 hypertensive and 18 normotenisve pregnancies). In vitro tubule length and branching were not associated with in vivo measures at birth, but there was a graded positive association between in vitro total tubule length and the loss of in vivo microvascular density over the first 3 postnatal months  and branching (P=0.007 and P<0.001) were evident in both preterm and term hypertensive pregnancies compared with term normotensive pregnancies .In view of the association between preterm birth and hypertensive pregnancy disorders, we additionally performed analysis separately in those born term and preterm. TVD was higher in offspring born preterm to both hypertensive and normotensive pregnancies than offspring born term pregnancies Figure A, i, andr=0.85; P=0.007; Figure S1). By 3 months, levels had fallen to very low values and no longer reflected either late gestation or early postnatal values. Therefore, associations identified with measures at 5 days are likely to relate to variation during pregnancy. There was a graded relationship between maternal sFlt-1 level and offspring microvessel loss between birth and 3 months . Similar relations were evident between maternal sFlt-1 level and in vitro offspring tube formation . To study whether these associations represented coassociation with other factors linked to hypertensive pregnancy, we performed a sensitivity analysis in normotensive pregnancies. Interestingly, significant differences across tertiles of sFlt-1 in mothers who had not developed hypertension were still evident for offspring TVD change .Maternal postnatal blood samples were available for 107 mother and offspring dyads. Samples were collected on average 5 days after birth, at which point, maternal soluble endoglin levels were still significantly higher in hypertensive mothers with a trend for higher sFlt-1 and lower vascular endothelial growth factor  and branching .To study the role of other perinatal factors, we performed bivariable regression analyses with in vitro and in vivo measures (Table S2). For TVD, there were associations with blood pressure at birth, birthweight Z score, gestational age, and exposure to antenatal steroids. However, there was significant colinearity between antenatal steroid exposure and preterm birth with no differences in those born in late gestation who had received antenatal steroids compared with those who had not (data not shown). Therefore, offspring blood pressure at birth, birthweight Z score, and gestational age were taken forward into a multivariate model with maternal hypertension Table . In thisThis study provides the first evidence of an ≈2-fold greater postnatal reduction in microvascular density in neonates born after pregnancies complicated by new onset hypertension compared with normotensive pregnancies. Degree of microvessel loss was predicted by the vasculogenic capacity of their endothelial cells at birth, which, in turn, related to maternal angiogenic factors. These phenomena were evident across the spectrum of hypertensive pregnancy disorders and not attenuated by an increased vascular density in those born preterm. Intriguingly, associations were present in normotensive pregnancies if maternal antiangiogenic factors had been higher around the time of birth. These findings identify a critical postnatal microvascular developmental window and provide a potential explanation for how pregnancy pathophysiology links with microvascular rarefaction in the offspring in later life.23 occurs as the disorderly fetal capillary network remodels into a horizontal subpapillary plexus and singular papillary loops structure. We hypothesized that this may be a critical period for microvascular remodeling, sensitive to inherent changes in infant endothelial cell function. Our observation that, at birth, normotensive and hypertensive pregnancy offspring had similar vessel density but then there was a loss of vessel density in the hypertensive pregnancy group and highlights the apparent importance of the postnatal window. Similar changes were seen across the spectrum of hypertensive pregnancy disorders. However, clinical diagnostic criteria may have lacked specificity for identification of offspring at the greatest risk, and maternal biomarkers may better reflect disease severity.24 Consistent with this hypothesis, maternal sFlt-1 after birth predicted offspring vascular postnatal changes. Strikingly, sFlt-1 associated with vascular phenotype when analysis was restricted to normotensive, full-term or appropriate for gestational age pregnancy groups. Hypertensive pregnancy syndromes may sit at one end of a spectrum,25 with subclinical endothelial activation, low-grade inflammation, and cardiovascular dysfunction26 evident in a broader group of apparently clinically normal pregnancies.7 Normotensive mothers who have hypertension risk factors tend to have an antiangiogenic pregnancy profile.29 Therefore, our findings may have relevance to a broader group of offspring than defined by hypertensive pregnancy alone.A small reduction in TVD during the first 3 postnatal months28 but differences in placental growth factor are most evident in midpregnancy.31 Biological reasons for persistent, postpartum elevation of antiangiogenic markers could be relevant to the underlying mechanisms for postnatal offspring differences as this would identify mothers with an inherent, abnormal antiangiogenic response or an extraplacental sources of sFlt-1.32 However, our longitudinal study of maternal sFlt-1 levels suggests that there is a general persistent elevation for several days after delivery and that values at this timepoint do not reflect baseline values measured 3 months postnatally. Nevertheless, adults born to hypertensive pregnancies have differences in circulating levels of sFlt-1 in later life,16 and persistent elevations in antiangiogenic factors in the infant may also be relevant. Serum from preeclamptic mothers inhibits normal HUVEC tube formation33 and angiogenic factors in umbilical cord blood, although significantly lower, reflect maternal levels.11 However, in our in vitro assays, with control media, tubulogenesis was still reduced, suggesting a specific alteration in cellular phenotype. As endothelial colony-forming cells account for a proportion of HUVECs,34 our findings may indicate a common endothelial cell dysfunctional phenotype previously described for cord blood endothelial colony-forming cells collected after preeclamptic pregnancies. These exhibited delayed colony development13 and, after preterm birth, were fixed in an antiangiogenic state.35 If so, we have linked for the first time this altered in vitro cellular behavior with in vivo vascular responses and maternal measures.On placental delivery, maternal circulating profile starts to normalize. For practical purposes, our samples were collected at the postnatal infant assessment. However, in a validation study, we were able to demonstrate measures at this timepoint, although lower, still clearly reflect levels in late gestation. The reduction in absolute levels may be why there was only a trend with soluble endoglin and timing may also explain why there was no association with placental growth factor. A recent report linked midpregnancy placental growth factor to childhood retinal vasculature,18 but our range of gestational ages demonstrated that increased vessel density is a feature of prematurity rather than hypertensive disorders. Interestingly, gestational age was also an independent predictor of postnatal microvessel loss, along with maternal hypertension, which may explain a previous observation of capillary rarefaction in adults born preterm to normotensive pregnancies.16 In the present study, endothelial cells were not available from normotensive preterm pregnancies to explore whether prematurity associated with in vitro cellular function, but altered cord blood endothelial colony-forming cell function has been reported in preterm offspring.35 In our large sample, we did not replicate the previous finding of reduced vessel density at birth in hypertensive pregnancy offspring born at term. In bivariable analysis, although maternal body mass index was not related to microvessel density change, birthweight Z score was related but, in our study, the association was not independent of a history of hypertension pregnancy and preterm birth in regression models.37 However, this factor may be of value to explore further because experimental models show that restrictive diet pregnancies can induce epigenetic cardiovascular changes.38 An association between low infant systolic blood pressure at birth and microvessel change persisted in multivariate analysis, which raises the possibility that complications that result in a low cardiac output or peripheral vasodilatation, for example, hypoxia or infection, may also affect postnatal microvascular development. It will be of interest to investigate whether the changes in dermal microvasculature reflect a generalized phenomenon involving other organ-specific vascular beds such as cardiac and pulmonary systems. Future longitudinal follow-up of this cohort planned over the next few years should provide definitive information on the associations between neonatal microvasculature development and emergence of cardiovascular risk evident in early life including elevated blood pressure and metabolic abnormalities.Our study is associative and does not prove causality, but our case control recruitment approach meant the number of pregnancies with complications that we could study was comparable to large population-based samples. The study size meant we could undertake detailed clinical, physiological, and sample data collection along with repeated measures over short time frames. Therefore, we could undertake detailed analysis of potential-related factors that could affect vascular development, independent of the hypertensive pregnancy. Higher skin capillary density has previously been reported in infants born preterm after hypertensive pregnancy,39 These changes may have long-term relevance as in adulthood offspring of complicated pregnancies are known to have microvascular rarefaction and higher blood pressure.39 Blood pressures were similar at 3 months of age in our neonates, despite reductions in vessel density, consistent with these microvascular changes being a primary event, as seen in hypertensive models and at-risk populations.40 Additional studies will help define mechanisms underlying the altered vasculogenic capacity and determine whether these changes are tractable to reduce the long-term cardiovascular and hypertensive risk.In conclusion, we have found offspring born to hypertensive pregnancies have reduced endothelial capacity for microtubulogenesis in vitro at birth. The degree of impairment predicts the degree of reduction in vascular density during the first 3 months of postnatal life, as the fetal microvasculature remodels into its postnatal ex utero structure. Intriguingly, these changes can also be predicted by the circulating biomarker profile of the mother around the time of birth. Collectively, these findings suggest a close association between the maternal biological state during pregnancy and offspring vasculogenic capacity. As a result, although the offspring maintain microvascular structure in utero, perhaps as a compensatory response to the relative hypoxia of the hypertensive pregnancy, on transition to the normal ex utero environment, there is failure of appropriate remodeling.This is the first demonstration that neonates born after hypertensive pregnancies have ≈2-fold greater postnatal reduction in microvascular density compared with offspring of normotensive pregnancies and that umbilical endothelial cell tube formation predicts the degree of this postnatal microvessel reduction. Furthermore, these vascular phenotypes are predicted by levels of angiogenic factors in the maternal circulation around the time of birth, an association that is evident if the mother did not develop hypertension during pregnancy.We are grateful to all the pregnant women and babies who participated in this study.This work was supported by the British Heart Foundation , the NIHR Oxford Biomedical Research Centre, the Oxford BHF Centre for Research Excellence (RE/13/1/30181) and the Wellcome Trust Summer Studentship Program (109264/Z/15/Z). Support was also provided by NHS Blood and Transplant.None.


Individuals often rely on simple heuristics when they face complex choice situations under uncertainty. Traditionally, it has been proposed that cognitive processes are the main driver to evaluate different choice options and to finally reach a decision. Growing evidence, however, highlights a strong interrelation between judgment and decision-making (JDM) on the one hand, and emotional processes on the other hand. This also seems to apply to judgmental heuristics, i.e., decision processes that are typically considered to be fast and intuitive. In this study, participants are exposed to different probabilities of receiving an unpleasant electric shock. Information about electric shock probabilities is either positively or negatively framed. Integrated skin conductance responses (ISCRs) while waiting for electric shock realization are used as an indicator for participants' emotional arousal. This measure is compared to objective probabilities. I find evidence for a relation between emotional body reactions measured by ISCRs and the framing effect. Under negative frames, participants show significantly higher ISCRs while waiting for an electric shock to be delivered than under positive frames. This result might contribute to a better understanding of the psychological processes underlying JDM. Further studies are necessary to reveal the causality underlying this finding, i.e., whether emotional processes influence JDM or vice versa. Evaluating the probability of uncertain events is fundamental for human judgment and decision-making (JDM). In order to assess the likelihood of uncertain outcomes, people often apply rules of thumb, so-called judgmental heuristics. On the one hand, heuristics might be advantageous by shortening the decision process or by shifting attention to important aspects of a choice problem. On the other hand, they can lead to discrepancies between an individual's assessment of a situation and objective measures  took part in the study in exchange for course credit points. Participants gave written informed consent and could decide to discontinue participation at any time. The research design was approved by the Ethics Committee of the German Psychological Society and performed in agreement with the Declaration of Helsinki.Forty undergraduate psychology students  pause until the electric shock was applied or not with the previously stated probability. The outcome of this lottery was visualized by a red screen in the case of an electric shock and a green screen in the case of no electric shock. The next round started after 10 s. Three different electric shock probabilities were applied–20, 50, and, 80%–while each probability was presented four times in a positive frame and four times in a negative frame. The order of electric shock probabilities and their outcomes were randomized.www.psychtoolbox.org) running on MATLAB 7.1  was used for stimulus presentation and response acquisition.Participants were first instructed in written form and then verbally. In addition, participants completed a short questionnaire testing whether they could infer the probability of receiving an electric shock from both negative and positive framed statements. The average duration of one session was approximately 25 minutes (min). The software package Psychtoolbox-3  ; duration of the whole stimulation burst: 115 ms; power range: 0.5–206 milliwatt). The stimulation was administered via two flat AG-AGCL electrodes of 10 millimeters (mm) in diameter being placed at the medial phalanges of digits II and III of the dominant hand. Individual levels of electric shock stimulation were calibrated using the following standard procedure: electric shocks were presented in an ascending series of intensity until the participant indicated that the electric shock was painful. Once a painful level was reached, the previous non-painful stimulation level was used during the experiment.I used a 16-channel bioamplifier  and the corresponding recording software Biotrace (Mind Media B.V.) to record electrodermal responses. Two flat AG-AGCL 10-mm-diameter electrodes were placed at the medial phalanges of digits II and III of the non-dominant hand. In accordance with common recommendations  applying continuous decomposition analysis to disentangle phasic components from tonic activity  × sign(ISCR)  method where necessary.Figure Additionally, Figure aernbach . Please As a result, I find evidence for emotional body reactions corresponding to the framing effect. Under negative frames, participants show significantly higher ISCRs while waiting for an electric shock to be delivered than under positive frames. This finding challenges the assumptions of rational economic theory, which state that changes in frames do not alter individual assessments of a situation in a systematic way. Furthermore, it is relevant, because it points toward a connection between emotion and JDM, which is also indicated in recent theories, e.g., the somatic marker theory by Damasio and colleagues . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To investigate delays in first and third dose diphtheria–tetanus–pertussis (DTP1 and DTP3) vaccination in low-birth-weight infants in Ghana, and the associated determinants.We used data from a large, population-based vitamin A trial in 2010–2013, with 22 955 enrolled infants. We measured vaccination rate and maternal and infant characteristics and compared three categories of low-birth-weight infants  with infants weighing ≥ 2.5 kg. Poisson regression was used to calculate vaccination rate ratios for DTP1 at 10, 14 and 18 weeks after birth, and for DTP3 at 18, 22 and 24 weeks .n = 18 979), those with low birth weight (n = 3382) had an almost 40% lower DTP1 vaccination rate at age 10 weeks  and at age 18 weeks . Infants weighing 1.5–1.9 kg (n = 386) had vaccination rates approximately 25% lower than infants weighing ≥ 2.5 kg at these time points. Similar results were observed for DTP3. Lower maternal age, educational attainment and longer distance to the nearest health facility were associated with lower DTP1 and DTP3 vaccination rates.Compared with non-low-birth-weight infants (Low-birth-weight infants are a high-risk group for delayed vaccination in Ghana. Efforts to improve the vaccination of these infants are warranted, alongside further research to understand the reasons for the delays. Our primary objectives were to assess whether low birth weight is a determinant of delayed first and third dose diphtheria–tetanus–pertussis (DTP1 and DTP3) vaccination; and whether maternal education or socioeconomic status modified the association between birth weight and vaccination with DTP1 and DTP3. As a secondary objective, we aimed to quantify other determinants of delayed DTP1 and DTP3 vaccination.We studied a cohort of infants nested within a large randomized, double-blind, placebo-controlled trial of neonatal vitamin A supplementation conducted in Ghana between August 2010 and February 2013.Ethics approval for the study was granted by the ethics committees of the World Health Organization (WHO), the London School of Hygiene & Tropical Medicine and the Kintampo Health Research Centre.DTP vaccination in Ghana is recommended at 6, 10 and 14 weeks of age. Children are vaccinated at health facilities, community health planning system compounds or mobile outreach clinics. For each administered vaccine, the date and place of administration and vaccine batch number are usually documented in the child health record book. These may also be documented on a vaccination card or in the mother’s antenatal card. Infants who have never attended a child health clinic may not have a written record.Trained fieldworkers enrolled all consenting women aged 15–49 years residing in the study area into a reproductive surveillance system to document pregnancies and deliveries. All infants born in the study area were assessed for eligibility  and mothers were asked for informed written consent for enrolment in the trial. Infants were weighed using calibrated electronic  or spring  scales, to record birth weights to the nearest 0.1 kg  or 0.2 kg . Only five (0.2%) infants were weighed later than 72 hours after delivery. The fieldworkers collected data on infant (sex and multiple delivery), maternal  and household characteristics .The enrolled infants were visited monthly for the first year of life to collect data on the types and dates of vaccines given. We looked for written documentation of vaccines from all possible sources, including the child health record book, the mother’s antenatal card and vaccination cards. The infant’s caregiver  was also asked to recall what vaccines had been given. We also collected data on the infant’s vital status and on illnesses since the previous visit.Follow-up started at birth. It ended at the vaccination date for vaccinated infants, and the end of the risk period for unvaccinated infants not lost to follow-up. For those lost to follow-up before the end of the risk period, follow-up ended on the last date the written record was viewed, for unvaccinated infants whose record was viewed; or on the last date the infant was seen, for unvaccinated infants whose record was never viewed; or on the date of death, for unvaccinated infants who died before the end of the risk period and whose record was viewed after their death.For the analyses we included all infants from the trial with known vaccination status and dates and with complete data on covariates. We excluded infants who were lost to follow-up or died before the vaccination due date.We classified infants’ vaccination status as follows: (i) vaccinated, date known (written record had a plausible vaccination date); (ii) vaccinated, date unknown ; (iii) unvaccinated ; or (iv) vaccination status unknown .,We categorized birth weight into four standard categories: ≥ 2.5 kg (i.e. non-low birth weight); 2.0–2.4 kg; 1.5–1.9 kg; < 1.5 kg.–The study outcomes were delayed receipt of DTP1 and DTP3. There is no standard approach to the assessment of delayed vaccination and several definitions based on predefined cut-offs have been described.The data were double-entered and processed at the Kintampo Health Research Centre using the SQL Server 2008 data management system . Inconsistencies and errors in the vaccination dates were corrected, with senior fieldworkers visiting mothers to review the written record and verify the dates if necessary.,–All analyses were conducted using the Stata package version 13.1 . We generated Kaplan–Meier curves of time to vaccination in low-birth-weight compared with non-low-birth-weight infants in the first year of life for DTP1 and DTP3. Vaccination rate ratios, adjusted for a priori selected factors, were obtained for each risk period using multivariable Poisson regression, informed by a hierarchical framework of the recognized determinants of vaccination .12,16–18Two sets of sensitivity analyses were undertaken. First, to assess whether delayed DTP3 vaccination simply reflected delayed DTP1 vaccination, we repeated the DTP3 analyses, starting follow-up at receipt of DTP1 vaccination and ending 12 weeks after receipt of DTP1. Second, to examine the effect of possible misclassification of vaccine status for infants categorized as never vaccinated but whose written record was never viewed, we excluded these infants and repeated the analyses of DTP1 vaccination up to 18 weeks from birth and DTP3 vaccination up to 26 weeks.Of 27 330 live births identified in the study area, 26 414 infants were screened for eligibility for the trial and 22 955 were enrolled ; 22 361 Although uptake of vaccination was high (> 95%) for all infants by 1 year of age, low birth weight was associated with later vaccination for both DTP1 and DTP3. Median ages at DTP1 vaccination were 8 weeks  for infants weighing ≥ 2.5 kg at birth; 8.3 weeks (IQR: 6.9–9.9) for those 2.0–2.4 kg; 8.4 weeks (IQR: 6.9–10.7) for those 1.5–1.9 kg and 9 weeks (IQR: 7.4–11.9) for those < 1.5 kg. For DTP3, the corresponding median ages at vaccination were 18.4 weeks (IQR: 16.3–22.1), 18.6 weeks (IQR: 16.6–22.3), 19.6 weeks (IQR: 16.6–23.3) and 20.4 weeks (IQR: 17.7–25.1), respectively.). After adjustment for other variables, there was evidence of progressively delayed vaccination with decreasing birth weight . Infants weighing < 1.5 kg at birth had a DTP1 vaccination rate approximately 40% lower than non-low-birth-weight infants by the age of 10 weeks  and age 18 weeks . Infants weighing 1.5–1.9 kg had vaccination rates approximately 25% lower than non-low-birth-weight infants at these time points .The Kaplan–Meier curves showed that DTP1 vaccination rates over the days since birth were also lower for infants weighing < 1.5 kg and those weighing 1.5–1.9 kg compared with those weighing ≥ 2.5 kg . After aSimilar results were observed for DTP3 . The finAdjusting for illness had little effect on the magnitude of the association between birth weight and vaccination for both DTP1 and DTP3 .http://www.who.int/bulletin/volumes/94/5/15-159699). In the final model  low socioeconomic status of mothers was associated with a 15% increased DTP3 vaccination rate at 18 weeks, whereas no association with DTP1 vaccination was observed. Muslim religion and larger family size were associated with > 10% reduction in DTP3 vaccination rates but had no, or only a small, association with DTP1 vaccination rates. None of the other variables measured had notable associations with DTP1 or DTP3 vaccination rates at any ages.Younger maternal age, lower educational attainment, and longer distance to the nearest health facility were associated with moderate reductions in the DTP1 and DTP3 vaccination rates of approximately 10–20% at ages 10 and 18 weeks, whereas higher employment grade was associated with moderate increased vaccination rates at these ages  compared with an aRR of 0.82 (95% CI: 0.73–0.92) at 12 weeks after the DTP3 due date, but the effect size for infants weighing < 1.5 kg was largely unchanged .Excluding unvaccinated infants whose written record was never seen had little impact on the effect size of the explanatory variables for DTP1 or DTP3.P-values for interaction all > 0.4), or that the rate of vaccination with DTP1 varied by maternal education, when measured at age 10 weeks (P = 0.3338) or age 18 weeks (P = 0.2675). However, for DTP3 vaccination there was some evidence that the effect of birth weight on the vaccination rate at age 18 weeks (P = 0.0219) and age 26 weeks (P = 0.0813) varied with maternal education, with a more pronounced reduction in vaccination rate among smaller infants born to mothers with higher educational attainment . When infants with delayed receipt of DTP1 were excluded from the analysis, this effect was no longer apparent.When we looked at other factors that might modify the association between birth weight and delayed vaccination there was no evidence that the effect of birth weight on vaccination with DTP1 or DTP3 varied by socioeconomic status  than non-low-birth-weight infants. Those excluded could have experienced greater delay in receiving their vaccines compared with the included low-birth-weight infants, possibly causing some underestimation of the association between low birth weight and timely vaccination in our population. As less than 5% of enrolled infants were excluded, this was unlikely to have changed the results appreciably and important delays in vaccination were still observed among low-birth-weight infants. Mothers of enrolled infants were asked about their infant’s vaccination status at monthly visits, possibly increasing their awareness of the need to vaccinate their infants. This increased awareness, however, would not have been differentially affected by birth weight and would lead to an overall underestimation of delayed vaccination.Other limitations are that we did not have reliable data on gestational age and therefore we were not able to assess whether delayed vaccination was associated with prematurity or whether all low-birth-weight infants were affected regardless of gestational age. This study was also not designed to assess the association between delayed vaccination and clinical outcomes such as vaccine-preventable diseases or hospitalizations. Consequently, we do not know whether those infants who had delayed vaccination were more likely to contract vaccine-preventable diseases or to report elevated rates of illness or hospitalization. Eleven explanatory variables were included in our secondary analysis, thus increasing the potential for type 1 errors . Finally, we did not collect any qualitative data on the reasons for delayed vaccination of low-birth-weight infants in our study sample. This limits our interpretation of the findings. It may be that vaccination was delayed for reasons beyond the control of both the caregivers and the vaccine providers, such as lack of vaccines or staff, although it is reasonable to assume that these would not be distributed differently among low-birth-weight compared with non-low-birth-weight infants.,Current global policy on vaccination advocates the identification of groups that are underserved by vaccination,Efforts to improve the vaccination of low-birth-weight infants, for example by education of caregivers and vaccine-providers, are warranted. Further research is needed in low-income countries to understand the reasons for delayed vaccination of low-birth-weight infants and to inform strategies to improve the timeliness of vaccination.


C) at age 15.5 years after adjusting for height and weight [beta = − 0.18 ], with a stronger association in males compared to females (P = 0.01 for gender interaction), but an equivalent association was not seen at 17.7 years. In further analyses performed on data from age 15.5 years, the association between birth weight and PC was unaffected by adjustment for puberty (Tanner stage at age 13.5 years), bone resorption  at age 15.5 years) or insulin (fasting insulin at age 15.5 years). In contrast, the association with BMDC was attenuated by approximately 30% after adjustment for puberty or bone resorption, and by 50% after adjustment for both factors combined. We conclude that the inverse relationship between birth weight and BMDC is in part mediated by effects of puberty and bone resorption, which may help to explain the transitory nature of this association, in contrast to the more persisting relationship with PC.To examine the influence of intrauterine environment on subsequent bone development, we investigated the relationship between birth weight and cortical bone parameters, and the role of puberty, bone resorption and insulin as possible mediators. Bone outcomes were obtained from mid-tibial pQCT scans performed at age 15.5 years in 1960 males and 2192 females from the ALSPAC birth cohort. Birth weight was positively related to periosteal circumference (PC) [beta = 0.40 ], which was largely but not completely attenuated after adjustment for height and weight [beta = 0.07 ] (SD change in outcome per 1 kg increase in birth weight with 95% CI). Based on our height and weight adjusted model, the association was stronger in females compared to males (P = 0.02 for gender interaction), and persisted in 2842 participants with equivalent results at age 17.7 years. Conversely, birth weight was inversely related to cortical bone mineral density (BMD •Birth weight (BW) was positively related to periosteal circumference (PC) at age 15, even after height and weight adjustment.•The association of BW with PC was stronger in females, and was also seen at age 17.7 years.•C) at age 15.5 years after height and weight adjustment.BW was inversely related to cortical bone mineral density (BMD•The inverse association of BW with BMDC was stronger in males, but there was no association at 17.7 years.•The association of BW with BMDC was attenuated by approximately 50% after adjustment for puberty and bone resorption. Nutritional deprivation during pregnancy may increase the risk of developing a range of chronic diseases in later life, including osteoporosis, as a result of programming Whereas birth weight appears to be positively related to subsequent bone size, it is less clear how other skeletal characteristics are affected. In DXA-based studies, no associations were seen between birth weight and bone mineral density (BMD), following adjustment for height and weight C), a further potential pathway is insulin, which is positively related to BMI but inversely related to BMDCC as measured by pQCT of the mid tibia in adolescents from the ALSPAC cohort. We also studied the role of possible causal pathways contributing to these relationships, including age of puberty onset, a measure of bone resorption and insulin.In terms of biological pathways involved in mediating these relationships, conceivably, birth weight and bone size may be regulated by common mechanisms involved in growth such as the GH/IGF1 axis, but in a previous study this was not found to contribute to these relationships http://ije.oxfordjournals.org/content/early/2012/04/14/ije.dys064.full.pdf+html>. The total sample size for analyses using any data collected after the age of seven is therefore 15,247 pregnancies, resulting in 15,458 foetuses. Of this total sample of 15,458 fetuses, 14,775 were live births and 14,701 were alive at 1 year of age. The study website contains details of all the data that is available through a fully searchable data dictionary: http://www.bris.ac.uk/alspac/researchers/data-access/data-dictionary/.ALSPAC is a geographically based UK cohort that recruited pregnant women residing in Avon (South-west England) with an expected date of delivery between April 1st 1991 and December 31st 1992 The present study is based on research clinics to which the whole cohort was invited, held when participants were mean ages of 15.5 years. Ethical approval was obtained from the ALSPAC Law and Ethics committee, and the Local Research Ethics Committees. Parental consent and child's assent were obtained for all measurements made. Birth weight was abstracted from obstetric records.C and bone mineral content (BMCC) of the mid  right tibia were obtained using a Stratec XCT2000L  during the age 15.5 year research clinic to which all ALSPAC participants were invited as part of a study investigating the effects of physical activity on cortical bone as previously published 3C) subsequently derived. Strength strain index (SSI) for a circular ring model was calculated according to the formula published by the manufacturer.BMDParticipants were asked to fast overnight (for those attending in the morning) or for a minimum of six hours for those attending after lunch. Blood plasma samples (EDTA) were immediately spun and frozen at − 80 °C. Measurements were assayed shortly (3–9 months) after samples were taken with no previous freeze-thaw cycles. Insulin was measured by an ultrasensitive ELISA  automated microparticle enzyme immunoassay that does not cross-react with pro-insulin. Its sensitivity was 0.07 mu/L and inter and intra-assay CVs were < 6%. Electrochemiluminescence immunoassays (ECLIA)  were used to measure plasma concentrations of βCTX (detection limit 0.01 ng/mL). Inter- and intra-assay coefficients of variation (CVs) were < 6% across the working range.Gestational age was calculated from the last menstrual period  and the actual date of delivery. Height at clinic attendance was measured using a Harpenden stadiometer  and weight was measured to the nearest 50 g using Tanita weighing scales . Data on lean mass and fat mass were obtained from total body DXA scans performed at the age 15.5 year clinic, using a Lunar Prodigy scanner  with paediatric scanning software . Puberty was assessed using a Tanner stage questionnaire at age 13.5 years (pubic hair domain) (range from 13.1 to 14.4 years), as previously found to be related to hip development as assessed by DXA Linear regression was used to explore the linear effects of birth weight on pQCT outcomes. Adjustment was initially made for gender, gestation and age at scan. To examine whether birth weight also influenced pQCT parameters via a pathway that was independent of body size, further analyses adjusted for height and weight. Since relationships between many of these measures and pQCT outcomes varied by gender C was higher in girls, whereas measures of cortical bone size  and strength (SSI) were greater in boys . BMD in boys . Birth wC, in our basic regression model  , or following adjustment for maternal education and paternal social class as indicators of socio economic status (Supplementary Table 3).In analyses of males and females combined, a positive association was observed between birth weight and PC and CT, but an inverse association with BMD gender) . SubsequC was stronger in males (P = 0.01 for gender interaction). Increasing quartile of birth weight was associated with progressive decreases in BMDC particularly in males . In addition, there was evidence of a positive association between birth weight and SSI in females but not males (P = 0.02 for gender interaction). Conversely, the inverse association between birth weight and BMDin males , whereasin males .C.Subsequently, we compared associations between birth weight and pQCT characteristics at age 15.5 and 17.7 years, in the dataset with participants with scans at both time points. In this subset, socio-economic status was slightly higher than those with data at age 15 only, as reflected by maternal education and paternal social class (Supplementary Table 1). However, similar stronger inverse associations between birth weight with PC and SSI were observed in females and a similar stronger positive association between birth weight with BMDc was observed in males for this subset compared to the wider cohort . Adjustment for βCTX in the 2286 participants where this was available led to a 42% reduction in regression coefficient for the association between birth weight and BMDC (Supplementary Table 5). Although evidence for a gender interaction for the association between birth weight and BMDC was somewhat weaker in this subgroup as judged by the interaction P-value, regression coefficients were approximately 70% higher in males, which difference was attenuated by βCTX adjustment. Adjustment for insulin levels was without effect. Associations between birth weight and PC were unaffected by adjustment for insulin, βCTX or Tanner stage.Higher birth weight was associated with lower Tanner stage at age 13.5 years, lower insulin concentration at 15.5 years, and greater bone resorption at 15.5 years as reflected by βCTX concentration . Since pC .Finally, we examined possible additive effects of adjustment for βCTX and puberty, in male and female participants where both these measures were available. There was some evidence that βCTX and Tanner stage adjustment led to additive attenuation of the association between birth weight and BMDHaving examined the relationship between birth weight and pQCT parameters of the mid-tibia, we observed a moderate positive association with PC at age 15.5 years, with a one SD increase in birth weight associated with approximately a 0.22 SD increase in PC. The greater portion of this relationship was mediated by shared association with height and weight, but even after adjustment for body size there was still evidence of a positive relationship in girls. Since we are reporting associations from an observational study, it is not possible to distinguish causal effects of birth weight on subsequent bone development, for example through potentially modifiable environmental effects, from shared dependence on constitutional factors. The latter may include common factors which affect bone and body size, given the substantial attenuation we observed after adjusting for height and weight.Theoretically, the associations we observed may relate to future fracture risk, given the important contribution of bone size to overall bone strength. Consistent with this possibility, birth weight was also positively related to predicted bone strength in girls, as reflected by SSI. Although our findings relate to strength of the tibia, they may also have relevance for bone strength and fracture risk at other weight bearing sites such as the hip. However, in a previous study, birth weight was not associated with hip fracture in later life, as assessed in 6370 women born in Helsinki between 1934 and 1944 To some extent, our findings are consistent with previous observations that birth weight is positively associated with overall bone size as assessed by pQCT, including similar measures to those obtained at the mid-tibia in the present study Our finding that birth weight is positively associated with subsequent bone size is also supported by DXA-based studies. For example, in analyses for height and weight, birth weight was positively related to proximal femur bone area (BA) and bone mineral content (BMC) in 496 individuals aged 23–24 from Brazil C as measured at age 15.5 years. By age 17.7 years, this relationship with BMDC had completely attenuated, and there was partial attenuation of the relationship with CT. The lack of a persistent association of birth weight with BMDC is consistent with similar negative findings in studies based on older adults C in large part reflects cortical porosity which is in turn related to bone resorption, and CT may also reflect bone resorption due to its dependence on endosteal expansion. Taken together, these findings may reflect an underlying positive relationship between birth weight and bone resorption, which is more marked around the time of puberty.In contrast, birth weight was inversely related to both CT and BMDC partially attenuated after adjustment for either puberty or bone resorption may have reflected a pathway by which greater birth weight led to later puberty at age 13.5 years, and hence greater skeletal immaturity and faster growth at age 15.5 years. The finding that the association between birth weight and BMDC was stronger in boys compared to girls is consistent with this conclusion, since bone growth is likely to have largely ceased at age 15.5 years in girls, irrespective of their age of puberty onset. That gender differences in the association between birth weight and BMDC are explained by differing relationships with puberty is supported by our observation that gender differences in the birth weight–BMDC association were attenuated by puberty adjustment. Nevertheless, since there was some evidence that adjustment for puberty and bone resorption appeared to be additive, birth weight may also influence BMDC via a pathway involving bone resorption that is partly independent of puberty.Consistent with a possible interaction between birth weight, bone resorption and puberty, higher birth weight was associated with greater bone resorption and later onset of puberty, as reflected by CTX and Tanner stage respectively; and it is well established that puberty is associated with a transient elevation in CTX, presumably secondary to the associated peak in skeletal growth and modelling C, we were unable to explain the pathway by which birth weight was related to PC, beyond the role of shared relationships with height and weight. For example, birth weight was inversely related to insulin concentration in the present study, and we previously reported that insulin is inversely related to PC after adjusting for height and body composition In contrast to the association with BMDOne of the limitations of this study is that since it was performed on a subset of the original cohort, it may no longer comprise a truly representative sample of the population, thereby reducing the generalisability of our findings. Theoretically, loss to follow up may also bias sample statistics, such as mean BMDc, for instance due to reducing the number of participants with low birth weight, but this is unlikely to have led to spurious associations being observed between birth weight and pQCT data C at age 15.5 years, which association was stronger in males compared to females, and was largely attenuated by age 17.7 years. Further analysis suggested that the relationship between birth weight and BMDC was mediated by effects on puberty and bone resorption, which may help to explain the transitory nature of this association, in contrast to the more persisting relationship with PC.Having investigated relationships between birth weight and subsequent cortical bone development in a large population based cohort from southwest UK, we found that birth weight is positively related to tibial PC at age 15.5 years. This relationship was largely but not completely explained by co-association with height and weight, was stronger in girls compared to boys, and persisted at age 17.7 years. Conversely, birth weight was inversely related to BMD


Patients with a porencephalic cyst frequently develop intractable temporal lobe epilepsy (TLE). We report a surgically-treated male patient with intractable mesial TLE (mTLE) secondary to a porencephalic cyst. Although magnetic resonance imaging showed no hippocampal abnormalities, long-term video-electrocorticography revealed seizure onset discharges in the hippocampus. Temporal lobectomy brought an end to the patient's seizures. Hippocampal sclerosis was histopathologically confirmed . Careful evaluation of hippocampal epileptogenicity is required, and temporal lobectomy, which is less invasive than hemispherectomy, can be a treatment of choice for patients with mTLE secondary to a porencephalic cyst. In these patients, the traditional neurosurgical approach has been hemispherectomy because of the difficulty in localizing precise epileptogenic foci Recent studies have shown that hippocampal sclerosis (HS) frequently coexists with porencephalic cysts, and these patients with intractable temporal lobe epilepsy (TLE) are good surgical candidates for temporal lobectomy Determining the optimal treatment for patients who present with TLE and negative magnetic resonance imaging (nMRI) is more challenging. We successfully treated a patient with intractable nMRI TLE secondary to a porencephalic cyst with temporal lobectomy, after a useful presurgical electrocorticography (ECoG) to localize the precise epileptogenic focus, avoiding invasive hemispherectomy.2A 29-year-old right-handed man suffered from intractable epilepsy from the age of 12. Habitual seizures manifested as loss of consciousness, staring, and automatism, followed by postictal confusion. Seizures occurred several times a week and were not controlled by 6 prior antiepileptic drugs. The patient had a history of lumbar myelomeningocele, which was surgically treated soon after his birth. At 26 years of age, he underwent resection of a lumbar lipoma and filum terminale. He had no history of neonatal asphyxia, febrile convulsion, or head trauma. He had normal mental status and no hemiplegia.99mTc-ethyl cysteinate dimer (99mTc-ECD) single-photon emission computed tomography (SPECT) revealed decreased cerebral blood flow in the mesial left temporal lobe. Ictal ECD SPECT was not performed because of technical limitations.Magnetic resonance imaging revealed a large porencephalic cyst in the left parietotemporal region with atrophic changes in the surrounding cortex, no cortical dysgenesis, and, importantly, no atrophy or abnormal signal alteration in the bilateral hippocampi . Long-teAlthough clinical features, EEG, and interictal SPECT suggested that the patient's seizures were due to mesial TLE (mTLE), MRI showed no abnormalities in the hippocampus, suggesting that the porencephalic cyst was the potential epileptogenic focus. To further determine the epileptogenic focus, long-term ECoG was performed, using subdural grid electrodes covering the left mesial temporal region, lateral temporal cortex, and parietal cortex surrounding the porencephalic cyst. We recorded 3 seizures over 7 days. All ictal discharges originated from the left mesial temporal region, and none originated in the area surrounding the porencephalic cyst . We conc3Porencephalic cysts occur as a component of vascular cerebral infarction during the prenatal or perinatal period and commonly manifest as congenital hemiplegia, intellectual impairment, and epilepsy However, if the seizure manifestation and scalp and further invasive ECoG suggest a specific epileptogenic focus in a patient with a porencephalic cyst, a more restricted resection might be preferable in view of anticipated motor function losses and perioperative morbidity and mortality The seizure semiology, interictal EEG, and interictal SPECT of the present patient suggested mTLE, but MRI findings showed no abnormalities in the hippocampus, i.e., hippocampal atrophy or signal alterations indicative of HS. Thus, we could not exclude the possibility that epileptogenic discharges around the porencephalic cyst propagated to the left mesial temporal lobe. Subsequent ECoG showed that the epileptogenic focus was the hippocampus and not the area surrounding the porencephalic cyst. Thus, we performed temporal lobectomy, which effectively eliminated the patient's seizures. Histopathology revealed mild HS.To the best of our knowledge, there have been a total of 4 reports on 14 patients undergoing temporal lobectomy due to intractable TLE secondary to a porencephalic cyst  [1], [3]Recent studies have emphasized dual pathology with HS and porencephalic cyst. Hippocampal sclerosis frequently coexists with a porencephalic cyst in patients with mTLE While most patients with mTLE may show the characteristic features of HS on MRI, including an atrophic hippocampus with a hyperintense signal on long repetition time sequences, up to 15% of patients with mTLE may have normal MRI Of the 14 reported patients with porencephalic cyst and TLE , 13 showWe emphasize that the absence of radiological changes in the hippocampus does not preclude hippocampal epileptogenicity in mTLE with a porencephalic cyst. Thus, careful evaluation of hippocampal epileptogenicity is essential. Such cases can benefit from the less invasive temporal lobectomy rather than hemispherectomy.


Radicular cysts are by far the most common cystic lesions of the jaw. However, those arising from primary teeth are comparatively rare, comprising only 0.5 to 3.3%. The aim of this paper is to present clinical, radiographic and histopathological characteristics of radicular cyst associated with a primary mandibular molar causing unusual displacement of the permanent successor. Extraction of primary tooth along with extirpation of cyst was done under local anesthesia. The displaced premolar was also extracted and then replanted in the socket after proper alignment. Healing was uneventful and the space of missing primary molar was maintained by band and loop space maintainer. The relationship between intracanal medicaments and rapid growth of cyst, as mentioned in literature was observed in our case too. Thus, pulpotomy treated primary teeth should receive periodic postoperative radiographic examination and absence of clinical symptoms does not mean that a pulpotomy treated tooth is healthy.How to cite this article: Lamba G, Ravi GR. Replantation of Displaced Underlying Successor and Marsupialization of Radicular Cyst associated with a Primary Molar. Int J Clin Pediatr Dent 2015;8(1):70-74. Those arising from primary teeth are, however, rare, with a prevalence of 0.5 to 3.3%.23Children are victims of many pathological lesions involving the jaw bones. These lesions can be neoplastic, developmental or Inflammatory in origin. Most common among the Inflammatory lesions is radicular cyst. These cysts are usually seen at the apices of the teeth with infected and necrotic pulp. It arises from epithelial residues in the periodontal ligament as a result of Inflammation, usually following death of pulp.1 Intracanal medicaments used for pulp therapy and distinctive intraepithelial inclusions found in cyst wall, may also provide a site for continuous antigenic stimulation.4Most radicular cysts develop slowly and do not become very large. They are usually asymptomatic unless there is a sign of acute Inflammatory exacerbation. They are often detected only during routine radiographic examination. If the cyst does become large, symptoms include swelling, mild sensitivity, tooth mobility and sometimes displacement of underlying tooth. Caries is the most frequent cause for radicular cyst in primary dentition. They may also form following traumatic injuries to primary teeth.5 Shear3 reported that resorption of primary teeth is rare in cases of radicular cyst although Neville6 et al stated it is common during cyst development. A definitive diagnosis should be based upon radiographic, clinical and histological pattern. The treatment for radicular cyst includes total enucleation if the cyst is small, marsupiali-zation for decompression of larger cysts or a combination of two techniques. Inflammatory cysts do not recur after adequate treatment.1According to Formigli et al, radicular cysts represent potent bone destroying lesions of the maxillofacial region.The aim of this report is to present clinical, radio-graphical and histological characteristics of radicular cyst associated with a primary molar following incomplete endodontic treatment, and the various conservative treatment modalities available to treat radicular cyst.An Indian girl, 12 years old, was referred to Department of Pedodontics and Preventive Dentistry of Dental College, for inspection of a painless swelling in the mandibular left primary molar region since 6 months. Past dental history revealed that she had undergone incomplete endodontic treatment with the same tooth a year ago. Her oral hygiene was good and was overall in good health. Extraoral examination revealed, a diffuse, bony nontender swelling on left side of jaw extending from corner of mouth to angle of mandible. While, intraoral examination revealed a grossly carious and mobile left primary second molar tooth . PanaromFrom history and clinical examination a provisional diagnosis of radicular cyst associated with them andibular left primary second molar was made which could be due to either secondary caries or the medicament used duri ng endodontic treatment. Differential diagnosis included periapical granuloma or dentigerous cyst.Primary left second molar was extracted under local anesthesia and cystic cavity was exposed. Cystic lining was removed as much as was accessible and sent for histopathological examination . The sucHistopathological features were consistent with provisional diagnosis of radicular cyst. Histological examination revealed the cystic cavity to be lined by a nonkeratinized stratified squamous epithelium with mixed Inflammatory infiltration. The patient returned once every 3 months for regular checkup. At 6 months follow-up, tooth had almost aligned vertically and was on the path of eruption . At 18 m7 In our case also, the large radicular cyst was an incidental finding on panoramic radiograph.A radicular cyst is one which arises from the epithelial residues in the periodontal ligament as a result of Inflam-mation. The Inflammation usually follows the death of the dental pulp and cysts arising due to this are most commonly found at the apices of the involved tooth. Many radicular cyst s are sy mptomless and a re discovered when periapical radiographs are taken of teeth with nonvital pulps.3 while Lustman in an extensive review from 1898 to 1985, found only 28 cases to which they added 23 cases.2 Nagata et al in their review reported 112 cases till 2004. Since then, there have been few individual case reports.8 However, according to Mass et al, some factors characteristic of primary dentition can lead to an underestimation of real frequency of these lesions. Periapical radiolucencies relating to primary teeth tend to be neglected and mostly resolve after removal of the tooth.9 In addition, formation of sinus or fstula causes less severe symptoms as compared to permanent teeth and these radicular lesions may remain untreated. Other factors, such as diagnostic errors, extraction of primary tooth without referral for pathological examination and regression of the lesion due to endodontic treatment may also influence the reported frequency.1According to Shear and Lustman, radicular cysts are considered to be rare in primary dentition, accounting to less than 1% of all cases,3 In primary molars, cyst is located in interradicular area and around the roots, whereas in permanent incisors, it is usually located at the apex. This can be explained by the short and sometimes partially resorbed roots of primary molars and also the presence of accessory canals. Thus, the term periradicular cyst in primary molars is more appropriate than radicular cyst.7There are several differences between radicular cysts originating from primary teeth and those originating from permanent teeth. In primary teeth mandibular molars are more commonly involved while in permanent teeth, maxillary anteriors are more commonly involved. The difference in site distribution may be explained by different etiologic factors. In primary dentition, caries is the most frequent etiologic factor and mandibular molars are more frequently affected teeth. In permanent maxillary incisors, the high frequency of radicular cyst results from trauma, caries and old silicate restorations.4 But, the histological similarity between the lining of these two cysts points out the difficulty of differentiating between these two cysts on the basis of their histological features alone.10Periapical radiolucencies relating to primary teeth tend to be mi sdiag nosed as a periapical gra nu loma of pri mary teeth or dentigerous cyst from permanent successors. Radiographically, a dentigerous cyst is characterized by a unilocular radiolucent area that is associated with crown of an unerupted permanent tooth.On the other hand, periapical granulomas are radiographically indistinguishable from radicular cysts. Radicular cyst development is the next stage following formation of periapical granuloma.4 The growth rate estimated by Livingston11 and Hill12 were 5 and 4 mm annually, respectively. Grundy, Adkins and Savage reported a series of cases of radicular cysts associated with deciduous teeth that had been treated endodontically with materials containing formocresol, which in combination with tissue proteins, is antigenic and has shown to elicit a humoral and cell mediated response.13 This could be the probable reason for rapid growth of the cyst, displacing the underlying premolar buccolingually. In our case, the lesion was approximately 2 cm and during the surgical procedure, it was noticed that the lining was not attached to the crown of the underlying tooth, ruling out the diagnosis of dentigerous cyst. Also, as suggested by patient’s history relating to previous treatment, there could be a probability of use of formocresol. Thus, all these factors along with histological confirmation, together contributed to reach the final diagnosis of radicular cyst.Furthermore, larger the lesion, the greater the probability it will be a radicular cyst. Nearly all lesions > 2 cm in diameter are diagnosed as cysts.The most common clinical and radiographic features of radicular cyst in primary molars include the following: Mandibular buccal cortical plate expansion Well-defined unilocular radiolucency Thin reactive cortex Displacement of succedaneous tooth2 Misleading preoperative diagnosisOur case was diagnosed as a radicular cyst in the primary dentition for following reasons: presence of large and painless radiolucent lesion in relation to roots of a nonvital primary tooth, size larger than 2 cm, no clinical and radiographic involvement with successive permanent tooth, displacement of the underlying successive tooth, histological confirmation of cystic epithelial lining, and surgical confirmation that lesion was not associated with the successive permanent tooth.14Treatment choices include extraction of the primary tooth and preservation of underlying permanent tooth. If there is no threat of damage to underlying permanent tooth bud, complete curettage can be performed. If permanent tooth is severely damaged, complete enuclea-tion of the cyst to include the permanent tooth bud has been recommended.15 The premolar was again replanted into the cystic cavity and the cystic cavity was sutured. Following the removal of sutures after 7 days a short band and loop was cemented to maintain the space till the eruption of the permanent premolar. The patient is under regular follow-up.In the present case, curettage was adopted, along with removal of the underlying premolar, as it was not properly aligned. Extraoral time in this treatment was around 6 to 8 minutes. According to Kratchman extraoral time should not exceed 10 minutes.On the basis of our case, we conclude that: Practitioners should investigate cases of delayed exfoliation and expansion of cortical plate in vicinity of primary molars. Pulpal therapeutic agents may causeantigenic stimuli but it does not imply prohibition of use of medicaments. Regular clinical and radiographic follow-up of endo-dontically treated primary teeth should be done. Absence of clinical symptoms does not imply that the tooth is healthy. Bone grafts for large lesions are not required in children because of high propensity for bone regeneration.


Catalytic C–H borylation of arenes has been widely used in organic synthesis because it allows the introduction of a versatile boron functionality directly onto simple, unfunctionalized arenes. We report herein the use of diisopropylaminoborane as a boron source in C–H borylation of arenes. An iridium(I) complex with 1,3-dicyclohexylimidazol-2-ylidene is found to efficiently catalyze the borylation of arenes and heteroarenes. The resulting aminoborylated products can be converted to the corresponding boronic acid derivatives simply by treatment with suitable diols or diamines.