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STUDY QUESTION: Which add-ons are safe and effective to be used in ART treatment? SUMMARY ANSWER: Forty-two recommendations were formulated on the use of add-ons in the diagnosis of fertility problems, the IVF laboratory and clinical management of IVF treatment. WHAT IS KNOWN ALREADY: The innovative nature of ART combined with the extremely high motivation of the patients has opened the door to the wide application of what has become known as 'add-ons' in reproductive medicine. These supplementary options are available to patients in addition to standard fertility procedures, typically incurring an additional cost. A diverse array of supplementary options is made available, encompassing tests, drugs, equipment, complementary or alternative therapies, laboratory procedures, and surgical interventions. These options share the common aim of stating to enhance pregnancy or live birth rates, mitigate the risk of miscarriage, or expedite the time to achieving pregnancy. STUDY DESIGN, SIZE, DURATION: ESHRE aimed to develop clinically relevant and evidence-based recommendations focusing on the safety and efficacy of add-ons currently used in fertility procedures in order to improve the quality of care for patients with infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: ESHRE appointed a European multidisciplinary working group consisting of practising clinicians, embryologists, and researchers who have demonstrated leadership and expertise in the care and research of infertility. Patient representatives were included in the working group. To ensure that the guidelines are evidence-based, the literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, recommendations were based on the professional experience and consensus of the working group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 46 independent international reviewers. A total of 272 comments were received and incorporated where relevant. MAIN RESULTS AND THE ROLE OF CHANCE: The multidisciplinary working group formulated 42 recommendations in three sections; diagnosis and diagnostic tests, laboratory tests and interventions, and clinical management. LIMITATIONS, REASONS FOR CAUTION: Of the 42 recommendations, none could be based on high-quality evidence and only four could be based on moderate-quality evidence, implicating that 95% of the recommendations are supported only by low-quality randomized controlled trials, observational data, professional experience, or consensus of the development group. WIDER IMPLICATIONS OF THE FINDINGS: These guidelines offer valuable direction for healthcare professionals who are responsible for the care of patients undergoing ART treatment for infertility. Their purpose is to promote safe and effective ART treatment, enabling patients to make informed decisions based on realistic expectations. The guidelines aim to ensure that patients are fully informed about the various treatment options available to them and the likelihood of any additional treatment or test to improve the chance of achieving a live birth. STUDY FUNDING/COMPETING INTEREST(S): All costs relating to the development process were covered from ESHRE funds. There was no external funding of the development process or manuscript production. K.L. reports speakers fees from Merck and was part of a research study by Vitrolife (unpaid). T.E. reports consulting fees from Gynemed, speakers fees from Gynemed and is part of the scientific advisory board of Hamilton Thorne. N.P.P. reports grants from Merck Serono, Ferring Pharmaceutical, Theramex, Gedeon Richter, Organon, Roche, IBSA and Besins Healthcare, speakers fees from Merck Serono, Ferring Pharmaceutical, Theramex, Gedeon Richter, Organon, Roche, IBSA and Besins Healthcare. S.R.H. declares being managing director of Fertility Europe, a not-for-profit organization receiving financial support from ESHRE. I.S. is a scientific advisor for and has stock options from Alife Health, is co-founder of IVFvision LTD (unpaid) and received speakers' fee from the 2023 ART Young Leader Prestige workshop in China. A.P. reports grants from Gedeon Richter, Ferring Pharmaceuticals and Merck A/S, consulting fees from Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, speakers fees from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S, Theramex and Organon, travel fees from Gedeon Richter. The other authors disclosed no conflicts of interest. DISCLAIMER: This Good Practice Recommendations (GPRs) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation.ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or bedeemedinclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results.Theydo not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type.Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE.
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Infertilidade , Medicina Reprodutiva , Gravidez , Feminino , Humanos , Infertilidade/terapia , Coeficiente de Natalidade , Resultado do Tratamento , Preparações FarmacêuticasRESUMO
INTRODUCTION: Extracellular matrix proteins play a crucial role in influencing the invasion of trophoblast cells. However the role of collagens and collagen type IV (col-IV) in particular at the implantation site is not clear. METHODS: Immunohistochemistry was used to determine the distribution of collagen types I, III, IV and VI in endometrium and decidua during the menstrual cycle and the first trimester of pregnancy. Expression of col-IV alpha chains during the reproductive cycle was determined by qPCR and protein localisation by immunohistochemistry. The structure of col-IV in placenta was examined using transmission electron microscopy. Finally, the expression of col-IV alpha chain NC1 domains and collagen receptors was localised by immunohistochemistry. RESULTS: Col-IV alpha chains were selectively up-regulated during the menstrual cycle and decidualisation. Primary extravillous trophoblast cells express collagen receptors and secrete col-IV in vitro and in vivo, resulting in the increased levels found in decidua basalis compared to decidua parietalis. A novel expression pattern of col-IV in the mesenchyme of placental villi, as a three-dimensional network, was found. NC1 domains of col-IV alpha chains are known to regulate tumour cell migration and the selective expression of these domains in decidua basalis compared to decidua parietalis was determined. DISCUSSION: Col-IV is expressed as novel forms in the placenta. These findings suggest that col-IV not only represents a structural protein providing tissue integrity but also influences the invasive behaviour of trophoblast cells at the implantation site.
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Colágeno Tipo IV/metabolismo , Decídua/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismo , Vilosidades Coriônicas/metabolismo , Implantação do Embrião/fisiologia , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Regulação para CimaRESUMO
Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2011 there were twelve themed workshops, five of which are summarized in this report. These workshops related to various aspects of placental biology: 1) immunology; 2) epigenetics; 3) comparative placentation; 4) trophoblast differentiation; 5) stem cells.
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Nível de Saúde , Placenta/fisiologia , Animais , Pesquisa Biomédica/tendências , Diferenciação Celular , Epigênese Genética , Feminino , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imunomodulação , Masculino , MicroRNAs/fisiologia , Fisiologia Comparada/tendências , Placenta/citologia , Placenta/imunologia , Placentação , Gravidez , Proteínas da Gravidez/genética , Proteínas da Gravidez/metabolismo , Transplante de Células-Tronco/tendências , Células-Tronco/citologia , Células-Tronco/imunologia , Trofoblastos/citologia , Trofoblastos/imunologiaRESUMO
Formation of the placenta is a crucial step in mammalian pregnancy. Apart from its function in ensuring an optimal supply of nutrients and oxygen to the fetus, the placenta is also the interface at which allo-recognition of invading trophoblast cells by the maternal immune system can potentially occur. We summarise here the "state of the art" on how variability of immune system genes that code for major histocompatibility complex (MHC) molecules and natural killer receptors (NKR) may impact on human placentation. MHC and NKR are the most polymorphic human genes. Our recent reports point out that specific combinations of fetal MHC and maternal NKR genes in humans correlate with the risk of pre-eclampsia, recurrent miscarriage (RM) and fetal growth restriction (FGR). Research in this field is still at an early stage and future studies in mouse and humans will be needed before the results can be translated to clinical applications. We discuss our recent work, as well as the opportunities offered by mouse genetics, to understand the cellular and molecular mechanisms underlying immune interactions at the maternal-fetal interface.
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Genes MHC da Classe II/genética , Placentação/imunologia , Receptores de Células Matadoras Naturais/imunologia , Útero/imunologia , Aborto Habitual/imunologia , Animais , Feminino , Humanos , Células Matadoras Naturais/imunologia , Complexo Principal de Histocompatibilidade , Camundongos , Modelos Animais , Placenta/imunologia , Pré-Eclâmpsia/imunologia , Gravidez , Útero/citologiaRESUMO
We have examined the transcriptional changes associated with differentiation from villous to extravillous trophoblast using a whole genome microarray. Villous trophoblast (VT) is in contact with maternal blood and mediates nutrient exchange whereas extravillous trophoblast (EVT) invades the decidua and remodels uterine arteries. Using highly purified first trimester trophoblast we identified over 3000 transcripts that are differentially expressed. Many of these transcripts represent novel functions and pathways that show co-ordinated up-regulation in VT or EVT. In addition we identify new players in established functions such as migration, immune modulation and cytokine or angiogenic factor secretion by EVT. The transition from VT to EVT is also characterised by alterations in transcription factors such as STAT4 and IRF9, which may co-ordinate these changes. Transcripts encoding several members of the immunoglobulin-superfamily, which are normally expressed on leukocytes, were highly transcribed in EVT but not expressed as protein, indicating specific control of translation in EVT. Interactions of trophoblast with decidual leukocytes are involved in regulating EVT invasion. We show that decidual T-cells, macrophages and NK cells express the inhibitory collagen receptor LAIR-1 and that EVT secrete LAIR-2, which can block this interaction. This represents a new mechanism by which EVT can modulate leukocyte function in the decidua. Since LAIR-2 is detectable in the urine of pregnant, but not non-pregnant women, trophoblast-derived LAIR-2 may also have systemic effects during pregnancy.
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Vilosidades Coriônicas/metabolismo , Perfilação da Expressão Gênica , Primeiro Trimestre da Gravidez/genética , Trofoblastos/metabolismo , Adulto , Estudos de Casos e Controles , Linhagem Celular Tumoral , Células Cultivadas , Análise por Conglomerados , Feminino , Redes Reguladoras de Genes , Genoma Humano/fisiologia , Humanos , Análise em Microsséries , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/urina , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Trofoblastos/citologiaRESUMO
UNLABELLED: In this study, 250 women with osteoporosis were randomized to 12 months with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly, then crossed over to the other treatment. The primary endpoint, treatment adherence at 12 months, was 76.6% for alendronate and 87.3% for denosumab. INTRODUCTION: The purpose of this study is to evaluate treatment adherence with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly. METHODS: In this multicenter, randomized, open-label, 2-year, crossover study, 250 postmenopausal women with low bone mineral density received denosumab or alendronate for 12 months, then the other treatment for 12 months. The alendronate bottle had a medication event monitoring system cap to monitor administration dates. Definitions were as follows: compliance, receiving both denosumab doses 6 (± 1) months apart or 80-100% of alendronate doses; persistence, receiving both denosumab doses and completing the month 12 visit within the visit window or ≥ 2 alendronate doses in the final month; adherence, achieving both compliance and persistence. This report includes data from the first 12 months. RESULTS: The primary study endpoint, adherence in the first 12 months, was 76.6% (95/124) for alendronate and 87.3% (110/126) for denosumab. Risk ratios for denosumab compared with alendronate at 12 months were 0.58 (p = 0.043) for non-adherence, 0.48 (p = 0.014) for non-compliance, and 0.54 (p = 0.049) for non-persistence. Subject ratings for treatment necessity, preference, and satisfaction were significantly greater for denosumab and ratings for treatment bother were significantly greater for alendronate. Adverse events were reported by 64.1% of alendronate-treated subjects and 72.0% of denosumab-treated subjects (p = 0.403). The most common adverse events were arthralgia, back pain, pain in extremity, cough, and headache (each in <10% of subjects in each group). CONCLUSIONS: Significantly greater treatment adherence was observed for subcutaneous administration of denosumab every 6 months than for oral alendronate once weekly.
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Alendronato/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Osteoporose Pós-Menopausa/tratamento farmacológico , Administração Oral , Idoso , Alendronato/administração & dosagem , Alendronato/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Colúmbia Britânica , Denosumab , Métodos Epidemiológicos , Feminino , Humanos , Injeções Subcutâneas , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Osteoporose Pós-Menopausa/psicologia , Preferência do Paciente/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Resultado do TratamentoRESUMO
UNLABELLED: In this Phase 2 study of postmenopausal women with low bone, arzoxifene (a selective estrogen receptor modulator (SERM)) significantly reduced bone turnover marker levels and increased bone mineral density (BMD) versus placebo. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene, a SERM in current clinical use. Arzoxifene's safety profile appeared similar to raloxifene. INTRODUCTION: This 6-month, Phase 2, double-blind, placebo- and raloxifene-controlled study was designed to assess the effects of arzoxifene on bone turnover and overall safety in postmenopausal women with low bone mass. METHODS: Postmenopausal women (N = 219; mean age, 59 years) with a T-score between -1 and -2.5 were randomly assigned to daily arzoxifene 5, 10, 20, or 40 mg, raloxifene 60 mg, or placebo. All received daily calcium. RESULTS: All arzoxifene doses significantly reduced osteocalcin (primary endpoint), type 1 collagen C-telopeptide, bone specific alkaline phosphatase, and procollagen type I amino-terminal propeptide versus placebo, and increased lumbar spine BMD. Arzoxifene generally had greater effects on bone turnover and BMD than raloxifene. Arzoxifene decreased cholesterol, low-density lipoprotein cholesterol, and fibrinogen versus placebo. Endometrial thickness change with arzoxifene was not significantly different from placebo or raloxifene; no cases of endometrial hyperplasia or adenocarcinoma were observed. Adverse event reporting with arzoxifene was similar to that with raloxifene, as were hot flush and night sweat reporting. CONCLUSIONS: Arzoxifene suppressed bone turnover and increased BMD. Within the limitations of this study, the endometrial safety profile of arzoxifene appeared similar to that of raloxifene. While no clear dose effect was evident, arzoxifene 20 and 40 mg/day appeared the optimal doses for reducing bone turnover.
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Conservadores da Densidade Óssea/uso terapêutico , Lipídeos/sangue , Osteoporose Pós-Menopausa/tratamento farmacológico , Piperidinas/uso terapêutico , Tiofenos/uso terapêutico , Idoso , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Remodelação Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/fisiopatologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiopatologiaRESUMO
OBJECTIVE: Pre-eclampsia, recurrent miscarriage and infertility may all partly be caused by unsuccessful placentation early in pregnancy. If so, one will expect these disorders to be associated in population studies. The aim of the present investigation was to estimate the risk of pre-eclampsia in women with recurrent miscarriage and infertility. DESIGN: Cohort study. SETTING: The Norwegian Mother and Child Cohort Study (MoBa), a large population-based pregnancy cohort. SAMPLE: The sample consisted of 20,846 singleton pregnancies to nulliparous women participating in the MoBa, 1999-2005. METHODS: Information on miscarriage, infertility and potential confounders was self-reported in postal questionnaires, whereas the diagnosis of pre-eclampsia was retrieved from the Medical Birth Registry of Norway. Risk estimation and confounder control was performed with multiple logistic regression. MAIN OUTCOME MEASURES: Pre-eclampsia according to history of miscarriage and infertility. RESULTS: An increased risk of pre-eclampsia, although not statistically significant, was found for women with recurrent miscarriages (adjusted OR 1.51, 95% CI 0.80-2.83). Women who had ever been treated for infertility also had increased risk (adjusted OR 1.29, 95% CI 1.05-1.60). When these two risk factors were combined, the adjusted odds ratio for pre-eclampsia was 2.40 (95% CI 1.11-5.18). CONCLUSIONS: The study supports the hypothesis that infertility, recurrent miscarriage and pre-eclampsia share elements of the same aetiological factors.
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Aborto Habitual/etiologia , Infertilidade Feminina/etiologia , Pré-Eclâmpsia/etiologia , Aborto Habitual/epidemiologia , Adulto , Métodos Epidemiológicos , Feminino , Humanos , Infertilidade Feminina/epidemiologia , Noruega/epidemiologia , Pré-Eclâmpsia/epidemiologia , Gravidez , Adulto JovemRESUMO
BACKGROUND: The natural killer (NK) cells at the site of placentation express killer-cell immunoglobulin-like receptors (KIR) that can bind to human leukocyte antigen (HLA)-C molecules on trophoblast cells. Both these gene systems are polymorphic and an association of particular maternal KIR/fetal HLA-C genotypes has been shown in pre-eclampsia. Pre-eclampsia and recurrent miscarriage (RM) share the pathogenesis of defective placentation and therefore we have now genotyped couples with RM. METHODS AND RESULTS: DNA was obtained from the male (n = 67) and female (n = 95) partners of couples with three or more spontaneous miscarriages and genotyped for HLA-C groups and 11 KIR genes using the PCR-sequence-specific primer method (SSP). The frequency of the HLA-C2 group was increased in both parents (reaching significance only in the male partners, P = 0.018) compared with a parous control population. The KIR gene frequencies of the male partners were similar to controls, but the women had a high frequency of KIR AA haplotypes that lack activating KIR. In particular, the activating KIR for HLA-C2 groups (KIR2DS1) was significantly lower in these women (P = 0.00035, odds ratio 2.63, confidence interval 1.54-4.49). CONCLUSIONS: This is the first report to identify a genetic male factor that confers risk in RM. These findings support the idea that successful placentation depends on the correct balance of NK cell inhibition and activation in response to trophoblast.
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Aborto Habitual/imunologia , Antígenos HLA-C/genética , Placentação/imunologia , Receptores KIR/imunologia , Trofoblastos/imunologia , Feminino , Genótipo , Antígenos HLA-C/imunologia , Haplótipos , Humanos , Masculino , Reação em Cadeia da Polimerase , Pré-Eclâmpsia/imunologia , GravidezRESUMO
An immunological aura has hovered over the study of pre-eclampsia for many years but there has still been little progress in explaining the various 'immune' phenomena associated with this elusive disease. When considering the primary defect of placentation that leads to pre-eclampsia the focus should be on the intermingling of the invasive placental trophoblast cells with maternal leukocytes in the uterine wall. The MHC status of trophoblast cells is a crucial factor to be considered, as these molecules can act as ligands for uterine immune cells, including T cells, NK cells and myelomonocytic cells. Extravillous trophoblast cells express an unusual combination of HLA-C, HLA-G and HLA-E molecules and only one of these HLA molecules, HLA-C, shows any appreciable polymorphism. In humans, uNK cells express an array of receptors, some of which are known to bind to the HLA class I molecules expressed by extravillous trophoblast cells. HLA-C is the dominant ligand for killer immunoglobulin-like receptors (KIR) expressed by uterine NK cells that may deliver an inhibitory or activating signal. KIR haplotypes comprise two groups, A and B; these differ principally by having additional activating receptors in the B haplotype. In any pregnancy, the maternal KIR genotype could be AA (no activating KIR) or AB/BB (presence of between one and five activating KIRs). The HLA-C ligands for KIR on trophoblast cells may belong to two groups, C1 and C2 that are defined by a dimorphism at position 80 of the alpha1 domain. This maternal-fetal immunological interaction, occurring at the site of placentation, therefore involves two polymorphic gene systems, maternal KIRs and fetal HLA-C molecules. Uterine NK-cell function is thus likely to vary in each pregnancy. In pre-eclamptic pregnancies we have found that some KIR/HLA-C combinations appear unfavourable to trophoblast-cell invasion due to the overall signals that the NK cell receives. The academic excitement of this work is the realisation that this is a novel form of allorecognition based on NK cells that operates entirely differently from self/non-self discrimination used by T cells.
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Células Matadoras Naturais/imunologia , Placentação/imunologia , Pré-Eclâmpsia/imunologia , Feminino , Feto/imunologia , Antígenos HLA/imunologia , Humanos , Sistema Imunitário , Gravidez , Receptores Imunológicos/imunologia , Trofoblastos/imunologiaRESUMO
OBJECTIVES: Major histocompatibility complex class I (MHC-I) proteins exist at the cell surface in antigen presenting forms and as beta2m-independent free heavy chains (FHCs). FHCs have been implicated in spondyloarthritis, but little is known about their expression in healthy individuals. We studied FHC expression on various human cell types, comparing spondyloarthropathy patients with healthy and rheumatoid arthritis (RA) patient controls. METHODS: MHC-I expression was analysed by flow cytometry. FHC levels were normalized for overall MHC-I to generate a relative expression level. Relative FHC levels were analysed for peripheral blood and trophoblast samples from healthy volunteers, RA and spondyloarthropathy patients. Macrophages and dendritic cells were cultured in vitro to analyse changes following activation. Peripheral blood leucocytes from patients with ankylosing spondylitis (AS) and RA were treated with inflammatory stimuli and subsequent alterations in their relative FHC levels were analysed. RESULTS: We found consistent patterns of differential relative FHC expression across lymphocyte subpopulations and particularly high expression on extravillous trophoblast. FHCs were present at higher levels in a reactive arthritis (ReA) population than in healthy controls and RA patients; differences not merely due to the presence of Human Leucocyte Antigen (HLA) B27. Treatment of leucocytes from arthritic patients with bacterial lipopolysaccharide resulted in significant up-regulation of FHC compared with an HLA B27+ control population. CONCLUSIONS: Our findings define normal levels and tissue expression of FHCs, and support the hypothesis that disregulation of heavy chain expression may play a pathogenic role in spondyloarthropathy.
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Antígenos de Histocompatibilidade Classe I/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Espondiloartropatias/imunologia , Adulto , Artrite Reativa/imunologia , Artrite Reumatoide/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Citometria de Fluxo , Antígeno HLA-B27/metabolismo , Humanos , Leucócitos/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Proibitinas , Trofoblastos/imunologiaRESUMO
The placenta is unique amongst normal tissues in transcribing numerous different human endogenous retroviruses at high levels. In this study, RT-PCR and immunohistochemistry were used to investigate the expression of syncytin in human trophoblast. Syncytin transcripts were found in first-trimester trophoblast cells with both villous and extravillous phenotypes and also in the JAR and JEG-3 choriocarcinoma cell lines. Syncytin protein was detected in villous trophoblast and in all extravillous trophoblast subpopulations of first- and second-trimester placental tissues. It was also present in ectopic trophoblast from tubal implantations. This study confirms that syncytin is expressed widely by a variety of normal human trophoblast populations, as well as choriocarcinoma cell lines.
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Retrovirus Endógenos/genética , Produtos do Gene env/genética , Produtos do Gene env/metabolismo , Proteínas da Gravidez/genética , Proteínas da Gravidez/metabolismo , Trofoblastos/metabolismo , Trofoblastos/virologia , Linhagem Celular Tumoral , Coriocarcinoma/metabolismo , Coriocarcinoma/virologia , Vilosidades Coriônicas/metabolismo , Vilosidades Coriônicas/virologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Gravidez , Gravidez Tubária/metabolismo , Gravidez Tubária/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/virologiaRESUMO
The Workshop discussed five topics which were considered to be topical. 1) A comparison was made between rodents and primates regarding how uNK cells are distributed at the implantation site in these species. 2) The possibility that the functions of uNK cells may be different in mice and humans are discussed. 3) Trophoblast MHC expression in the Rhesus monkey (haemochorial) and the sheep (epitheliochorial) was compared in order the gauge the importance of these molecules in these two fundamentally different types of placentation. 4) New data were presented on the intriguing molecule, HLA-G, whose function is still unclear. 5) A discussion was initiated to debate the role of the innate and the adaptive immune systems in human implantation.
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Implantação do Embrião , Células Matadoras Naturais/fisiologia , Gravidez , Útero/imunologia , Animais , Feminino , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade Inata , Modelos Biológicos , Gravidez/imunologia , Gravidez/fisiologia , Trofoblastos/imunologia , Trofoblastos/metabolismo , Útero/fisiologiaRESUMO
The survival of the allogeneic conceptus has long been an immunological paradox. Medawar was the first to propose an evasive mechanism based on the concept of self/non-self recognition described in classical transplantation immunology. Since then, several newer models of self/non-self recognition have been proposed, such as the PAMP/PRR system, the Missing Self and the Danger Hypothesis. The present paper considers the fetal-maternal relationship in the context of all these models. The conclusion reached is that none of them is really appropriate because the interface between trophoblast cells of the fetal placenta and the leukocytes of the maternal decidua is unique. Pregnancy is not simply a case of acceptance or rejection like a transplant. The immunological mechanism must provide a balanced environment whereby the conceptus is nurtured by the mother and yet prevented from excessive invasion. Future identification of trophoblast ligands and their respective receptors on uterine Natural Killer cells and other leukocytes is likely to offer the best insight as to how this symbiotic state is achieved.
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Gravidez/imunologia , Feminino , Humanos , Sistema Imunitário/fisiologia , Células Matadoras Naturais/imunologia , Placenta/imunologia , Trofoblastos/imunologiaRESUMO
The placenta is unique amongst normal tissues in transcribing many different human endogenous retrovirus (HERV) families at high levels and this has led to the suggestion that HERVs may fulfil important functions in reproduction. This review discusses our current knowledge of the placental expression of HERVs, in particular the envelope proteins of ERV3 and HERV-W which may have critical roles in placental function.
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Retrovirus Endógenos/metabolismo , Placenta/virologia , Adulto , Retrovirus Endógenos/genética , Feminino , Humanos , Placenta/metabolismo , Gravidez , Proteínas do Envelope ViralRESUMO
In human pregnancy, the embryo implants into the specialized mucosal wall of the uterus (decidua) and the placenta starts to form. Cells from the placenta (trophoblasts) invade into the uterine mucosa in order to open up maternal uterine arteries to ensure an adequate supply of blood to the developing fetus. The trophoblasts have a unique immunological phenotype compared to most cells especially with regard to their expression of major histocompatibility complex (MHC) antigens. On the other side of the interaction, the uterine mucosa (endometrium) differentiates in preparation for implantation. One of the changes that takes place is the appearance in the endometrium of a large number of maternal leukocytes in the final part of the menstrual cycle. If pregnancy ensues, these leukocytes continue to increase in number and are found in close contact with trophoblasts. The composition of this population of maternal immune cells is unusual compared to that seen at other mucosal sites. A lot of research has focused on whether maternal T-cell responses are suppressed or modified during pregnancy. Research has also concentrated on the specialized uterine natural killer (NK) cells, which are found in the decidua in large numbers during early pregnancy. These uterine NK cells have been shown to express receptors for trophoblast MHC antigens, but their role in pregnancy is still mysterious. The purpose of this review is to give an overview of what is known about the immunology at the implantation site and also to provide an update of some of the most recent findings in this field.
Assuntos
Desenvolvimento Embrionário e Fetal/imunologia , Células Matadoras Naturais/imunologia , Placenta/imunologia , Trofoblastos/imunologia , Útero/imunologia , Feminino , Humanos , Complexo Principal de Histocompatibilidade/imunologia , Gravidez , Linfócitos T/imunologiaRESUMO
Both hormone replacement therapy (HRT) and bisphosphonates are efficacious in the prevention and treatment of postmenopausal osteoporosis. Combined therapy with bisphosphonate and HRT is likely to be used in clinical practice, and limited data are available regarding its efficacy and safety. This was a 1-yr, double blind, placebo-controlled study in which 524 postmenopausal women received daily treatment with conjugated equine estrogens (0.625 mg) alone or in combination with risedronate (5 mg). Women who had not undergone hysterectomy received medroxyprogesterone acetate (up to 5 mg, daily or cyclically) at the discretion of the investigator. The primary efficacy end point was the percent change from baseline in mean lumbar spine bone mineral density (BMD) at 1 yr. Changes in BMD at the proximal femur and forearm, bone turnover markers, and histology and histomorphometry were also assessed. At 12 months, significant (P < 0.05) increases from baseline in lumbar spine BMD were observed in both treatment groups (HRT-only, 4.6%; combined risedronate-HRT, 5.2%); the difference between the two groups was not statistically significant. Both therapies led to significant increases in BMD at 12 months at the femoral neck (1.8% and 2.7%, respectively), femoral trochanter (3.2% and 3.7%), distal radius (1.7% and 1.6%), and midshaft radius (0.4% and 0.7%). The differences between groups were statistically significant (P < 0.05) at the femoral neck and midshaft radius. Both combined risedronate-HRT and HRT-only produced significant decreases in the biochemical markers of bone turnover, with somewhat greater decreases in the combined treatment group. Bone biopsy data showed normal bone structure and normal mineralization with either treatment. Expected decreases in bone turnover were observed and were greater in the combined treatment group (68-79% reduction relative to baseline values, P < 0.005). Overall, combined treatment had a safety profile similar to that of HRT-only, including bone and gastrointestinal safety profiles. In conclusion, the combined treatment with risedronate and HRT had a favorable effect on BMD similar to that of HRT alone at the lumbar spine and slightly, but significantly, greater than that of HRT alone at the femoral neck and midshaft radius. The combined treatment was well tolerated, and there were no adverse effects on the skeleton.
Assuntos
Densidade Óssea/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Ácido Etidrônico/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Osso e Ossos/patologia , Método Duplo-Cego , Quimioterapia Combinada , Terapia de Reposição de Estrogênios/efeitos adversos , Ácido Etidrônico/efeitos adversos , Ácido Etidrônico/análogos & derivados , Feminino , Fraturas Ósseas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Ácido RisedrônicoRESUMO
We report a mother and son who each presented in infancy with hypotonia and global developmental delay. Subsequently, in both subjects, mild mental handicap was diagnosed in association with temporal lobe arachnoid cysts. Mendelian inheritance of this phenotype seems likely and macroscopic cerebral dysplasia in general may be underdiagnosed in people with familial, mild mental handicap.
Assuntos
Cistos Aracnóideos/genética , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Adulto , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
Measurement of the rate and direction of ground water flow beneath Wollaston Beach, Quincy, Massachusetts by use of a heat-pulsing flowmeter shows a mean velocity in the bulk sediment of 40 cm d(-1). The estimated total discharge of ground water into Quincy Bay during October 1990 was 1324-2177 m(3) d(-1), a relatively low ground water discharge rate. The tides have only a moderate effect on the rate and direction of this flow. Other important controls on the rate and volume of ground water flow are the limited thickness, geographic extent, and permeability of the aquifer. Comparisons of published streamflow data and estimates of ground water discharge indicate that ground water makes up between 7.4-12.1% of the gaged freshwater input into Quincy Bay. The data from this study suggest the ground water discharge is a less important recharge component to Quincy Bay than predicted by National Urban Runoff Program (NURP) models.The high nitrate and low nitrite and ammonia concentrations in the ground water at the backshore well sites and low nitrate and high nitrite and ammonia concentrations in the water flowing from the foreshore suggests that denitrification is active in the sediments. The low ground water flow rates and low nitrate concentrations in the foreshore samples suggest that little or no nitrate is surviving the denitrification process to affect the planktonic community. Similarly, oxidizing conditions in the aquifer and low trace metal concentrations in the ground water samples suggest that the metals may be precipitating and binding to sedimentary phases before impacting the bay.
RESUMO
Thirty drug-resistant epilepsy patients were given 20-30 mg of clobazam in addition to their other anticonvulsants and followed up for 2-3 years in an open-ended study. Fit frequency was markedly reduced in 43% of patients, few side effects occurred and psychological parameters including the Crown-Crisp questionnaire, showed improvement. It therefore seems that clobazam is a useful additional drug added to conventional anticonvulsant regimes.