Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.     

p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.     

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.     

CREB regulates hepatic gluconeogenesis through the coactivator PGC-1

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined. Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycaemia [corrected] and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in liver contributes importantly to the pathogenesis of this disease.     

心脏瓣膜置换术后妊娠的处理（附8例）

目的：探讨心脏瓣膜置换术后妊娠的临床情况及处理。方法：分析经治的8例心脏瓣膜置换术后妊娠患者的临床表现、处理及结局。结果：8例心脏瓣膜置换术后妊娠患者经过合理抗凝,适时剖宫产分娩,母婴平安出院。结论：对心脏瓣膜置换术后妊娠患者应予重视,合理抗凝、密切监护,以保证患者在孕期和分娩期的安全。     

Tumour biology: herceptin acts as an anti-angiogenic cocktail

Malignant tumours secrete factors that enable them to commandeer their own blood supply (angiogenesis), and blocking the action of these factors can inhibit tumour growth. But because tumours may become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules, a cocktail of multiple anti-angiogenic agents should be more effective. Here we show that herceptin, a monoclonal antibody against the cell-surface receptor HER2 (for human epidermal growth factor receptor-2; ref. 4), induces normalization and regression of the vasculature in an experimental human breast tumour that overexpresses HER2 in mice, and that it works by modulating the effects of different pro- and anti-angiogenic factors. As a single agent that acts against multiple targets, herceptin, or drugs like it, may offer a simple alternative to combination anti-angiogenic treatments.     

Rheb在诱导和改善胰岛素抵抗中的作用

Rheb是Ras超家族中GTP结合蛋白,具有调节多种生理学功能的作用。为进一步弄清楚Rheb在胰岛素抵抗发生中的作用及在胰岛素抵抗改善过程中的作用,通过先建立胰岛素抵抗小鼠为模型,再通过有氧运动改善胰岛素抵抗状况的方法,研究并检测前后两阶段小鼠组织的Rheb、mTOR和PGC-1α表达情况。结果表明在小鼠诱导胰岛素抵抗发生阶段Rheb和mTOR的表达是同步升高的,PGC-1α表达是降低的;然后经有氧运动改善其胰岛素抵抗的阶段时Rheb与mTOR是同步降低的,而PGC-1α表达是升高的。可见Rheb是通过mTOR通路在高脂饮食诱导胰岛素抵抗中也发挥着重要作用,同时其表达下降后也可有效调控机体代谢状况,改善胰岛素抵抗。     

高容量血液滤过治疗严重颅脑损伤后多器官功能障碍的研究

探讨高容量血液滤过治疗严重颅脑损伤后多器官功能障碍患者的预后及与肿瘤坏死因子(TNF-α)、白介素-1、白介素-10水平的变化。无肝素化血液滤过治疗重度颅脑损伤多脏器衰竭患者,监测病人14 d死亡率及监测病人、24 h、48 h TNF-α、IL-1、IL-10变化。结果血液滤过治疗24 h及48 h的TNF-α、IL-1、IL-10水平明显低于血滤治疗前。治疗14 d后治疗组死亡率明显低于对照组。高容量血液滤过治疗严重颅脑损伤后多器官功能障碍的患者,能够降低炎症介质改善其预后。     

“我”的出走与回归——晚清新小说女性形象分析

晚清新小说塑造了众多与传统迥异的女性形象,集中呈现了晚清女性生活的新因素,其中最为重要的是女性对自我的体察与感悟。从“我”之初现,到被“大我”淹没的“我”,到歧路上畸态的“我”,再到对“旧我”的皈依,晚清新小说的女性形象对作为个体的“我”的认知走过了艰难的探索之路,具有深刻的时代印记。     

论“贫女诗”与唐代社会变革

“贫女诗”是唐代中后期较为集中地出现的诗歌主题。根据诗歌文本与作者的写作意图，“贫女诗”可分为白描“贫女难嫁”和隐喻“寒士难举”两种类型。“贫女难嫁”和“寒士难举”现象具有深刻的社会历史根源，并且都与唐代社会变革密切相关：“贫女难嫁”是唐代社会结构变动、士族门阀走向解体对人们婚姻观念的影响，“寒士难举”则反映了科举制替代官僚世袭制的变革。     

N级编码理论的逻辑梳理

N级编码理论旨在揭示一个文本之所以深刻和厚重的奥秘所在。为什么有些作品能够经久传世？为什么有些作品让人感受到超越文字表面含意的博大和宏伟？并会出现“仁者见仁、智者见智”的多重解读空间？用N级编码理论来分析，可知有些创作隐含了更为复杂的象征体系，其意义编织和呈现的方式有着丰富的层次，我们在阅读的过程中需要穿过一层一层的编码规则，才能到达其意指的灵魂。而这种复杂性和对司空见惯符号的异化处理正是更高审美感受的来源。     

妊娠期急性脂肪肝4例临床分析

目的:总结妊娠期急性脂肪肝的诊断和治疗经验.方法:收集我院2003年-2008年收治4例妊娠期急性脂肪肝病例进行分析.结果:妊娠期急性脂肪肝临床经过酷似重症肝炎,妊娠晚期发病,短期内凝血因子缺乏、多器官功能衰竭.4例病例死亡3例,出生5个新生儿存活4个.结论:早期诊断,最大限度纠正凝血功能,尽早终止妊娠可显著改善母婴结局.