Assessment of fetal growth trajectory identifies infants at high risk of perinatal mortality.

OBJECTIVE: To analyze perinatal risks associated with three distinct scenarios of fetal growth trajectory in the latter half of pregnancy compared with a reference group. METHODS: This cohort study included women with a singleton pregnancy that delivered between 32 + 0 and 41 + 6 weeks' gestation and had two or more ultrasound scans, at least 4 weeks apart, from 18 + 0 weeks. We evaluated three different scenarios of fetal growth against a reference group, which comprised appropriate-for-gestational-age fetuses with appropriate forward-growth trajectory. The comparator growth trajectories were categorized as: Group 1, small-for-gestational-age (SGA) fetuses (estimated fetal weight (EFW) or abdominal circumference (AC) persistently < 10th centile) with appropriate forward growth; Group 2, fetuses with decreased growth trajectory (decrease of ≥ 50 centiles) and EFW or AC ≥ 10th centile (i.e. non-SGA) at their final ultrasound scan; and Group 3, fetuses with decreased growth trajectory and EFW or AC < 10th centile (i.e. SGA) at their final scan. The primary outcome was overall perinatal mortality (stillbirth or neonatal death). Secondary outcomes included stillbirth, delivery of a SGA infant, preterm birth, emergency Cesarean section for non-reassuring fetal status and composite severe neonatal morbidity. Associations were analyzed using logistic regression. RESULTS: The final study cohort comprised 5319 pregnancies. Compared to the reference group, the adjusted odds of perinatal mortality were increased significantly in Group 2 (adjusted odds ratio (aOR), 4.00 (95% CI, 1.36-11.22)) and Group 3 (aOR, 7.71 (95% CI, 2.39-24.91)). Only Group 3 had increased odds of stillbirth (aOR, 5.69 (95% CI, 1.55-20.93)). In contrast, infants in Group 1 did not have significantly increased odds of demise. The odds of a SGA infant at birth were increased in all three groups compared with the reference group, but was highest in Group 1 (aOR, 111.86 (95% CI, 62.58-199.95)) and Group 3 (aOR, 40.63 (95% CI, 29.01-56.92)). In both groups, more than 80% of infants were born SGA and nearly half had a birth weight < 3rd centile. Likewise, the odds of preterm birth were increased in all three groups compared with the reference group, being highest in Group 3, with an aOR of 4.27 (95% CI, 3.23-5.64). Lastly, the odds of composite severe neonatal morbidity were increased in Groups 1 and 3, whereas the odds of emergency Cesarean section for non-reassuring fetal status were increased only in Group 3. CONCLUSION: Assessing the fetal growth trajectory in the latter half of pregnancy can help identify infants at increased risk of perinatal mortality and birth weight < 3rd centile for gestation. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Effect of reverse osmosis and ultra-high-pressure homogenization on the composition and microstructure of sweet buttermilk.

Buttermilk (BM), the by-product of butter making, is similar to skim milk (SM) composition. However, it is currently undervalued in dairy processing because it is responsible for texture defects (e.g., crumbliness, decreased firmness) in cheese and yogurt. One possible way of improving the incorporation of BM into dairy products is by the use of technological pretreatments such as membrane filtration and homogenization. The study aimed at characterizing the effect of preconcentration by reverse osmosis (RO) and single-pass ultra-high-pressure homogenization (UHPH) on the composition and microstructure of sweet BM to modify its techno-functional properties (e.g., protein gel formation, syneresis, firmness). The BM and RO BM were treated at 0, 15, 150, and 300 MPa. Pressure-treated and control BM and RO BM were ultracentrifuged to fractionate them into the following 3 fractions: a supernatant soluble fraction (top layer), a colloidal fraction consisting of a cloudy layer (middle layer), and a high-density pellet (bottom layer). Compositional changes in the soluble fraction [lipid, phospholipid (PL), protein, and salt], as well as its protein profile by PAGE analysis, were determined. Modifications in particle size distribution upon UHPH were monitored by laser diffraction in the presence and absence of sodium citrate to dissociate the casein (CN) micelles. Microstructural changes in pressure-treated and non-pressure-treated BM and RO BM particles were monitored by confocal laser scanning microscopy. Particle size analysis showed that UHPH treatment significantly decreased the size of the milk fat globule membrane fragments in BM and RO BM. Also, pressure treatment at 300 MPa led to a significant increase in the recovery of total lipids, CN, calcium, and phosphate in the BM soluble fraction (top layer) following ultracentrifugation. However, PL were primarily concentrated in the pellet cloud (middle layer), located above the pellet in BM concentrated by RO. In contrast, PL were evenly distributed between soluble and colloidal phases of BM. This study provides insight into the modifications of sweet BM constituents induced by RO and UHPH from a compositional and structural perspective.

Interobserver agreement in analysis of cardiotocograms recorded during trial of labor after cesarean.

Introduction: To examine interobserver agreement in intrapartum cardiotocography (CTG) classification in women undergoing trial of labor after a cesarean section (TOLAC) at term with or without complete uterine rupture. Materials and methods: Nineteen blinded and independent Danish obstetricians assessed CTG tracings from 47 women (174 individual pages) with a complete uterine rupture during TOLAC and 37 women (133 individual pages) with no uterine rupture during TOLAC. Individual pages with CTG tracings lasting at least 20 min were evaluated by three different assessors and counted as an individual case. The tracings were analyzed according to the modified version of the Federation of Gynaecology and Obstetrics (FIGO) guidelines elaborated for the use of STAN (ST-analysis). Occurrence of defined abnormalities was recorded and the tracings were classified as normal, suspicious, pathological, or preterminal. The interobserver agreement was evaluated using Fleiss' kappa. Results: Agreement on classification of a preterminal CTG was almost perfect. The interobserver agreement on normal, suspicious or pathological CTG was moderate to substantial. Regarding the presence of severe variable decelerations, the agreement was moderate. No statistical difference was found in the interobserver agreement between classification of tracings from women undergoing TOLAC with and without complete uterine rupture. Conclusions: The interobserver agreement on classification of CTG tracings from high-risk deliveries during TOLAC is best for assessment of a preterminal CTG and the poorest for the identification of severe variable decelerations.

[Reirradiation of head and neck cancers]. / Réirradiation des cancers des voies aérodigestives supérieures.

Locoregional relapse in previously irradiated region for head and neck tumours is associated with a bad locoregional and distant prognosis. Reirradiation might be exclusive, or feasible in addition with surgery and/or chemotherapy, according to histopronostic factors. Data show that reirradiation is feasible with some severe toxicity due to the bad prognosis of this situation. Hyperfractionnated regimen with split course or normofractionnated regimen without split course are possible with similar efficacy. If tumour size is small, stereotactic ablative radiotherapy may be considered, and if the treatment centre has proton therapy, it could be proposed because of better organs at risk sparing. There is no standard regarding reirradiation schedules and several trials have to be done in order to determine the best technique. Nevertheless, it is agreed that a total dose of 60Gy (2Gy per fraction) is needed. Other trials testing the association with new systemic agents have to be performed, among them agents targeting the PD1/PD-L1 axis.

Long-term effects of prenatal progesterone exposure: neurophysiological development and hospital admissions in twins up to 8 years of age.

OBJECTIVES: To perform a neurophysiological follow-up at 48 or 60 months of age in children exposed prenatally to progesterone compared with a placebo and evaluate their medical histories up to 8 years of age. METHODS: In this study, Danish participants of the PREDICT study, including 989 surviving children from 498 twin pregnancies, were followed-up. PREDICT was a placebo-controlled randomized clinical trial examining the effect of progesterone for prevention of preterm delivery in unselected twin pregnancies. Medical histories of the children were reviewed and neurophysiological development was evaluated by the parent-completed Ages and Stages Questionnaire (ASQ) at either 48 or 60 months after the estimated date of delivery. We used the method of generalized estimating equation to account for the correlation within twins. RESULTS: A total of 492 children had been exposed prenatally to progesterone and 497 to placebo. There was no difference in the number of admissions to or length of stay in hospital between the treatment groups, and we found no overall difference in the rates of diagnoses made. However, the odds ratios (ORs) for a diagnosis concerning the heart was 1.66 (95% CI, 0.81-3.37), favoring placebo, among all children, 2.38 (95% CI, 1.07-5.30) in dichorionic twins and 8.19 (95% CI, 1.02-65.6) in all children when excluding diagnoses made at outpatient clinic visits. ASQ scores were available for 437 children (progesterone, n = 225; placebo, n = 212). Mean ASQ score was slightly higher in the progesterone group compared with the placebo group (P = 0.03). In dichorionic twins, the risk of having a low ASQ score (< 10(th) centile) was decreased in the progesterone group (OR, 0.34 (95% CI, 0.14-0.86)). CONCLUSION: Second- and third-trimester exposure of the fetus to progesterone does not seem to have long-term harmful effects during childhood, but future studies should focus on cardiac disease in the child. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Endoglin is required in Pax3-derived cells for embryonic blood vessel formation.

Mutations in endoglin, a TGFß/BMP coreceptor, are causal for hereditary hemorrhagic telangiectasia (HHT). Endoglin-null (Eng-/-) mouse embryos die at embryonic day (E)10.5-11.5 due to defects in angiogenesis. In part, this is due to an absence of vascular smooth muscle cell differentiation and vessel investment. Prior studies from our lab and others have shown the importance of endoglin expression in embryonic development in both endothelial cells and neural crest stem cells. These studies support the hypothesis that endoglin may play cell-autonomous roles in endothelial and vascular smooth muscle cell precursors. However, the requirement for endoglin in vascular cell precursors remains poorly defined. Our objective was to specifically delete endoglin in neural crest- and somite-derived Pax3-positive vascular precursors to understand the impact on somite progenitor cell contribution to embryonic vascular development. Pax3Cre mice were crossed with Eng+/- mice to obtain compound mutant Pax3(Cre/+);Eng+/- mice. These mice were then crossed with homozygous endoglin LoxP-mutated (Eng(LoxP/LoxP)) mice to conditionally delete the endoglin gene in specific lineages that contribute to endothelial and smooth muscle constituents of developing embryonic vessels. Pax3(Cre/+);Eng(LoxP/)(-) mice showed a variety of vascular defects at E10.5, and none of these mice survived past E12.5. Embryos analyzed at E10.5 showed malformations suggestive of misdirection of the intersomitic vessels. The dorsal aorta showed significant dilation with associated vascular smooth muscle cells exhibiting disorganization and enhanced expression of smooth muscle differentiation proteins, including smooth muscle actin. These results demonstrate a requirement for endoglin in descendants of Pax3-expressing vascular cell precursors, and thus provides new insight into the cellular basis underlying adult vascular diseases such as HHT.

Abnormally invasive placenta-prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries.

OBJECTIVE: The objective was to investigate prevalence, estimate risk factors, and antenatal suspicion of abnormally invasive placenta (AIP) associated with laparotomy in women in the Nordic countries. DESIGN: Population-based cohort study. SETTING AND POPULATION: A 3-year Nordic collaboration among obstetricians to identify and report on uterine rupture, peripartum hysterectomy, excessive blood loss, and AIP from 2009 to 2012 The Nordic Obstetric Surveillance Study (NOSS). METHODS: In the NOSS study, clinicians reported AIP cases from maternity wards and the data were validated against National health registries. MAIN OUTCOME MEASURES: Prevalence, risk factors, antenatal suspicion, birth complications, and risk estimations using aggregated national data. RESULTS: A total of 205 cases of AIP in association with laparotomy were identified, representing 3.4 per 10 000 deliveries. The single most important risk factor, which was reported in 49% of all cases of AIP, was placenta praevia. The risk of AIP increased seven-fold after one prior caesarean section (CS) to 56-fold after three or more CS. Prior postpartum haemorrhage was associated with six-fold increased risk of AIP (95% confidence interval 3.7-10.9). Approximately 70% of all cases were not diagnosed antepartum. Of these, 39% had prior CS and 33% had placenta praevia. CONCLUSION: Our findings indicate that a lower CS rate in the population may be the most effective way to lower the incidence of AIP. Focused ultrasound assessment of women at high risk will likely strengthen antenatal suspicion. Prior PPH is a novel risk factor associated with an increased prevalence of AIP. TWEETABLE ABSTRACT: An ultrasound assessment in women with placenta praevia or prior CS may double the awareness for AIP.

[Management of locally advanced anal canal carcinoma with modulated arctherapy and concurrent chemotherapy]. / Place de l'arcthérapie modulée et de la chimiothérapie concomitante dans la prise en charge des cancers du canal anal localement évolués.

The standard treatment of locally advanced (stage II and III) squamous cell carcinoma of the anal canal consists of concurrent chemoradiotherapy (two cycles of 5-fluoro-uracil, mitomycin C, on a 28-day cycle), with a dose of 45 Gy in 1.8 Gy per fraction in the prophylactic planning target volume and additional 14 to 20 Gy in the boost planning target volume (5 days per week) with a possibility of 15 days gap period between the two sequences. While conformal irradiation may only yield suboptimal tumor coverage using complex photon/electron field junctions (especially on nodal areas), intensity modulated radiation therapy techniques (segmented static, dynamic, volumetric modulated arc therapy and helical tomotherapy) allow better tumour coverage while sparing organs at risk from intermediate/high doses (small intestine, perineum/genitalia, bladder, pelvic bone, etc.). Such dosimetric advantages result in fewer severe acute toxicities and better potential to avoid a prolonged treatment break that increases risk of local failure. These techniques also allow a reduction in late gastrointestinal and skin toxicities of grade 3 or above, as well as better functional conservation of anorectal sphincter. The technical achievements (simulation, contouring, prescription dose, treatment planning, control quality) of volumetric modulated arctherapy are discussed.

The personality trait self-directedness predicts the amygdala's reaction to appetizing cues in fMRI.

Personality and neural response to food cues in various mesolimbic brain structures have been linked to eating disorders. We investigated the question of whether personality traits in healthy individuals correlate with the brain activation induced on confrontation with appetizing visual stimuli. Personality was assessed in 27 normal-weight participants (14 women, mean age=26.0, SD=3.3 years) with the Temperament and Character Inventory (TCI). After an overnight fast, participants viewed blocks of pictures, half containing appetizing food and the other half showing scrambled pictures as control. After each block, participants rated their appetite. Brain activation was measured using a 3T MR scanner. Food compared to control stimuli elicited a significantly higher appetite rating, as well as strong activation in the ventral and dorsal visual stream, the fusiform gyrus and consecutive limbic centres such as the parahippocampal gyrus, the amygdala, the thalamus, the insula, the ventral striatum and the orbitofrontal cortex. In a region-of-interest analysis, the TCI trait self-directedness was negatively correlated with mean blood oxygenation level dependent (BOLD) signal change in the right amygdala (r=-.43, p=.025). Ultimately, amygdala reactivity might provide a risk factor for the development of eating disorders.

Reduced striatal activation during reward anticipation due to appetite-provoking cues in chronic schizophrenia: a fMRI study.

The occurrence of weight gain in schizophrenia (SZ) has profound clinical impact and interacts with antipsychotic medication, life style and disease severity. The functional neuroanatomy underlying altered nutritional behavior is unraveled, but dysregulated reward anticipation might be one of the involved neuronal mechanisms. The striatum, a core region of the reward network and salience attribution, was previously shown to regulate appetite perception and eating behavior. We studied patients suffering from chronic schizophrenia with a stable medication in comparison to age and gender matched healthy adults. Every subject had to undergo a 6h fasting period before a newly developed, appetite-provoking fMRI task was applied. Subjects saw visual stimuli of appetitive food items in a 3Tesla scanner. In healthy controls food images elicited stronger activation in the striatum compared to SZ patients. When adjusting a ROI-based striatal activation for medication and weight, the group difference remained still significant. This points an effect of illness independent of antipsychotic medication. These data underscore the involvement of the striatum into salience attribution, reward anticipation and the neuronal pathways leading to altered eating behavior and weight gain in schizophrenia.

Molecular basis of hyperparathyroidism and potential targets for drug development.

Our appreciation of the molecular pathogenesis of primary hyperparathyroidism (HPT) has seen great advances over the past decade. This improved understanding may well lead to the development of new treatment options that are specifically targeted to defective pathways. This review summarizes recent advances in the molecular basis of HPT and associated endocrinopathies, and discusses the potential for these and future findings to provide targets for alternative approaches to therapy. The only proven contributors to common sporadic HPT, by virtue of clonal genetic abnormalities, are the cyclin D1 and MEN1 genes. Cyclin D1 is an oncogene that encodes a key regulator of the cell cycle, while MEN1 is a tumor suppressor gene that has also been implicated in familial multiple endocrine neoplasia type 1 (MEN1), in which primary HPT is common. In addition, other key parathyroid regulatory pathways may play a role in HPT pathogenesis. 1,25 (OH)2-vitamin D. Ca2+ and phosphate are regarded as principal regulators of parathyroid cell proliferation and PTH secretion. Therefore, prime candidate targets include the Ca2+ sensing receptor (CASR) gene, the vitamin D receptor (VDR) gene, a putative phosphate receptor gene, their cognate gene products, and other genes or proteins involved in their respective biochemical pathways. Attempts to identify new therapies based specifically on the defective pathways in HPT could complement or eventually supplant traditional approaches.

Long-term outcome in term breech infants with low Apgar score--a population-based follow-up.

OBJECTIVE: To investigate the relation between low Apgar score in breech infants and handicap in childhood. STUDY DESIGN: A case-control study. A questionnaire to mothers of 323 non-malformed, singleton infants delivered in breech presentation at term, 105 cases with Apgar score below 7 at 5 min and 218 controls. RESULTS: Four cases (4.6%) and one control (0.5%) had cerebral palsy. In infants without cerebral palsy, speech/language problems were more frequent than controls (10.6 versus 3.2%) (P=0.02). There were no differences in rates of deficits in attention, motor control and perception (DAMP), epilepsy, cognitive developmental delay or learning disabilities. Absence of any handicap or disability was reported in 65 cases (75%) compared to 172 controls (92%) (OR: 3.9; 95% CI: 1.9-7.9). CONCLUSION: Even though low Apgar score indicates an increased risk of neurological sequelae, most (75%) breech infants with low Apgar score are without a handicap/disability at follow-up.

Studies on the mechanism of action of a targeted chemotherapeutic drug in living cancer cells by two photon laser scanning microspectrofluorometry.

In this study, we present a spectroscopic study of the entry pattern of a chemotherapeutic drug (AN-152) and its carrier hormone ([D-Lys(6)]LH-RH) into living cancer cells, with the help of our two-photon probes and a home-built localized microspectrofluorometer coupled with two photon laser scanning microscope (TPLSM). Due to the inherent localization ability of TPLSM, we were able to identify the drug and carrier location in different compartments of the cancer cells in vitro. The apparent doxorubicin-assisted nucleic accumulation of AN-152 suggests a possible nuclear action of the drug on cell proliferation.

Thermal destruction of benzene.

The thermal destruction of benzene in methane/air flue gas is studied experimentally using an atmospheric laminar flow reactor in laboratory scale. The reactor is operated at four different fuel equivalent ratios (phi = 0.06, 0.1,0.5, 3.7), and temperatures in the range from 850 to 973 K and realises a residence time of 5 s. Stable-species concentrations are measured by gas chromatography (GC) and high-pressure liquid chromatography (HPLC), where phenol, acetylene, formaldehyde, acrolein, methane and acetaldehyde are the major hydrocarbon products besides CO and CO2. The augmentation of the temperature from 850 to 973 K increases the benzene conversion rate from 55% to 99%. The experimental results for one fuel equivalent ratio (phi = 0.5) are compared to the benzene model proposed by Emdee et al. (J. Phys. Chem. 92 (1992) 2151-2161). A fair agreement is observed for the benzene consumption and the CO production throughout the temperature range considered here. The small hydrocarbons are not very well matched, which requires further research on the sub-models. Our experimental results on laboratory scale provide a database for the modelling of benzene oxidation in waste incinerators.

An innovative path to improving cancer care in Indian country.

The Native American Cancer Survivors' Support Network is an innovative public health program designed to improve survival from cancer and the quality of life after a cancer diagnosis for American Indians, Alaska Natives, and Canadian Aboriginal patients and their loved ones. The Network, initiated in 1999, now has more than 300 survivors enrolled as members. This article briefly describes the process that led to its formation and preliminary findings, primarily for breast cancer survivors, of ongoing qualitative and quantitative research. Network data show patterns of cancer care that are partially responsible for poor survivorship outcomes.

The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway.

We have identified a gene encoding a novel protein that is transcriptionally regulated by the Notch signaling pathway in mammals. This gene, named Nrarp (for Notch-regulated ankyrin-repeat protein), encodes a 114 amino acid protein that has a unique amino-terminus and a carboxy-terminal domain containing two ankyrin-repeat motifs. A Xenopus homolog of the Nrarp gene was previously identified in a large-scale in situ hybridization screen of randomly isolated cDNA clones. We demonstrate that in T-cell and myoblast cell lines expression of the Nrarp gene is induced by the intracellular domain of the Notch1 protein, and that this induction is mediated by a CBF1/Su(H)/Lag-1 (CSL)-dependent pathway. During mouse embryogenesis, the Nrarp gene is expressed in several tissues in which cellular differentiation is regulated by the Notch signaling pathway. Expression of the Nrarp gene is downregulated in Notch1 null mutant mouse embryos, indicating that expression of the Nrarp gene is regulated by the Notch pathway in vivo. Thus, Nrarp transcript levels are regulated by the level of Notch1 signaling in both cultured cell lines and mouse embryos. During somitogenesis, the Nrarp gene is expressed in a pattern that suggests that Nrarp expression may play a role in the formation of somites, and Nrarp expression in the paraxial mesoderm is altered in several Notch pathway mutants that exhibit defects in somite formation. These observations demonstrate that the Nrarp gene is an evolutionarily conserved transcriptional target of the Notch signaling pathway.

Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor.

Targeting chemotherapy selectively to cancers can reduce the toxic side effects. AN-152, a conjugate of doxorubicin and [D-Lys6]-luteinizing hormone-releasing hormone (LH-RH), is more potent against LH-RH receptor-bearing cancers and produces less peripheral toxicity than doxorubicin. Many cancers, e.g., 50% of breast cancers, but few normal tissues express these receptors, providing a selective target for this cytotoxic conjugate. In this study, the effectiveness of AN-152 was heightened by receptor up-regulation. The cytotoxic effect of AN-152 can be regulated by the number of active LH-RH receptors on cancer cells. LH-RH receptor-positive (MCF-7) and -negative (UCI-107) cancer cells were treated with epidermal growth factor (EGF) or the somatostatin analogue, RC-160. EGF and RC-160 have been shown previously to regulate LH-RH receptors through phosphorylation. The effect of receptor regulation, by hormone exposure, on the cytotoxicity of AN-152 and doxorubicin and on the cellular uptake of AN-152, [D-Lys6]LH-RH, or doxorubicin was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by two-photon laser scanning microscopy. The results demonstrated that the cellular entry of the conjugate was: (a) specific for cancers with LH-RH receptors; (b) up-regulated by EGF; (c) down-regulated by RC-160; and (d) the cytotoxicity of the AN-152 paralleled the efficiency of entry. This study illustrates the potential use of receptor regulation for increasing the efficacy of chemotherapeutic approaches that are directed to cell surface receptors.

Notch signaling is essential for vascular morphogenesis in mice.

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of the Notch4 gene, we generated Notch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene. Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.