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See detailEstetrol Attenuates Neonatal Hypoxic-Ischemic Encephalopathy: Preclinical Studies
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

Poster (2016, June 17)

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter ... [more ▼]

Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal hypoxic-ischemic encephalopathy (HIE) accompanied by gray and white matter injuries occurring in neonates. Perinatal HIE still remains a challenge in perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities. So far no medical treatment provides important neuroprotection against HIE. Studies of new neuroprotective agents in animal models of HIE may have importance for the development of new compounds and treatment strategies for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate for the first time that E4 has a significant neuroprotective and therapeutic effects. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailUse of Estetrol with other Steroids for Attenuation of Neonatal Hypoxic-Ischemic brain injury:to combine or not to combine?
Tskitishvili, Ekaterine ULg; Pequeux, Christel ULg; Munaut, Carine ULg et al

in Oncotarget (2016)

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal ... [more ▼]

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated. The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival. In vivo pretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4. [less ▲]

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See detailEndométriose minime et légère: quel impact sur la fertilité?
BRICHANT, Géraldine ULg; AUDEBERT, Alain; NISOLLE, Michelle ULg

in Revue Médicale de Liège (2016), 71(5), 236-241

L’endométriose minime ou légère (stades I/II) est fréquemment identifiée chez les femmes hypofertiles, surtout en cas de stérilité inexpliquée. L’impact de ces lésions sur la fertilité est controversé ... [more ▼]

L’endométriose minime ou légère (stades I/II) est fréquemment identifiée chez les femmes hypofertiles, surtout en cas de stérilité inexpliquée. L’impact de ces lésions sur la fertilité est controversé, certains les considérant comme paraphysiologiques. Elles sont hétérogènes dans leur étendue, leur activité biologique, l’inflammation qui les caractérise ou les adhérences qu’elles peuvent induire. La diminution de la qualité ovocytaire, et de la mobilité des spermatozoïdes ainsi que les altérations endométriales apparaissent comme les mécanismes les plus pertinents pour expliquer l’hypofertilité. La fécondité spontanée des femmes présentant une endométriose minime ou légère est diminuée en comparaison avec celle des femmes pour lesquelles le diagnostic de stérilité inexpliquée a été posé. L’insémination intra-utérine avec stimulation de l’ovulation améliore la fertilité des femmes traitées. L’ablation coelioscopique des lésions endométriosiques améliore de façon modeste la fécondité, conduisant à recommander cette pratique compte tenu de ses faibles risques. La fécondation in vitro (FIV) est le moyen le plus efficace permettant d’obtenir des résultats similaires ou légèrement inférieurs à ceux observés chez les femmes témoins présentant une infertilité tubaire. L’impact des endométrioses minimes et légères sur la fertilité apparaît très probable, au moins pour certaines lésions qui demandent à être identifiées. [less ▲]

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See detailNeonatal Hypoxic-Ischemic Encephalopathy: a new view of an old problem
Tskitishvili, Ekaterine ULg; VIELLEVOYE, Renaud ULg; Gérard, Céline et al

in Références en Gynécologie Obstétrique (2016), 17(1-1),

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation ... [more ▼]

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a challenge of perinatal medicine. It is an important cause of long term morbidity, including motor and behavioral deficits, mental retardation, seizures and cerebral palsy, and mortality in newborns. This paper reviews the pathophysiology and current concepts of the management of neonatal HIE as well as the future potential neuroprotective strategies for attenuation of this disease. [less ▲]

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See detailEstetrols’ Potential for Neuroprotection Following the injury to the Developing Brain: Preclinical Studies
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 17th World Congress of Gynecological Endocrinology, Florence 2-5 March 2016 (2016, March)

Context: Hypoxic-Ischemic encephalopathy (HIE) remains a major cause of perinatal brain injury. The brain rapidly increases in size, shape and complexity during the second and third trimesters. A sentinel ... [more ▼]

Context: Hypoxic-Ischemic encephalopathy (HIE) remains a major cause of perinatal brain injury. The brain rapidly increases in size, shape and complexity during the second and third trimesters. A sentinel event in late pregnancy or the intrapartum period may have an acute profound effect on a previously neurologically intact fetus, leading to the development of (HIE). The nature of the deficits is dependent on the gestational age and severity of the insult, though it is seldom reported in preterm infants. Studies in animal models of HIE may provide important information for the development of treatment for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. Objective: In this study, we evaluated E4’s neuroprotective and therapeutic potency in neonatal (in vivo) HIE model of the immature 7-day-old newborn rat. Methods: Rat pups body temperatures were examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of markers for neuronal early grey matter damage (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of two markers of brain damage (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Results: Our results demonstrate that E4 has a significant neuroprotective and therapeutic effects. Estetrol decreases the early gray matter loss, and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Conclusion: Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailLE CAS CLINIQUE DU MOIS Thrombose veineuse ovarienne gauche et extension à la veine rénale
JEAN, FLORENCE; CLAUDOT, A.; ISTACE, B. et al

in Revue Médicale de Liège (2016), 71(1), 17-21

Ovarian vein thrombosis is a rare, but potentially serious postpartum complication. In 80 % of the cases, it occurs on the right side and in less than 6 % on the left side; it is bilateral in 14 % of ... [more ▼]

Ovarian vein thrombosis is a rare, but potentially serious postpartum complication. In 80 % of the cases, it occurs on the right side and in less than 6 % on the left side; it is bilateral in 14 % of cases. The usual clinical features include abdominal pain, fever and leucocytosis. However, the diagnosis is often complicated by other non specific signs and symptoms. Ovarian vein thrombosis may cause sepsis, pulmonary thromboembolism, and thrombosis of the inferior vena cava and the renal vein. The diagnosis can be established by CT scan or nuclear magnetic resonance imaging, which has a high sensitivity and specificity. Treatment for the ovarian vein thrombosis includes antibiotics and anticoagulation. The complications can sometimes be surgically managed. Prompt diagnosis and treatment can decrease the morbidity and the mortality. Nowadays, the fatal issue is rare as the appropriate treatment is quickly instaured. [less ▲]

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See detailElastin density: Link between histological and biomechanical properties of vaginal tissue in women with pelvic organ prolapse?
DE LANDSHEERE, Laurent ULg; Brieu, Mathias; Blacher, Silvia ULg et al

in International Urogynecology Journal & Pelvic Floor Dysfunction (2016)

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples ... [more ▼]

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples were collected from the anterior [point Ba; POP Questionnaire (POP-Q)] and/or posterior (point Bp; POP-Q) vaginal wall of 15 women who underwent vaginal surgery for POP. Both histological and biomechanical assessments were performed from the same tissue samples in 14 of 15 patients. For histological assessment, the density of collagen and elastin fibers was determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. For biomechanical testing, uniaxial tension tests were performed to evaluate vaginal tissue stiffness at low (C0) and high (C1) deformation rates. RESULTS: Biomechanical testing highlights the hyperelastic behavior of the vaginal wall. At low strains (C0), vaginal tissue appeared stiffer when elastin density was low. We found a statistically significant inverse relationship between C0 and the elastin/collagen ratio (p = 0.048) in the lamina propria. However, at large strain levels (C1), no clear relationship was observed between elastin density or elastin/collagen ratio and stiffness, likely reflecting the large dispersion of the mechanical behavior of the tissue samples. CONCLUSION: Histological and biomechanical properties of the vaginal wall vary from patient to patient. This study suggests that elastin density deserves consideration as a relevant factor of vaginal stiffness in women with POP. [less ▲]

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See detailA pilot double-blind, randomized, placebo-controlled trial of the efficacy of trace elements in the treatment of endometriosis-related pain: study design and methodology
OBERWEIS, Didier; MANDELENAT, Patrick; Nisolle, Michelle ULg

in Nutrition and Dietary Supplements (2016), 8

Endometriosis is one of the most common benign gynecological disorders, affecting almost 10%–15% of all women of reproductive age and .30% of infertile women. The pathology is associated with various ... [more ▼]

Endometriosis is one of the most common benign gynecological disorders, affecting almost 10%–15% of all women of reproductive age and .30% of infertile women. The pathology is associated with various distressing symptoms, particularly pelvic pain, which adversely affect patients’ quality of life. It is an estrogen-dependent disease. There is evidence both in animals and in humans that metal ions can activate the estrogen receptors. They are defined as a variety of xenoestrogens, called metalloestrogens, which could act as endocrine disruptors. Therefore, it could be considered to act on this gynecological disorder using food supplements containing trace elements (ie, nutripuncture). The assumption is that they could modulate estrogen receptors and thus influence the tropism and the survival of cells involved in endometriosis. By a modulation of the antioxidant system, they might also interact with various parameters influencing tissue biochemistry. The objective of this article is to describe and discuss the design and methodology of an ongoing double-blind, randomized, placebo-controlled study aiming to evaluate the efficacy of metal trace elements on the reduction of pain and improvement of quality of life, in patients with a revised American Fertility Society Score Stages II–IV endometriosis, combined or not with adenomyosis, during a treatment period of 4 months. Trace elements or placebo is proposed in the absence of any other treatment or as an add-on to current therapies, such as sexual hormones, nonsteroidal anti-inflammatory drugs, and surgery. A placebo run-in period of one menstrual cycle or 30 days for women in amenorrhea has been scheduled to eliminate the patients who are responding too much to the placebo. After a 1:1 ratio randomization on Day 0, the treatment with trace elements or placebo will last for 4 monts (120 days). [less ▲]

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See detailSupplementation of transport and freezing media with anti-apoptotic drugs improves ovarian cortex survival
HENRY, Laurie ULg; Fransolet, Maïté ULg; LABIED, Soraya ULg et al

in Journal of Ovarian Research (2016)

Background: Ovarian tissue preservation is proposed to patients at risk of premature ovarian failure, but this procedure still needs to be optimized. To limit injury during ovarian tissue cryopreservation ... [more ▼]

Background: Ovarian tissue preservation is proposed to patients at risk of premature ovarian failure, but this procedure still needs to be optimized. To limit injury during ovarian tissue cryopreservation, anti-apoptotic drugs were added to the transport and freezing media of ovarian cortex tissue. Methods: Sheep ovaries were transported, prepared and frozen in solutions containing vehicle or anti-apoptotic drugs (Z-VAD-FMK, a pan-caspase inhibitor, or sphingosine-1-phosphate (S1P), a bioactive lipid). After the tissue was thawed, the ovarian cortex was cultured for 2 or 6 days. Follicular quantification and morphological and proliferation analyses were performed on histological sections. Results: After 2 days of culture, S1P improved the quality of primordial follicles; higher densities of morphologically normal and proliferative primordial follicles were found. Z-VAD-FMK displayed similar effects by preserving global primordial follicular density, but this effect was evident after 6 days of culture. This drug also improved cell proliferation after 2 and 6 days of culture. Conclusions: Our results showed that the addition of S1P or Z-VAD-FMK to the transport and freezing media prior to ovarian tissue cryopreservation improves primordial follicular quality and therefore improves global tissue survival. This should ultimately lead to improved fertility restoration after auto-transplantation. [less ▲]

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See detailG-CSF as a non-invasive predictive marker for embryo implantation
Munaut, Carine ULg; NOEL, Laure ULg; Lédée, N et al

Scientific conference (2015, December 07)

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See detailREGISTRE BELGE ET CENTRES DE RÉFÉRENCE POUR LES MALADIES TROPHOBLASTIQUES GESTATIONNELLES
DELCOMINETTE, Sarah ULg; TIMMERMANS, Marie ULg; DELBECQUE, Katty ULg et al

in Revue Médicale de Liège (2015), 70(11), 550-556

Gestational trophoblastic diseases include placental pathologies comprising fertilization abnormalities (hydatidiform moles) and malignant lesions (choriocarcinoma, placental site trophoblastic tumor and ... [more ▼]

Gestational trophoblastic diseases include placental pathologies comprising fertilization abnormalities (hydatidiform moles) and malignant lesions (choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor). Due to their low incidence and heterogeneity, their diagnosis, management and treatment are not always optimal. Following the example of other European countries, a national registration system with two reference centers has been set up to guide physicians and patients and to propose individualized management. The centers offer their expertise through a systematic centralised pathology review by a panel of experts. HCG values are plotted in regression curves. In case of gestational trophoblastic neoplasia, an imaging work-up is proposed, from which the FIGO score and stage are derived and will guide the choice of treatment. Belgian centers offer a multidisciplinary approach, in partnership with the referent physician. More information for practitioners and patients is available on a web site: www.mole-chorio-bgog.eu, which also harbours a forum of discussion. [less ▲]

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See detailMétroplasties (utérus en T après l'ère DES, septum): quel bénéfice?
BRICHANT, Géraldine ULg; CLOSON, François ULg; MASEREEL, Marie-Caroline ULg et al

in Louvain Medical (2015), 134

Mûllerian anomalies are associated with infertility and obstetric complications, such as recurrent pregnancy loss, preterm labor or birth, as well as malpresentation. The most common anomalies inlude ... [more ▼]

Mûllerian anomalies are associated with infertility and obstetric complications, such as recurrent pregnancy loss, preterm labor or birth, as well as malpresentation. The most common anomalies inlude septate uterus, uterus bicornuate, and uterus didelphys (Class II and III according to ESHRE/ESGE classification). Hypoplastic uteri are rare, being usually caused by in utero exposure to diethylstilbestrol. Hysteroscopic metroplasty has been shown to improve both fertility and obstetrical outcomes in patients with hypoplastic or septate uterus [less ▲]

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See detailLaparoscopic management of bladder endometriosis
BRICHANT, Géraldine ULg; NICOLAS, Hubert; NISOLLE, Michelle ULg

Conference (2015, October)

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See detailAnti-D Prophylaxis Reviewed in the Erea of Foetal RHD Genotyping
MINON, Jean-Marc; GERARD, CH; CHANTRAINE, Frédéric ULg et al

in Journal of Blood Disorders & Transfusion (2015), 6(5),

A few years ago, the prevention of anti-D immunization was currently based on systematic postnatal prophylaxis associated with targeted antenatal injection in high-risk situations of foeto-maternal ... [more ▼]

A few years ago, the prevention of anti-D immunization was currently based on systematic postnatal prophylaxis associated with targeted antenatal injection in high-risk situations of foeto-maternal haemorrhage. The failures of prevention are mainly due to the non-respect of established guidelines for RhIG prophylaxis, and to spontaneous undetected foetal-maternal haemorrhages without any obvious cause during the third trimester of pregnancy. In order to reduce the rate of residual post-pregnancy anti-D immunization, several countries decided to associate the classical prophylaxis to a routine antenatal anti-D prophylaxis (RAADP) during the 28th or 29th week of gestation. Since about ten years, the foetal RHD genotyping in maternal plasma enables us to limit the antenatal prophylaxis only to those D- women carrying a D+ foetus. This paper deals with: the advantages of an antenatal prevention in the light of non invasive foetal RHD genotyping, the rules rendering prevention protocols efficient whatever the algorithm applied, and the recommended immuno-haematology follow-up of women who have received RhIG. [less ▲]

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See detailIn vitro evaluation of an anti-apoptotic drug, Z-VAD-FMK, for further use in ovarian tissue transplantation
Fransolet, Maïté ULg; HENRY, Laurie ULg; LABIED, Soraya ULg et al

Poster (2015, June 14)

Study question: In a model reproducing early ischemia after ovarian tissue transplantation, does the pan-caspase inhibitor Z-VAD-FMK could prevent granulosa cell apoptosis? Summary answer: Results ... [more ▼]

Study question: In a model reproducing early ischemia after ovarian tissue transplantation, does the pan-caspase inhibitor Z-VAD-FMK could prevent granulosa cell apoptosis? Summary answer: Results obtained with HGL5 granulosa cell line suggest that Z-VAD-FMK is efficient to protect granulosa cells from etoposide or CoCl2 induced apoptosis. What is known already: Removal, cryopreservation and subsequent graft of ovarian strips after cancer treatment have been successfully used to re-establish female fertility. However, the pregnancy rate after autografting of cryopreserved tissue is about 30%. Indeed, the major problem after transplantation is follicular loss due to ischemic reperfusion injury. Study design, size, duration: Three human granulosa cell lines (GC1a, HGL5 and COV434) were cultured during 48h with Z-VAD-FMK with or without etoposide to induce apoptosis. To reproduce the ischemic phase of the graft, cells were cultured without serum under reduced O2 (1%) or with CoCl2 (chemical hypoxia). Participants/materials, setting, methods: Granulosa cells were used as a model since they are essential for oocyte survival. Metabolic cell activity was evaluated by the WST-1 assay. Cell apoptosis was analyzed by flow cytometry after annexin V-FITC and propidium iodide double staining. The mRNA levels and protein expression of apoptotic markers were evaluated using RT-qPCR and western blot analysis. Main results and the role of chance: Flow cytometry showed that cells co-treated with etoposide and Z-VAD-FMK displayed a higher percentage of viable cells as compared to etoposide alone. When in vivo ischemic stage was mimicked (1% O2), no beneficial effect of the Z-VAD-FMK was detected. However, a significant decrease of the number of early apoptotic cells was evidenced by flow cytometry for HGL5 cells treated with Z-VAD-FMK. RT-qPCR and western blot analysis revealed that apoptotic molecules were not modulated. Metabolic activity of the 3 cell lines was reduced by CoCl2. For HGL5 cells, this decrease was partially reversed by Z-VAD-FMK. The number of viable cells was reduced by CoCl2 in HGL5 cells but Z-VAD-FMK allowed to preserve a similar number of viable and apoptotic cells than in control condition. Limitations, reasons for caution: In this study we used 3 different cell lines but granulosa cells represent only a part of the cell types present in ovarian tissue biopsies. Experiences on the effect of Z-VAD-FMK on primary culture of granulosa cells have not yet been realized. Wider implications of the findings: This study suggests that the use of an antiapoptotic drug could be efficient to improve ovarian tissue transplantation outcomes. Ovarian tissue grafting studies using our xenograft murine model will be performed to test the potential efficacy of this drug to improve tissue viability and primordial follicles preservation after transplantation. [less ▲]

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