Fertilization and early embryology: The chromosomal complements of multipronuclear human zygotes resulting from intracytoplasmic sperm injection

Implementation of intracytoplasmic sperm injection (ICSI) in human in-vitro fertilization (IVF) has highlighted the need for information about the risk of nuclear spindle damage caused by this procedure. For this purpose we studied the final products of oocyte meiosis at the first cleavage division of multipronuclear zygotes arising after ICSI, and compared the results with abnormally fertilized oocytes after conventional in-vitro insemination. Of 37 successfully analysed tripronuclear zygotes, 18 had three individual metaphases. Abnormal complements of 11 zygotes in this group indicated that non-disjunction occurred predominantly at the second meiotic division of the oocytes. Nine of the 37 tripronuclear zygotes exhibited two individual metaphases. Seven were abnormal and there were some indications that non-disjunction took place during oocyte meiosis. Of the 37 tripronuclear zygotes, 10 had a single metaphase and three showed an aneuploid number of chromosomes. The overall rate of aneuploidy among tripronuclear microinjected zygotes was 56.7%. In addition, seven zygotes with more than three pronuclei arising after ICSI displayed severely depleted chromosome complements. The incidence of non-disjunction in oocytes fertilized by conventional in-vitro insemination was significantly lower (20.0%, P < 0.01), since only four zygotes had an aneuploid number of chromosomes. Our findings suggest that ICSI might interfere with regular chromosome segregation at the second meiotic division of the oocyte

Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen

Premenopausal women have a lower risk for cardiovascular events, and mortality due to coronary vascular disease (CVD) in premenopausal women is rare. These facts suggest that endogenous estrogens, such as estradiol, protect the cardiovascular system, and several observational studies and a few small clinical studies conducted in healthy and younger postmenopausal women support this hypothesis. In contrast, two large randomized clinical trials (RCTs), using conjugated equine estrogens and conducted in older women with established CVD or without overt CVD, failed to demonstrate protection against CVD by exogenous estrogens. These divergent findings have resulted in confusion with regard to the association between estrogen deficiency and CVD in postmenopausal women. In order to reconcile these contradictory findings, it is necessary to examine the pathophysiology associated with age-dependent changes within the vessel wall and to compare the pharmacology of different types of estrogens. Understanding age-dependent changes in vascular pathology and the pharmacology of different estrogens may facilitate the development of therapeutic strategies for hormone replacement therapy (HRT) that would be effective in delaying vascular remodeling leading to CVD following menopause. In this review we provide an overview of the impact of menopause and estrogen deficiency on vascular remodeling and emphasize the importance of timing and type of estrogen to achieve maximum benefits with regard to reducing the risk of CV

Sex hormones and hypertension

Gender has an important influence on blood pressure, with premenopausal women having a lower arterial blood pressure than age-matched men. Compared with premenopausal women, postmenopausal women have higher blood pressures, suggesting that ovarian hormones may modulate blood pressure. However, whether sex hormones are responsible for the observed gender-associated differences in arterial blood pressure and whether ovarian hormones account for differences in blood pressure in premenopausal versus postmenopausal women remains unclear. In this review, we provide a discussion of the potential blood pressure regulating effects of female and male sex hormones, as well as the cellular, biochemical and molecular mechanisms by which sex hormones may modify the effects of hypertension on the cardiovascular syste

Andrology: Effects of nitric oxide on human spermatozoa: evidence that nitric oxide decreases sperm motility and induces sperm toxicity

Endogenous nitric oxide (NO) is an important functional mediator in several physiological systems, including the reproductive system. However, when generated in excessive amounts for long periods, mainly during immunological reactions, NO is cytotoxic and cytostatic for invading microbes, as well as for the cells generating it and the tissues present around it. Since infertility associated with urogenital tract infection in males and females is also accompanied by reduced sperm motility and viability, it is possible that reduced fertility in these patients is due to NO-induced sperm toxicity. We therefore evaluated the direct effects of NO, chemically derived from S-nitroso-N-acetylpenicillamine (SNAP, 0.012-0.6 mM) and sodium nitroprusside (SNP, 0.25-2.5 mM), on the motility and viability of human spermatozoa. Furthermore, we tested whether inhibition of NO synthesis prevents sperm motility and viability by incubating washed total cells present in the semen (spermatozoa, round cells) with N-nitro-L-arginine-methyl-ester (L-NAME), a NO synthesis inhibitor. Treatment of purified spermatozoa with SNAP or SNP decreased forward progressive sperm motility and straight line velocity, and also increased the percentage of immotile spermatozoa in a concentration-dependent manner. Furthermore, the percentage of immotile spermatozoa positively correlated with the percentage of dead spermatozoa. In contrast to freshly prepared SNAP, SNAP preincubated for 48 h had no effect on the motility and viability of the spermatozoa. Furthermore, as compared to untreated controls, a significantly higher percentage of forward progressive sperm motility as well as viability (P < 0.05) was maintained in washed semen incubated with L-NAME (0.15 mM). Seminal plasma concentrations of nitrite-nitrate (stabile metabolites of NO/106 spermatozoa correlated positively (P < 0.05) with the percentage of immotile spermatozoa. Our results suggest that NO can cause sperm toxicity as well as inhibit sperm motility. In conclusion, excessive NO synthesis in response to infection and inflammation could be an important factor contributing to functional change of the spermatozoa, leading to their dysfunction and to infertilit

Испытание технологии выравнивания профиля приемистости с применением модифицированного состава на основе полиакрилонитрила на нефтяном месторождении «S» (Томская область)

В работе рассматривается технология выравнивания профиля приемистости с применением модифицированного состава на основе полиакрилонитрила на одном из месторождений Западной Сибири. Используемый реагент предназначен для применения в технологиях повышения нефтеотдачи пласта с целью выравнивания профиля приёмистости в нагнетательных скважинах и ограничение водопритоков в добывающих скважинах. В работе проведен анализ эффективности рассматриваемой технологии.The technology of equalization of the injectivity profile using a modified composition based on polyacrylonitrile at one of the fields in Western Siberia is considered. The reagent used is intended for use in enhanced oil recovery technologies in order to equalize the injectivity profile in injection wells and to limit water inflows in producing wells. The analysis of the efficiency of the technology in question is conducted

Childlessness in Patients with Inflammatory Bowel Disease - Data from the Prospective Multi-center Swiss IBD Cohort Study

BACKGROUND AND AIMS: Childlessness and infertility represent a frequent and important issue in inflammatory bowel disease (IBD) patients. Nevertheless, until now epidemiological data remains scarce. Therefore, main objectives of this study were to evaluate the rate of childlessness and the cumulative probability of reproduction in female and male IBD patients within the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), a large prospective multicenter nationwide cohort. METHODS: Prospectively collected data of SIBDCS was used, comprising more than 3,300 patients with Crohn's disease (CD) and ulcerative colitis (UC). We analyzed the following groups of patients: 1) female IBD patients aged ≥40 years and diagnosed before age of 30 years with at least one follow-up, 2) female IBD patients who reported actively trying to conceive, with IBD diagnosed <35 years and with age at enrolment <45 years (longitudinal observation), with at least one follow-up, and 3) childless males who actively tried to conceive. RESULTS: A total of 1,412 female patients from the SIBDCS [843 CD, 539 UC, 30 indeterminate colitis (IC)] with available data were included in our analyses. Out of those 184 females (70.1% CD and 29.9 % UC) were aged ≥ 40 years and have been diagnosed with IBD before the age of 30 years. Among these, 184 women 32.1% were childless. The portion of childless females (36.4%) was significantly higher in CD vs. UC (36.4% vs. 21.8%; p=0.026), equaling a relative risk of childlessness of 1.7 in CD vs. UC. and higher than in the Swiss general population (21%). The mean number of children per female patient was 1.32 (median 1, min 0, max 6), per female with CD 1.12 (median 1, min 0, max 4), per female with UC/IC 1.78 (median 2, min 0, max 6; P=0.001). The longitudinal analysis of female IBD patients trying to conceive revealed that one out of two women neither were pregnant nor had born a child five years after first trying to conceive. CONCLUSIONS: The rate of childlessness in females with CD is higher compared to the general Swiss population, whereas it is similar in women with UC. Moreover, the mean number of children is lower in CD than in UC. Females with CD remain more often childless compared to their UC counterparts. Although the exact underlying mechanisms are largely unknown, this discrepancy should alert healthcare professionals treating CD patients to actively address this topic

Piperine decreases binding of drugs to human plasma and increases uptake by brain microvascular endothelial cells

We previously reported that piperine, an active alkaloidal principal of black and long peppers, enhances drug bioavailability by inhibiting drug metabolism. Another mechanism influencing drug availability/uptake is its free fraction. Since piperine is highly lipophilic, we hypothesize that it could also interact with drugs through binding displacement and influence their bioavailability. Accordingly, using equilibrium dialysis, we investigated whether piperine alters the binding of model drug ligands, that is flunitrazepam, diazepam, warfarin, salicylic acid, propranolol, lidocaine, and disopyramide to human plasma (n = 4). Since alterations in binding influence drug disposition, we also studied the effects of piperine on the uptake of plasma bound 3 H-propranolol and 14 C-warfarin by cultured bovine brain microvascular endothelial cells (BMECs). Piperine (1-1000 μM) increased the free fraction (fu) of both albumin and alpha-acid glycoprotein bound drugs in a concentration-dependent manner (p < 0.01). Moreover, piperine (10 μM) increased the uptake of 3 H-propranolol and 14 C-warfarin by BMECs (p < 0.01). In conclusion, our findings provide the first evidence that piperine displaces plasma bound drugs from both albumin and alpha-acid glycoprotein and facilitates drug uptake across biological membranes (e.g. BMEC). Moreover, it is feasible that piperine may similarly facilitate the transport of drugs into tissues, in vivo, and alter both pharmacokinetics and pharmacodynamics of administered drugs

Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

Pericytes facilitate blood–brain barrier (BBB) integrity; however, the mechanisms involved remain unclear. Hence, using co-cultures of human cerebral microvascular endothelial cells (ECs) and vascular pericytes (PCs) in different spatial arrangements, as well as PC conditioned media, we investigated the impact of PC-EC orientation and PC-derived soluble factors on EC barrier function. We provide the first evidence that barrier-inducing properties of PCs require basolateral contact with ECs. Gene expression analysis (GEA) in ECs co-cultured with PCs versus ECs alone showed significant upregulation of 38 genes and downregulation of 122 genes. Pathway enrichment analysis of modulated genes showed significant regulation of several pathways, including transforming growth factor-β and interleukin-1 regulated extracellular matrix, interferon and interleukin signaling, immune system signaling, receptor of advanced glycation end products (RAGE), and cytokine–cytokine receptor interaction. Transcriptomic analysis showed a reduction in molecules such as pro-inflammatory cytokines and chemokines, which are known to be induced during BBB disruption. Moreover, cytokine proteome array confirmed the downregulation of key pro-inflammatory cytokines and chemokines on the protein level. Other molecules which influence BBB and were favorably modulated upon EC-PC co-culture include IL-18 binding protein, kallikrein-3, CSF2 CSF3, CXCL10, CXCL11 (downregulated) and IL-1-R4; HGF, PDGF-AB/BB, PECAM, SERPIN E1 (upregulated). In conclusion, we provide the first evidence that (1) basolateral contact between ECs and PCs is essential for EC barrier function and integrity; (2) in ECs co-cultured with PCs, the profile of BBB disrupting pro-inflammatory molecules and cytokines/chemokines is downregulated; (3) PCs significantly modulate EC mechanisms known to improve barrier function, including TGF-β regulated ECM pathway, anti-inflammatory cytokines, growth factors and matrix proteins. This human PC-EC co-culture may serve as a viable in vitro model for investigating BBB function and drug transport

Contraceptive drugs mitigate experimental stroke-induced brain injury

Aims: Effective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavorable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells. Methods and Results: MCAO was induced in female, female ovariectomized (modeling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favoring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro. Conclusions: For the first time, here we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke

Does endometriosis affect professional life? A matched case-control study in Switzerland, Germany and Austria.

OBJECTIVES Endometriosis is a gynaecological disease most commonly causing severe and chronic pelvic pain as well as an impaired quality of life. The aim of this study was to investigate if and how endometriosis affects choices regarding professional life as well as the quality of daily working life. DESIGN, SETTING AND PARTICIPANTS In the context of a multicentre case-control study, we collected data from 505 women with surgically/histologically confirmed diagnosis of endometriosis and 505 matched controls. Study participants were recruited prospectively in hospitals and doctors' practices in Switzerland, Germany and Austria. Using a detailed questionnaire, the study investigated work-life and career choices of study participants. MAIN OUTCOME MEASURES Associations between endometriosis/disease symptoms and limitations in career development as well as ability to work. RESULTS Women with endometriosis were less often able to work in their desired profession than women from the control group (adjusted OR=1.84, 95% CI: 1.15 to 2.94, R2=0.029, p=0.001) and they had to take health-related limitations into consideration in their career decisions to a significantly higher degree than women in the control group (OR=4.79, 95% CI: 2.30 to 9.96, R2=0.063, p<0.001). Among women with endometriosis, chronic pain was significantly associated with increased sick leave (OR=3.52, 95% CI: 2.02 to 6.13, R2=0.072, p<0.001) as well as with loss of productivity at work (OR=3.08, 95% CI: 2.11 to 4.50, R2=0.087, p<0.001). CONCLUSIONS Endometriosis is associated with impairment of professional life, in particular with regard to career choices. Further research to develop strategies to support endometriosis-affected women in realising professional opportunities is recommended. TRIAL REGISTRATION NUMBER NCT02511626; Pre-results