静脉导管与胎儿畸形的关系研究

目的 应用彩色多普勒超声检测胎儿的静脉导管（DV）,探讨DV异常与胎儿畸形的相关性.方法 采用彩色超声诊断仪经腹检查330例孕11～40周单胎胎儿DV血流频谱,结合病理对照分析.结果 52例DV异常,胎儿畸形50例,胎儿正常2例;278例DV正常,胎儿畸形38例,胎儿正常240例.DV异常与胎儿畸形有显著关系（P＜0.01）.其中,胎儿DV异常与心脏畸形、胎儿颈部水囊瘤有显著关系（P＜0.01）;与胎儿神经系统畸形无显著关系（P＞0.05）.结论 胎儿DV血流频谱异常可作为孕早期胎儿先天性心脏畸形的一个筛查指标.多普勒超声检测胎儿DV血流频谱在早期诊断胎儿畸形方面具有重要的临床意义.     

妊娠期糖尿病胎儿静脉导管血流波形的变化及临床意义

目的：探讨胎儿静脉导管血流波形及各项参数在中晚孕妊娠期糖尿病（ GDM）中的变化及临床意义。方法选取23例24～40孕周GDM胎儿（ GDM组）及60例正常胎儿（对照组）,应用彩色多普勒超声检查,在静脉导管入下腔静脉处记录静脉导管血流波形,测定心室收缩期和舒张期峰值流速（ DVS和DVD）、心房收缩期最大流速（ DVA）、DVS/DVA,静脉导管阻力指数（ DVRI DVRI＝（ DVS-DVA）/DVS）。结果 GDM组胎儿静脉导管的DVS（42．72±3．63）cm/s、DVA（12．34±3．11）cm/s及DVRI（0．49±0．08）与对照组差异均有统计学意义（t＝3．232、9．664、2．470,均P＜0．05）。结论彩色多普勒超声检测妊娠期糖尿病胎儿静脉导管的血流频谱曲线对监测、评估胎儿在宫内健康状况有临床意义。     

The aryl hydrocarbon receptor is required for developmental closure of the ductus venosus in the neonatal mouse

A developmental role for the Ahr locus has been indicated by the observation that mice harboring a null allele display a portocaval vascular shunt throughout life. To define the ontogeny and determine the identity of this shunt, we developed a visualization approach in which three-dimensional (3D) images of the developing liver vasculature are generated from serial sections. Applying this 3D visualization approach at multiple developmental times allowed us to demonstrate that the portocaval shunt observed in Ahr-null mice is the remnant of an embryonic structure and is not acquired after birth. We observed that the shunt is found in late-stage wild-type embryos but closes during the first 48 h of postnatal life. In contrast, the same structure fails to close in Ahr-null mice and remains open throughout adulthood. The ontogeny of this shunt, along with its 3D position, allowed us to conclude that this shunt is a patent developmental structure known as the ductus venosus (DV). Upon searching for a physiological cause of the patent DV, we observed that during the first 48 h, most major hepatic veins, such as the portal and umbilical veins, normally decrease in diameter but do not change in Ahr-null mice. This observation suggests that failure of the DV to close may be the consequence of increased blood pressure or a failure in vasoconstriction in the developing liver.     

胎心监护联合肾动脉、大脑中动脉及静脉导管分流率预测胎儿宫内窘迫的临床分析

目的：分析胎心监护联合肾动脉、大脑中动脉及静脉导管分流率预测胎儿宫内窘迫的临床价值。方法选择本院收治的68例胎儿宫内窘迫孕妇为观察组,另选择同期于本院产科分娩的60例正常孕妇为对照组,分别对两组孕妇的胎心率及肾动脉和大脑中动脉RI、PI、S/D值及静脉导管（DV）分流率进行检查,对比分析两组孕妇各指标值及各指标预测胎儿宫内窘迫的阳性率。结果观察组胎儿的肾动脉RI、PI、S/D值均高于对照组（P〈0.05）,大脑中动脉RI、PI、S/D值均低于对照组（P〈0.05）,DV分流率高于对照组（P〈0.05）。观察组胎儿的胎心率以及肾动脉和大脑中动脉RI、PI、S/D值及DV分流率预测胎儿宫内窘迫的阳性率均高于对照组（P〈0.05）,且4项联合预测胎儿宫内窘迫的阳性率均高于各项单独预测的阳性率（P〈0.05）。结论胎心监护联合肾动脉、大脑中动脉及DV分流率在胎儿宫内窘迫预测中具有良好的临床应用价值。     

Alteration of gene expression in human cells treated with the agricultural chemical diazinon: possible interaction in fetal development

Agricultural chemicals frequently alter human health or development, typically because they have endocrine agonist or antagonist activities and alter hormone-regulation of gene expression. The insecticide, diazinon, was evaluated for gene expression disrupting activity using MCF-7 cells, an estrogen-dependent human cell line, to examine the capacity of the insecticide to disrupt gene expression essential for morphological development, immune system development or function, and/or central nervous system development and function. MCF-7 cells were treated with 30, 50 or 67 ppm diazinon, and gene expression was measured in treated cells compared to expression in untreated or estrogen-treated cells. DNA microarray analysis of diazinon-treated cells showed significant up- or down-regulation of a large number of genes compared to untreated cells. Of the 600 human genes on the Phase 1 chip utilized for these studies, two specific genes--calreticulin and TGF-beta3--were selected for corroboration using quantitative real time PCR (qrtPCR). qrtPCR, completed to assess gene expression levels for calreticulin and TGFbeta3, confirmed results showing significant up-regulation of these two genes obtained from the microarray data. These studies were designed to provide baseline data on the gene expression-altering capacity of a specific chemical, diazinon, and allow a partial assessment of the potentially deleterious effects associated with exposure of human cells to this chemical. Currently, it is not known whether results from cells in vitro can be extrapolated to human health consequences of chemical exposure.     

Indomethacin and paracetamol: interaction with prostaglandin synthesis in the rat stomach

Using ex vivo incubation of mucosal strips the production of prostaglandins (I2- and E-like PGs) in the rat stomach was demonstrated by bioassay. Indomethacin inhibited this PG synthesis 1 and 4 h after oral drug administration. Paracetamol stimulated the production of PGs when given by itself but could not prevent the inhibitory action of indomethacin. Protection of the stomach by paracetamol against the injuring effect of indomethacin is therefore not due to preservation of the production of protective PGs.     

Furosemide interaction with the prostaglandin and kallikrein-kinin systems of the kidneys

Indomethacin (3 mg/kg, orally for 5 days) prevented the increase of blood flow in the internal zone of the renal cortical layer but failed to interfere with the increase of diuresis and sodium secretion produced by furosemide (2 mg/kg, subcutaneously) in anesthetized rats. Contrykal (6000 ED, subcutaneously) failed to alter the character of the hemodynamic changes in the renal cortex but enhanced the diuretic and natriuretic effects of furosemide. In unanesthetized rats indomethacin prevented creatinine urine excretion but didn't attenuate the diuretic and natriuretic effects of furosemide.     

vitA对胎兔动脉导管发育的影响

目的了解vitA对胎兔动脉导管发育的影响。方法8只孕兔随机分为4组，每组2只（每只均受孕，每只产胎兔5只以上，随机选5只备用）：分别在受孕第25天单独与第25和26两天连续运用3000IU／kgvitA，另外在受孕第二周后运用隔天给药5000IU／d的给药方法，加上对照组（生理盐水）共4组，于第27天内（早产期内）解剖孕兔，每组取10只仔兔，取仔兔的动脉导管，部分动脉导管固定后HE染色了解内膜增殖情况，部分导管做导管内钙测定。结果三种给药时间方法下均显示能促进动脉导管发育，但程度不同，在促进动脉导管发育上：孕后两周隔天给药〉连续给药两天〉单独运用一天（见附图）。结论vitA能促进动脉导管发育，隔天用药的方法效果较好，在预防持续胎儿循环和提高早产儿成活率上有一定作用。     

C-reactive protein: interaction with the vascular endothelium and possible role in human atherosclerosis

C-reactive protein (CRP) is the first acute phase protein that has been described in the literature. It is phylogenetically ancient and - with serum amyloid P - belongs to proteins named as "pentraxin". After being considered a marker of acute inflammation for several decades and fruitfully used in clinical practice, CRP has been recently considered as a potential contributor to inflammatory diseases including atherosclerosis as well as a marker of cardiovascular risk. With regard to the first topic, inflammation is now believed to represent the underlying mechanism leading to the formation of human atheroma and favouring both the destabilization of vulnerable plaques and the formation of occlusive thrombi. In this regard, numerous studies indicated that modest changes in circulating CRP levels, as detected by highly sensitive methods, can be extremely useful in predicting cardiovascular and perhaps cerebrovascular diseases in apparently healthy individuals as well as in patients affected by atherosclerosis. Subjects manifesting with identical low density cholesterol and/or blood pressure levels have different rates of cardiovascular accidents on the basis of different circulating CRP concentrations. In addition, women with identical cardiovascular risk profiles developed more type 2 diabetes in the presence of higher circulating CRP levels and thereby are expected to display divergent cardiovascular prognosis. Therefore, even slight changes in circulating CRP concentrations - assuming that blood is collected appropriately and CRP is measured with correct methods - could help clinicians in defining individual cardiovascular risk. In this review, we have firstly described the current understanding of the structure of CRP, its function, and interaction with the vascular endothelial cell. Then, we have discussed how to measure circulating CRP and the more recent findings on the suggested role of circulating CRP as a novel cardiovascular risk factor.     

Comparison of effects of cyclooxygenase inhibitors on myometrial contraction and constriction of ductus arteriosus in rats

The aim of this study was to compare the tocolytic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), indomethacin and nimesulide on myometrial strips isolated from rats in both lipopolysaccharide-induced preterm labour and term labour. We also compared the constrictor effects of DFU and indomethacin on the fetal ductus arteriosus. Myometrial strips were obtained from preterm and term labour Wistar albino rats and were mounted in organ baths for the recording of isometric tension. DFU, nimesulide and indomethacin significantly inhibited KCl-, oxytocin-, prostaglandin E(2)- and prostaglandin F(2 alpha)-stimulated contractions of myometrial strips isolated from rats in preterm and term labour. The E(max) value of indomethacin was significantly lower than those for DFU and nimesulide (P<0.05), with no change-log (10) EC(50) values. There was no significant difference between in -log (10) EC(50) and E(max) values of DFU and nimesulide for any of the tissues (P>0.05). In addition, there was no significant difference between -log (10) EC(50) and E(max) values for each of these three agents in myometrial tissues isolated from rats in preterm and term labour (P>0.05). Fetal ductus arteriosus was significantly constricted by DFU (10 or 100 mg/kg) in preterm and term rats, although DFU (10 or 100 mg/kg)-induced constriction ratios were significantly lower than those for indomethacin (P<0.05). These data demonstrate that DFU, a specific cyclooxygenase-2 inhibitor, could be considered as a new therapeutic agent for preterm labour. However, careful attention should be given to constriction of the fetal ductus arteriosus.     

On the interaction of specific prostaglandin H synthase-2 inhibitors with prostaglandin H synthase-1

Previous studies with both intact cells and ram seminal vesicles microsomes have shown that the specific PGHS-2 inhibitors NS-398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide) and DuP-697 (5-bromo-2[4-fluorophenyl]-3-[4-methylsulfonylphenyl]-thiophene) attenuate the inhibition of PGHS-1 caused by aspirin and indomethacin. This effect occurs at concentrations of PGHS-2 inhibitors that do not inhibit the cyclooxygenase activity of PGHS-1. Here we study the effect of NS-398 and ibuprofen, a nonspecific inhibitor, on the indomethacin-induced inhibition of purified PGHS-1 and compare this effect with that observed with microsomal enzyme. Dissociation constants are obtained for the interaction of NS-398 with the purified and microsomal PGHS-1 using curve fitting of experimental data on the interaction of indomethacin with the enzyme. The dissociation constants for ibuprofen and NS-398 for interaction with PGHS-1 are similar. This finding indicates that specific PGHS-2 inhibitors are similar to ibuprofen in their ability to compete with aspirin, an irreversible time-dependent inhibitor of PGHS-1 often used for prevention of spontaneous thrombosis. Importantly, the concentrations at which PGHS-2 inhibitors attenuate the inhibition induced by aspirin and indomethacin are well below those required to cause inhibition of PGHS-1. Our results suggest that arachidonic acid not only competes with PGHS-2 inhibitors for binding to the cyclooxygenase site of PGHS-1 but it also reduces the affinities of PGHS-1 for these inhibitors by an additional, as yet unresolved mechanism.     

DEHP, bis(2)-ethylhexyl phthalate, alters gene expression in human cells: possible correlation with initiation of fetal developmental abnormalities

Diethylhexylphthalate (DEHP) is a widely distributed phthalate, to which humans are exposed to due to its variety of commercial and manufacturing uses. As a plasticiser, it is found in a wide number of products, and metabolites of DEHP have been detected in urine samples from a high percentage of the people screened for phthalates. We utilised DNA microarray analysis to evaluate DEHP for gene expression disrupting activity using the human cell line MCF-7, and found that DEHP significantly dysregulated approximately 34% of the 2400 genes spotted on the NEN2400 chip we used. The results suggest that DEHP, a known estrogen agonist and probable androgen antagonist, alters the expression of a number of genes, many of which are critical for fetal development. Down-regulation of two genes, FGD1 and PAFAH1B1, related in that both are essential for fetal brain development, was corroborated using quantitative real time PCR. These studies show DEHP to be a highly effective human gene expression-altering chemical, and that, at appropriate concentrations, it has the possibility of altering fetal central nervous system development, resulting in the birth defects lissencephaly and/or faciodigitogenital dysplasia.     

Endothelial dysfunction in DOCA-salt hypertension: possible involvement of prostaglandin endoperoxides

The effects of the arachidonic acid metabolism inhibitors on the acetylcholine responses of aortae from control (CR) and deoxycorticosterone acetate (DOCA)-salt hypertensive (HR) rats were investigated. The acetylcholine decreased response observed in HR [relaxation (%): CR 95.5+/-2.7, n = 4; HR 52.0+/-6.3, n = 5, p < 0.05] was restored by the cyclooxygenase inhibitor piroxicam [relaxation (%): CR 99.8+/-0.2, n = 4; HR 86.0+/-4.0, n = 5] and by the thromboxane synthetase inhibitor and the thromboxane A2/prostaglandin H2 receptor antagonist ridogrel [relaxation (%): CR 92.1+/-4.4, n = 7; HR 93.1+/-2.0, n = 7] but not by the inhibitors of thromboxane synthetase, prostacyclin synthetase, cytochrome P-450 monooxygenase, and lipoxygenase. So, endoperoxide intermediates seem to be involved in the decreased endothelium-dependent relaxation to acetylcholine in DOCA-salt hypertension.     

Sodium nitroprusside: pharmacological aspects of its interaction with hydroxocobalamin and thiosulphate

Hydroxocobalamin (HOCb), when mixed with sodium nitroprusside (SNP) in a 10:1 or 1:1 molar ratio and injected (i.v.) into the anaesthetized rat, prolonged the depressor response to SNP by 25-50%, but did not affect the degree of blood pressure lowering. Both the 'onset' and 'offset' components of the response were prolonged. Injecting [14C]SNP along with a 10-fold molar excess of HOCb resulted in a 2- to 3-fold elevation of plasma radioactivity which was maintained during the first 10 min of a 40 min experimental period. These effects of HOCb on the pharmacodynamics and pharmacokinetics of SNP are probably due to complex formation between the two compounds. Sodium thiosulphate (ST) added to SNP (12:1 molar ratio) had no effect on the depressor response to SNP. This mixing of ST and SNP had a less-marked influence on the plasma [14C] SNP-derived radioactivity than occurred with HOCb. There was no initial elevation of radioactivity, but the levels were raised by 50-60% at 4, 6 and 10 min. Since the depressor response to SNP was unaffected by ST, it is presumed that the higher concentrations of radioactivity were due to inactive degradation products rather than the active species itself.     

Metoprolol-paroxetine interaction in human liver microsomes: stereoselective aspects and prediction of the in vivo interaction.

This study in human liver microsomes was undertaken to establish whether paroxetine stereoselectively inhibits the oxidative metabolism of metoprolol in vitro, and whether the in vivo observed magnitude of the paroxetine-metoprolol interaction was predictable from these in vitro data. Two distinct approaches were used: inhibitory effect of paroxetine on 1) the formation of alpha-hydroxymetoprolol and O-desmethylmetoprolol from the individual metoprolol enantiomers and 2) on the depletion of the enantiomers from the incubation mixture. Nonspecific binding of both metoprolol and paroxetine to human liver microsomes was also investigated. Whereas metoprolol displayed negligible binding, paroxetine was extensively bound to microsomal proteins. This was taken into account in order to obtain unbiased K(i) values and unbound concentrations of paroxetine. In the substrate depletion experiments, the intrinsic clearance (CL(int)) of (R)-metoprolol was larger than that of (S)-metoprolol. Paroxetine caused a concentration-dependent decrease in CL(int) of both enantiomers and abolished the stereoselectivity. In the metabolite formation experiments paroxetine did not stereoselectively affect alpha-hydroxylation, but preferentially inhibited the O-demethylation of the (R)-enantiomer versus the (S)-enantiomer. The use of unbound paroxetine concentrations in the two in vitro methods yielded comparable predicted increases in area under the curve (1.7-1.9 and 2.2-2.5 for (S)- and (R)-metoprolol, respectively) but underestimated the in vivo observed changes of about 7- and 10-fold, respectively. In conclusion, this study showed that paroxetine abolishes the stereoselective metabolism of metoprolol due to a stereoselective inhibition of the O-demethylation toward (R)-metoprolol. Furthermore, the extent of the in vivo metoprolol-paroxetine interaction was substantially underestimated by either one of the two in vitro approaches used when a competitive mechanism was assumed.     

Ethanol and methadone in man: A possible drug interaction

Possible opiate-ethanol interaction was studied in five selected stable non-alcoholic chronic methadone-maintained patients. Ethanol and methadone levels were determined during oral methadone, ethanol and combined methadone-ethanol tolerance tests. The data do not suggest a significant acute interaction between ethanol and methadone as reflected by the rates of disappearance in the blood.     

Interactions between indomethacin, noradrenaline and vasodilators in the fetal rabbit ductus arteriosus.

1. Interactions between indomethacin, noradrenaline and vasodilators were studied in rings of ductus arteriosus isolated from fetal rabbits. The effect of incubation with prostaglandin E2 (PGE2) on the noradrenaline concentration-contraction response curve was studied in the presence and absence of indomethacin. Also, the ductus was pre-contracted with 10 microM noradrenaline and concentration-relaxation response curves (CRRC) to PGE2, cicaprost, cromakalim and forskolin were obtained in the presence and absence of indomethacin. 2. In the absence of indomethacin, PGE2 (from 1 nM to 100 nM) decreased the pEC50 to noradrenaline to a maximum of 0.4 to 0.5 log units (i.e. an approximately three fold increase in EC50 [M]). In the presence of 1 microM indomethacin, PGE2 (0.1 nM to 100 nM) decreased the pEC50 to noradrenaline by 2.39 log units (i.e. a 245 fold increase in EC50). By comparing the control pEC50 to noradrenaline with the relationship between the pEC50 to noradrenaline and [PGE2] in 1 microM indomethacin, the effect of endogenous PGE2 synthesized in the vessel wall was estimated as being equivalent to a bath concentration of approximately 1 nM exogenous PGE2. 3. When the vessel was pre-contracted with 10 microM noradrenaline, indomethacin had no effect on the CRRC to PGE2 but did alter the CRRC to other vasodilators. The sensitivity of the vessel to cicaprost, cromakalim and forskolin was decreased in 1 microM indomethacin compared with control. Forskolin caused complete relaxation in the presence and absence of indomethacin. Indomethacin decreased the maximum response to cromakalim but increased the maximum response to cicaprost.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple aspects of the interaction of biomacromolecules with inorganic surfaces

The understanding of the mechanisms involved in the interaction of biological systems with inorganic materials is of interest in both fundamental and applied disciplines. The adsorption of proteins modulates the formation of biofilms onto surfaces, a process important in infections associated to medical implants, in dental caries, in environmental technologies. The interaction with biomacromolecules is crucial to determine the beneficial/adverse response of cells to foreign inorganic materials as implants, engineered or accidentally produced inorganic nanoparticles. A detailed knowledge of the surface/biological fluids interface processes is needed for the design of new biocompatible materials. Researchers involved in the different disciplines face up with similar difficulties in describing and predicting phenomena occurring at the interface between solid phases and biological fluids. This review represents an attempt to integrate the knowledge from different research areas by focussing on the search for determinants driving the interaction of inorganic surfaces with biological matter.