Objective: To promote knowledge and awareness about cardiovascular disease (CVD) among women with recent preeclampsia so that this population may develop more accurate perceptions of their personal CVD risk. Design: An exploratory single group, pretest/posttest educational intervention study. Setting: Telephone-based interviews. Participants: Sixty-four women with preeclampsia in the most recent pregnancy completed the study. The sample was predominately African American. Methods: Knowledge about CVD and the study covariates (age, race, parity, income, marital status, education, and history of previous preeclampsia) were measured prior to CVD education. Levels of CVD risk perception were measured both before and after the CVD educational intervention. Intervention: Structured CVD education by telephone. Results: After CVD education, levels of CVD risk perception were significantly higher than at baseline. Conclusion: As an intervention, CVD education provided by telephone served as a practical and effective approach to contact postpartum women with recent preeclampsia and demonstrated effectiveness in increasing perception of CVD risk.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18125号 / 医博第3845号 / 新制||医||1001(附属図書館) / 30983 / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 柳田 素子, 教授 岩井 一宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

ABSTRACT Preeclampsia (PE) is a one of the more common pregnancy complications that affects 5-8% of pregnancies worldwide and produces significant morbidity and mortality for mother and fetus. Shallow trophoblast invasion and insufficient maternal spiral artery remodeling early in gestation is believed to lead to a relatively hypoxic placenta with inflammatory and trophoblast endoplasmic reticulum (ER) stress. These stresses cause an imbalance in trophoblast expression of angiogenic/anti-angiogenic molecules with decreased placental growth factor (PGF) and increased soluble fms like tyrosine kinase-1 receptor (sFlt-1) production. The decrease in trophoblast PGF seems to be mediated at the transcriptional level while increased expression of sFlt-1 is mediated by alternative splicing. Two variants known to be elevated in PE are the sFlt-1i13 and sFlt-1e15a isoforms. Both share the first 13 exons of Flt-1. A read through into intron 13 and utilization of an alternative poly (A) signal sequence produces the sFlt-1i13 variants protein, while sFlt-1e15a results from alternative splicing of exon 14 to exon 15a, rather than exon 15, and utilization of an alternative poly (A) signal sequence. This angiogenic imbalance contributes to the clinical manifestations of PE later in pregnancy including maternal hypertension and proteinuria. Currently, there are no pharmacological options available for the prevention of PE and the only way to reverse PE symptoms is by delivery. The overall goal of my project was (1) to investigate potential therapeutic mechanisms that could be used to relieve the maternal symptoms of PE by correcting the angiogenic imbalance, and (2) to gain a better understanding of the alternative splicing mechanisms responsible for producing sFlt-1 gene expression in human trophoblast. PE shares some similar pathophysiology and risk factors with cardiovascular diseases. This has prompted use of statins as a potential therapy for PE. However, existing preclinical investigations for statin use has been mostly restricted to PE animal models without elucidating the cell types that respond to statin treatment. Therefore, we sought to determine the effect of statins on angiogenic gene expression in cells that are in direct contact with maternal blood during pregnancy and could contribute to PE: primary trophoblast and endothelial cells. Placental tissue and isolated cells were cultured under hypoxic stress (1% O2) as a model for the hypoxic environment noted in PE. We compared the effectiveness of two types of statins (hydrophilic vs hydrophobic) on angiogenic and anti-angiogenic gene expression from the human tissues and cells. Human placenta villus explants, umbilical vein endothelial cells (HUVECs), and cytotrophoblast were isolated from normal term placentae and cultured under low oxygen tension (1% O2) with serial concentrations of statins. Expression of proangiogenic genes (VEGF and PGF) and the prominent anti-angiogenic sFlt-1 isoforms (sFlt-1i13 & sFlt-1e15a) were analyzed. In villus explants, hypoxia (1% O2) tended to alter angiogenic gene expression in their predicted fashion, by increasing VEGF mRNA (hypoxia marker), decreasing PGF mRNA, and increasing both sFlt-1i13 and sFlt-1e15a mRNA expression. However, the changes in gene expression were quite variable and statistically not significant. Hypoxia significantly increased both sFlt-1i13 and sFlt-1e15a mRNA and protein expression in primary trophoblast but had limited effects on expression in HUVECs. Hypoxia significantly decreased PGF mRNA and protein expression in primary trophoblast, yet significantly increased PGF mRNA and protein expression in HUVECs. Concentrations of pravastatin or simvastatin used had limited effects on altering PGF mRNA and protein expression in any of the cell types. In primary trophoblast, lower concentrations of pravastatin (100/500 µg/ml) had no significant effects on sFlt-1i13 or sFlt-1e15a mRNA expression while higher concentrations (1000 µg/ml) significantly decreased sFlt-1i13 and tended to decrease sFlt-1e15a mRNA expression. Secreted sFlt-1 protein from trophoblast decreased with increasing concentrations of pravastatin. Similarly, simvastatin had limited effects and did not significantly decrease sFlt-1i13 or sFlt-1e15a expression in hypoxic primary trophoblast. Both pravastatin and simvastatin significantly down-regulated sFlt-1i13 and sFlt-1e15a mRNA expression and sFlt-1 protein production in HUVECs. To overcome the effects of statin treatments on sFlt-1 expression, primary HUVECs were treated with farnesyl pyrophosphate ammonium salt (FPP), an intermediate in the cholesterol synthesis pathway. FPP partially restored sFlt-1i13 and sFlt-1e15a mRNA expression. Our data support that the angiogenic imbalance seen in PE can be medicated by hypoxia, and that statin could be a promising medication to limit PE symptoms. The effect of statins may be more evident on endothelial cells than on trophoblast, and the reduction in sFlt-1 expression by statins seems to be partially mediated through the cholesterol synthesis pathway in endothelial cells. The antiangiogenic protein, sFlt-1, plays a central role in the pathophysiology of PE. Excessive amounts of the sFlt-1 receptor in maternal circulation leads to maternal endothelial cell dysfunction and subsequent clinical symptoms of PE. However, the mechanism governing sFlt-1 mRNA expression in trophoblast remains unclear. Jumonji C domain containing gene 6 (JMJD6) has been shown to be involved in splicing of sFlt-1i13 in endothelial cells, although with conflicting outcomes as to whether it increases or decreases alternative splicing of sFlt-1i13. It is unknown if JMJD6 functions to regulate splicing in human primary trophoblast. Therefore, we assessed whether JMJD6 expression is altered in primary trophoblast under hypoxia or ER stress and its ability to regulate alternative splicing of sFlt-1. Human cytotrophoblast were isolated from normal term placentae and were cultured in the presence or absence of ER stress inducer (tunicamycin) or at 1% O2 to simulate trophoblast stressors during PE. Expression of JMJD6, C/EBP homologous protein (CHOP), and sFlt-1 (sFlt-1i13, and sFlt-1e15a) variants were analyzed. Hypoxic stress significantly increases JMJD6, sFlt-1i13, and sFlt-1e15a mRNA expression. ER stress also tended to increase JMJD6, sFlt-1i13, and sFlt-1e15a mRNA expression in primary trophoblast. Collectively, our results show that low oxygen tension (1% O2) or ER stress increase JMJD6 mRNA expression which may contribute to increased sFlt-1i13 and sFlt-1e15a variant expression in primary trophoblast. Similarly, JMJD6 knock down with siRNA tends to slightly decrease sFlt-1i13 and sFlt-1e15a mRNA expression in primary trophoblast. JMJD6 overexpression in HTR-8 cells (choriocarcinoma) tended to increase sFlt-1i13 and sFlt-1e15a mRNA expression; however, results using HTR-8 were inconsistent due to extremely low expression of endogenous Flt-1 mRNA. To overcome this, a Flt-1 minigene plasmid was transfected into HTR-8 cell line. Under 1%O2 these cells increased expression of the sFlt-1i13 isoform. To more directly confirm effects of JMJD6 and hypoxia on sFlt-1 expression, HEK293 and JEG3 stable clones harboring the Flt-1 minigene were generated. Preliminary results from selected single colony isolates show that several stable clones express the Flt-1 minigene products. HEK293 and JEG3 stable clones harboring the Flt-1 minigene, HEK293-Flt1#5 and JEG3-Flt1#5 respectively, were cultured at 1%O2 for 48 or 72 hours. Hypoxic stress had no significant on altering sFlt-1 variant production or JMJD6 mRNA expression in HEK293-Flt1#5 cells. However, hypoxic JEG3-Flt1#5 cells significantly increased sFlt-1i13 isoform mRNA expression (˜6 fold) and mFlt-1 mRNA expression (2.5 Fold) and also increased JMJD6 mRNA expression (1.8 Fold). In summary, these data suggest a role for statins as a potential therapeutic approach for the prevention and treatment of PE by decreasing systemic sFlt-1 expression in endothelial cells. This effect seems most significant in endothelial cells. If substantiated by clinical studies, use of statins would offer an affordable and easily accessible therapy to lessen PE symptoms. Moreover, our preliminary data suggest a potential involvement of JMJD6 in splicing process of sFlt-1i13. Confirming of JMJD6 role in splicing of Flt-1 may provide therapeutic strategies to treat Flt-1 associated disorder.

Preeclampsia (PE), a hypertensive disease of pregnancy, occurring at or after gestational week 20. PE can have life threating consequences for both the mother and the baby. PE is a highly heterogenous disease which makes it challenging to identify any effective therapeutic interventions. We previously discovered three molecular subclasses of PE disease. One of these subclasses is characterized by heightened placental inflammation (inflammation-driven PE). Since it is a newly identified form of PE, we currently do not know about the molecular mechanisms driving this inflammation-driven form of PE. Interestingly, we have observed that placentas from this inflammatory PE subclass uniquely express higher levels of NAD+ consuming enzymes- PARPs - and thus exhibit a decrease in NAD+ content. NAD+ is a regulator of cellular energy metabolism and mitochondrial function. Several studies in the non-pregnant populations suggested that pro-inflammatory disease conditions can trigger hyperactivation of NAD+ consuming enzymes causing a depletion in total NAD+ content, leading to mitochondrial dysfunction and organ failure. Thus, we tested the hypothesis that NAD+ depletion causes placental mitochondrial dysfunction in the inflammatory subclass of PE and that boosting NAD+ could prevent development of this form of placental disease. We aimed to profile PARP activity, NAD+ availability, and mitochondrial health in human cases of all three PE subclasses. We examined the causal relationship between inflammation and dysregulated NAD+ signalling in both an in vitro human trophoblast culture model and in a rodent model of inflammation-driven PE. We also evaluated the therapeutic potential of NAD+ booster, nicotinamide riboside (NR) to improve placental health and function in the rodent model of inflammation-driven PE. Our results suggest that along with increased activity of PARP enzymes and decreased NAD+ levels, human inflammatory PE placentas also exhibit decreased levels of mitochondrial proteins and increased oxidative DNA damage. Using an in vitro human placental (HTR8 cell line) inflammation model we showed that increasing NAD+ under an inflammatory condition improved trophoblast mitochondrial and cellular function. Using an in vivo LPS induced rat model of inflammation-driven PE, we demonstrated that NAD+ boosting during pregnancy improved placental mitochondrial function, reduced inflammation and oxidative stress. This subsequently resulted in improved pregnancy outcomes demonstrated by reduced maternal blood pressure, increased placental/fetal weights and increased fetal survival in the LPS model. Overall, this study identifies targeting NAD+ signaling as a promising intervention for PE. NAD+ boosting through NR has been tested in non-pregnant human populations and found to be safe and effective in enhancing NAD+ levels. Thus, findings of this thesis lay the ground to test NAD+ boosting strategies in PE patients in near future.

Thesis (MSc)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Pre-eclampsia is a condition unique to pregnancy and primarily affects the maternal and placental vascular endothelium. It has significant morbidity and mortality consequences for both mother and infant. Despite global research into the aetiology of the condition, the cause for this condition remains unknown. Several factors, including a strong family history of hypertension in pregnancy point to a familial or genetic component in the pathophysiology of this complication. The purpose of this research project was to investigate candidate genes implicated in endothelial damage. Common methylene-tetra-hydrofolate reductase (MTHFR) gene mutations C677T and A1298C, factor V Leiden mutation R506Q and prothrombin mutation A20210G were investigated in 50 patients with an uncomplicated pregnancy outcome (controls) and 350 patients with various clinical manifestations of preeclampsia, including severe, early onset forms and abruptio placentae. Fasting homocystein levels were determined biochemically on all participants. In addition, 126 consecutive pregnant patients were recruited at booking, fasting lipograms were performed on them as well as mutation screening of 7 common mutations in the low-density lipoprotein receptor gene. This was correlated with eventual pregnancy outcome, and those with an uncomplicated outcome were selected as an additional control group. A significant association between hyperhomocysteinaemia and early onset severe pre-eclampsia could be demonstrated. Mutant allele T of the C677T mutation could be associated with hyperhomocysteinaemia but not with pre-eclampsia whilst mutant allele C of mutation A1298C demonstrated a significant correlation with diastolic blood pressure. In addition, combined heterozygosity for these mutations may serve as a marker for abruptio placentae. / ENGLISH ABSTRACT: Pre-eklampsie is 'n hipertensiewe toestand uniek aan menslike swangerskap en dit affekteer hoofsaaklik die vaskulêre endoteel. Die toestand hou ernstige morbiditeit en mortaliteit vir beide ma en baba in en na jare se navorsing is die oorsaak van hierdie toestand steeds onbekend. Epidemiologiese studies toon 'n duidelike familiële verband aan wat die vermoede laat ontstaan dat daar 'n onderliggende genetiese aspek tot die ontwikkeling van die siektetoestand is. Die doel van hierdie navorsingsprojek was om gene te ondersoek wat geïmpliseer word in endoteel skade. Twee algemene mutasies, C677T en A1298C in die MTHFR geen asook faktor V Leiden R506Q en protrombien A20210G mutasies is ontleed in 50 pasiënte met 'n ongekompliseerde swangerskapsverloop en in 350 pasiënte met 'n swangerskap gekompliseer deur verskillende kliniese manifestasies van die siekteproses, insluitende vroeë aankoms erge pre-eklampsie en abruptio placentae. Op alle pasiënte is ook 'n vastende homosistiën vlak biochemies bepaal. 'n Verdere 126 opeenvolgende pasiënte is gewerf tydens hulle eerste besoek aan die voorgeboortekliniek en vastende lipogramme is op almal uitgevoer. Mutasie sifting vir 7 algemene mutasies in die lae-digtheids lipoproteïen reseptor geen is op hierdie groep gedoen en die resultaat is met die uiteindelike swangerskapsuitkoms gekorreleer. Pasiënte met 'n uitkoms ongekompliseer deur hipertensie is gekies om deel te wees van 'n verdere kontrolegroep. Daar was 'n betekenisvolle verband tussen hiperhomositiënemie en erge, vroeë aankoms pre-eklampsie. Die T alleel van die C677T mutasie is geassosieer met hiperhomosistiënemie maar nie met pre-eklampsie nie. Die C alleel van die A 1298C mutasie toon 'n betekenisvolle verband met diastoliese bloeddruk. Gekombineerde heterosigositeit vir beide MTHFR mutasies kan 'n moontlike merker vir abruptio placentae wees.

Pre-eclampsia is a multi-organ system disorder that occurs after the 20th week of gestation in pregnancy and is characterized by hypertension and proteinuria with or with out oedema. It is a major cause of morbidity and mortality for the woman and her child. Based on surveillance data, pre-eclampsia is one of the leading causes of maternal mortality in Namibia. However, there is no depth study done in Namibia that looks at the extent of confirmed pre-eclampia and its contribution to maternal and perinatal morbidity and mortality. There is also no standard management protocol currently recommended in Namibia. The aim of this study was to evaluate the outcomes and quality of care given to pre-eclamptic patients treated in Windhoek Central and Katutura referral hospitals in Namibia within the period of January 2003 to December 2004.

Submitted by admin tede (tede@pucgoias.edu.br) on 2016-10-07T13:33:46Z No. of bitstreams: 1 TÚLIO SÉRGIO DE OLIVEIRA.pdf: 820156 bytes, checksum: 904d8a04a1677fa8754a3159741cd43a (MD5) / Made available in DSpace on 2016-10-07T13:33:46Z (GMT). No. of bitstreams: 1 TÚLIO SÉRGIO DE OLIVEIRA.pdf: 820156 bytes, checksum: 904d8a04a1677fa8754a3159741cd43a (MD5) Previous issue date: 2016-06-24 / Preeclampsia is an exclusive pathology of pregnancy, characterized by hypertension associated with proteinuria. It occurs after 20 weeks of pregnancy. Its prevalence is 8% in singleton pregnancies and 14% in twin pregnancies. It has an unknown etiology up to date. It is currently accepted that genetic factors are important in the development of preeclampsia due to the increased risk in women with family history of preeclampsia, with a history of preeclampsia in a previous pregnancy and on those with partners whose mothers or previous partner have a history of preeclampsia. Preeclampsia figures as the main cause of maternal mortality in Brazil and for this reason, its study is of great interest to public health. The objective of this study was to identify the scientific publications about on preeclampsia and possible associations with genetic alterations during the period of 2005-2015, in the Scopus platform. Different approaches were carried out to evaluate the articles, using as a method, scientometrics. As a result, we observed a significant increase in research and publications on polymorphism in preeclampsia, with a prevalence of authors, publications and institutions of developed countries and a significant association of 45 polymorphisms of genes with preeclampsia. We observed that polymorphisms of genes and the relationship between them is not clear and needs further studies to obtain more results that are consistent. / Pré-eclâmpsia é uma patologia exclusiva da gravidez, caracterizada por hipertensão arterial e proteinúria após 20 semanas de gestação. Sua prevalência é de 8% em gestações únicas e 14% em gestações gemelares. Possui etiopatogenia desconhecida até o momento. Atualmente é aceito que fatores genéticos são importantes no desenvolvimento da doença, devido ao aumento do risco em gestantes com histórico familiar, pré-eclâmpsia em gestação anterior e em parceiro cujas mães ou parceiras anteriores possuem histórico de pré-eclâmpsia. A pré-eclâmpsia figura como principal causa de mortalidade materna no Brasil e por essa razão, seu estudo é de grande interesse em saúde pública. O objetivo deste estudo foi identificar as publicações cientificas, durante o período de 2005 a 2015, presentes na plataforma SCOPUS sobre pré-eclâmpsia e possíveis associações com alterações genéticas. Foram realizadas diferentes abordagens de avaliação sobre os artigos, utilizando como método, a cienciometria. Como resultados, observamos um aumento significativo de pesquisas e publicações sobre polimorfismo na pré-eclâmpsia, com prevalência de autores, publicações e instituições de países desenvolvidos e uma associação significativa de 45 polimorfismos de genes com a pré-eclâmpsia. Observamos que os polimorfismos de genes e a relação entre eles, ainda não está esclarecido, necessitando estudos complementares para se obter resultados mais consistentes.

Pre-eclampsia is a multi-organ system disorder that occurs after the 20th week of gestation in pregnancy and is characterized by hypertension and proteinuria with or with out oedema. It is a major cause of morbidity and mortality for the woman and her child. Based on surveillance data, pre-eclampsia is one of the leading causes of maternal mortality in Namibia. However, there is no depth study done in Namibia that looks at the extent of confirmed pre-eclampia and its contribution to maternal and perinatal morbidity and mortality. There is also no standard management protocol currently recommended in Namibia. The aim of this study was to evaluate the outcomes and quality of care given to pre-eclamptic patients treated in Windhoek Central and Katutura referral hospitals in Namibia within the period of January 2003 to December 2004.

Thesis (MSc (Genetics))—University of Stellenbosch, 2007. / In South Africa, pre-eclampsia is the second highest cause of maternal deaths. The incidence of this disease in the Western Cape alone is 6.8% and places a large burden of health care facilities. The placenta and implantation thereof is thought to play the most significant role in the onset of this disease. Among the many theories for its aetiology, is the acknowledged two - stage theory. This is based on evidence that pre-eclamptic placentas demonstrate altered remodelling and invasion into the uterine endometrium and myometrium. The sub-optimal endometrium invasion leads to less oxygenation of the placental environment causing transient hypoxia. Consequently, the placenta is thought to release unknown factors into the maternal circulation which then culminates in clinical features associated with pre-eclampsia. Neurokinin B is thought to be one of these placental factors and subsequently binds to the NKB receptor in the maternal system. Endothelium-derived nitric oxide synthase has recently been shown to activate this receptor. The aim of this study was to investigate the role of neurokinin B (TAC3) and the neurokinin B receptor (TACR3) genes in the predisposition of pre-eclampsia and their interaction with eNOS in the South African coloured population together with a matched control cohort.

Master of Public Health - MPH / Pre-eclampsia is a multi-organ system disorder that occurs after the 20th week of gestation in pregnancy and is characterized by hypertension and proteinuria with or with out oedema. It is a major cause of morbidity and mortality for the woman and her child. Based on surveillance data, pre-eclampsia is one of the leading causes of maternal mortality in Namibia. However, there is no depth study done in Namibia that looks at the extent of confirmed pre-eclampia and its contribution to maternal and perinatal morbidity and mortality. There is also no standard management protocol currently recommended in Namibia. The aim of this study was to evaluate the outcomes and quality of care given to pre-eclamptic patients treated in Windhoek Central and Katutura referral hospitals in Namibia within the period of January 2003 to December 2004. / South Africa