Low-dose warfarin does not decrease the rate of thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy, radiation, and erythropoeitin

OBJECTIVES: We had previously reported an association between the use of recombinant human erythropoietin (rHuEPO) and thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy and radiation. We hypothesized that low-dose warfarin would be effective prevention for thromboembolic events in this setting. METHODS: A retrospective analysis of patients with cervical or vulvo-vaginal carcinoma receiving chemoradiation and rHuEpo was performed. Thirty-two patients received rHuEpo alone, and 24 received warfarin (1-2 mg) and rHuEpo. The primary endpoint was objectively proven symptomatic venous thrombosis. RESULTS: There was no difference in the baseline characteristics (e.g. age, stage, body mass index, mean and peak hemoglobin, WBC and platelet counts, and number of transfusions) between these two groups. The rate of thrombosis also was not statistically different (P = 0.62). Nine of 24 patients had a symptomatic deep vein thrombosis (DVT) while receiving warfarin compared to 10 of 32 patients not on warfarin. There was no difference between the two groups in the percentage of patients with upper extremity DVT (P = 0.83) or lower extremity DVT (P = 0.64). CONCLUSION: Daily low-dose warfarin did not alter the incidence of symptomatic DVT in patients with cervical or vulvo-vaginal cancer who received rHuEpo in conjunction with chemoradiation.     

Effective treatment of beta-thalassemia intermedia during pregnancy with rHuEpo. A case report

The anemia of pregnancy in presence of beta-thalassemia intermedia usually aggravates pregnancy procedure. In the present study we investigated whether the administration of recombinant human erythropoietin (rHuEpo) recombinant human erythropoietin in combination with iron and folic acid may ameliorate blood indices as an alternative choice to blood transfusion.     

Recombinant human erythropoietin in a triplet pregnancy: a case report

BACKGROUND: Women carrying triplets are at greater risk for both anemia, due to the increased demands of the developingfetuses, and peripartum hemorrhage. Jehovah's witnesses are a unique obstetric population since women of this faith refuse blood transfusion. CASE: A Jehovah's Witness with a triplet pregnancy was successfully administered recombinant human erythropoietin (rHuEpo), 200 IU/kg 3 times per week subcutaneously, in order to correct her peripartum anemia. No side effects were observed during rHuEpo therapy, and the patient delivered healthy triplets. CONCLUSION: rHuEpo can be safely administered, with a beneficial effect in pregnancy, and seems to be an effective option in preventing transfusions as demonstrated in this case in a Jehovah's Witness.     

Effect of short-term erythropoietin therapy in anemic premature infants.

OBJECTIVE: To determine the effectiveness of a 10-day subcutaneous erythropoietin (rHuEpo) course of 300 units per kg per dose plus oral iron compared to oral iron alone in anemic infants during their convalescent phase of illness. STUDY DESIGN: Prospective, randomized trial performed at a 40-bed, teaching, referral, level III, neonatal intensive care unit. Infants with a gestational age at birth of less than 32 weeks, hematocrit of less than or equal to 28% with a corrected reticulocyte count of less than or equal to 5%, postconceptual age of less than 48 weeks or 5 months chronological age, and a diagnosis of anemia of prematurity were considered for inclusion. Major outcome parameters included hematocrit, corrected reticulocyte count and red cell transfusion requirements. RESULTS: A total of 60 infants were enrolled (n=30 per group). Infants randomized to rHuEpo had a significantly higher post-treatment hematocrit and corrected reticulocyte count than infants in the iron only group (p<0.001). There was a trend towards fewer red cell requirements in the rHuEpo group. CONCLUSIONS: The rHuEpo regimen studied here was associated with an acute improvement in hematocrit and corrected reticulocyte counts. This study did not demonstrate a statistically significant decrease in transfusion therapy, in part related to increased subsequent use of rHuEpo in the control group. Taken together, these data demonstrate that this regimen can effectively treat anemia in convalescent premature infants.     

Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis

OBJECTIVE: To reconcile apparently conflicting evidence regarding the use of hormone therapy as a health-preserving strategy in postmenopausal women in light of that fact that findings from animal studies, human observation studies, and human clinical trials are consistent for outcomes such as fracture and breast cancer but differ for coronary heart disease (CHD). DESIGN: Literature review and generation of a unified hypothesis consistent with all of the data. SETTING: Animal trials, human observational studies, human studies of biologic intermediates, and human clinical trials. PATIENT(S): Premenopausal and postmenopausal women with or without antecedent CHD. MAIN OUTCOME MEASURE(S): Coronary heart disease events, proxies, risk factors, and related mechanisms. RESULT(S): The complex CHD responses to hormone therapy in recent human trials likely reflect a combination of [1] early erosion/rupture of "vulnerable" coronary plaque, which is made worse by hormone therapy, [2] long-term reduction in plaque formation, which is improved by hormone therapy, and [3] modulation of the vasculoprotective actions of estrogens by systemic progestogens. CONCLUSION(S): The unified hypothesis predicts that hormone therapy initiated at the time of menopause should produce a decrease in CHD over time. In contrast, hormone therapy begun years after menopause should produce an increase in CHD events shortly after therapy is begun, followed later by benefit. In women who require progestogens for endometrial protection, there should be greater CHD benefit from use of progestogens with less systemic activity. The unified hypothesis is consistent both with plausible biologic mechanisms and with evidence from animal studies, human observational studies, and human clinical trials such as the Women's Health Initiative. In the absence of evidence from human trials that specifically involve initiation of hormone therapy in perimenopausal women, practitioners and patients can use the unified hypothesis as a rational tool to guide decisions about clinical management.     

Effects of In Utero Ultrasound Exposure In Humans

ABSTRACT: A review and analysis of studies of the effects of ultrasound exposure on human fetuses leads to a conclusion that there is no association of exposure with birthweight, hearing loss, or major congenital anomalies. Conflicting data from studies on birthweight is probably due to methodologic problems with the studies that have found positive associations. There have been few sound studies of the effects of in utero ultrasound exposure in humans. Limited studies to date are mostly reassuring, but it is premature to say that ultrasound has been proven safe for the human fetus. Further research on the question of biological effects of ultrasound in humans is needed, particularly the question of a possible association of ultrasound with dyslexia.     

Human ovarian receptors to human prolactin: implications in infertility

In the human, hyperprolactinemia may interfere with fertility. To find out whether or not prolactin (PRL) can act directly on human ovarian tissues, in vitro studies involving specific binding of human PRL to various human ovarian elements were carried out. Human PRL was isolated from amniotic fluid, and its intact monomeric iodinated isohormone B was prepared. Labeled PRL was incubated with plasma membranes of either granulosa or whole follicular homogenates. Relatively high specific binding sites were obtained. Saturation studies and Scatchard analysis showed a single class of binding sites with high binding affinity (Kd = 1.8 x 10(8) M) and a concentration of 7.9 x 10(-15) moles/mg protein. These results clearly demonstrate the existence of specific receptors to isoprolactin B in ovarian elements with binding capacity and concentration at least equal to that found in other targets for PRL. It is reasonable to assume that hyperactivation of these receptors in states of hyperprolactinemia constitutes the cause for the disturbances in ovarian functions that lead to infertility.     

Pheromone, Körpergeruch und Partnerwahl

In animals, olfactory communication, particularly for mate choice, is widespread and well studied. With the increasing number of studies on the biological constraints and mechanisms of mate choice and the discovery of the human vomeronasal organ (VNO), scientific interest in the importance of body odor as a possible signaling system for human mate choice has also increased. Humans and other primates were considered to be mainly visually guided, but the assumption that humans, in particular use mainly optical signals for mate choice has had to be revised. Recent studies show that pheromones (olfactory messengers) can play an important role in the behavior and reproductive biology of humans, although some earlier assumptions require modification. This article provides an overview of the current hypotheses and ‘evidence’ for the effects of human pheromones, and discusses their importance for human sexual behavior.     

Increased cleavage rate of human nuclear transfer embryos after 5-aza-2′-deoxycytidine treatment

As an abundant source that involves fewer ethical considerations, human abnormally fertilized zygotes are superior to oocytes as therapeutic cloning recipients of nuclear transfer. However, more effective manipulation conditions should be developed for somatic cell nuclear transfer (SCNT) studies using human abnormally fertilized zygotes as recipients. The present study found that the use of cytochalasin B was not necessary for, and even harmful to, the enucleation of human zygotes. This study also decreased the DNA methylation levels in reconstructed embryos using a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC), in an attempt to correct the abnormalities in DNA methylation that might play an important role in the failure of embryo development. After 5-aza-dC treatment and nuclear transfer (NT-Aza group), 32.7% of reconstructed embryos developed to the 8-cell stage, which is a much higher percentage than that of the nuclear transfer only (NT) group (11.1%). The DNA methylation level in the NT-Aza group was significantly lower than that of the NT group, as determined by 5-methylcytosine immunodetection. Based on the present results, this study recommends performing the enucleation procedure without cytochalasin B treatment and using 5-aza-dC in the culture of reconstructed embryos in human SCNT studies.As an abundant source that involves fewer ethical considerations, human abnormally fertilized zygotes are superior to oocytes as therapeutic cloning recipients of nuclear transfer. However, more effective manipulation conditions should be developed for somatic cell nuclear transfer (SCNT) studies using human abnormally fertilized zygotes as recipients. In the present study, the effects of cytochalasin B (CB) treatment on the survival rate of the manipulated zygotes and the effects of 5-aza-2′-deoxycytidine (5-aza-dC) treatment on the cleavage rate of the reconstructed embryos were observed. Human polyspermic zygotes were enucleated in metaphase with or without CB treatment and injected with human cumulus cells. The reconstructed embryos were cultured in medium supplemented with or without 5-aza-dC for developmental potential comparison. The DNA methylation levels of the embryos were determined using 5-methylcytosine immunodetection. CB treatment lowered the survival rate of manipulated zygotes. After the 5-aza-dC treatment (NT-Aza group), 32.7% of the reconstructed embryos developed to the 8-cell stage, a much higher percentage than that of the nuclear transfer only (NT) group (11.1%). The DNA methylation level in the NT-Aza group was significantly lower than that in the NT group. Based on the present results, we recommend performing the enucleation procedure without CB treatment and using 5-aza-dC in the culture of reconstructed embryos in human SCNT studies.     

Characterization of a TGFbeta-responsive human trophoblast-derived cell line

The placenta is formed by developing trophoblast cells to facilitate fluid, gas and nutrient exchange with the mother. Inappropriate trophoblast responsiveness can lead to life threatening complications during pregnancy including intrauterine growth retardation, pre-eclampsia, spontaneous abortion and malignancy that could lead to fetal loss. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine required for embryonic development and is an important regulator of human trophoblast function. Although TGFbeta is critical for placental and embryonic development, there are currently no established TGFbeta-responsive human trophoblast-derived cell lines available to study the mechanisms by which TGFbeta regulates trophoblast function. Our studies have examined the transformed human trophoblast-derived cell line, ED27, to determine if it is responsive to TGFbeta. Our data indicate that TGFbeta dose responsively and reversibly inhibits cell growth in ED27 cells and induces classic TGFbeta response genes, fibronectin and plasminogen activator inhibitor 1 (PAI-1). TGFbeta also induces an inhibitor of trophoblast invasion, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in ED27 cells. Our studies have identified a human trophoblast-derived cell line that parallels isolated primary human trophoblasts in their responses to TGFbeta. This cell line may provide us with the opportunity to determine TGFbeta-mediated responses on human trophoblast functions not previously possible.     

Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents

OBJECTIVE: To review evidence regarding the effects of male age on germinal and heritable chromosomal abnormalities using available human and rodent studies and to evaluate possible underlying mechanisms. DESIGN: Review of English language-published research using MEDLINE database, excluding case reports and anecdotal data. RESULT(S): There was little evidence from offspring or germ cell studies for a generalized male age effect on autosomal aneuploidy, except in rodents. Sex chromosomal nondisjunction increased with age in both human and rodent male germ cells. Both human and rodent data showed age-related increases in the number of sperm with chromosomal breaks and fragments and suggest that postmeiotic cells are particularly vulnerable to the effects of aging. Translocation frequencies increased with age in murine spermatocytes, at rates comparable to mouse and human somatic cells. Age-related mechanisms of induction may include accumulation of environmental damage, reduced efficiency of DNA repair, increased genomic instability, genetic factors, hormonal influences, suppressed apoptosis, or decreased effectiveness of antioxidants and micronutrients. CONCLUSION(S): The weight of evidence suggests that the increasing trend toward fathering at older ages may have significant effects on the viability and genetic health of human pregnancies and offspring, primarily as a result of structural chromosomal aberrations in sperm.     

Omega-3 polyunsaturated fatty acids and IVF treatment

Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids, derived mostly from fish oil, that have a significant anti-inflammatory effect. Data from animal studies support their role in the reproductive mechanism, and recent human studies suggest a positive effect on sperm quality and natural conception. Their general role in human fertility, and specifically in IVF treatment, however, is not clear. A few small, prospective cohort studies have examined the relationship between serum PUFAs and outcome measures and success in IVF, with conflicting results. Some have demonstrated a better chance of live birth with increased levels of serum omega-3 PUFAs, whereas others have failed to show such a correlation, and the reasons for such differences are not clear. Moreover, no well-designed, published studies have assessing whether the administration of omega-3 PUFAs before IVF treatment can improve clinical pregnancy and live birth rates. The development of safe and well-tolerated pharmaceutical forms of the active omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), mean that assessment of this question is now possible and future studies are warranted.     

Prenatal long-chain polyunsaturated fatty acid status: the importance of a balanced intake of docosahexaenoic acid and arachidonic acid

This review addresses the effect of prenatal long-chain polyunsaturated fatty acid (LCPUFA) status on neurodevelopmental outcome. It focuses on the major LPCUFA doxosahexaenoic acid (DHA; 22:6omega3) and arachidonic acid (AA; 20:4omega6). Due to enzymatic competition high DHA intake results in lower tissue levels of AA. LCPUFA accumulation in the brain starts early and increases during the third trimester. Initially brain AA-accretion exceeds DHA-accretion; after term age DHA-accretion surpasses AA-accretion. Animal studies indicated that early omega3-depletion results in poorer developmental outcome. They also showed that early omega3-supplementation had no effect on cognitive outcome, promotes visual development and impairs auditory and motor development. Only limited human data are available. Correlational studies suggest that neonatal AA status shows a positive relation with early neurodevelopmental outcome and that neonatal DHA status also might be correlated with improved outcome beyond infancy. Results of human intervention studies are equivocal: most studies were unable to demonstrate a positive effect of prenatal omega3-supplementation. It is concluded that only limited evidence exists to support the notion that prenatal omega3-supplementation favours developmental outcome. Caution is warranted for an unbalanced high DHA intake during the first two trimesters of pregnancy, i.e., DHA without additional AA supplementation.     

Potencies of oral contraceptives

This letter is a response to the discussion by Edgren and Sturtevant (125:1029, 1976) on potencies of oral contraceptives (OCs). It is agreed that the results of studies in animal models on OC potencies may not necessarily reflect true potencies in human subjects, however, these animal models do allow the evaluation of the biological effects and interactions of the components of OCs. Data obtained in animal studies are acknowledged to be valuable aids in the study of human diseases. Likewise, mouse uterine response to contraceptive steroids is 1 criterion to be used in evaluating steroid potency. As previously reported, the importance of the mouse uterine response is that the contribution of the progestin component to the total estrogenic potency of the OC is demonstrated.     

Cell phones and male infertility: dissecting the relationship

There has been a tremendous increase in the use of mobile phones in the past decade and concerns are growing about the possible hazardous effects of radio-frequency electromagnetic waves (EMW) emitted by these devices on human health. Preliminary studies, though with limitations in study design, suggest a possible link between cell phone use and infertility. A recent study found that use of cell phones adversely affects the quality of semen by decreasing the sperm counts, motility, viability and morphology. Evidence of detrimental effect of mobile phones on male fertility is still equivocal as studies have revealed a wide spectrum of possible effects ranging from insignificant effects to variable degrees of testicular damage. Although previous studies suggested a role of cell phone use in male infertility, the mode of action of EMW emitted from cell phones on the male reproductive system is still unclear. EMW can affect the reproductive system via an EMW-specific effect, thermal molecular effect or combination of both. Studies performed on human males are scarce and therefore further studies with a careful design are needed to determine the effect of cell phone use on male-fertilizing potential.     

Disposition of pesticides and toxicants in the human reproductive system in cases of acute poisoning

The aim of this study was to estimate the penetration of some of the pesticides and toxicant substances in the human reproductive system. This knowledge is valuable because of the possible adverse influence of these substances on the human reproduction system and the development of the foetus during pregnancy. The existing data is mainly concerned with the results of experimental studies on animals or epidemiological studies. Here we report data concerning the disposition of several toxic xenobiotics (pesticides and solvents) in the tissues of the human reproductive system as well as in other organs and glands. Data was collected from cases of acute poisonings and derived mostly from autopsy materials. Xenobiotics were found to penetrate sampled tissues such as the testes, ovaries, epididymis, uterus, thyroid gland, as well as other human tissues. Further studies will clarify and confirm peculiarities of the penetration of a wide range of substances in various body tissues and will be the base of the estimation of the role of these toxicants in human reproductive ability and the outcome of pregnancy in humans.     

The effects of various hormones on human chorionic gonadotropin production in early and late placental explant cultures

Although human chorionic gonadotropin production peaks in early pregnancy, little is known of the factors regulating it at this time. We have compared human chorionic gonadotropin output in placental explants of 6 to 12 and 37 to 40 weeks' gestational age after addition of hormones on days 4 and 5 of 8 days of culture. Human chorionic gonadotropin production was sevenfold greater in early versus late cultures. In early cultures human chorionic gonadotropin output was increased threefold to fourfold by progesterone, dehydroepiandrosterone, and cortisol whereas late cultures responded only to progesterone and dehydroepiandrosterone. The output of combinations of steroids was additive or better (up to fifteenfold). Gonadotropin-releasing hormone increased human chorionic gonadotropin output only slightly (onefold to twofold) while testosterone was inhibitory (early) or ineffective (late). Estradiol had no effect. These studies demonstrate that explants of early placental tissue provide a useful model for study of human chorionic gonadotropin production, that there are many similarities but some clear differences between early and late secretion, and that steroids exert significant effects on human chorionic gonadotropin production of placental cultures.     

Synergistic cytotoxic effects of recombinant human tumor necrosis factor and Etoposide (VP16) or Doxorubicin on A2774 human epithelial ovarian cancer cell line

Recombinant human tumor necrosis factor (rHuTNF) is a cytokine, with some antitumor activity, released by stimulated monocytes-macrophages. In vivo and in vitro cytotoxicity studies testing the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents have been carried out. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone or in combination with Etoposide (VP16) or Doxorubicin (Doxo), some topoisomerase II (Topo II) targeted drugs, or in combination with Cisplatin (CDDP), a not Topo II interactive drug. Our results suggest that rHuTNF is directly cytotoxic and that it is also able to induce a potentiation of VP16- or Doxo-cytotoxicity, but it is unable to potentiate CDDP-cytotoxicity. These data represent a reasonable basis for combining rHuTNF with Topo II inhibitors within phase I studies. The combination regimen could be tested in ovarian cancer patients.     

Bisphenol A,oocyte maturation,implantation, and IVF outcome: review of animal and human data

Recent data have raised concerns about the detrimental effect of chronic exposure to environmental chemicals. Some chemicals affect the endocrine system (endocrine disruptors) and have been linked to several diseases, including infertility. One such endocrine disruptor is bisphenol A (BPA), a monomer widely used in the plastic industry, with nearly ubiquitous exposure. In this review, data on the effects of BPA on female fertility are summarized. Specifically, its effect is considered on folliculogenesis, oocyte maturation, embryo quality, and implantation, both in animal and human models. Animal studies have shown that BPA might impair prophase I, follicular growth, and implantation, and may be associated with spindle abnormalities. In humans, while in-vitro studies have suggested an association between BPA exposure and impaired oocyte meiosis, clinical evidence indicate possible adverse effects of BPA exposure on IVF outcomes. As human clinical data are still scarce, larger studies are required to further elucidate the effects of BPA exposure on female fertility.     

Native alpha 2-macroglobulin binds to a surface component of human placental trophoblast

Immunofluorescence and radiobinding studies have shown that native human alpha 2-macroglobulin (alpha 2M), but not alpha 2M-trypsin complexes, binds to isolated human placental syncytiotrophoblast microvillous plasma membrane vesicles. Inhibition studies have indicated that alpha 2M may bind to a trophoblast surface protease. This interaction is of significance for the control of trophoblast invasiveness and haemostasis within the placental bed.