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Advanced maternal age (AMA; ≥35 years of age) is associated with an increased risk of adverse pregnancy outcomes. To explore causes of adverse pregnancy outcomes in AMA, and to test candidate therapies, an increasing number of murine AMA models have been developed. The aim of this study was to systematically review the literature to assess whether murine AMA models demonstrate a reproducible effect on pregnancy outcomes. PubMed, Ovid, Web of Science and Google Scholar were searched. Studies that reported on pregnancy outcomes in AMA mice and rats were included; the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool evaluated the risk of bias. Eleven mouse and six rat studies were included. AMA mice and rats had reduced litter size (standardised mean difference (SMD): -1.59, 95% confidence interval (CI): -1.84, -1.34 for mice; SMD: -1.66, 95% (CI): -2.09, -1.23 for rats) and reduced fetal weight (SMD: -0.87, 95% CI: -1.24, -0.49 for mice; SMD: -1.05, 95% CI: -1.40, -0.69 for rats). Placental weight was increased in AMA mice (SMD: 0.62, 95% CI: 0.16, 1.08). Subgroup analysis indicated that C57Bl/6 mice had less heterogeneity than other, mostly outbred, mouse strains with regards to litter size (C57 strain I² = 68.2% vs other strain types I² = 85.7%). The risk of bias was high, mostly due to the lack of methodological detail and unclear reporting of findings. Murine models of AMA demonstrate similar adverse pregnancy outcomes to those observed in large human epidemiological studies. The reproducible phenotypes in AMA murine models allow the exploration of mechanisms underpinning poor pregnancy outcomes and the pursuit of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Well differentiated liposarcoma (WD‐LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy‐ and radiotherapy‐resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD‐LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia‐associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Pathological complete response (pathCR) in rectal cancer is beneficial, as up to 75% of patients do not experience regrowth of the primary tumour, but it is poorly understood. We hypothesised that the changes seen in the pre-treatment biopsies of pathCR but not seen in residual tumour after chemoradiotherapy were the determinants of responsiveness.Methods: Two groups of patients with either complete response (pathCR group, N = 24) or no response (poor response group, N = 24) were retrieved. Pre-treatment biopsies of cancers from these patients underwent high read depth amplicon sequencing for a targeted panel, exome sequencing, methylation profiling and immunohistochemistry for DNA repair pathway proteins.Results: Twenty four patients who underwent pathCR and twenty-four who underwent poor response underwent molecular characterisation. Patients in the pathCR group had significantly higher tumour mutational burden and neoantigen load, frequent copy number alterations but fewer structural variants and enrichment for driver mutations in the PI3K/AKT/mTOR signalling pathway. There were no significant differences in tumour heterogeneity as measured by MATH score. Methylation analysis demonstrated enrichment for hypomethyation in the PI3K/AKT/mTOR signalling pathway.Discussion: The phenomenon of pathCR in rectal cancer may be related to immunovisibility caused by a high tumour mutational burden phenotype. Potential therapy resistance mechanisms involve the PI3K/AKT/mTOR signalling pathway, but tumour heterogeneity does not seem to play a role in resistance. [ABSTRACT FROM AUTHOR]

Background: In humans, stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually. In high-income countries, up to half of stillbirths have an unknown cause and are described as "unexplained stillbirths"; this lack of understanding impairs efforts to prevent stillbirth. There are also few animal models of stillbirth, but those that have been described usually have significant placental abnormalities. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology. Methods: Phenotypic characterisation and histological analysis of the mutant mouse model was conducted. The mRNA distribution of the early cardiomyocyte marker Nkx2-5 was assessed via in situ hybridisation. Cardiac structure was quantified and cellular morphology evaluated by electron microscopy. Immunostaining was employed to quantify placental structure and cell characteristics on matched heterozygous and homozygous mutant placental samples. Results: There were no structural abnormalities observed in hearts of mutant embryos. Comparable Nkx2-5 expression was observed in hearts of mutants and controls, suggesting normal cardiac specification. Additionally, there was no significant difference in the weight, placenta dimensions, giant cell characteristics, labyrinth tissue composition, levels of apoptosis, proliferation or vascularisation between placentas of homozygous mutant mice and controls. Conclusion: Embryonic lethality in the ErbB2 homozygous mutant mouse cannot be attributed to placental pathology. As such, we conclude the ErbB2M802R mutant is a model of stillbirth with a non-placental cause of death. The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects. [ABSTRACT FROM AUTHOR]

Background: Surgical site infection (SSI) is associated with morbidity, mortality and increased care costs; many SSIs are considered preventable. The aim of the present study was to test implementation of a pragmatic, evidence-based bundle designed to reduce incisional SSI after emergency laparotomy and elective major lower gastrointestinal surgery. Method: This was a prospective before-and-after study. Data were collected before the intervention and for two separate subsequent time periods. An evidence-based bundle of care (BOC) was implemented; the primary outcome measure was incisional SSI at 30 days. The secondary outcome measure was 30-day unplanned readmissions. The initial post-intervention group, Group 2, assessed a variable number of potential impacting factors; however, due to funding and staffing levels the second post-bundle group, Group 3, focused on the core aspects of the BOC and rates of incisional SSI and readmission. Results: In total, 99 patients were included in the 'before' group; and 71 in Group 2 and 92 in Group 3, the post-intervention groups. The incisional SSI rate was 29.3% (29/99) before and 28.2% (20/71) in Group 2 (P =0.873) and 21.7% (20/92) in Group 3 (P =0.234) after the intervention. After adjustment for confounders, the care bundle was associated with a non-significant reduction in SSI (Group 2: odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.45–1.93, P =0.0843). However, it was associated with significantly reduced readmissions 18.1% (18/99) before versus 5.6% (4/71) in Group 2 (OR = 0.236, 95% CI = 0.077–0.72, P =0.012) and 8.7% (8/92) in Group 3 (OR = 0.38, 95% CI = 0.16–0.9, P =0.029). Comparing the pre-bundle group to the post-bundle groups, there was an overall significant reduction in readmissions (P =0.003). This implies a number needed to treat of 8–11 patients to prevent one readmission. Adherence to antibiotic prophylaxis with the Trust guidelines increased from 91% to 99% (1 vs. 2, P =0.047). Conclusion: Introduction of the bundle was associated with a reduction in the observed rate of incisional SSI from 29.3% to 21.7%; significantly fewer patients required unplanned readmission. Use of the bundle was associated with significantly improved compliance with appropriate antimicrobial prophylaxis. [ABSTRACT FROM AUTHOR]

Key points: Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health.A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus.Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR.Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy.Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (Kmf) of 14C‐glutamine and 14C‐glutamate (glutamineKmf and glutamateKmf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamineKmf and glutamateKmf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamineKmf remained elevated whereas glutamateKmf was similar between groups. In summary, we provide evidence that glutamineKmf and glutamateKmf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth. Key points: Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health.A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus.Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR.Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy.Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. Background: Identifying patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma remains a challenge. Previous studies have demonstrated the potential utility of epigenetic markers for identifying this group. Methods: A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with nondysplastic Barrett esophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing. Results: In all, 12 patients with "progressive" versus 12 with "nonprogressive" nondysplastic Barrett esophagus were analyzed via methylation array. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adenocarcinoma or remain static. Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P = 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma. There were no differences in copy number between the 2 groups, but a global trend towards hypomethylation in the progressor group was observed. Conclusion: Hypomethylation of OR3A4 has the ability to risk stratify the patient with nondysplastic Barrett esophagus and may form the basis of a future surveillance program. [ABSTRACT FROM AUTHOR]

Fetal delivery of calcium, via the placenta, is crucial for appropriate skeletal mineralization. We have previously demonstrated that maternofetal calcium transport, per gram placenta, is increased in the placental specific insulin-like growth factor 2 knockout mouse (P0) model of fetal growth restriction (FGR) compared to wild type littermates (WTL). This effect was mirrored in wild-type (WT) mice comparing lightest vs. heaviest (LvH) placentas in a litter. In both models increased placental calcium transport was associated with normalization of fetal calcium content. Despite this adaptation being observed in small normal (WT), and small dysfunctional (P0) placentas, mechanisms underpinning these changes remain unknown. Parathyroid hormone-related protein (PTHrP), elevated in cord blood in FGR and known to stimulate plasma membrane calcium ATPase, might be important. We hypothesized that PTHrP expression would be increased in LvH WT placentas, and in P0 vs. WTL. We used calcium pathway-focused PCR arrays to assess whether mechanisms underpinning these adaptations in LvH WT placentas, and in P0 vs. WTL, were similar. PTHrP protein expression was not different between LvH WT placentas at E18.5 but trended toward increased expression (139%; P = 0.06) in P0 vs. WTL. PCR arrays demonstrated that four genes were differentially expressed in LvH WT placentas including increased expression of the calcium-binding protein calmodulin 1 (1.6-fold; P < 0.05). Twenty-four genes were differentially expressed in placentas of P0 vs. WTL; significant reductions were observed in expression of S100 calcium binding protein G (2-fold; P < 0.01), parathyroid hormone 1 receptor (1.7-fold; P < 0.01) and PTHrP (2-fold; P < 0.05), whilst serum/glucocorticoid-regulated kinase 1 (SGK1), a regulator of nutrient transporters, was increased (1.4 fold; P < 0.05). Tartrate resistant acid phosphatase 5 (TRAP5 encoded by Acp5) was reduced in placentas of both LvH WT and P0 vs. WTL (1.6- and 1.7-fold, respectively; P < 0.05). Signaling events underpinning adaptations in calcium transport are distinct between LvH placentas of WT mice and those in P0 vs. WTL. Calcium binding proteins appear important in functional adaptations in the former whilst PTHrP and SGK1 are also implicated in the latter. These data facilitate understanding of mechanisms underpinning placental calcium transport adaptation in normal and growth restricted fetuses. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) presents with an increased risk of stillbirth and childhood and adulthood morbidity. Melatonin, a neurohormone and antioxidant, has been suggested as having therapeutic benefit in FGR. We tested the hypothesis that melatonin would increase fetal growth in two mouse models of FGR which together represent a spectrum of the placental phenotypes in this complication: namely the endothelial nitric oxide synthase knockout mouse (eNOS-/-) which presents with abnormal uteroplacental blood flow, and the placental specific Igf2 knockout mouse (P0+/-) which demonstrates aberrant placental morphology akin to human FGR. Melatonin (5 μg/ml) was administered via drinking water from embryonic day (E)12.5 in C57Bl/6J wild-type (WT), eNOS-/-, and P0+/- mice. Melatonin supplementation significantly increased fetal weight in WT, but not eNOS-/- or P0+/- mice at E18.5. Melatonin did, however, significantly increase abdominal circumference in P0+/- mice. Melatonin had no effect on placental weight in any group. Uterine arteries from eNOS-/- mice demonstrated aberrant function compared with WT but melatonin treatment did not affect uterine artery vascular reactivity in either of these genotypes. Umbilical arteries from melatonin treated P0+/- mice demonstrated increased relaxation in response to the nitric oxide donor SNP compared with control. The increased fetal weight in WT mice and abdominal circumference in P0+/-, together with the lack of any effect in eNOS-/-, suggest that the presence of eNOS is required for the growth promoting effects of melatonin. This study supports further work on the possibility of melatonin as a treatment for FGR. [ABSTRACT FROM AUTHOR]

The eNOS-/- mouse provides a well-characterized model of fetal growth restriction (FGR) with altered uterine and umbilical artery function and reduced utero- and feto-placental blood flow. Pomegranate juice (PJ), which is rich in antioxidants and bioactive polyphenols, has been posited as a beneficial dietary supplement to promote cardiovascular health. We hypothesized that maternal supplementation with PJ will improve uterine and umbilical artery function and thereby enhance fetal growth in the eNOS-/- mouse model of FGR. Wild type (WT, C57Bl/6J) and eNOS-/- mice were supplemented from E12.5-18.5 with either PJ in their drinking water or water alone. At E18.5 uterine (UtA) and umbilical (UmbA) arteries were isolated for study of vascular function, fetuses and placentas were weighed and fetal biometric measurements taken. PJ supplementation significantly increased UtA basal tone (both genotypes) and enhanced phenylephrine-induced contraction in eNOS-/- but not WT mice. Conversely PJ significantly reduced UtA relaxation in response to both acetylcholine (Ach) and sodium nitroprusside (SNP), endothelium dependent and independent vasodilators respectively from WT but not eNOS-/- mice. UmbA sensitivity to U46619-mediated contraction was increased by PJ supplementation in WT mice; PJ enhanced contraction and relaxation of UmbA to Ach and SNP respectively in both genotypes. Contrary to our hypothesis, the changes in artery function induced by PJ were not associated with an increase in fetal weight. However, PJ supplementation reduced litter size and fetal abdominal and head circumference in both genotypes. Collectively the data do not support maternal PJ supplementation as a safe or effective treatment for FGR. [ABSTRACT FROM AUTHOR]

Introduction: The ratio of birthweight to placental weight (BW:PW) is often used as a measure of placental efficiency in humans and animals. However, ratios have properties that are known to lead to spurious results. An alternative approach is the use of residuals from regression, which reflect whether birthweight is higher or lower than expected for a given placental weight, given the population pattern. We hypothesized that biologically meaningful measures of placental efficiency would differ between placentas with and without pathology, and between adverse and normal perinatal and postnatal outcomes.Methods: We examined associations between measures of placental efficiency (BW:PW ratio or residuals) and placental pathology, Apgar scores and infant death using National Collaborative Perinatal Project data (4645 preterm births and 28497 term births).Results: BW:PW ratios and residuals were significantly lower in placentas showing pathologies including signs of large infarcts or hemorrhage, although many of these differences were small. Low BW:PW ratios and residuals were also associated with low Apgar scores and increased risk of postnatal death. Whereas residuals were lower in term placentas that appeared immature by microscopic examination, the opposite was true for BW:PW ratios.Conclusion: The BW:PW ratio produced an artefact whereby histologically less mature placentas at term appeared to be more "efficient" than mature placentas, illustrating a known problem with the use of ratios. For other traits, residuals generally showed differences between placentas with and without pathology that were as great as those seen with BW:PW ratios, and often showed stronger associations with adverse outcomes. [ABSTRACT FROM AUTHOR]

Objectives The objective of this systematic review is to identify and summarise studies which examine epigenetic biomarkers in patients with Barrett's oesophagus (BO) and their association with progression to oesophageal adenocarcinoma (OADC). BO is a precursor lesion for OADC. There is no clinical test to predict patients who are likely to progress to OADC. An epigenetic biomarker could predict patients who are at high risk of progression from BO to OADC which could facilitate earlier diagnosis and spare those unlikely to develop cancer from regular invasive surveillance endoscopy. Setting A systematic search was conducted of the following databases: MEDLINE, MEDLINE in Process, EMBASE, Cochrane Central, ISI Conference Proceedings Citation Index and the British Library's ZETOC. Studies were conducted in secondary and tertiary care settings. Participants All studies measuring epigenetic change in patients over 18 years old who progressed from non-dysplastic BO to OADC were included. Genetic, in vitro and studies which did not measure progression in the same patient cohort were excluded. Study inclusion and risk of bias of individual eligible studies were assessed in duplicate by two reviewers using a modified Quality in Prognostic Studies tool. Results 14 studies met the inclusion criteria. 42 epigenetic markers were identified, and 5 studies developed models aiming to predict progression to OADC. Conclusions The evidence from this systematic review is suggestive of a role for p16 as an epigenetic biomarker for the progression of BO to OADC. Prospero number CRD42016038654. [ABSTRACT FROM AUTHOR]

by Linda J. Dunbar (Aldershot: Ashgate, 2002; pp. xix + 239. 49.50 £). In various ways the Scottish Reformation was unique. The last in time and the only one not [...]

Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α-induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved. [ABSTRACT FROM AUTHOR]

Appropriate fetal growth relies upon adequate placental nutrient transfer. Birthweight:placental weight ratio (BW:PW ratio) is often used as a proxy for placental efficiency, defined as the grams of fetus produced per gram placenta. An elevated BW:PW ratio in an appropriately grown fetus (small placenta) is assumed to be due to up-regulated placental nutrient transfer capacity i.e., a higher nutrient net flux per gram placenta. In fetal growth restriction (FGR), where a fetus fails to achieve its genetically pre-determined growth potential, placental weight and BW:PW ratio are often reduced which may indicate a placenta that fails to adapt its nutrient transfer capacity to compensate for its small size. This review considers the literature on BW:PW ratio in both large cohort studies of normal pregnancies and those studies offering insight into the relationship between BW:PW ratio and outcome measures including stillbirth, FGR, and subsequent postnatal consequences. The core of this review is the question of whether BW:PW ratio is truly indicative of altered placental efficiency, and whether changes in BW:PW ratio reflect those placentas which adapt their nutrient transfer according to their size. We consider this question using data from mice and humans, focusing upon studies that have measured the activity of the well characterized placental system A amino acid transporter, both in uncomplicated pregnancies and in FGR. Evidence suggests that BW:PW ratio is reduced both in FGR and in pregnancies resulting in a small for gestational age (SGA, birthweight <10th centile) infant but this effect is more pronounced earlier in gestation (<28 weeks). In mice, there is a clear association between increased BW:PW ratio and increased placental system A activity. Additionally, there is good evidence in wild-type mice that small placentas upregulate placental nutrient transfer to prevent fetal undergrowth. In humans, this association between BW:PW ratio and placental system A activity is less clear and is worthy of further consideration, both in terms of system A and other placental nutrient transfer processes. This knowledge would help decide the value of measuring BW:PW ratio in terms of determining the risk of poor health outcomes, both in the neonatal period and long term. [ABSTRACT FROM AUTHOR]

Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu27]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu27]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS-/-; FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mgµkg-1µday-1 [Leu27]IGF-II was delivered via a subcutaneous min-iosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu27]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu27] IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional 14CMeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu27]IGF-II-treated WT animals (P < 0.01). In eNOS-/- mice, [Leu27]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS-/- litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) affects 3-8% of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assessment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evaluation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significant agonist-induced contraction, and endothelium-dependent and endothelium- independent relaxation. Sex-specific alterations in reactivity were noted in both strains. Maternal treatment with SC significantly attenuated endothelium-dependent and endothelium-independent relaxation of fetal aortic rings. Mouse fetal abdominal aortas reproducibly respond to vasoactive agents. Study of these vessels in mouse genetic models of pregnancy complications may 1) help to delineate early signs of abnormal vascular reactivity and 2) inform whether treatments given to the mother during pregnancy may impact upon fetal vascular function. [ABSTRACT FROM AUTHOR]

Background: Emergency surgery or transarterial embolization (TAE) are options for the treatment of recurrent or refractory nonvariceal upper gastrointestinal bleeding. Surgery has the disadvantage of high rates of postoperative morbidity and mortality. Embolization has become more available and has the advantage of avoiding laparotomy in this often unfit and elderly population. Objective: To carry out a systematic review and meta-analysis of all studies that have directly compared TAE with emergency surgery in the treatment of major upper gastrointestinal bleeding that has failed therapeutic upper gastrointestinal endoscopy. Methods: A literature search of Ovid MEDLINE, Embase, and Google Scholar was performed. The primary outcomes were all-cause mortality and rates of rebleeding. The secondary outcomes were length of stay and postoperative complications. Results: A total of nine studies with 711 patients (347 who had embolization and 364 who had surgery) were analyzed. Patients in the TAE group were more likely to have ischemic heart disease (odds ratio [OR] =1.99; 95% confidence interval [CI]: 1.33, 2.98; P=0.0008; I2=67% [random effects model]) and be coagulopathic (pooled OR =2.23; 95% CI: 1.29, 3.87; P=0.004; I2=33% [fixed effects model]). Compared with TAE, surgery was associated with a lower risk of rebleeding (OR =0.41; 95% CI: 0.22, 0.77; P,0.0001; I2=55% [random effects]). There was no difference in mortality (OR =0.70; 95% CI: 0.48, 1.02; P=0.06; I2=44% [fixed effects]) between TAE and surgery. Conclusion: When compared with surgery, TAE had a significant increased risk of rebleeding rates after TAE; however, there were no differences in mortality rates. These findings are subject to multiple sources of bias due to poor quality studies. These findings support the need for a well-designed clinical trial to ascertain which technique is superior. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5th centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5th centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. 14C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR. [ABSTRACT FROM AUTHOR]

Cyclic adenosine monophosphate (cAMP) drives genetic polycystic kidney disease (PKD) cystogenesis. Yet within certain PKD families, striking differences in disease severity exist between affected individuals, and genomic and/or environmental modifying factors have been evoked to explain these observations. We hypothesized that PKD cystogenesis is accentuated by an aberrant fetal milieu, specifically by glucocorticoids. The extent and nature of cystogenesis was assessed in explanted wild-type mouse embryonic metanephroi, using 8-Br-cAMP as a chemical to mimic genetic PKD and the glucocorticoid dexamethasone as the environmental modulator. Cysts and glomeruli were quantified by an observer blinded to culture conditions, and tubules were phenotyped using specific markers. Dexamethasone or 8-Br-cAMP applied on their own produced cysts predominantly arising in proximal tubules and descending limbs of loops of Henle. When applied together, however, dexamethasone over a wide concentration range synergized with 8-Br-cAMP to generate a more severe, glomerulocystic, phenotype; we note that prominent glomerular cysts have been reported in autosomal dominant PKD fetal kidneys. Our data support the idea that an adverse antenatal environment exacerbates renal cystogenesis. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to "placental insufficiency": inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS-/-) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS-/- fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS-/- dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS-/- fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal 14C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent 14C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS-/- fetuses, indicating diminished placental nutrient transport. eNOS-/- mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS-/- mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates "uteroplacental hypoxia," providing a new framework for understanding the etiology of FGR in human pregnancy. [ABSTRACT FROM AUTHOR]

The ANP knockout mouse is reported to exhibit pregnancy-associated hypertension, proteinuria and impaired placental trophoblast invasion and spiral artery remodeling, key features of pre-eclampsia (PE). We hypothesized that these mice may provide a relevant model of human PE with associated fetal growth restriction (FGR). Here, we investigated pregnancies of ANP wild type (ANP(+/+)), heterozygous (ANP(+/-)) and knockout (ANP(-/-)) mice. Maternal blood pressure did not differ between genotypes (E12.5, E17.5), and fetal weight (E18.5) was unaffected. Placental weight was greater in ANP(-/-) versus ANP(+/+) mice. Therefore, in our hands, the ANP model does not express phenotypic features of PE with FGR. [ABSTRACT FROM AUTHOR]

The article explores the story of the Curle-Mowbray family of Scotland in the sixteenth century. This story has diverse elements that are all closely linked to the person of Mary Queen of Scots. The origins of the last name of the Mowbrays are indicated. In addition, this article discusses the position and social status of Gilbert Curle during the period.