Effects of different inspired oxygen fractions on lipid peroxidation during general anaesthesia for elective Caesarean section.

BACKGROUND: During general anaesthesia (GA) for Caesarean section (CS), fetal oxygenation is increased by administering an inspired oxygen fraction (Fi(o(2))) of 1.0. However, it is unclear whether such high Fi(o(2)) will increase oxygen free radical activity. METHODS: We randomized 39 ASA I-II parturients undergoing elective CS under GA to receive 30% (Gp 30), 50% (Gp 50), or 100% (Gp 100) oxygen with nitrous oxide and sevoflurane adjusted to provide equivalent minimum alveolar concentration. Baseline maternal arterial blood before preoxygenation and maternal arterial, umbilical arterial and venous blood at delivery were sampled for assays of the by-product of lipid peroxidation, isoprostane, and for measurement of blood gases and oxygen content. RESULTS: Maternal and umbilical isoprostane concentrations were similar among the three groups at delivery, despite significantly increased maternal and fetal oxygenation in Gp 100. However, paired comparisons of maternal delivery vs baseline concentration of isoprostane showed an increase at delivery for all groups [Gp 30: mean 342 (sd 210) vs 154 (65) pg ml(-1), P=0.016; Gp 50: 284 (129) vs 156 (79) pg ml(-1), P=0.009; Gp 100: 332 (126) vs 158 (68) pg ml(-1), P<0.001]. The magnitude of increase was similar in all three groups and independent of the Fi(o(2)) or duration after induction. CONCLUSIONS: GA for CS is associated with a marked increase in free radical activity in the mother and baby. The mechanism is unclear but it is independent of the inspired oxygen in the anaesthetic mixture. Therefore, when 100% oxygen is administered with sevoflurane for GA, fetal oxygenation can be increased, without inducing an increase in lipid peroxidation.

Supplementary oxygen for emergency Caesarean section under regional anaesthesia.

BACKGROUND: Controversy still exists if the administration of supplementary oxygen to patients having emergency Caesarean section (CS) under regional anaesthesia is beneficial or potentially harmful. Therefore, in a prospective double-blinded study, we randomized patients having emergency CS under regional anaesthesia to receive either air or 60% oxygen until delivery and compared the effects on fetal oxygenation and lipid-peroxidation in the mother and baby. METHODS: We recruited 131 women having emergency CS under regional anaesthesia. Either 21% (air group) or 60% oxygen (oxygen group) was administered using a Venturi-type facemask until delivery. We compared the oxygen exposure duration, umbilical arterial (UA) and venous (UV) blood gases and oxygen content, and plasma concentration of 8-isoprostane. Subanalysis was performed according to whether or not fetal compromise was considered present. RESULTS: Data from 125 patients were analysed. For the oxygen group vs the air group, there were greater values for UA PO(2) [mean 2.2 (SD 0.5) vs 1.9 (0.6) kPa, P=0.01], UA O(2) content [6.6 (2.5) vs 4.9 (2.8) ml dl(-1), P=0.006], UV PO(2) [3.8 (0.8) vs 3.2 (0.8) kPa, P<0.0001], and UV O(2) content [12.9 (3.5) vs 10.4 (3.8) ml dl(-1), P=0.001]. There was no difference between the groups in maternal, UA, or UV 8-isoprostane concentration. Apgar scores and UA pH were similar between the groups. Similar changes were observed regardless of whether fetal compromise was considered present (n=37) or not (n=88). CONCLUSIONS: Breathing 60% oxygen during emergency CS under regional anaesthesia increased fetal oxygenation with no associated increase in lipid-peroxidation in the mother or fetus.

Anti-angiogenic effects of green tea catechin on an experimental endometriosis mouse model.

BACKGROUND: The development of new blood vessels plays an essential role in growth and survival of endometriosis. Epigallocatechin gallate (EGCG) from green tea has powerful anti-angiogenic properties and our aim was to evaluate these properties in experimental endometriosis. METHODS AND RESULTS: Eutopic endometrium from endometriosis patients was transplanted s.c. to severely compromised immunodeficient mice, randomly treated i.p. with EGCG (anti-angiogenic and -oxidant), Vitamin E (a non-angiogenic antioxidant) or saline for 2 weeks. The endometrial implant, including adjacent host outer skin and subcutaneous layers plus inner abdominal muscle and peritoneum, was collected. New microvessels were determined by species-specific immunohistochemistry. Angiogenic factors in lesions and abdominal muscle were detected by quantitative real-time PCR. Apoptosis was studied by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling and quantitative real-time PCR. In saline control, endometrial implants developed new blood vessels with proliferating glandular epithelium and were tightly adhered to host subcutaneous and abdominal muscle layers. After EGCG, endometriotic lesions were smaller than control (P < 0.05), and glandular epithelium was smaller and eccentrically distributed. Angiogenesis in lesions from the implant and adjacent tissues was under-developed, and microvessel size and density were lower (both P < 0.01) than control. mRNA for angiogenic vascular endothelial growth factor A, but not hypoxia inducible factor 1, alpha subunit, was significantly down-regulated in lesions after EGCG (P < 0.05). In addition, apoptosis in the lesions was more obvious, and nuclear factor kappa B and mitogen activated protein kinase 1 mRNA levels were up-regulated (P < 0.05) after EGCG treatment. No differences were observed with Vitamin E treatment. CONCLUSIONS: EGCG significantly inhibits the development of experimental endometriosis through anti-angiogenic effects.

High isoprostane level in cardinal ligament-derived fibroblasts and urine sample of women with uterine prolapse.

We studied the isoprostane level, a well-recognised biomarker of oxidative stress, from women with uterine prolapse and age-matched female controls without prolapse. Cardinal ligament-derived fibroblasts explanted from women with prolapse showed a significant increased level of isoprostane production (P < 0.05) compared with those derived from controls. This concurs with elevated urinary isoprostane levels identified among women with prolapse (P < 0.001) compared with controls. In addition, the matrix metalloproteinase 2 mRNA was significantly increased (P= 0.004) among women with uterine prolapse. Parallel findings of increased isoprostane in cardinal ligament and urine sample among women with prolapse suggest that oxidative stress might be involved in the development of uterine prolapse.

Sonographic examination of uteroplacental separation during the third stage of labor.

OBJECTIVES: To characterize patterns of uteroplacental separation during the third stage of labor, and to investigate their association with previous history of Cesarean section (CS), delays in placental separation and blood loss. METHODS: In this cohort observational study, continuous ultrasound imaging of uteroplacental separation was performed during the third stage of labor in 78 vaginal deliveries. All women were primiparous and were divided into two groups: those with a previous vaginal delivery (n = 62) and those who had undergone CS (n = 16). RESULTS: Three patterns of separation were observed: 'down-up' (n = 64), 'up-down' (n = 12) and 'bipolar' (n = 2). Bipolar separation was observed only with fundal placentae. Up-down separation was significantly associated with a history of CS (P < 0.001; odds ratio 14.0; 95% CI, 3.4-57.4) and a longer second stage of labor (P = 0.02). CONCLUSIONS: In most cases, uteroplacental separation begins at the lower placental pole and proceeds upwards. Women with a history of CS have a higher rate of up-down separation, possibly owing to impaired lower uterine segment contractility.

Avoiding manual removal of placenta: evaluation of intra-umbilical injection of uterotonics using the Pipingas technique for management of adherent placenta.

BACKGROUND: Manual removal of placenta is performed in 1-3% of cases, and whilst a well established and relatively safe procedure, it is not without complications, which include infection, hemorrhage, uterine rupture, and occasional maternal death. METHODS: A three-arm randomized controlled trial of 50 IU Syntocinon (in 30 ml N saline) versus 800 mcg misoprostol (in 30 ml N saline) versus 30 ml N saline alone (control), injected into the placental bed via the umbilical vein using the Pipingas method. A group sequential research model (triangular test: PEST4) was adopted to minimize the sample size, as retained placenta is a relatively uncommon condition. RESULTS: No significant difference in the rate of manual removal was observed between the control and Syntocinon groups. On triggering the automatic stopping rule for this arm of the trial all subsequent cases recruited were allocated to receive either Syntocinon or misoprostol. After a total of 54 cases a significant reduction in manual removal of placenta was observed in the misoprostol group, triggering the automatic stopping rule and terminating the trial. CONCLUSION: Misoprostol (800 mcg) dissolved in 30 ml N saline and administered by intraumbilical injection using the Pipingas technique significantly reduces the need for manual removal for retained adherent placenta, whereas Syntocinon has similar effectiveness to injection of N saline alone.

Uptake and distribution of catechins in fetal organs following in utero exposure in rats.

BACKGROUND: Although catechins are known to be powerful antioxidants, no reports have shown their transport to fetal organs. We investigated the distribution of catechins in fetal rat organs after maternal exposure to green tea extract (GTE). METHODS: GTE (550 mg/kg) or water was fed orally to pregnant dams at 15.5 days of gestation, the dams were sacrificed and fetal organs were dissected 0, 0.5, 1, 2, 3, 5, and 8 h later. Catechins and catechin gallates were determined by high-performance liquid chromatography (HPLC) after solid-phase extraction. RESULTS: In the GTE-treated group, catechins were detected in most of the fetal organs studied, including the brain, eyes, heart, lungs, kidneys and liver but not in the control group. The first peak times (T(max)) were about 0.5-1 h. The maximum concentrations (C(max)) of catechins in the fetal eye were about 2-10 times higher than in the other organs, ranging from 249 pmol/g for epicatechin (EC) to 831 pmol/g for epigallocatechin gallate (EGCG). Catechin gallates were generally more readily taken up by fetal organs than catechins. EGCG had the highest level of uptake according to area under the curve (AUC) plots and the highest C(max) in all organs. CONCLUSIONS: Various fetal organs had low but significant levels of catechins after GTE intake by the dams, and organ levels were found to be related to catechin structure. EGCG could be a potential candidate for antioxidant supplementation of the fetus in utero.

Oxidative stress in midpregnancy as a predictor of gestational hypertension and pre-eclampsia.

OBJECTIVES: To explore the relationship between the levels of maternal oxidative stress and glycaemia during pregnancy and to compare the predictive values of 8-epimer of prostaglandin F(2alpha) (8-isoPGF(2alpha)) and mean arterial pressure (MAP) in midpregnancy for the development of hypertensive complications in later pregnancy. DESIGN: Prospective observational study as an ancillary study to the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study. SETTING: Obstetric clinics and wards of a university teaching hospital in Hong Kong. POPULATION: Selected women with singleton pregnancies attending the antenatal clinic. METHODS: Pregnant women who met HAPO inclusion criteria were recruited for the study. Glucose tolerance was assessed by a 75-g 2-hour oral glucose tolerance test (OGTT) at 24-32 weeks of gestation. Fasting plasma samples for 8-isoPGF(2alpha) estimation and urine samples for 8-isoPGF(2alpha) and 2,3-dinor 8-isoPGF(2alpha) assays were collected and blood pressures measured during the OGTT visit. Random plasma and urine samples were also obtained at 34-37 weeks. Glucose results were unblinded to the attending obstetrician if limits preset under the HAPO protocol were met. MAIN OUTCOME MEASURES: Maternal plasma 8-isoPGF(2alpha) and urinary 8-isoPGF(2alpha) and 2,3-dinor 8-isoPGF(2alpha) both at the time of OGTT (24-32 weeks) and at 34-37 weeks of gestation. Incidence of pre-eclampsia and gestational hypertension. RESULTS: Of the 408 women who attended for OGTT at 24-32 weeks, two met the glucose criteria for unblinding and 25 had missing 8-isoPGF(2alpha) values and thus were excluded from analysis. Of the 381 women, 338 (88.7%) attended for random plasma samples at 34-37 weeks. Significant correlations were observed between maternal fasting plasma isoprostane and both fasting (r= 0.20; P < 0.001) and 2-hour (r= 0.39; P < 0.001) plasma glucose levels at the time of OGTT. Gestational hypertension/pre-eclampsia occurred in 17 (4.2%) women, and at the time of OGTT, they had significantly higher fasting plasma 8-isoPGF(2alpha) (P < 0.001), urine 8-isoPGF(2alpha) (P < 0.005) and urine 2,3-dinor 8-isoPGF(2alpha) to creatinine ratios (P < 0.001), as well as higher MAP (P < 0.001) than women who remained normotensive. At 34-37 weeks, only random plasma 8-isoPGF(2alpha) was significantly higher (P < 0.001) among the women with gestational hypertension/pre-eclampsia. CONCLUSIONS: Plasma markers of oxidative stress were positively correlated with plasma glucose at the time of OGTT (24-32 weeks). Women who subsequently developed gestational hypertension/pre-eclampsia had significantly higher plasma and urine markers of oxidative stress at the time of OGTT but only higher plasma markers at 34-37 weeks. Plasma 8-isoPGF(2alpha) appears to be a very good predictor of subsequent gestational hypertension/pre-eclampsia when measured at the time of OGTT, but its ability to discriminate deteriorates as pregnancy advances.

Status of anti-thyroid peroxidase during normal pregnancy and in patients with hyperemesis gravidarum.

Autoimmune thyroid diseases (AITD) comprising Hashimoto's thyroiditis, primary myxedema, and Graves' disease are associated with autoantibodies directed against thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO occur in 10% of pregnant women, half of whom reportedly develop postpartum thyroid dysfunction. We recently published data on the thyroid function reference ranges in pregnant Chinese but the AITD status of our cohort was unknown. In view of this missing information we have measured anti-TPO in specimens from our cohort stored at -80 degrees C, and compared these to those of patients with hyperemesis gravidarum (HG) and nonpregnant controls. After eliminating 3 outliers from 47 nonpregnant controls, the anti-TPO concentration range was 2.2-14.7 kIU/L (n = 44). In 282 pregnant control subjects, the anti-TPO levels were less than 14.7 kIU/L (upper limit of nonpregnant controls) in 189 (67%); between 14.7-55 kIU/L in 82 (29.1%); and greater than 55 kIU/L in 11 (3.9%). The percentage of women with anti-TPO greater than 14.7 kIU/L during the first, second, and third trimesters were 47% (30/64), 39% (49/126), and 16% (15/92), respectively. Anti-TPO level was significantly higher in pregnant controls compared to nonpregnant controls and patients with HG. With reference to other studies in which anti-TPO levels greater than 60 kIU/L were considered pathologic, we conclude that more than 96% of our pregnant controls were without AITD and the data on thyroid function reference ranges we previously reported remain valid.

Molecular characterization of the developmental gene in eyes: through data-mining on integrated transcriptome databases.

OBJECTIVES: Our aim was to utilize publicly available and proprietary sources to discover candidate genes important for ocular development. DESIGN AND METHODS: The collated information on our 5092 non-redundant clusters was grouped and functional annotation was conducted using gene ontology (FatiGO) for categorizing them with respect to molecular function. The web-based viewer technological platform (H-InvDB) was employed for transcription analyses of in-house high quality fetal eye Expressed Sequence Tags (ESTs). Eye-specific ESTs were also analyzed across species by using EMBEST. RESULTS: According to adult eye cDNA libraries, nucleic acid binding and cell structure/cytoskeletal protein genes were the most abundant among the ESTs of fetal eyes. Using cDNA assembly in H-InvDB, 20 (80%) of the 25 most commonly expressed genes in the human eye are also expressed in extraocular tissues. The crystalline gamma S gene is highly expressed in the eye, but not in other tissues. We used EMBEST to compare human fetal eye and octopus eye ESTs and the expression similarity was low (1.6%). This indicated that our fetal eye library contains genes necessary for the developmental process and biological function of the eye, which may not be expressed in the fully developed octopus eyes. The human fetal eye cDNA library also contained highly abundant eye tissue genes, including alphaA-crystallin, eukaryotic translation elongation factor 1 alpha 1 (EEF1A1), bestrophin (VMD2), cystatin C, and transforming growth factor, beta-induced (BIGH3). CONCLUSIONS: Our annotated EST set provides a valuable resource for gene discovery and functional genomic analysis. This display will help to appreciate the strengths and weaknesses of the different technological platforms, so that in future studies the maximum amount of beneficial information can be derived from the appropriate use of each method.

Genomic annotation of 15,809 ESTs identified from pooled early gestation human eyes.

To complement cDNA libraries from the human eye at early gestation and to discover candidate genes associated with early ocular development, we used freshly dissected human eyeballs from week 9-14 of gestation to construct the early human fetal eye cDNA library. A total of 15,809 clones were isolated and sequenced from the unamplified and unnormalized library. We screened 11,246 good-quality ESTs, leading to the identification of 5,534 nonredundant clusters. Among them, 4,010 (72%) genes matched in the human protein database (Ensembl). The remaining 28% (1,524) corresponded to potentially novel or previously unidentified ESTs. We used BLASTX to compare our EST data with eight organisms and found common expression of a high portion of genes: Caenorhabditis briggsae (26%), Caenorhabditis elegans (27%), Anopheles gambiae (37%), Drosophila melanogaster (32%), Danio rerio (42%), Fugu rubripes (49%), Rattus norvegicusvalitus (52%), and Mus musculus (59%). Nevertheless, 48% (2,680 of 5,534) of the genes expressed in the early developing eye were not shared with current NEIBank human eye cDNA data. In addition, eight known retinal disease genes existed in our ESTs. Among them, six (COL11A1, BBS5, PDE6B, OAT, VMD2, and PGK1) were conserved among the genomes of other organisms, indicating that our annotated EST set provides not only a valuable resource for gene discovery and functional genomic analysis but also for phylogenetic analysis. Our foremost early gestation human eye cDNA library could provide detailed comparisons across species to identify physiological functions of genes and to elucidate evolutionary mechanisms.

Proteomic signatures and aberrations of mouse embryonic stem cells containing a single human chromosome 21 in neuronal differentiation: an in vitro model of Down syndrome.

Neurodegeneration in fetal development of Down syndrome (DS) patients is proposed to result in apparent neuropathological abnormalities and to contribute to the phenotypic characteristics of mental retardation and premature development of Alzheimer disease. In order to identify the aberrant and specific genes involved in the early differentiation of DS neurons, we have utilized an in vitro neuronal differentiation system of mouse ES cells containing a single human chromosome 21 (TT2F/hChr21) with TT2F parental ES cells as a control. The paired protein extracts from TT2F and TT2F/hChr21 cells at several stages of neuronal differentiation were subjected to two-dimensional polyacrylamide gel electrophoresis protein separation followed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to identify the proteins differentially expressed between TT2F and TT2F/hChr21 cells. We provide here a novel set of specific gene products altered in early differentiating DS neuronal cells, which differs from that identified in adult or fetal brain with DS. The aberrant protein expression in early differentiating neurons, due to the hChr21 gene dosage effects or chromosomal imbalance, may affect neuronal outgrowth, proliferation and differentiation, producing developmental abnormalities in neural patterning, which eventually leads to formation of a suboptimal functioning neuronal network in DS.

Outcome in laparoscopic management of persistent adnexal mass during the second trimester of pregnancy.

BACKGROUND: This study evaluated the safety of laparoscopic management for persistent adnexal mass in the second trimester of pregnancy. METHODS: Between April 1994 and March 2003, 67 consecutive women underwent laparoscopic removal of adnexal masses that had persisted into the second trimester of pregnancy in an academic tertiary referral center. Operative complications, pregnancy, and labor outcomes were evaluated. RESULTS: The median gestation was 10.5 weeks (range, 5-25 weeks) at diagnosis and 16 weeks (range, 12-25 weeks) at the time of operation. Only two women required for conversion to laparotomy. Cystectomy was performed for 55 women, oophorectomy for 9 women and fenestration in 3 women. There were no intraoperative complications or major postoperative complications. No women were given tocolytic therapy, and none experienced uterine contractions. There was one spontaneous abortion 6 weeks after the operation, and one patent was lost to follow up. Of the remaining 65 women, the median gestation at delivery was 39 weeks (range, 33-42 weeks), and the median birthweight was 3,160 g (range, 2,220-4,200 g). CONCLUSIONS: Laparosocpic surgery for persistent adnexal masses in the second trimester of pregnancy is safe when performed by experienced surgeons.

Supplementary oxygen for elective Caesarean section under spinal anaesthesia: useful in prolonged uterine incision-to-delivery interval?

BACKGROUND: The benefit of administering supplementary oxygen during elective Caesarean section under regional anaesthesia is controversial. It has been hypothesized that its use would improve fetal oxygenation in the event of a prolonged uterine incision-to-delivery (U-D) interval. Our aim was to test this hypothesis in a prospective, randomized, double-blinded, controlled study. METHODS: We allocated randomly 204 women having elective Caesarean section under spinal anaesthesia to breathe 21, 40 or 60% oxygen. We recorded the U-D interval, umbilical arterial (UA) and venous (UV) blood gases and oxygen content and Apgar scores. Subgroup analysis was performed according to whether the U-D interval was prolonged (>180 s) or not. RESULTS: The U-D interval was <180 s in 159 patients and >180 s in 45 patients. There were no differences in UV or UA blood gases, oxygen content or Apgar scores between cases with and without a prolonged U-D interval. In cases without a prolonged U-D interval, administering 60% oxygen increased UV PO(2) (mean 4.3 (SD 1.1) vs 3.7 (1.0) kPa, P=0.003) and oxygen content (14.4 (3.3) vs 12.9 (2.7) ml dl(-1), P=0.007) compared with air. In cases with a prolonged U-D interval, administering 60% oxygen increased UV PO(2) (4.6 (0.6) vs 3.9 (0.8) kPa, P=0.019) compared with air but there was no difference in UV oxygen content. There was no increase in the UV PO(2) or oxygen content when 40% oxygen was administered compared with air. CONCLUSIONS: Supplementary oxygen did not increase fetal oxygenation in cases where the U-D interval was prolonged. Our data do not support the routine administration of supplementary oxygen during elective Caesarean section for this purpose.

Second-trimester ultrasonographic assessment of the umbilical coiling index.

OBJECTIVE: To determine the relationship between gestational age and the ultrasonic measurement of umbilical coiling index (UCI), and to assess the ability of second-trimester ultrasonic measurements of UCI to predict the true UCI, determined at birth. SUBJECTS/METHODS: Five hundred and thirty-one consecutive women with uncomplicated pregnancies, booking for delivery with a singleton pregnancy, were recruited during a routine second-trimester fetal morphology scan. Multiple ultrasonographic measurements of the intercoil distance were performed between two to three coils of the umbilical cord, along its entire visible length. Three hundred and seventy-four patients (70%) were followed until delivery when the true UCI was measured. RESULTS: An adequate portion of umbilical cord for assessment of coiling was visualized in 99% of cases. Adequate ultrasonographic visibility rates for the fetal, middle and placental regions of the cord were different. All three regions of the umbilical cord could only be visualized adequately in 10% of cases, and two regions were visible in 75%. The UCI progressively decreased along the cord from the fetal insertion to the placental insertion. The mean decrease in UCI with increasing gestational age was similar in all parts of the cord before the 23rd week (160 days) of pregnancy, and plateaued off after this point, except in measurements performed near the fetal insertion. The sensitivity of second-trimester ultrasound examination for predicting hypercoiling at birth was 17.3% and for predicting hypocoiling was 9.1%. DISCUSSION: Whilst UCI can be measured easily and reliably in the second trimester these estimates do not accurately reflect the UCI at term. Our original assumption that umbilical coiling does not alter after the initial formation of coils in the first trimester is incorrect; mixed patterns occurred in about 25% of cases. These patterns develop during the second and third trimesters, presumably due to snarls in the cord, and influence the final coiling number and therefore the relationship between the two measurements of UCI.

Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation.

BACKGROUND: Oxygen supplementation is given routinely to parturients undergoing Caesarean section under regional anaesthesia. While the aim is to improve fetal oxygenation, inspiring a high oxygen fraction (FIO2) can also increase free radical activity and lipid peroxidation in both the mother and baby. In this prospective, randomized, double-blind study, we investigated the effect of high inspired oxygen fraction (FIO2) on maternal and fetal oxygenation and oxygen free radical activity in parturients having Caesarean section under spinal anaesthesia. METHODS: Forty-four healthy parturients were randomized to breathe either 21% (air group) or 60% oxygen (oxygen group) intraoperatively via a ventimask. Maternal arterial blood was collected at 5-min intervals from baseline until delivery, and umbilical arterial and venous blood was collected at delivery. We measured blood gases and the products of lipid peroxidation (8-isoprostane, malondialdehyde (MDA), hydroperoxide (OHP)) and purine metabolites. RESULTS: At delivery, the oxygen group had greater maternal arterial PO2 [mean 30.0 (SD 6.3) vs 14.2 (1.9) kPa; mean difference 15.8 kPa, 95% confidence interval 12.9-18.7 kPa, P<0.001] and greater umbilical venous PO2 [4.8 (1.0) vs 4.0 (1.4) kPa; mean difference 0.8 kPa, 95% confidence interval 0.0-1.5 kPa, P=0.04] compared with the air group. Maternal and umbilical plasma concentrations of lipid peroxides (8-isoprostane, MDA, OHP) were greater in the oxygen group than in the air group (P<0.05). CONCLUSIONS: We conclude that breathing high FIO2 modestly increased fetal oxygenation but caused a concomitant increase in oxygen free radical activity in both mother and fetus.

Cervical intraepithelial neoplasia is associated with increased polyamine oxidase and diamine oxidase concentrations in cervical mucus.

OBJECTIVE: The aim of this study was to establish whether reactive oxygen species, generated during oxidation of amines, catalyzed by polyamine oxidase (PAO) and diamine oxidase (DAO) in cervical secretions may play a role in the etiology of cervical cancer. METHODS: Cervical mucus was obtained from women attending the gynecological outpatient department: 139 with and 154 without cytological evidence of cervical intraepithelial neoplasia were recruited. The mucus was freeze dried in liquid nitrogen, weighed, and later resuspended for assay of PAO and DAO concentrations using a chemiluminescence method. The two groups were compared by group sequential analysis using PEST3 software. RESULTS: Patients with a colposcopic diagnosis of a high-grade squamous intraepithelial lesion (SIL) had significantly higher enzyme activities than control cases (L(N)PAO 1.37 (0.37) versus 1.18 (0.35): Student t test: P < 0.001; L(N)DAO 1.37 (0.36) versus 1.15 (0.37): Student t test: P < 0.001). CONCLUSION: It is probable that this rise in enzyme activity precedes cytological changes and plays some part in the etiology of cervical cancer, as the cells that undergo premalignant change are normally squamous in origin, whereas mucus is a product of columnar epithelium. Higher enzyme activity in patients with SIL than in controls may be a reflection of higher risk of exposure to amine substrates in semen through multiple sexual partners.

Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma.

We have explored the mechanism of the antiangiogenic effects of thalidomide by structure-activity studies. These investigations revealed that angiogenesis inhibition correlates with teratogenicity but not with tumor necrosis factor-alpha (TFA-alpha) inhibition. Additionally, one analog of thalidomide, 3-aminothalidomide, exhibited an unusual capacity to directly inhibit myeloma cell proliferation. This activity did not correlate with TNF-alpha inhibition. Thus 3-aminothalidomide was found to inhibit multiple myeloma through effects on both the tumor and vascular compartment. The effects of an inhibitor of both the tumor and vascular compartments of a tumor on tumor growth may be synergistic.

Crystal structure of the precursor of galactose oxidase: an unusual self-processing enzyme.

Galactose oxidase (EC ) is a monomeric enzyme that contains a single copper ion and catalyses the stereospecific oxidation of primary alcohols to their corresponding aldehydes. The protein contains an unusual covalent thioether bond between a tyrosine, which acts as a radical center during the two-electron reaction, and a cysteine. The enzyme is produced in a precursor form lacking the thioether bond and also possessing an additional 17-aa pro-sequence at the N terminus. Previous work has shown that the aerobic addition of Cu(2+) to the precursor is sufficient to generate fully processed mature enzyme. The structure of the precursor protein has been determined to 1.4 A, revealing the location of the pro-sequence and identifying structural differences between the precursor and the mature protein. Structural alignment of the precursor and mature forms of galactose oxidase shows that five regions of main chain and some key residues of the active site differ significantly between the two forms. The precursor structure provides a starting point for modeling the chemistry of thioether bond formation and pro-sequence cleavage.