Prognosis in fertilisation rate and outcome in IVF cycles in patients with and without endometriosis: a population-based comparative cohort study with controls

Background: Subfertility occurs in 30-40% of endometriosis patients. Regarding the fertilisation rate with in vitro fertilisation (IVF) and endometriosis, conflicting data has been published. This study aimed to compare endometriosis patients to non-endometriosis cycles assessing fertilisation rates in IVF.Methods: A population-based cohort study was conducted at the Leiden University Medical Center. IVF cycles of endometriosis patients and controls (unexplained infertility and tubal pathology) were analysed. The main outcome measurement was fertilisation rate.Results: 503 IVF cycles in total, 191 in the endometriosis group and 312 in the control. The mean fertilisation rate after IVF did not differ between both groups, 64.1%+/- 25.5 versus 63.9%+/- 24.8 (p=0.95) respectively, independent of age and r-ASRM classification. The median number of retrieved oocytes was lower in the endometriosis group (7.0 versus 8.0 respectively, p=0.19) and showed a significant difference when corrected for age (p=0.02). When divided into age groups, the statistical effect was only seen in the group of <= 35 years (p=0.04). In the age group <= 35, the endometriosis group also showed significantly more surgery on the internal reproductive organs compared to the control group (p<0.001). All other outcomes did not show significant differences.Conclusion: Similar fertilisation rates were found in endometriosis IVF cycles compared to controls. The oocyte retrieval was lower in the endometriosis group, however this effect was only significant in the age group <= 35 years. All other secondary outcomes did not show significant differences. In general, endometriosis patients with an IVF indication can be counselled positively regarding the chances of becoming pregnant, and do not need a different IVF approach.Gynecolog

Recognition of S100 proteins by signal inhibitory receptor on leukocytes-1 negatively regulates human neutrophils

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL-1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. In this study, we identify S100 proteins as SIRL-1 ligands. S100 proteins are composed of two calcium-binding domains. Various S100 proteins are damage-associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL-1 recognizes individual calcium-binding domains of all tested S100 proteins. Blocking SIRL-1 on human neutrophils enhanced S100 protein S100A6-induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL-1. Taken together, SIRL-1 is an inhibitory receptor recognizing the S100 protein family of DAMPs. This may help limit tissue damage induced by activated neutrophils.Chemical Immunolog

Single-cell reconstruction of follicular remodeling in the human adult ovary

The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in) fertility

Signal Inhibitory Receptor on Leukocytes-1 is highly expressed on lung monocytes, but absent on mononuclear phagocytes in skin and colon

Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is expressed on human blood monocytes and granulocytes and inhibits myeloid effector functions. On monocytes, but not granulocytes, SIRL-1 expression is low or absent in individuals with the single nucleotide polymorphism (SNP) rs612529C. The expression of SIRL-1 in tissue and the influence of rs612529 hereon is currently unknown. Here, we used flow cytometry to determine SIRL-1 expression on immune cells in human blood and three barrier tissues; skin, colon and lung. SIRL-1 was expressed by virtually all neutrophils and eosinophils in these tissues. In contrast, SIRL-1 was not expressed by monocytederived cells in skin and colon, whereas it was highly expressed by lung classical monocytes. Lung monocytes from individuals with a rs612529C allele had decreased SIRL-1 expression, consistent with the genotype association in blood. Within the different monocyte subsets in blood and lung, SIRL-1 expression was highest in classical monocytes and lowest in nonclassical monocytes. SIRL-1 was not expressed by dendritic cells in blood and barrier tissues. Together, these results indicate that SIRL-1 is differentially expressed on phagocyte subsets in blood and barrier tissues, and that its expression on monocytes is genotype- and tissue-specific. Immune regulation of monocytes by SIRL-1 may be of particular importance in the lun

Effect of parental and ART treatment characteristics on perinatal outcomes

Funding This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). Acknowledgements We thank the Foundation of the Netherlands Perinatal Registry for permission to use their registry data (approval number 12.43). We thank G.P. Kroon and H.W.W. van Leeuwen for their assistance in collecting the necessary IVF data. Furthermore, we thank the medical informatics students A. Wong for the first deterministic data linkage and S. Wortel for assisting in the database validation process. In addition, we thank all care providers for the registration of the perinatal data as well as the IVF laboratory data.Peer reviewedPublisher PD

Stronger T-Cell Alloreactivity and Diminished Suppressive Capacity of Peripheral Regulatory T Cells in Infertile Women Undergoing In Vitro Fertilization

ProblemIncreasing evidence suggests modulation of the maternal immune response to be essential for successful pregnancy. We studied the immunophenotypic profile and function of peripheral blood T lymphocytes in infertile women undergoing in vitro fertilization (IVF) and fertile control population. MethodWe collected peripheral blood mononuclear cells (PBMC) from infertile patients with recurrent implantation failure (RIF), infertile patients with successful IVF (IVFs), and normal fertile women. Cells were phenotypically analyzed, and the proliferative response and cytokine production were studied in mixed lymphocyte cultures (MLC), using lymphocytes of the own partner, or a third-party male as stimulators cells. To examine the suppressive capacity of regulatory regulatory T cells (Tregs), we performed MLC studies with a CD45(+) fraction depleted for CD4(+)CD25(bright) T cells. ResultsNo significant differences in proportions of subsets of circulating T lymphocytes were observed. The proliferative allo-immune response of PBMC of IVF women (RIF and IVFs) was significantly higher, with higher production of T-helper cells (Th1) and Th2 cytokines, compared to the fertile women. This difference in proliferation and cytokine production was associated with a diminished suppressive capacity of Tregs in these women. ConclusionThe higher allo-immune response of the IVF women compared to fertile women might be the result of a diminished suppressive capacity of Tregs and emphasizes the important role of Tregs during conception

Signal inhibitory receptor on leukocytes-1 recognizes bacterial and endogenous amphipathic alpha-helical peptides

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is a negative regulator of myeloid cell function and dampens antimicrobial responses. We here show that different species of the genus Staphylococcus secrete SIRL-1-engaging factors. By screening a library of single-gene transposon mutants in Staphylococcus aureus, we identified these factors as phenol-soluble modulins (PSMs). PSMs are amphipathic alpha-helical peptides involved in multiple aspects of staphylococcal virulence and physiology. They are cytotoxic and activate the chemotactic formyl peptide receptor 2 (FPR2) on immune cells. Human cathelicidin LL-37 is also an amphipathic alpha-helical peptide with antimicrobial and chemotactic activities, structurally and functionally similar to alpha-type PSMs. We demonstrate that alpha-type PSMs from multiple staphylococcal species as well as human cathelicidin LL-37 activate SIRL-1, suggesting that SIRL-1 recognizes alpha-helical peptides with an amphipathic arrangement of hydrophobicity, although we were not able to show direct binding to SIRL-1. Upon rational peptide design, we identified artificial peptides in which the capacity to ligate SIRL-1 is segregated from cytotoxic and FPR2-activating properties, allowing specific engagement of SIRL-1. In conclusion, we propose staphylococcal PSMs and human LL-37 as a potential new class of natural ligands for SIRL-1.Chemical Immunolog

Untangling the web of European regulations for the preparation of unlicensed radiopharmaceuticals: a concise overview and practical guidance for a risk-based approach

Radiopharmaceuticals are highly regulated, because they are controlled both as regular medicinal products and as radioactive substances. This can pose a hurdle for their development and clinical use. Radiopharmaceuticals are fundamentally different from other medicinal products and these regulations are not always adequate for their production. Strict compliance may have a huge resource impact, without further improving product quality. In this paper we give an overview of the applicable legislation and guidelines and propose a risk-based approach for their implementation. We focus on a few controversial Good Manufacturing Practice topics: cleanroom classification, air pressure regime, cleanroom qualification and microbiological monitoring. We have developed an algorithm to assess the combined risk of microbiological contamination of a radiopharmaceutical preparation process and propose corresponding Good Manufacturing Practice classification levels. In our opinion, the risk of carry-over of radiopharmaceuticals by individuals cannot be contained by pressure differences, and complicated regimes with underpressured rooms are not necessary in most situations. We propose a sterility assurance level of 10(-2) for radiopharmaceuticals that are administered within a working day, irrespective of their use. We suggest the adoption of limits for environmental monitoring of microbial contamination, as proposed by Bruel and colleagues, on behalf of the French Society of Radiopharmacy. Recently launched regulatory documents seem to breathe a more liberal spirit than current legislation and recognize the need for the use of risk assessment. We argue that future legislation be further harmonized and state risk assessment as the gold standard for implementation of drug quality regulations for the preparation of unlicensed radiopharmaceuticals

Development of the follicular basement membrane during human gametogenesis and early folliculogenesis

Stem cells & developmental biolog