OBJECTIVE:To determine whether absence of end-diastolic flow in the umbilical artery and/or fetal aorta impacts postnatal neuro-development in preterm-born children.METHODS:The study group, consisting of 43 fetuses with absent end-diastolic flow in the umbilical artery and/or fetal aorta, was compared with a control group, consisting of 30 fetuses, matching for gestational age but with normal doppler-flow results. The children's neuro-developmental status was assessed using the 'Munich functional developmental diagnostics' (MFDD), between the 2nd and 3rd year of life.RESULTS:Gestational age at birth was 33 + 6 weeks in the study group and 34 + 4 weeks in the control group. A brain-sparing effect was observed in 37.3% of fetuses in the study group compared with 10.0% in the control group (p = 0.014). For all seven MFDD domains, the number of children with deficiencies was higher in the study group. For the domains perception, active speech and comprehension this effect was statistically significant (p < 0.05). Overall, 30.2% of children in the study group and 16.7% of the control group had pathologic test results (p < 0.013).CONCLUSION:Pathological doppler-flow in the umbilical artery and/or fetal descending aorta in preterm born children is associated with neuro-developmental deficiencies. Intensive pediatric care is recommended to mitigate these deficiencies during early childhood.

Background Antigen-derived HLA class I-restricted peptides can generate specific CD8 + T-cell responses in vivo and are therefore often used as vaccines for patients with cancer. However, only occasional objective clinical responses have been reported suggesting the necessity of CD4 + T-cell help and possibly antibodies for the induction of an effective anti-tumor immunity in vivo. The SSX2 gene encodes the cancer testis antigen (CTA) HOM-MEL-40/SSX2, which is frequently expressed in a wide spectrum of cancers. Both humoral and cellular immune responses against SSX2 have been described making SSX2 an attractive candidate for vaccine trials. Methods SYFPEITHI algorithm was used to predict five pentadecamer peptides with a high binding probability for six selected HLA-DRB1 subtypes (*0101, *0301, *0401, *0701, *1101, *1501) which are prevalent in the Caucasian population. Results Using peripheral blood cells of 13 cancer patients and 5 healthy controls, the HOM-MEL-40/SSX2-derived peptide p101-111 was identified as an epitope with dual immunogenicity for both CD4 + helper and cytotoxic CD8 + T cells. This epitope also reacted with anti-SSX2 antibodies in the serum of a patient with breast cancer. Most remarkably, SSX2/p101-111 simultaneously induced specific CD8, CD4, and antibody responses in vitro. Conclusions p101-111 is the first CTA-derived peptide which induces CD4 + , CD8 + , and B-cell responses in vitro. This triple-immunogenic peptide represents an attractive vaccine candidate for the induction of effective anti-tumor immunity.

BACKGROUND:This study was conducted to assess the bleeding pattern, tolerance and patient satisfaction associated with an oral contraceptive (OC) containing 3 mg of drospirenone and 30 mcg of ethinyl estradiol under real-life conditions.STUDY DESIGN:A multicenter, prospective and observational six-cycle study was conducted in 12 countries in Europe, the Middle East and Canada. The efficacy variables included an assessment of bleeding patterns, premenstrual symptoms of water retention and patient satisfaction as determined by a visual analog scale.RESULTS:A total of 3488 women was enrolled in the study. The percentage of women with intermenstrual bleeding decreased from 27.9% at baseline to 5.4% at the end of Cycle 6, while dysmenorrhea decreased from 67% to 17.7%. Also, amenorrhea decreased from 21.3% to 7.5%. The decreases in all three parameters were statistically significant (p<.0001). Approximately 70% of the women reported abdominal bloating and/or breast tenderness at baseline and less than 38% did so at the end of Cycle 6 (p<.0001). Patient satisfaction increased for all investigated items. Upon completion of the study, 86.2% of the women answered "yes" to continuing treatment with this OC.CONCLUSION:The OC containing 3 mg of drospirenone and 30 mcg of ethinyl estradiol has beneficial effects on bleeding pattern, symptoms of water retention and patient satisfaction.

Objectives: To evaluate the efficacy of a levonorgestrel-releasing intrauterine system (LNG-IUS) compared with a combined oral contraceptive containing 1 mg norethindrone acetate and 20 mu g ethinyl estradiol (OC1/20) in reducing menstrual blood loss (MBL) in women with idiopathic menorrhagia.Methods: A prospective, randomized, open-label study was conducted in nine centres in Canada. Healthy women over 30 years of age suffering from idiopathic menorrhagia were treated either with LNG-IUS (n = 20) or with OC1/20 (n = 19) over 12 months. The primary endpoint was the change in MBL from baseline to 12 months. Secondary endpoints included treatment success (defined as a MBL score < 100 after 12 months), hemoglobin levels, and the menorrhagia severity score.Results: In both treatment groups, MBL decreased significantly from baseline to 12 months (P < 0.001). For the primary endpoint, the MBL score decreased significantly more in the LNG-IUS group (median from 228 to 13, mean percent change-83%) compared to the OC1/20 group (median from 290 to 72; mean percent change-68%) (P = 0.002) after 12 months.In the LNG-IUS group, 80% of subjects had treatment success compared with 36.8 % in the OC1/20 group (P < 0.009).Both treatments increased hemoglobin concentrations significantly between baseline and 12 months.The menorrhagia severity score was consistently lower in the LNG-IUS group at all study time points and was significantly lower (P = 0.045) at six months. Both treatments were well tolerated.Conclusion: Both the LNG-IUS and the combined oral contraceptive effectively decreased menstrual blood loss in women with idiopathic menorrhagia. The overall clinical benefit was more pronounced with LNG-IUS than with OC1/20.

BACKGROUND:Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17beta-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 [in the form of estradiol valerate (E2V); 1 mg of E2V contains 0.76 mg of E2] was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies, the ovulation-inhibition potency of four variations of this regimen was assessed. STUDY DESIGN:Two randomized, open-label, Phase II studies were performed. The first study compared two regimens (Regimens 1A and 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of Regimen 2A was most suitable, but that the dosages of DNG were too low for effective ovulation inhibition, a second study, which compared two regimens (Regimens 2B and 2C) with similar lengths of application but with increased dosages of DNG, was undertaken. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5 or 6 during Cycle 2. RESULTS:The full analysis set comprised 192 and 203 women in Studies 1 and 2, respectively. In Study 1, 10 women (10.9%) in Regimen 1A and 6 women (6.4%) in Regimen 2A had a Hoogland score of 5 or 6. In Study 2, three women (3.1%) in Regimen 2B and one woman (1.0%) in Regimen 2C had a Hoogland score of 5 or 6. There were no safety concerns with any of the regimens. CONCLUSION:The results of these studies identified a four-phasic COC preparation comprising E2V/DNG that provides efficient ovulation inhibition. It is expected that this regimen will lead to an innovative COC containing E2 instead of EE.

Approximately 30% of reproductive age women and 35% of reproductive age men in the United States smoke cigarettes. Substantial harmful effects of cigarette smoke on fecundity and reproduction have become apparent but are not generally appreciated.

Many studies have concluded that IVF/ICSI pregnancies carry an increased risk for multiplicity, perinatal mortality, preterm birth and low birth weight in comparison with pregnancies after spontaneous conception. Others have investigated the incidence of congenital malformations in IVF/ICSI conceptions and reported a possible increase in the incidence of central nervous system defects, chromosomal abnormalities, urogenital abnormalities and limb malformations. Concerns have been raised that assisted reproduction technology (ART) might increase the malformation rate in offspring, particularly after intracytoplasmic sperm injection (ICSI). However, other studies have concluded that there is no evidence of an increase in the occurrence of malformations. The aim of this study is to summarize the present knowledge concerning malformations after ART in comparison to the spontaneously conceived children and whether this increased risk could be related to ART procedures or whether it is mainly related to parental characteristics. For this study, the literature and results from a survey as well as our data were analyzed. A total of 151 infants were born after ART at our department, among which one case of trisomy (0.66%) and one case of Potter syndrome (0.66%) were observed. In this paper, no increase in the malformation risk of infants born after ART treatment is defended.

OBJECTIVES:To evaluate the impact of an oestrogen-reduced, continuous combined hormone replacement therapy preparation containing 1 mg oestradiol valerate (1EV) and 2 mg dienogest (2DNG) on metabolism.METHODS:In a randomized double-blind study, 1EV/2DNG was compared with a reference preparation containing 1 mg 17Beta-oestradiol and 0.5 mg norethisterone acetate (E2/NETA). For the primary variable, i.e. the ratio of HDL cholesterol (week 52 to baseline), at least 98 case evaluations were planned. Secondary variables were other lipid parameters, haemostasis factors and carbohydrate metabolism.RESULTS:After 1 year of treatment, the mean HDL cholesterol levels had decreased by 4.5 +/- 14.8% in the 1EV/2DNG group and by 6.1 +/- 13.9% in the E2/NETA group (treatment difference NS). The ratio of HDL cholesterol (week 52 to baseline) was 0.944 for 1EV/2DNG and 0.929 for E2/NETA (geometric means). The primary efficacy variable, the ratio of the geometric means of the two treatments (1EV/2DNG/E2/NETA) was 1.016, with a lower one-sided 95% confidence limit of 0.973, which was clearly above the prespecified non-inferiority bound of 0.85 (p-value < 0.001). HDL2 cholesterol increased by 0.3 +/- 34.4% (1EV/2DNG) and decreased by 6.2 +/- 34.3% (E2/NETA; treatment difference NS); HDL3 cholesterol decreased by 4.4 +/- 19.9% (1EV/2DNG) and 8.2 +/- 17.7% (E2/NETA; treatment difference NS). Changes in the haemostasis and carbohydrate variables were very similar in both treatment groups.CONCLUSION:This study provides evidence that a new oestrogen-reduced HRT preparation containing 1 mg oestradiol valerate and 2 mg dienogest has no major impact on lipid variables. Minimal changes were seen in haemostatic and carbohydrate variables.

Objectives To evaluate the effects of an oral contraceptive containing 3 mg drospirenone (DRSP) and 30 μg ethinyl oestradiol (EE) on somatic and psychological symptoms related to water retention, and on body weight. Methods This prospective study was performed in 26 centres in Canada over six treatment cycles. The first primary efficacy variable was the individual change in the water retention score of the Moos Menstrual Distress Questionnaire (MDQ) from baseline to the final examination in women with significant somatic symptoms related to water retention (n = 43). The second primary target variable was the change in body weight (n = 305). Results Forty-three women met the criteria for the first primary target variable. In the premenstrual phase, the score decreased from 6.49 (SEM 0.45) at baseline to 3.19 (SEM 0.54) at the final examination (p = 0.0001). The data for the menstrual phase were 4.70 (SEM 0.30) at baseline and 2.35 (SEM 0.32) at the final examination (p < 0.0001). Baseline data from 299 women were assessed for the second primary target variable. Body weight did not change significantly, having increased only by 0.14 kg (SEM 0.13) at the final visit (p = 0.3082). Conclusion An oral contraceptive containing 3 mg DRSP and 30 μg EE significantly reduced the clinical symptoms of water retention. Body weight did not change.

Purpose: The purpose of this study was to determine the in-vitro induced nuclear chromatin decondensation (NCD) of human spermatozoa and its value in combination with routine semen analysis in predicting the outcome of in-vitro fertilization (IVF).

Differences in follicle cell function and follicular fluid biochemistry have been suggested to influence the developmental potential of human oocytes at both cellular and chromosomal levels. Follicular fluids provide the environment in which oocyte maturation occurs. Therefore, follicular fluids may affect fertilization and early embryonic development. In humans, it has been shown that follicular fluid exerts chemotactic activity towards neutrophilic granulocytes and that the concentrations of this activity are related to the outcome of in vitro fertilization (IVF) treatment. The present study focuses on growth and cytokine presence in serum and follicular fluid of patients of reproductive age and their role in ovarian follicles, fertilization, embryo development, and implantation and to find out which growth factor could be a useful predictive parameter of IVF/intracytoplasmic sperm injection outcome.

Similar effects on the lipid and carbohydrate profiles were found for both preparations. The balanced one-third EE dose reduction in this new oral contraceptive caused slightly lower, but insignificant, changes in the lipid and carbohydrate variables compared with the reference treatment.

BACKGROUND The concentration of total homocysteine (tHcy) is higher in newborns than in older children. Vitamin B-12 is the major determinant of tHcy in newborns. Maternal status of folate, vitamin B-12, and vitamin B-6 during pregnancy may affect the biochemical markers of these micronutrients in newborns. OBJECTIVE Our objective was to study the relation between concentrations of the metabolites and B vitamins in maternal sera and concentrations in the umbilical venous blood of the corresponding newborns. DESIGN We studied healthy pregnant women at the time of labor who were expecting healthy, full-term, appropriate-birth-weight babies. Samples were available from 82 mother-infant pairs. RESULTS Concentrations of B vitamins were higher in cord samples than in maternal blood (folate, 2-fold; vitamin B-12, 1.5-fold; and vitamin B-6, 6-fold). Concentrations of cystathionine and methylmalonic acid (MMA) were also higher in the infants than in the mothers (x +/- SD: cystathionine, 462 +/- 189 and 343 +/- 143 nmol/L; MMA, 353 +/- 144 and 233 +/- 110 nmol/L). No significant differences in tHcy concentrations were observed between fetal and maternal samples. Concentrations of vitamin B-12 did not differ significantly between mothers of infants from different quartiles of cord MMA. Higher fetal MMA concentrations were related to higher maternal MMA and vitamin B-12 concentrations and lower fetal concentrations of vitamin B-12. Fetal concentrations of cystathionine were predicted by maternal cystathionine, gestational age, fetal vitamin B-6, and fetal tHcy. CONCLUSIONS Maternal concentrations of the metabolic markers of B vitamins predict values in fetal blood at delivery. Fetal tHcy concentrations were low but were predicted by the vitamin status of the mother. The effect of increasing maternal intake of vitamins B-12 and B-6 during pregnancy on the fetal concentrations of the metabolites should be investigated.

Excess body weight can influence the hormone production and consequently the chance of achieving pregnancy of patient undergoing ovarian hyperstimulation for in vitro fertilization embryo transfer, could be reduced. Besides, maternal obesity leads to major maternal and fetal complications. Even moderate obesity has a significant deleterious effect on pregnancy outcome. In addition, obesity is also a risk factor for breast and endometrial cancer. However, the morbidity and mortality of obesity could be minimized through appropriate obesity management. Therefore, the aim of this review was to find out the association between overweight, obesity and the reproduction outcome especially of patients undergoing controlled ovarian hyperstimulation for assisted reproduction therapy.

Objective: To study changes in uteroplacental and fetal circulation after maternal exercise in appropriate-for-gestational- age fetuses (AGA) and intrauterine-growth-retarded fetuses (IUGR). Materials and method: 33 women with an uncomplicated course of pregnancy and ten women with IUGR were examined. Physical stress was caused through a bicycle ergometer with 1.25 W/kg maternal weight. Doppler examinations were performed in the umbilical artery, fetal aorta, middle cerebral and in the uterine artery. Fetal heart rate was documented by monitoring. Maternal lactate and glucose levels as well as maternal blood pressure and heart rate were recorded. Results: No significant changes after cycling could be observed in umbilical and uterine vessels either in the normal pregnancies or in pregnancies with IUGR. In contrast, in the fetal aorta an increase of the RI was recorded in both groups (an increase of 16% [P<0.01] and 18% [P<0.05], respectively for AGA and IUGR cases). In cerebral arteries a decrease of the RI was observed after cycling in both groups (a decrease of 24% [P<0.01] and 13% [P<0.05], respectively for AGA and IUGR cases). In AGA fetuses the RI of the aorta and middle cerebral artery returned to pre-test level by the 18 th minute of examination. In IUGR fetuses the RI of the aorta and middle cerebral artery did not return to pre-test levels at the end of the test. Fetal heart rate remained unchanged in both groups. Maternal blood pressure and heart rate increased during the exertion phase but returned to initial values at the end of the test. A 21% and 24% (for AGA and IUGR groups respectively) reduction of maternal glucose values after exercise was observed (P<0.001). Lactate values doubled in both groups after exercise (P<0.001). Conclusion: From the results obtained we conclude that maternal exercise does not significantly alter uterine and umbilical perfusion in AGA and IUGR pregnancies, suggesting an absence of change in the uterine vascular bed resistance. However, submaximal maternal exercise was followed by fetal cerebral vasodilatation and an increase of resistance in the fetal aorta that was more evident in IUGR fetuses. This might be due to slight fetal hemoglobin desaturation in those cases.

Serum inhibin A, inhibin B, pro-alphaC, and activin A levels in 30 women with idiopathic premature ovarian failure (POF), 30 postmenopausal women, and 30 age-matched fertile women were determined. Women with POF showed low levels of inhibin A and inhibin B, but not of activin A, whereas the levels of pro-alphaC were significantly higher than in postmenopausal women. Thus, the circulating level of pro-aC could be a marker for assessing residual ovarian function in women with POF. (C) 2004 by American Society for Reproductive Medicine.

OBJECTIVE: The aim of this study was (i) to investigate the existence of fibroblast growth factor (FGF), soluble intracellular adhesion molecule-1 (sICAM-1), and stem cell factor (SCF) in serum and human follicular fluid (FF) of intracytoplasmic sperm injection (ICSI) patients, and (ii) to determine the relationship between these parameters and ICSI outcome.MATERIAL AND METHOD: Seventy-five patients undergoing controlled ovarian hyperstimulation with human menopausal gonadotropin (hMG) after down-regulation with GnRHa were included in this study. The concentrations of FGF, SCF, and sICAM-1 were measured by using commercially available enzyme-linked immunosorbent assay test kits.RESULTS: The FGF, sICAM-1, and SCF concentrations in the serum of women who become pregnant (group I) were 8.5 +/- 1.5 pg/mL, 235.8 +/- 81.1 ng/mL, and 597.7 +/- 139.9 pg/mL, and the corresponding concentrations of women who did not (group II) were 6.4 +/- 3.6 pg/mL, 230.6 +/- 66.5 ng/mL, and 569.6 +/- 91.4 pg/mL respectively. No significant difference was observed between the two investigated groups with regard to the number of hMG ampoules administered for controlled ovarian hyperstimulation, estradiol concentration on the day of human chorionic gonadotropin (hCG) injection, number of retrieved oocytes and fertilization rate.CONCLUSION: The concentration of FGF, sICAM-1, and SCF did not differ significantly between the two groups in serum or in FF. Besides, the ICSI outcome was not related to their concentrations in serum or FF. Therefore, these parameters could not be used as a prognostic factor in ICSI program.

HOM-MEL-40/SSX2 is a SEREX-defined cancer testis antigen with frequent expression in various human neoplasms. To search for HLA-A*0201 restricted peptides that induce HOM-MEL-40/SSX2-specific CD8+ responses in breast cancer patients, we used the SYFPEITHI algorithm to identify three HOM-MEL-40/SSX2-derived nonamers with high binding affinity for HLA-A*0201, which has a prevalence of 40% in the Caucasian population. Of the three peptides, p41-49 and p103-111 but not p167-175 had been shown to be processed by the proteasome. Only stimulation with p103-111 induced HOM-MEL-40-specific CTLs in 5/7 patients with HOM-MEL-40/SSX2 positive breast cancers and in 6/11 healthy controls. HLA-A*0201 restriction of p103-111 was demonstrated by blocking with specific antibodies. The natural processing and presentation of p103-111 was demonstrated by the recognition of the HOM-MEL-40/SSX2 positive cell line SK-MEL-37 and of COS7/A2 cells transfected with HOM-MEL-40/SSX2 by p103-111 specific CD8+ cells. No correlation was found between CD8+ T-cell responses against p103-111 and anti-HOM-MEL-40/SSX2 antibody titers in the serum of patients, suggesting that CD8+ and B-cell responses against HOM-MEL-40/SSX2 are regulated independently. p103-111 holds promise as a broadly applicable peptide vaccine for patients with HOM-MEL-40/SSX2 positive neoplasms.

OBJECTIVE: The aims of the present study were to (i) determine the presence and concentration of albumin fractions (α1, α2, β, γ), immunoglobulins (IgA, IgG, IgM) and cytokines [interleukin (IL)‐6, IL‐8, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)] in periovulatory ovarian follicular fluid (FF) of in vitro fertilization (IVF) patients, (ii) examine the relationship between these parameters and the etiology of infertility as well as the IVF outcome and (iii) find out if these parameters in FF could be used as a predictive factor of IVF outcome.