ORCID Profile
0000-0001-8751-6146
Current Organisations
Vanderbilt University Medical Center
,
University of Kansas Medical Center
,
Monash Medical Centre
,
Yale School of Medicine
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Oxford University Press (OUP)
Date: 11-2011
Publisher: Springer Science and Business Media LLC
Date: 07-05-2012
DOI: 10.1038/PR.2012.58
Publisher: Springer Science and Business Media LLC
Date: 20-02-2023
DOI: 10.1007/S10943-023-01767-X
Abstract: While there is high patient acceptance for clinical staff discussing issues regarding spirituality with hospital inpatients, it is not clear which staff member patients prefer for these discussions. This unique exploratory study investigated inpatient preferences regarding which staff member should raise the topic of spirituality. A cross-sectional survey was conducted with inpatients at six hospitals in Sydney, Australia ( n = 897), with a subset invited to participate in qualitative interviews ( n = 41). Pastoral care staff (32.9%) were the preferred staff members with whom to discuss spiritual issues, followed by doctors (22.4%). Qualitative findings indicated that in idual characteristics of the staff member are more important than their role.
Publisher: Wiley
Date: 09-11-2011
Publisher: Elsevier BV
Date: 04-2008
Publisher: Elsevier BV
Date: 04-2000
Publisher: Oxford University Press (OUP)
Date: 03-05-2018
Publisher: American Academy of Pediatrics (AAP)
Date: 11-2020
Abstract: Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (& + 0/7 weeks’ gestation, & g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach.
Publisher: Elsevier
Date: 2002
DOI: 10.1016/S0083-6729(02)64002-6
Abstract: Synchronized development of the embryo to the active stage of the blastocyst, differentiation of the uterus to the receptive state, and a "cross talk" between the blastocyst and uterine luminal epithelium are essential to the process of implantation. In spite of considerable accumulation of information and the present state of the knowledge, our understanding of the definitive mechanisms that regulate these events remains elusive. Although there are species variations in the process of implantation, many basic similarities do exist among various species. This review focuses on specific aspects of the implantation process in mice with the hope that many of the findings will be relevant to the process in humans. To establish signaling mechanisms of embryo-uterine interactions during implantation, studies on both embryonic and uterine consequences are required to generate more meaningful information. Due to ethical restriction and experimental limitation, it is difficult to generate such information in humans. This review has attempted to provide a comprehensive, but not complete, narration of a number of embryonic and uterine factors that are involved in the process of implantation in autocrine, paracrine, and/or juxtacrine manners in mice at the physiological, cellular, molecular, and genetic levels.
Publisher: Springer Science and Business Media LLC
Date: 18-06-2014
DOI: 10.1038/PR.2014.82
Publisher: Springer Science and Business Media LLC
Date: 03-08-2022
DOI: 10.1007/S10943-022-01616-3
Abstract: While patients value engagement concerning their spirituality as a part of holistic healthcare, there is little evidence regarding the preferred way to engage in discussions about spirituality. This study investigated inpatient preferences regarding how they would like spirituality to be raised in the hospital setting. A cross-sectional survey was conducted with inpatients at six hospitals in Sydney, Australia ( n = 897), with a subset invited to participate in qualitative interviews ( n = 41). There was high approval for all proposed spiritual history prompts (94.0–99.8%). In interviews, the context dictated the appropriateness of discussions. Findings indicated a high level of patient acceptability for discussing spirituality in healthcare. Further research and more detailed analysis is required and proposed to be undertaken.
Publisher: Wiley
Date: 29-10-2018
Publisher: Elsevier BV
Date: 11-2015
Publisher: Public Library of Science (PLoS)
Date: 24-11-2015
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1016/S0303-7207(99)00033-7
Abstract: Prostaglandins (PGs) produced by cyclooxygenase (COX) participate in many aspects of female reproduction. The two isoforms of cyclooxygenase, COX-1 and COX-2, have distinct expression patterns in the mouse uterus during the peri-implantation period and suggest their independent contribution to uterine PGs. Using wild type and COX-1(-/-) mice, we examined the role of COX-1-derived PGs on day 4 of pregnancy, when its expression is maximal. Uterine vascular permeability was measured by 125I-labeled bovine serum albumin (BSA) uptake, and PG content was measured by gas chromatography-mass spectrometry. Vascular permeability and PG concentrations were reduced in COX-1(-/-) mice, but by less than the expected amount. After ovariectomy, uterine vascular permeability declined in both groups, but returned to baseline in wild type and was exaggerated in COX-1(-/-) females after treatment with ovarian steroids. Most importantly, COX-1(-/-) uteri displayed COX-2 expression on the morning of day 4, when COX-2 is normally absent. This hybridization pattern resembles the native expression of COX-1, and may partially offset the loss of COX-1-derived PGs. These data indicate that COX-1-derived PGs are important during uterine preparation for implantation, and that COX-2 compensation occurs in the absence of COX-1.
Publisher: The Endocrine Society
Date: 06-2004
DOI: 10.1210/ER.2003-0020
Publisher: Elsevier BV
Date: 09-2017
Publisher: Informa UK Limited
Date: 11-2020
DOI: 10.2147/IJWH.S265643
Publisher: Elsevier BV
Date: 11-2001
Publisher: Elsevier BV
Date: 05-2013
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/00469580211064125
Abstract: Despite remarkable progress in the reduction of under-five mortality, the rate of perinatal and neonatal mortality is still high especially in developing countries. The adverse outcome associated with preterm birth is one of the major public health challenges in Africa. However, there are limited and inconsistent studies conducted on the effect of preterm birth on adverse perinatal and neonatal outcomes in Ethiopia. Therefore, this systematic review and meta-analysis aimed to investigate the association between preterm birth and its adverse perinatal and neonatal outcomes in Ethiopia. We systematically searched several electronic databases like PubMed, Web of Science, SCOPUS, CINAHL, Google Scholar, African Journals Online databases and Science Direct. All identified observational studies were included. The I 1 statistics were used to assess the heterogeneity among the studies. A random-effects model was computed to estimate the pooled effect of preterm birth on adverse perinatal and neonatal outcomes. Thirty-three studies with a total of 20 109 live births were included in the final meta-analysis. Our meta-analysis showed that preterm birth increased the odds of perinatal mortality by 10-folds [POR = 9.56 (95% CI: 5.47, 19.69)] and there was a 5.44-folds risk of stillbirth [Odds Ratio = 5.44 (95% CI: 3.57, 8.28)] among women who gave birth before 37 weeks of gestation. In addition, preterm birth was significantly associated with neonatal hypothermia [OR=3.54 (95% CI: 2.41, 5.21)], neonatal mortality [OR= 3.16 (95% CI: 1.57, 6.34). The sub-group analysis of this meta-analysis showed that there was an increased risk of neonatal sepsis [OR=2.33 (95% CI: 1.15, 4.71)] among preterm babies. Preterm births significantly increased the risk of adverse perinatal and neonatal outcomes in Ethiopia. Therefore, scale-up strategies and improving the quality of maternal and child health care providers should be an area of intervention to reduce adverse outcomes associated with preterm birth. The Federal Ministry of Health and concerned bodies should work towards the prevention of preterm birth and its adverse outcomes.
Publisher: Bioscientifica
Date: 12-2014
DOI: 10.1530/REP-14-0388
Abstract: The mouse model has greatly contributed to understanding molecular mechanisms involved in the regulation of progesterone (P 4 ) plus estrogen (E)-dependent blastocyst implantation process. However, little is known about contributory molecular mechanisms of the P 4 -only-dependent blastocyst implantation process that occurs in species such as hamsters, guineapigs, rabbits, pigs, rhesus monkeys, and perhaps humans. We used the hamster as a model of P 4 -only-dependent blastocyst implantation and carried out cross-species microarray (CSM) analyses to reveal differentially expressed genes at the blastocyst implantation site (BIS), in order to advance the understanding of molecular mechanisms of implantation. Upregulation of 112 genes and downregulation of 77 genes at the BIS were identified using a mouse microarray platform, while use of the human microarray revealed 62 up- and 38 down-regulated genes at the BIS. Excitingly, a sizable number of genes (30 up- and 11 down-regulated genes) were identified as a shared pool by both CSMs. Real-time RT-PCR and in situ hybridization validated the expression patterns of several up- and down-regulated genes identified by both CSMs at the hamster and mouse BIS to demonstrate the merit of CSM findings across species, in addition to revealing genes specific to hamsters. Functional annotation analysis found that genes involved in the spliceosome, proteasome, and ubiquination pathways are enriched at the hamster BIS, while genes associated with tight junction, SAPK/JNK signaling, and PPARα/RXRα signalings are repressed at the BIS. Overall, this study provides a pool of genes and evidence of their participation in up- and down-regulated cellular functions athways at the hamster BIS.
Publisher: Future Medicine Ltd
Date: 08-2019
Abstract: Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74 95% CI 1.34–10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2018
Publisher: Springer Science and Business Media LLC
Date: 04-1998
Publisher: Springer Science and Business Media LLC
Date: 04-1998
Publisher: Public Library of Science (PLoS)
Date: 17-05-2018
Publisher: American Thoracic Society
Date: 04-2013
Publisher: John Wiley & Sons, Inc.
Date: 15-10-2002
Publisher: The Endocrine Society
Date: 29-09-2017
Publisher: Springer Science and Business Media LLC
Date: 12-03-2013
DOI: 10.1038/PR.2013.43
Publisher: Elsevier BV
Date: 08-2013
Publisher: The Endocrine Society
Date: 05-2000
Abstract: PRL and its homologs accomplish their biological effects through the PRL receptor (PRLR). We evaluated the expression and function of PRLR in the embryo and uterus during the periimplantation period because PRLR deficiency results in implantation failure. In wild-type mice, PRLR expression was localized to undecidualized stromal cells in the antimesometrial border on days 6-8 of pregnancy. A small population of PRLR-expressing cells was observed adjacent to the ectoplacental cone in the mesometrial stroma. Low levels of PRLR expression were also detected in the developing embryo on days 6-8. To determine the significance of PRLR expression in this distribution, we examined implantation and decidualization in PRLR-/- mice. Progesterone (P4) administration rescued infertility in PRLR-/- mice from the periimplantation period to midgestation. Artificially induced decidualization was absent in pseudopregnant PRLR-/- mice but was identical to wild-type in P4-treated PRLR-/- mice. Furthermore, wild-type and P4-treated PRLR-/- mice had similar expression of the implantation-specific genes, LIF, hiregulin, HB-EGF, COX-1, COX-2, PPARdelta, Hoxa-10, cyclin-D3, VEGF, and its receptors, Flk-1 and neuropilin-1. Together, these results show that luteal P4 production via ovarian PRLR signaling is required for implantation and early pregnancy. The function of uterine PRLR remains unclear. However, the eventual loss of pregnancy in P4-treated PRLR-/- mice suggests that uterine PRLR may be essential for the support of late gestation.
Publisher: SPIE
Date: 10-02-2011
DOI: 10.1117/12.881239
Publisher: Elsevier BV
Date: 11-2008
Publisher: SPIE
Date: 26-02-2015
DOI: 10.1117/12.2077775
Publisher: Elsevier BV
Date: 07-2004
Publisher: American Physiological Society
Date: 15-02-2012
DOI: 10.1152/AJPHEART.00866.2011
Abstract: The angiopoietins/Tie-2 system is essential for the maintenance of vascular integrity and angiogenesis. The functional role of angiopoietin-2 (Ang-2) in the regulation of angiogenesis is dependent on other growth factors such as VEGF and a given physiopathological conditions. This study investigates the potential role of Ang-2 in myocardial angiogenesis and fibrosis formation in the diabetic db/db mouse. Diabetic db/db mice received intramyocardial administration of either adenovirus Ang-2 (Ad-CMV-Ang-2) or Ad-β-gal. The levels of Tie-2, VEGF, caspase-3, Wnt7b, fibroblast-specific protein-1 (FSP-1), and adhesion molecules (ICAM-1 and VCAM-1) expression were measured. Apoptosis, capillary density, and cardiac fibrosis were also analyzed in the db/db mouse hearts. Overexpression of Ang-2 suppressed Tie-2 and VEGF expression in db/db mouse hearts together with significant upregulation of Wnt7b expression. Overexpression of Ang-2 also sensitizes ICAM-1 and VCAM-1 expression in db/db mouse hearts. Immunohistochemical analysis revealed that overexpression of Ang-2 resulted in a gradual apoptosis as well as interstitial fibrosis formation, these leading to a significant loss of capillary density. Data from these studies were confirmed in cultured mouse heart microvascular endothelial cells (MHMEC) exposed to excessive Ang-2. Exposure of MHMEC to Ang-2 resulted in increased caspase-3 activity and endothelial apoptosis. Knockdown of Ang-2 attenuated high glucose-induced endothelial cell apoptosis. Further, counterbalance of Ang-2 by overexpression of Ang-1 reversed loss of capillary density and fibrosis formation in db/db mouse hearts. Our data demonstrate that Ang-2 increases endothelial apoptosis, sensitizes myocardial microvascular inflammation, and promotes cardiac fibrosis and thus contributes to loss of capillary density in diabetic diseases.
Publisher: Public Library of Science (PLoS)
Date: 16-02-2021
DOI: 10.1371/JOURNAL.PONE.0247106
Abstract: Iodine deficiency disorder (IDD) is a global, regional, and national public health problem that is preventable. Universal salt iodization is a worldwide accepted strategy to prevent IDD. The level of iodine in the salt should be adequate at the household level (≥15ppm). Though there was fragmented evidence on the proportion of adequately iodized salt at the household level in Ethiopia, the national level proportion of adequately iodized salt at the household level was remaining unknown. Therefore, this systematic review and meta-analysis estimated the pooled proportion of adequately iodized salt at the household level in Ethiopia from 2013–2020. We systematically searched the databases: PubMed/MEDLINE, Google Scholar, and Science Direct for studies conducted in Ethiopia on the availability of adequately iodized salt at the household level since 2013. We have included observational studies, which were published between January first, 2013, and 10 August 2020. The report was compiled according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The quality of included studies was scored based on the Newcastle Ottawa quality assessment scale adapted for cross-sectional studies. The data were extracted in Microsoft excel and analyzed using Stata version 14.1 software. We employed a random-effects model to estimate the pooled proportion of adequately iodized salt at the household level in Ethiopia. The presence of statistical heterogeneity within the included studies was evaluated using the I-squared statistic. We used Egger’s regression test to identify evidence of publication bias. The pooled proportion with a 95% confidence interval (CI) was presented using tables and forest plots. We screened a total of 195 articles. Of these, 28 studies (with 15561 households) were included in the final systematic review and meta-analysis. In Ethiopia, the pooled proportion of adequately iodized salt at the household level was 37% (95% CI: 28, 46%). The subgroup analyses of 28 studies by residence revealed that the pooled proportion of adequately iodized salt at the household level was 32% (95% CI: 29, 35%) and 48% (95% CI: 31, 66%) in rural and urban areas, respectively. Based on geographic location, the highest proportion was found in Addis Ababa (81% 95%CI: 78, 83), and the lowest proportion found in Dire Dawa (20% 95%CI: 17, 22). Besides, the proportion of adequately iodized salt at the household level was significantly increased during 2017–2020 (42% 95% CI: 30, 53%) as compared with 2013–2016 (27% 95% CI: 17, 39%). In Ethiopia, the pooled proportion of adequately iodized salt at the household level was very low as compared to the world health organization’s recommendation. Thus, the Federal Ministry of Health of Ethiopia and different stakeholders should give more attention to improve the proportion of adequately iodized salt at the household level.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2012
Publisher: American Physiological Society
Date: 12-2006
DOI: 10.1152/AJPREGU.00259.2006
Abstract: Use of cyclooxygenase (COX) inhibitors to delay preterm birth is complicated by in utero constriction of the ductus arteriosus and delayed postnatal closure. Delayed postnatal closure has been attributed to loss of vasa vasorum flow and ductus wall ischemia resulting from constriction in utero. We used the murine ductus (which does not depend on vasa vasorum flow) to determine whether delayed postnatal closure may be because of mechanisms independent of in utero constriction. Acute inhibition of both COX isoforms constricted the fetal ductus on days 18 and 19 (term) but not earlier in gestation COX-2 inhibition constricted the fetal ductus more than COX-1 inhibition. In contrast, mice exposed to prolonged inhibition of COX-1, COX-2, or both COX isoforms (starting on day 15, when the ductus does not respond to the inhibitors) had no contractile response to the inhibitors on days 18 or 19. Newborn mice closed their ductus within 4 h of birth. Prolonged COX inhibition on days 11–14 of gestation had no effect on newborn ductal closure however, prolonged COX inhibition on days 15–19 resulted in delayed ductus closure despite exposure to 80% oxygen after birth. Similarly, targeted deletion of COX-2 alone, or COX-1/COX-2 together, impaired postnatal ductus closure. Nitric oxide inhibition did not prevent the delay in ductus closure. These data show that impaired postnatal ductus closure is not the result of in utero ductus constriction or upregulation of nitric oxide synthesis. They are consistent with a novel role for prostaglandins in ductus arteriosus contractile development.
Publisher: Public Library of Science (PLoS)
Date: 02-11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-01-2006
DOI: 10.1161/CIRCULATIONAHA.105.591537
Abstract: Background— Cyclooxygenase-1 (COX-1) has been implicated in the pathogenesis of atherothrombosis and is expressed by the major cell types of atherosclerotic lesions. COX-1–mediated platelet thromboxane (TX) production has been proposed to promote both early atherosclerosis and thrombosis. Here, we examined the impact of COX-1 deficiency in bone marrow–derived cells on early atherogenesis in the mouse. Methods and Results— LDL receptor (LDLR) −/− and apolipoprotein E (apoE) −/− recipient mice were lethally irradiated and transplanted with COX-1 −/− bone marrow. Mice reconstituted with COX-1 −/− marrow had nearly complete (99.7%) loss of platelet TXA 2 and significantly suppressed levels of macrophage and urinary TXA 2 metabolites. Serum lipid levels and lipoprotein distributions did not differ between recipients reconstituted with COX-1 +/+ and COX-1 −/− marrow. Surprisingly, the extent of atherosclerotic lesions in both LDLR −/− and apoE −/− mice reconstituted with COX-1 −/− marrow was increased significantly compared with control mice transplanted with COX-1 +/+ marrow. Peritoneal macrophages isolated from LDLR −/− mice reconstituted with COX-1 −/− marrow had increased lipopolysaccharide-induced levels of COX-2 mRNA and protein expression. Fetal liver cell transplantation studies revealed a 30% increase in atherosclerosis in COX-1 −/− →LDLR −/− mice compared with COX-1 +/+ →LDLR −/− mice, whereas the extent of atherosclerosis was unchanged in COX-1 −/− /COX-2 −/− →LDLR −/− mice. Conclusions— COX-1 deficiency in bone marrow–derived cells worsens early atherosclerosis in apoE −/− and LDLR −/− mice despite virtual elimination of platelet TX production. These data demonstrate that platelet TX production does not aggravate early atherosclerotic lesion formation and that upregulation of COX-2 expression in COX-1 −/− macrophages is proatherogenic.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2011
DOI: 10.1158/1940-6207.CAPR-11-0120
Abstract: COX-2 is a major contributor to the inflammatory response and cancer progression so it is an important target for prevention and therapy. COX-2 is absent or expressed at low levels in most epithelial cells but is found at high levels in inflammatory lesions, and many premalignant and malignant tumors. Thus, it is an attractive target for molecular imaging. We report a series of novel fluorinated imaging agents, derived from indomethacin or celecoxib that selectively inhibit COX-2. The most promising lead, compound 7, was a fluorinated derivative of celecoxib. Kinetic analysis revealed that this fluorinated compound is a slow, tight-binding inhibitor of COX-2 and exhibits minimal inhibitory activity against COX-1. Efficient incorporation of 18F into compound 7 by radiochemical synthesis and intravenous injection provided sufficient signal for in vivo positron emission tomography (PET) imaging. Selective uptake of 18F-7 was observed in inflamed rat paws compared with the noninflamed contralateral paws and uptake was blocked by pretreatment with the COX-2 inhibitor, celecoxib. Uptake of 18F-7 was not observed when inflammation was induced in COX-2–null mice. In nude mice bearing both a COX-2–expressing human tumor xenograft (1483) and a COX-2–negative xenograft (HCT116), 18F-7 selectively accumulated in the COX-2–expressing tumor. Accumulation was blocked by pretreatment of the animals with celecoxib. The in vitro and in vivo properties of compound 7 suggest it will be a useful probe for early detection of cancer and for evaluation of the COX-2 status of premalignant and malignant tumors. Cancer Prev Res 4(10) 1536–45. ©2011 AACR.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-05-2014
Abstract: Once sperm enter the female reproductive tract, they have an arduous task to find an egg at a distant, often concealed, location. McKnight et al. (p. 754 ) show that Caenorhabditis elegans make this task more or less difficult, depending on pheromones in the external environment. Pheromones perceived by female sensory neurons modulate the synthesis of ovarian prostaglandins, which provide sperm positional information. Thus, environmental cues can indirectly impact sperm function even when the sperm themselves are not directly exposed.
Publisher: Hindawi Limited
Date: 16-11-2021
DOI: 10.1155/2021/2433252
Abstract: Background. Fetal umbilical vein aneurysm is an uncommon anomaly without clear guidelines regarding the management of these pregnancies. Case Presentation. We describe an ultrasound diagnosis of this condition involving a 38-year-old multigravid woman who presented at 30 weeks and 3 days gestation with severe fetal growth restriction, reverse end-diastolic flow on umbilical artery dopplers, elevated ductus venosus doppler, and an umbilical vein aneurysm. Due to nonreassuring fetal assessment in the setting of an umbilical vein aneurysm, she underwent a cesarean delivery with a favorable neonatal outcome. Conclusions. There are currently no guidelines for the management of an umbilical vein aneurysm. This case demonstrates a successful multidisciplinary approach for creating a plan of care focused on achieving a favorable outcome for a fetus with a large umbilical vein aneurysm. The approach took into account timing of delivery given the potential for fetal morbidity and mortality, while factoring in the risk of prematurity.
Publisher: AIP
Date: 2010
DOI: 10.1063/1.3482605
Publisher: American Physiological Society
Date: 09-2016
DOI: 10.1152/AJPHEART.00822.2015
Abstract: Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN) however, a direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Hindawi Limited
Date: 08-02-2012
DOI: 10.1002/TERM.528
Publisher: American Physiological Society
Date: 2008
DOI: 10.1152/AJPLUNG.00034.2007
Abstract: Patients with familial pulmonary arterial hypertension inherit heterozygous mutations of the type 2 bone morphogenetic protein (BMP) receptor BMPR2. To explore the cellular mechanisms of this disease, we evaluated the pulmonary vascular responses to chronic hypoxia in mice carrying heterozygous hypomorphic Bmpr2 mutations ( Bmpr2 ΔEx2/+ ). These mice develop more severe pulmonary hypertension after prolonged exposure to hypoxia without an associated increase in pulmonary vascular remodeling or proliferation compared with wild-type mice. This is associated with defective endothelial-dependent vasodilatation and enhanced vasoconstriction in isolated intrapulmonary artery preparations. In addition, there is a selective decrease in hypoxia-induced, BMP-dependent, endothelial nitric oxide synthase expression and Smad signaling in the intact lungs and in cultured pulmonary microvascular endothelial cells from Bmpr2 ΔEx2/+ mutant mice. These findings indicate that the pulmonary endothelium is a target of abnormal BMP signaling in Bmpr2 ΔEx2/+ mutant mice and suggest that endothelial dysfunction contributes to their increased susceptibility to hypoxic pulmonary hypertension.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2013
DOI: 10.1038/PR.2013.59
Publisher: Proceedings of the National Academy of Sciences
Date: 21-09-2015
Abstract: The cyclooxygenase enzymes perform the initial steps in the synthesis of prostaglandins, potent signaling molecules with erse physiological functions. Recent data have suggested that these enzymes, although structural homodimers, act as functional heterodimers. Herein, we demonstrate that the heterodimeric nature of cyclooxygenase-2 leads to differential allosteric regulation of the enzyme by two of its substrates, arachidonic acid and the endocannabinoid 2-arachidonoylglycerol. We provide the first evidence (to our knowledge) that fatty acid-based modulation of COX-2 activity occurs in cellular settings. These findings demonstrate the complexity of the interaction of multiple substrates with COX-2, which involves competition for both the catalytic and allosteric sites in addition to differential allosteric regulation.
Publisher: BMJ
Date: 30-10-2015
Publisher: American Academy of Pediatrics (AAP)
Date: 03-2018
Publisher: Wiley
Date: 17-04-2014
DOI: 10.1111/APA.12630
Publisher: Wiley
Date: 15-04-2015
DOI: 10.1111/APA.12995
Publisher: Informa UK Limited
Date: 07-2016
DOI: 10.1080/15389588.2015.1136061
Abstract: Pelvic injuries are a serious and commonly occurring injury to motorcycle riders involved in crashes, yet there has been limited research investigating the mechanisms involved in these injuries. This study aimed to investigate the mechanisms involved in pelvic injuries to crashed motorcyclists. This study involved in-depth crash investigation and 2 convenience-based data sets were used. These data sets investigated motorcycle crashes in the Sydney, Newcastle, and Adelaide regions. Participants included motorcycle riders who had crashed either on a public road or private property within the study areas. The mechanism of injury and the type of injuries were investigated. The most frequent cause of pelvic injuries in crashed motorcyclists was due to contact with the motorcycle fuel tank during the crash (85%). For riders who had come into contact with the fuel tank, the injury types were able to be grouped into 3 categories based on the complexity of the injury. The complexity of the injury appeared to increase with impact speed but this was a nonsignificant trend. The pelvic injuries that did not occur from contact with the fuel tank in this s le differed in asymmetry of loading and did not commonly involve injury to the bladder. They were commonly one-sided injuries but this differed based on the point of loading however, a larger s le of these injuries needs to be investigated. Overall improvements in road safety have not been replicated in the amelioration of pelvic injuries in motorcyclists and improvements in the design of crashworthy motorcycle fuel tanks appear to be required.
Publisher: American Physiological Society
Date: 07-2014
DOI: 10.1152/PHYSIOLGENOMICS.00171.2013
Abstract: Failure of the ductus arteriosus (DA) to close at birth can lead to serious complications. Conversely, certain profound congenital cardiac malformations require the DA to be patent until corrective surgery can be performed. In each instance, clinicians have a very limited repertoire of therapeutic options at their disposal - indomethacin or ibuprofen to close a patent DA (PDA) and prostaglandin E1 to maintain patency of the DA. Neither treatment is specific to the DA and both may have deleterious off-target effects. Therefore, more therapeutic options specifically targeted to the DA should be considered. We hypothesized the DA possesses a unique genetic signature that would set it apart from other vessels. A microarray was used to compare the genetic profiles of the murine DA and ascending aorta (AO). Over 4,000 genes were differentially expressed between these vessels including a subset of ion channel-related genes. Specifically, the alpha and beta subunits of large-conductance calcium-activated potassium (BK Ca ) channels are enriched in the DA. Gain- and loss-of-function studies showed inhibition of BK Ca channels caused the DA to constrict, while activation caused DA relaxation even in the presence of O 2 . This study identifies subsets of genes that are enriched in the DA that may be used to develop DA-specific drugs. Ion channels that regulate DA tone, including BK Ca channels, are promising targets. Specifically, BK Ca channel agonists like NS1619 maintain DA patency even in the presence of O 2 and may be clinically useful.
Publisher: Elsevier BV
Date: 05-2014
Publisher: Wiley
Date: 25-01-2018
DOI: 10.1111/AJI.12816
Publisher: Springer Science and Business Media LLC
Date: 04-08-2013
DOI: 10.1038/NN.3480
Publisher: Springer Science and Business Media LLC
Date: 22-11-2018
Publisher: Springer Science and Business Media LLC
Date: 02-2018
Publisher: MyJove Corporation
Date: 24-06-2020
DOI: 10.3791/61464
Publisher: Elsevier BV
Date: 12-2018
Publisher: American Physiological Society
Date: 09-2014
DOI: 10.1152/AJPHEART.00838.2013
Abstract: Sepsis is strongly associated with patency of the ductus arteriosus (PDA) in critically ill newborns. Inflammation and the aminoglycoside antibiotics used to treat neonatal sepsis cause smooth muscle relaxation, but their contribution to PDA is unknown. We examined whether: 1) lipopolysaccharide (LPS) or inflammatory cytokines cause relaxation of the ex vivo mouse DA 2) the aminoglycosides gentamicin, tobramycin, or amikacin causes DA relaxation and 3) newborn infants treated with aminoglycosides have an increased risk of symptomatic PDA (sPDA). Changes in fetal mouse DA tone were measured by pressure myography in response to LPS, TNF-α, IFN-γ, macrophage-inflammatory protein 2, IL-15, IL-13, CXC chemokine ligand 12, or three aminoglycosides. A clinical database of inborn patients of all gestations was analyzed for association between sPDA and aminoglycoside treatment. Contrary to expectation, neither LPS nor any of the inflammatory mediators caused DA relaxation. However, each of the aminoglycosides caused concentration-dependent vasodilation in term and preterm mouse DAs. Pretreatment with indomethacin and N-(G)-nitro-L-arginine methyl ester did not prevent gentamicin-induced DA relaxation. Gentamicin-exposed DAs developed less oxygen-induced constriction than unexposed DAs. Among 488,349 infants who met the study criteria, 40,472 (8.3%) had sPDA. Confounder-adjusted odds of sPDA were higher in gentamicin-exposed infants, wk and wk. Together, these findings suggest that factors other than inflammation contribute to PDA. Aminoglycoside-induced vasorelaxation and inhibition of oxygen-induced DA constriction support the paradox that antibiotic treatment of sepsis may contribute to DA relaxation. This association was also found in newborn infants, suggesting that antibiotic selection may be an important consideration in efforts to reduce sepsis-associated PDA.
Publisher: The Endocrine Society
Date: 07-2001
Abstract: Cyclooxygenase (COX)-derived prostaglandins are critical in female reproduction. Gene targeting studies show that ovulation, fertilization, implantation, and decidualization are defective in COX-2 deficient mice. We used genetic and pharmacologic approaches to perturb COX function and examine the differential and synergistic effects of inhibition of COX-1, COX-2, or of both isoforms on reproductive outcomes during early pregnancy in mice. The results demonstrate that simultaneous inhibition of COX-1 and COX-2 produces more severe effects on early pregnancy events than inhibition of either isoform alone. The effects of pharmacological inhibition of COX-2 on female reproductive functions were less severe than the null mutation of the COX-2 gene. A combined approach showed that COX-2 inhibition in COX-1−/− mice induced complete reproductive failure, suggesting a lack of alternative sources of prostaglandin synthesis. This investigation raises caution regarding the indiscriminate use of COX inhibitors and shows for the first time the distinct and overlapping pathways of the cyclooxygenase systems in female reproduction.
Publisher: Computers, Materials and Continua (Tech Science Press)
Date: 23-11-2018
DOI: 10.1111/CHD.12714
Publisher: Wiley
Date: 14-08-2021
DOI: 10.1002/DVDY.408
Abstract: The ductus arteriosus (DA) is a unique fetal vascular shunt, which allows blood to bypass the developing lungs in utero. After birth, changes in complex signaling pathways lead to constriction and permanent closure of the DA. The persistent patency of the DA (PDA) is a common disorder in preterm infants, yet the underlying causes of PDA are not fully defined. Although limits on the availability of human DA tissues prevent comprehensive studies on the mechanisms of DA function, mouse models have been developed that reveal critical pathways in DA regulation. Over 20 different transgenic models of PDA in mice have been described, with implications for human DA biology. Similarly, we enumerate 224 human single‐gene syndromes that are associated with PDA, including a small subset that consistently feature PDA as a prominent phenotype. Comparison and functional analyses of these genes provide insight into DA development and identify key regulatory pathways that may serve as potential therapeutic targets for the management of PDA.
Publisher: Oxford University Press (OUP)
Date: 05-2008
Publisher: American Academy of Pediatrics (AAP)
Date: 07-2018
Abstract: Preterm infants are at increased risk for patent ductus arteriosus (PDA). Prolonged exposure to PDA may be deleterious and has been associated with neonatal morbidity and mortality. Although the molecular mechanisms underlying regulation of postnatal ductus arteriosus closure are not fully understood, clinical experience and research trials have informed recent changes in PDA management strategies and refocused treatment strategies on smaller subsets of infants who require intervention. This review examines current diagnostic and management approaches to PDA in preterm neonates.
Publisher: The Company of Biologists
Date: 2019
DOI: 10.1242/DMM.040808
Abstract: Fetal exposure to chorioamnionitis can impact the outcomes of the developing fetus both at the time of birth, and in the subsequent neonatal period. Infants exposed to chorioamnionitis have a higher incidence of GI pathology, including necrotizing enterocolitis, however that mechanism remains undefined. To simulate the fetal exposure to maternal inflammation (FEMI) induced by chorioamnionitis, pregnant mice (C57Bl/6J, IL-6−/−, RAG−/−, or TNFR1−/−) were injected intraperitoneally on e15.5 with lipopolysaccharide (LPS) 100 µg/kg. Pups were delivered at term, and reared to P0, P7, P14, P28 or P56. Serum and intestinal tissue s les were collected to quantify growth, inflammatory markers, histologic intestinal injury, and goblet and Paneth cells. To determine if FEMI increased subsequent susceptibility to intestinal injury, a secondary dose of LPS (100 µg/kg) was given on P5 prior to tissue harvesting on P7. FEMI had no effect on growth of the offspring or their small intestine. FEMI significantly decreased both goblet and Paneth cells numbers while simultaneously increasing serum levels of IL-1β, IL-10, KC/GRO, TNF, and IL-6. These alterations were IL-6-dependent, and importantly increased susceptibility to LPS-induced intestinal injury later in life. Our data show that FEMI impairs normal intestinal development by decreasing components of innate immunity and simultaneously increasing markers of inflammation. These changes increase susceptibility to intestinal injury later in life and provide novel mechanistic data to potentially explain why preterm infants exposed to chorioamnionitis prior to birth have a higher incidence of NEC and other gastrointestinal disorders.
Publisher: Elsevier BV
Date: 03-2012
Publisher: Wiley
Date: 28-05-2012
Publisher: Elsevier BV
Date: 08-2022
Publisher: Springer Science and Business Media LLC
Date: 28-07-2017
DOI: 10.1038/S41598-017-07047-5
Abstract: Monitoring cervical structure and composition during pregnancy has high potential for prediction of preterm birth (PTB), a problem affecting 15 million newborns annually. We use in vivo Raman spectroscopy, a label-free, light-based method that provides a molecular fingerprint to non-invasively investigate normal and impaired cervical remodeling. Prostaglandins stimulate uterine contractions and are clinically used for cervical ripening during pregnancy. Deletion of cyclooxygenase-1 (Cox-1), an enzyme involved in production of these prostaglandins, results in delayed parturition in mice. Contrary to expectation, Cox-1 null mice displayed normal uterine contractility therefore, this study sought to determine whether cervical changes could explain the parturition differences in Cox-1 null mice and gestation-matched wild type (WT) controls. Raman spectral changes related to extracellular matrix proteins, lipids, and nucleic acids were tracked over pregnancy and found to be significantly delayed in Cox-1 null mice at term. A cervical basis for the parturition delay was confirmed by other ex vivo tests including decreased tissue distensibility, hydration, and elevated progesterone levels in the Cox-1 null mice at term. In conclusion, in vivo Raman spectroscopy non-invasively detected abnormal remodeling in the Cox-1 null mouse, and clearly demonstrated that the cervix plays a key role in their delayed parturition.
Publisher: Elsevier BV
Date: 07-2017
Publisher: Elsevier BV
Date: 09-2016
Publisher: Elsevier BV
Date: 06-2018
Publisher: American Physiological Society
Date: 10-2023
DOI: 10.1152/AJPHEART.00294.2023
Abstract: EP 4 is the primary EP receptor in the ductus arteriosus (DA) and is critical during late gestation for its development and eventual closure. The “paradoxical” patent DA (PDA) phenotype of EP 4 -knockout mice arises from a combination of impaired contractile potential, altered signaling properties, and a failure to remodel associated with an underdeveloped immature vessel. These findings provide new mechanistic insights into women who receive NSAIDs to treat preterm labor, whose infants have unexplained PDA.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 04-2012
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 12-2016
Publisher: Proceedings of the National Academy of Sciences
Date: 29-02-2016
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 06-2013
Publisher: Elsevier BV
Date: 09-2011
Publisher: Elsevier BV
Date: 05-2018
Publisher: American Physiological Society
Date: 11-2022
DOI: 10.1152/AJPLUNG.00324.2022
Abstract: Neonatology pioneer Mildred (Millie) T. Stahlman celebrated her 100th birthday on July 31, 2022. Her distinguished career at Vanderbilt University Medical Center in Nashville, TN, is reviewed to commemorate this milestone. Stahlman was arguably the first to establish a modern neonatal intensive care unit in 1961, successfully utilizing negative pressure ventilation and umbilical arterial and venous catheters to monitor blood gasses and pH levels. She received early invaluable training in newborn physiology at the Karolinska Institute in Stockholm, Sweden, under John Lind and Petter Karlberg, and at Vanderbilt under Elliot V. Newman. Stahlman also consulted with luminaries Geoffrey Dawes, Donald Barron, and L. Stanley James. As director of the Vanderbilt NICU, she trained 80 fellows from more than 20 countries. The latter 20 years of her career were highlighted by collaborations with Jeff Whitsett. She was the recipient of the AAP Virginia Apgar Award, the APS John Howland Medal, and served as a member of the Institute of Medicine.
Publisher: American Physiological Society
Date: 10-2011
Abstract: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quantified the number of mucus-containing small intestinal goblet cells present in infants with NEC and found they had significantly fewer goblet cells and Paneth cells compared with controls. To test whether inflammation has a developmentally dependent effect on intestinal goblet cells, TNF-α was injected into mice at various stages of intestinal development. TNF-α caused a loss of mucus-containing goblet cells only in immature mice and induced Muc2 and Muc3 mRNA upregulation only in mature ileum. Only minimal changes were seen in apoptosis and in expression of markers of goblet cell differentiation. TNF-α increased small intestinal mucus secretion and goblet cell hypersensitivity to prostaglandin E2 (PGE 2 ), a known mucus secretagogue produced by macrophages. These TNF-α-induced changes in mucus mRNA levels required TNF receptor 2 (TNFR2), whereas TNF-α-induced loss of mucus-positive goblet cells required TNFR1. Our findings of developmentally dependent TNF-α-induced alterations on intestinal mucus may help explain why NEC is predominantly found in premature infants, and TNF-α-induced alterations of the intestinal innate immune system and barrier functions may play a role in the pathogenesis of NEC itself.
Publisher: Elsevier BV
Date: 04-2014
Publisher: American Society for Clinical Investigation
Date: 06-2000
DOI: 10.1172/JCI9621
Publisher: The Endocrine Society
Date: 04-2003
DOI: 10.1210/EN.2002-0033
Abstract: The periimplantation period is marked by edematous changes in the uterus. In the mouse, increased uterine vascular permeability occurs in response to estrogen and certain vasoactive mediators, but the mechanisms that regulate fluid transport during implantation are not fully understood. Aquaporins (AQPs) are a family of membrane channel proteins that facilitate bulk water transport. To assess their role in implantation, we examined the expression of AQPs 0-9 in the mouse uterus on d 1-8 of pregnancy. Our results show distinct uterine expression patterns for AQP1, AQP4, and AQP5. AQP1 is localized to the inner circular myometrium throughout the periimplantation period. AQP4 is highly expressed in the luminal epithelium on d 1 of pregnancy but barely detectable at the time of implantation. AQP5 is expressed at low levels in the glandular epithelium during early pregnancy but is markedly increased on d 5. By immunohistochemistry, AQP5 is localized in the basolateral region of the uterine glands. Treatment of adult ovariectomized mice with replacement steroids demonstrates an estrogen-induced shift in AQP1 signals from the myometrium to the uterine stromal vasculature, suggesting a role in uterine fluid imbibition. In contrast, AQP5 is induced only in estrogen-treated, progesterone-primed uteri. We also observed expression of AQP8 in the inner-cell mass and AQP9 in the mural trophectoderm of the implanting blastocyst. Collectively, these results suggest that members of the AQP family are involved in embryo and uterine fluid homeostasis during implantation.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2020
Publisher: The Endocrine Society
Date: 2006
DOI: 10.1210/EN.2005-0896
Abstract: Biochemical changes of cervical connective tissue, including progressive disorganization of the collagen network and increased water content, occur during gestation to allow for cervical dilatation during labor, but the mechanisms that regulate cervical fluid balance are not fully understood. We examined whether aquaporins (AQPs), a family of membrane channel proteins that facilitate water transport, help mediate fluid balance in the mouse cervix during parturition. Of the 13 known murine AQPs, AQP0–2, 6, 7, 9, 11, and 12 were absent or at the limits of detection. By Northern blot and real-time PCR, AQP3 expression was low in nongravid and mid-pregnancy cervices with peak expression on d 19 and postpartum d 1 (PP1). AQP4 expression was generally low throughout pregnancy but showed a small upward trend at the time of parturition. AQP5 and AQP8 expression were significantly increased on d 12–15 but fell to nongravid/baseline by d 19 and PP1. By in situ hybridization and immunohistochemistry, AQP3 was preferentially expressed in basal cell layers of the cervical epithelium, whereas AQP4, 5, and 8 were primarily expressed in apical cell layers. Females with LPS-induced preterm labor had similar trends in AQP4, 5, and 8 expression to mice with natural labor at term gestation. Mice with delayed cervical remodeling due to deletion of the steroid 5α-reductase type 1 gene showed significant reduction in the levels of AQP3, 4, and 8 on d 19 or PP1. Together, these studies suggest that AQPs 3, 4, 5, and 8 regulate distinct aspects of cervical water balance during pregnancy and parturition.
Publisher: The Endocrine Society
Date: 2014
DOI: 10.1210/EN.2013-1304
Publisher: Wiley
Date: 13-06-2023
Abstract: Leucine‐rich repeat containing 8A (LRRC8A) volume regulated anion channels (VRACs) are activated by inflammatory and pro‐contractile stimuli including tumor necrosis factor alpha (TNFα), angiotensin II and stretch. LRRC8A associates with NADPH oxidase 1 (Nox1) and supports extracellular superoxide production. We tested the hypothesis that VRACs modulate TNFα signaling and vasomotor function in mice lacking LRRC8A exclusively in vascular smooth muscle cells (VSMCs, Sm22α‐Cre, Knockout). Knockout (KO) mesenteric vessels contracted normally but relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) was enhanced compared to wild type (WT). Forty‐eight hours of ex vivo exposure to TNFα (10 ng/mL) enhanced contraction to norepinephrine (NE) and markedly impaired dilation to ACh and SNP in WT but not KO vessels. VRAC blockade (carbenoxolone, CBX, 100 μM, 20 min) enhanced dilation of control rings and restored impaired dilation following TNFα exposure. Myogenic tone was absent in KO rings. LRRC8A immunoprecipitation followed by mass spectroscopy identified 33 proteins that interacted with LRRC8A. Among them, the myosin phosphatase rho‐interacting protein (MPRIP) links RhoA, MYPT1 and actin. LRRC8A‐MPRIP co‐localization was confirmed by confocal imaging of tagged proteins, Proximity Ligation Assays, and IP/western blots. siLRRC8A or CBX treatment decreased RhoA activity in VSMCs, and MYPT1 phosphorylation was reduced in KO mesenteries suggesting that reduced ROCK activity contributes to enhanced relaxation. MPRIP was a target of redox modification, becoming oxidized (sulfenylated) after TNFα exposure. Interaction of LRRC8A with MPRIP may allow redox regulation of the cytoskeleton by linking Nox1 activation to impaired vasodilation. This identifies VRACs as potential targets for treatment or prevention of vascular disease.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Proceedings of the National Academy of Sciences
Date: 15-08-2000
Abstract: Cyclooxygenase (COX)-derived prostaglandins (PGs) regulate numerous maternal–fetal interactions during pregnancy. PGs stimulate uterine contractions and prepare the cervix for parturition, whereas in the fetus, PGs maintain patency of the ductus arteriosus (DA), a vascular shunt that transmits oxygenated placental blood to the fetal systemic circulation. However, the origin and site of action of these PGs remain undefined. To address this, we analyzed mice lacking COX-1 (null mutation) or COX-2 (pharmacologic inhibition) or pups with a double null mutation. Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that COX-1 −/− females experience parturition failure that is reversible by exogenous PGs. Using embryo transfer experiments, we also show that successful delivery occurs in COX-1 −/− recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition. Although patency of the DA is PG dependent, neither COX-1 nor COX-2 expression was detected in the fetal or postnatal DA, and offspring with a double null mutation died shortly after birth with open DAs. These results suggest that DA patency depends on circulating PGs acting on specific PG receptors within the DA. Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
Publisher: Elsevier BV
Date: 08-2018
Publisher: Bioscientifica
Date: 05-2018
DOI: 10.1530/REP-17-0647
Abstract: In mouse models used to study parturition or pre-clinical therapeutic testing, measurement of uterine contractions is limited to either ex vivo isometric tension or operative intrauterine pressure (IUP). The goal of this study was to: (1) develop a method for transcervical insertion of a pressure catheter to measure in vivo intrauterine contractile pressure during mouse pregnancy, (2) determine whether this method can be utilized numerous times in a single mouse pregnancy without affecting the timing of delivery or fetal outcome and (3) compare the in vivo contractile activity between mouse models of term and preterm labor (PTL). Visualization of the cervix allowed intrauterine pressure catheter (IUPC) placement into anesthetized pregnant mice (plug = day 1, delivery = day 19.5). The litude, frequency, duration and area under the curve (AUC) of IUP was lowest on days 16–18, increased significantly ( P 0.05) on the morning of day 19 and reached maximal levels during by the afternoon of day 19 and into the intrapartum period. An AUC threshold of 2.77 mmHg discriminated between inactive labor (day 19 am) and active labor (day 19 pm and intrapartum period). Mice examined on a single vs every experimental timepoint did not have significantly different IUP, timing of delivery, offspring number or fetal/neonatal weight. The IUP was significantly greater in LPS-treated and RU486-treated mouse models of PTL compared to time-matched vehicle control mice. Intrapartum IUP was not significantly different between term and preterm mice. We conclude that utilization of a transcervical IUPC allows sensitive assessment of in vivo uterine contractile activity and labor progression in mouse models without the need for operative approaches.
Publisher: American Physiological Society
Date: 02-2006
Publisher: SPIE
Date: 11-02-2010
DOI: 10.1117/12.843005
Publisher: Oxford University Press (OUP)
Date: 11-2010
Publisher: Bioscientifica
Date: 11-2013
DOI: 10.1530/REP-13-0153
Abstract: Alkaline phosphatase (AP) activity has been demonstrated in the uterus of several species, but its importance in the uterus, in general and during pregnancy, is yet to be revealed. In this study, we focused on identifying AP isozyme types and their hormonal regulation, cell type, and event-specific expression and possible functions in the hamster uterus during the cycle and early pregnancy. Our RT-PCR and in situ hybridization studies demonstrated that among the known Akp2 , Akp3 , Akp5 , and Akp6 murine AP isozyme genes, hamster uteri express only Akp2 and Akp6 both genes are co-expressed in luminal epithelial cells. Studies in cyclic and ovariectomized hamsters established that while progesterone (P 4 ) is the major uterine Akp2 inducer, both P 4 and estrogen are strong Akp6 regulators. Studies in preimplantation uteri showed induction of both genes and the activity of their encoded isozymes in luminal epithelial cells during uterine receptivity. However, at the beginning of implantation, Akp2 showed reduced expression in luminal epithelial cells surrounding the implanted embryo. By contrast, expression of Akp6 and its isozyme was maintained in luminal epithelial cells adjacent to, but not away from, the implanted embryo. Following implantation, stromal transformation to decidua was associated with induced expressions of only Akp2 and its isozyme. We next demonstrated that uterine APs dephosphorylate and detoxify endotoxin lipopolysaccharide at their sites of production and activity. Taken together, our findings suggest that uterine APs contribute to uterine receptivity, implantation, and decidualization in addition to their role in protection of the uterus and pregnancy against bacterial infection.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2014
DOI: 10.1038/JP.2014.151
Publisher: Springer Science and Business Media LLC
Date: 04-1999
Publisher: Springer Science and Business Media LLC
Date: 03-2009
Publisher: Humana Press
Date: 2006
DOI: 10.1385/1-59259-983-4:007
Abstract: Pregnancy begins with fertilization of the ovulated oocyte by the sperm. After fertilization, the egg undergoes time-dependent mitotic ision while trying to reach the blastocyst stage and the uterus for implantation. Uterine preparation for implantation is regulated by coordinated secretions and functions of ovarian sex steroids. The first sign of contact between the blastocyst and the uterus can be detected experimentally by an intravenous blue dye injection as early as the end of day 4 or the beginning of day 5 of pregnancy. This blastocyst-uterine attachment reaction leads to stromal decidual reaction only at sites of implantation. The process of implantation can be postponed and reinstated experimentally by manipulating ovarian estrogen secretion. Stromal decidualization can also be induced experimentally in the hormonally prepared uterus in response to stimuli other than the embryo. Fundamental biological questions surrounding these essential features of early pregnancy can be addressed through the application of various techniques and manipulation of this period of early pregnancy. This chapter describes the routine laboratory methodologies to study the events of early pregnancy, with special emphasis on the implantation process in mice.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2019
Publisher: Elsevier BV
Date: 04-2009
Publisher: The Endocrine Society
Date: 09-2006
DOI: 10.1210/EN.2006-0231
Abstract: Implantation occurs only in the progesterone (P4)-primed uterus in the majority of species, but little effort has been given to identify P4-mediated molecules in these species. Using hamsters as a model for P4-dependent implantation and three well-known uterine receptivity-associated P4-regulated genes, Indian hedgehog (Ihh), histidine decarboxylase (Hdc), and hiregulin (Areg), in mice that require ovarian estrogen for uterine receptivity and implantation, our strategy aimed to determine whether P4 regulates uterine expression of these genes in hamsters and whether the event- and cell-specific uterine expression patterns of these genes during the periimplantation period in hamsters follow similarly with their patterns in mice. We report here that P4-mediated Ihh signaling is important for uterine receptivity and implantation in hamsters because uterine epithelial Ihh expression was regulated by P4 and its expression patterns during the periimplantation period of hamsters closely follow its pattern in mice. In contrast, we noted no hormonal regulation of Hdc and Areg in the hamster uterus. However, this did not diminish their importance in hamsters because their expression patterns and functions are event and cell specific during the periimplantation period: whereas Hdc was expressed exclusively in d 4 uterine glands and regulated by the blastocyst, Areg was expressed on the decidual area adjacent to the embryo from d 5 onward and involved in stromal cell proliferation. We conclude that similarities and dissimilarities exist in uterine expression pattern of implantation-related genes, including hormonal regulation and their event-specific importance.
Publisher: The American Association of Immunologists
Date: 12-2007
DOI: 10.4049/JIMMUNOL.179.11.7899
Abstract: Although histamine plays an essential role in inflammation, its influence on cyclooxygenases (COX) and prostanoid homeostasis is not well understood. In this study, we investigated the effects of histamine on the expression of COX-1 and COX-2 and determined their contribution to the production of PGE2, prostacyclin (PGI2), and thromboxane A2 in human coronary artery endothelial cells (HCAEC). Incubation of HCAEC monolayers with histamine resulted in marked increases in the expression of COX-2 and production of PGI2 and PGE2 with no significant change in the expression of COX-1. Histamine-induced increases in PGI2 and PGE2 production were due to increased expression and function of COX-2 because gene silencing by small interfering RNA or inhibition of the catalytic activity by a COX-2 inhibitor blocked prostanoid production. The effects of histamine on COX-2 expression and prostanoid production were mediated through H1 receptors. In addition to the direct effect, histamine was found to lify LPS-stimulated COX-2 expression and PGE2 and PGI2 production. In contrast, histamine did not stimulate thromboxane A2 production in resting or LPS-activated HCAEC. Histamine-induced increases in the production of PGE2 and PGI2 were associated with increased expression of mRNA encoding PGE2 and PGI2 synthases. The physiological role of histamine on the regulation of COX-2 expression in the vasculature is indicated by the findings that the expression of COX-2 mRNA, but not COX-1 mRNA, was markedly reduced in the aortic tissues of histidine decarboxylase null mice. Thus, histamine plays an important role in the regulation of COX-2 expression and prostanoid homeostasis in vascular endothelium.
Publisher: American Physiological Society
Date: 09-2004
DOI: 10.1152/AJPREGU.00049.2004
Abstract: Patency of the fetal ductus arteriosus (DA) is maintained in an environment of low relative oxygen tension and a preponderance of vasodilating forces. In addition to prostaglandins, nitric oxide (NO), a potent vasodilator in the pulmonary and systemic vasculatures, has been implicated in regulation of the fetal DA. To further define the contribution of NO to DA patency, the expression and function of NO synthase (NOS) isoforms were examined in the mouse DA on days 17–19 of pregnancy and after birth. Our results show that endothelial NOS (eNOS) is the predominant isoform expressed in the mouse DA and is localized in the DA endothelium by in situ hybridization. Despite rapid constriction of the DA after birth, eNOS expression levels were unchanged throughout the fetal and postnatal period. Pharmacological inhibition of prostaglandin vs. NO synthesis in vivo showed that the preterm fetal DA on day 16 is more sensitive to NOS inhibition than the mature fetal DA on day 19, whereas prostaglandin inhibition results in marked DA constriction on day 19 but minimal effects on the day 16 DA. Combined prostaglandin and NO inhibition caused additional DA constriction on day 16. The contribution of vasa vasorum to DA regulation was also examined. Immunoreactive platelet endothelial cell adhesion molecule and lacZ tagged FLK1 localized to DA endothelial cells but revealed the absence of vasa vasorum within the DA wall. Similarly, there was no evidence of vasa vasorum by vascular casting. These studies indicate that eNOS is the primary source of NO in the mouse DA and that vasomotor tone of the preterm fetal mouse DA is regulated by eNOS-derived NO and is potentiated by prostaglandins. In contrast to other species, mechanisms for DA patency and closure appear to be independent of any contribution of the vasa vasorum.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8AN01989D
Abstract: A probe-based Raman spectroscopy system using a single laser module with two excitation wavelengths has been developed for measuring the fingerprint and high wavenumber regions with a single detector.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-06-2002
Abstract: Implantation involves a series of steps leading to an effective reciprocal signaling between the blastocyst and the uterus. Except for a restricted period when ovarian hormones induce a uterine receptive phase, the uterus is an unfavorable environment for blastocyst implantation. Because species-specific variations in implantation strategies exist, these differences preclude the formulation of a unifying theme for the molecular basis of this event. However, an increased understanding of mammalian implantation has been gained through the use of the mouse model. This review summarizes recognized signaling cascades and new research in mammalian implantation, based primarily on available genetic and molecular evidence from implantation studies in the mouse. Although the identification of new molecules associated with implantation in various species provides valuable insight, important questions remain regarding the common molecular mechanisms that govern this process. Understanding the mechanisms of implantation promises to help alleviate infertility, enhance fetal health, and improve contraceptive design. The success of any species depends on its reproductive efficiency. For sexual reproduction, an egg and sperm must overcome many obstacles to fuse and co-mingle their genetic material at fertilization. The zygote develops into a blastocyst with two cell lineages (the inner cell mass and the trophectoderm), migrates within the reproductive tract, and ultimately implants into a transiently permissive host tissue, the uterus. However, the molecular basis of the road map connecting the blastocyst with the endometrium across species is erse (1) and not fully understood. Recent advances have identified numerous molecules involved in implantation (1–4), yet new discoveries have not yielded a unifying scheme for the mechanisms of implantation.
Publisher: Oxford University Press (OUP)
Date: 03-1998
DOI: 10.1095/BIOLREPROD58.3.719
Abstract: Complex cellular interactions occur between the blastocyst and the uterus during implantation. The expression of various polypeptide growth factors and their receptors in the uterus and/or blastocyst during the periimplantation period suggest that growth factors participate in the implantation process. Neu differentiation factor (NDF) is a member of the epidermal growth factor (EGF) family of growth factors and is represented by multiple conserved isoforms. The expression of several EGF-like ligands in the periimplantation uterus has been characterized, including EGF, heparin binding-EGF, transforming growth factor alpha, hiregulin, betacellulin, and epiregulin. We analyzed the expression pattern of NDF in the periimplantation mouse uterus because of its mitogenic and differentiation-promoting effects. By using Northern analysis and isoform-specific polymerase chain reaction, we found that multiple isoforms are expressed in the periimplantation uterus. NDF displays a highly restricted temporal and spatial expression, with autoradiographic signals localized to the uterine stroma immediately surrounding the implanting blastocyst. NDF expression was absent in mice with delayed implantation but briefly reappeared with the same restricted distribution after termination of the delay by an injection of estrogen. Taken together, these results suggest that an activated blastocyst is required for the expression of NDF and that multiple isoforms may be involved in the complex network of cell-signaling events between the implanting blastocyst and the receptive uterus.
Publisher: Oxford University Press (OUP)
Date: 12-2004
Publisher: IEEE
Date: 03-2011
Publisher: Elsevier BV
Date: 03-2014
Publisher: Public Library of Science (PLoS)
Date: 24-04-2015
Publisher: Elsevier BV
Date: 02-2019
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 06-2010
Publisher: Elsevier BV
Date: 06-2008
Publisher: Elsevier BV
Date: 08-2003
Publisher: Oxford University Press (OUP)
Date: 12-2009
Publisher: Elsevier BV
Date: 06-2014
Location: United States of America
Location: United States of America
No related grants have been discovered for Jeff Reese.