Fetal dose from proton pencil beam scanning craniospinal irradiation during pregnancy: a Monte Carlo study

Objective: We conducted a Monte Carlo study to comprehensively investigate the fetal dose resulting from proton pencil beam scanning (PBS) craniospinal irradiation (CSI) during pregnancy. Approach: The gestational-age dependent pregnant phantom series developed at the University of Florida (UF) were converted into DICOM-RT format (CT images and structures) and imported into a treatment planning system (TPS) (Eclipse v15.6) commissioned to a IBA PBS nozzle. A proton PBS CSI plan (prescribed dose: 36 Gy) was created on the phantoms. The TOPAS MC code was used to simulate the proton PBS CSI on the phantoms, for which MC beam properties at the nozzle exit (spot size, spot divergence, mean energy, and energy spread) were matched to IBA PBS nozzle beam measurement data. We calculated mean absorbed doses for 28 organs and tissues and whole body of the fetus at eight gestational ages (8, 10, 15, 20, 25, 30, 35, and 38 weeks). For contextual purposes, the fetal organ/tissue doses from the treatment planning CT scan of the mother’s head and torso were estimated using the National Cancer Institute dosimetry system for CT (NCICT, Version 3) considering a low-dose CT protocol (CTDIvol: 8.97 mGy). Main Results: The majority of the fetal organ/tissue doses from the proton PBS CSI treatment fell within a range of 3 to 6 mGy. The fetal organ/tissue doses for the 38-week phantom showed the largest variation with the doses ranging from 2.9 mGy (adrenals) to 8.2 mGy (eye lenses) while the smallest variation ranging from 3.2 mGy (oesophagus) to 4.4 mGy (brain) was observed for the doses for the 20-week phantom. The fetal whole-body dose ranged from 3.7 mGy (25 weeks) to 5.8 mGy (8 weeks). Most of the fetal doses from the planning CT scan fell within a range of 7 to 13 mGy, approximately 2-to-9 times lower than the fetal dose equivalents of the proton PBS CSI treatment (assuming a quality factor of 7). Significance: The fetal organ/tissue doses observed in the present work will be useful for one of the first clinically informative predictions on the magnitude of fetal dose during proton PBS CSI during pregnancy.

Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex

The placenta is an endocrine fetal organ, which secretes a plethora of steroid- and proteo-hormones, metabolic proteins, growth factors, and cytokines in order to adapt maternal physiology to pregnancy. Central to the growth of the fetus is the supply with nutrients, foremost with glucose. Therefore, during pregnancy, maternal insulin resistance arises, which elevates maternal blood glucose levels, and consequently ensures an adequate glucose supply for the developing fetus. At the same time, maternal β-cell mass and function increase to compensate for the higher insulin demand. These adaptations are also regulated by the endocrine function of the placenta. Excessive insulin resistance or the inability to increase insulin production accordingly disrupts physiological modulation of pregnancy mediated glucose metabolism and may cause maternal gestational diabetes (GDM). A growing body of evidence suggests that this adaptation of maternal glucose metabolism differs between pregnancies carrying a girl vs. pregnancies carrying a boy. Moreover, the risk of developing GDM differs depending on the sex of the fetus. Sex differences in placenta derived hormones and bioactive proteins, which adapt and modulate maternal glucose metabolism, are likely to contribute to this sexual dimorphism. This review provides an overview on the adaptation and maladaptation of maternal glucose metabolism by placenta-derived factors, and highlights sex differences in this regulatory network.

Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.

Quantification of fetal organ sparing in maternal low-protein dietary models

Background: Maternal malnutrition can lead to fetal growth restriction. This is often associated with organ sparing and long-lasting physiological dysfunctions during adulthood, although the underlying mechanisms are not yet well understood. Methods: Low protein (LP) dietary models in C57BL/6J mice were used to investigate the proximal effects of maternal malnutrition on fetal organ weights and organ sparing at embryonic day 18.5 (E18.5). Results: Maternal 8% LP diet induced strikingly different degrees of fetal growth restriction in different animal facilities, but adjustment of dietary protein content allowed similar fetal body masses to be obtained. A maternal LP diet that restricted fetal body mass by 40% did not decrease fetal brain mass to the same extent, reflecting positive growth sparing of this organ. Under these conditions, fetal pancreas and liver mass decreased by 60-70%, indicative of negative organ sparing. A series of dietary swaps between LP and standard diets showed that the liver is capable of efficient catch-up growth from as late as E14.5 whereas, after E10.5, the pancreas is not. Conclusions: This study highlights that the reproducibility of LP fetal growth restriction studies between laboratories can be improved by careful calibration of maternal dietary protein content. LP diets that induce 30-40% restriction of prenatal growth provide a good model for fetal organ sparing. For the liver, recovery of growth following protein restriction is efficient throughout fetal development but, for the pancreas, transient LP exposures spanning the progenitor expansion phase lead to an irreversible fetal growth deficit.

Chick fetal organ spheroids as a model to study development and disease

Background Organ culture models have been used over the past few decades to study development and disease. The in vitro three-dimensional (3D) culture system of organoids is well known, however, these 3D systems are both costly and difficult to culture and maintain. As such, less expensive, faster and less complex methods to maintain 3D cell culture models would complement the use of organoids. Chick embryos have been used as a model to study human biology for centuries, with many fundamental discoveries as a result. These include cell type induction, cell competence, plasticity and contact inhibition, which indicates the relevance of using chick embryos when studying developmental biology and disease mechanisms. Results Here, we present an updated protocol that enables time efficient, cost effective and long-term expansion of fetal organ spheroids (FOSs) from chick embryos. Utilizing this protocol, we generated FOSs in an anchorage-independent growth pattern from seven different organs, including brain, lung, heart, liver, stomach, intestine and epidermis. These three-dimensional (3D) structures recapitulate many cellular and structural aspects of their in vivo counterpart organs and serve as a useful developmental model. In addition, we show a functional application of FOSs to analyze cell-cell interaction and cell invasion patterns as observed in cancer. Conclusion The establishment of a broad ranging and highly effective method to generate FOSs from different organs was successful in terms of the formation of healthy, proliferating 3D organ spheroids that exhibited organ-like characteristics. Potential applications of chick FOSs are their use in studies of cell-to-cell contact, cell fusion and tumor invasion under defined conditions. Future studies will reveal whether chick FOSs also can be applicable in scientific areas such as viral infections, drug screening, cancer diagnostics and/or tissue engineering.

PLACENTAL THICKNESS AND ITS CORRELATION TO GESTATIONAL AGE ESTIMATED BY FOETAL GROWTH PARAMETERS-A CROSS SECTIONAL ULTRASONOGRAPHIC STUDY

The placenta is a meterno-fetal organ and starts developing on the 5th week from chorionic villi at the implantation site. The placenta continues to increase in thickness and hence its thickness can be used to indicate the gestational age when the last menstruation date is not confirmed. The purpose of the study was to find out the correlation of placental thickness to the gestational age estimated by growth parameters of the fetus. The study was a cross-sectional analytical study conducted on 2000 participants. The study was conducted in the Department of Radiology Social Security Hospital, Multan Chungi Lahore. The inclusion-exclusion criteria were established and participants were observed using a Toshiba ultrasonography machine. The subjects were placed supine and placental thickness was measured to the accuracy of 1mm. Pearson’s correlation was applied to find out the correlation between placental thickness and gestational age of the participants. The mean age of the participants was 28.37 + 4.6. The youngest participant was age 18 and the eldest participant was age 40. The gestational age of the participants included ranged between 12th week to 40th week. Pearson’s correlation score indicated that the correlation value 0.896. Which indicated that the placental thickness and gestational age were strongly correlated? The P-value < 0.05 indicated that the results were significant. The study concluded a strong correlation between gestational age and placental thickness of the fetus. The thickness of the placenta increased with an increase in gestational age and hence could be used as a predictor and a parameter of gestational age prediction when the last menstruation is uncertain or is unknown.

Ovine Fetal and Placental Lesions and Cellular Tropism in Natural Rift Valley Fever Virus Infections

Infection with Rift Valley fever phlebovirus (RVFV) causes abortion storms and a wide variety of outcomes for both ewes and fetuses. Sheep fetuses and placenta specimens were examined during the 2010–2011 River Valley fever (RVF) outbreak in South Africa. A total of 72 fetuses were studied of which 58 were confirmed positive for RVF. Placenta specimens were available for 35 cases. Macroscopic lesions in fetuses were nonspecific and included marked edema and occasional hemorrhages in visceral organs. Microscopically, multifocal hepatic necrosis was present in 48 of 58 cases, and apoptotic bodies, foci of liquefactive hepatic necrosis (primary foci), and eosinophilic intranuclear inclusions in hepatocytes were useful diagnostic features. Lymphocytolysis was present in all lymphoid organs examined with the exception of thymus and Peyer’s patches, and pyknosis or karyorrhexis was often present in renal glomeruli. The most significant histologic lesion in the placenta was necrosis of trophoblasts and endothelial cells in the cotyledonary and intercotyledonary chorioallantois. Immunolabeling for RVFV was most consistent in trophoblasts of the cotyledon or caruncle. Other antigen-positive cells included hepatocytes, renal tubular epithelial, juxtaglomerular and extraglomerular mesangial cells, vascular smooth muscle, endothelial and adrenocortical cells, cardiomyocytes, Purkinje fibers, and macrophages. Fetal organ samples for diagnosis must minimally include liver, kidney, and spleen. From the placenta, the minimum recommended specimens for histopathology include the cotyledonary units and caruncles from the endometrium, if available. The diagnostic investigation of abortion in endemic areas should always include routine testing for RVFV, and a diagnosis during interepidemic periods might be missed if only limited specimens are available for examination.

A Study on Morphohistometric Changes of Placenta in Gestational Diabetes- A Comparative Analysis

Introduction:The placenta is a complex fetal organ that fulfills pleotrophic roles during fetal growth. Placenta is the most accurate record of the infant’s prenatal experience. Gestational diabetes is much common than preexisting diabetes .i.e. it complicates 2% to 5% of pregnancies. It seems reasonable to expect that biochemical changes occurring in the pregnant women with diabetes should be reflected in the placental structure. Aim & objectives: In the present study an attempt is made to know the morphological changes of placenta in gestational diabetes mellitus.Subjects and Methods:In this study totally 60 placentae were studied, of which 30 were nondiabetic placentae and 30 from Gestational Diabetic mothers were studied macroscopically. Morphologically the shape, site of attachment of umbilical cord, central thickness of placenta was noted. Birth weight of the neonate and the placental ratio were also recorded. By using routine staining techniques and direct microscopy tissues of Gestational Diabetic placenta were studied qualitatively and compared them with normal placenta.Results:Our study demonstrates that there is a significant increase in weight and central thickness of placenta. Neonatal weight and placental ratio were also increased; there was no change in shape and site of attachment of umbilical cord in case of diabetic placenta when compared to normal. Conclusion:On the basis of results of present study it is concluded that diabetic placentae showed increase in weight and central thickness. Neonatal weight and placental ratio were also increased. These findings indicate that control of hyperglycemia only partially prevents the development of placental abnormalities.