Embryo fragmentation represents a phenomenon generally characterized by the presence of membrane-bound extracellular cytoplasm into the perivitelline space. Recent evidence supports the cellular and molecular heterogeneity of embryo fragments. In this narrative review, we described the different embryo fragment-like cellular structures in their morphology, molecular content, and supposed function and have reported the proposed theories on their origin over the years. We identified articles related to characterization of embryo fragmentation with a specific literature search string. The occurrence of embryo fragmentation has been related to various mechanisms, of which the most studied are apoptotic cell death, membrane compartmentalization of altered DNA, cytoskeletal disorders, and vesicle formation. These phenomena are thought to result in the extrusion of entire blastomeres, release of apoptotic bodies and other vesicles, and micronuclei formation. Different patterns of fragmentation may have different etiologies and effects on embryo competence. Removal of fragments from the embryo before embryo transfer with the aim to improve implantation potential should be reconsidered on the basis of the present observations.
Globoid cell leukodystrophy (GLD) is a rare neurodegenerative lysosomal storage disease caused by an inherited deficiency of b-galactocerebrosidase (GALC). GLD pathogenesis and therapeutic correction have been poorly studied in patient neural cells. Here, we investigated the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression in induced pluripotent stem cell (iPSC)derived neural progenitors and neuronal/glial progeny obtained from two GLD patients. GLD neural progeny displayed progressive psychosine storage, oligodendroglial and neuronal defects, unbalanced lipid composition, and early activation of cellular senescence, depending on the disease-causing mutation. The partial rescue of the neural differentiation program upon GALC reconstitution and psychosine clearance suggests multiple mechanisms contributing to neural pathology in GLD. Also, the pathological phenotype associated to supraphysiological GALC levels highlights the need of regulated GALC expression for proper human neural commitment/differentiation. These data have important implications for establishing safe therapeutic strategies to enhance disease correction of GLD.
STUDY QUESTION Is oral Vitamin D supplementation able to modify the intrauterine milieu in terms of cytokine/chemokine pattern? SUMMARY ANSWER No significant differences were detected in cytokine and chemokine levels in endometrial secretions between patients undergoing ART with or without Vitamin D supplementation. WHAT IS KNOWN ALREADY Cytokines and chemokines secreted into the intrauterine environment are fundamental for the molecular crosstalk between the endometrium and the preimplantation embryo. Whether Vitamin D can regulate these mediators in the endometrial environment is still unclear. STUDY DESIGN, SIZE, DURATION This study was an analysis of a secondary outcome from the Supplementation Of Vitamin D And Reproductive Outcomes clinical trial, a multi-center randomized double-blinded trial designed to explore the effects of Vitamin D replacement in insufficient women with Vitamin D levels below 30 ng/ml undergoing autologous ART cycles. Uterine fluid samples were collected from both patients supplemented with Vitamin D (n = 17) and from the placebo group (n = 32). PARTICIPANTS/MATERIALS, SETTING, METHODS Based on cutoff points for Vitamin D insufficiency (20–29.9 ng/mL) or deficiency (<20 ng/mL), 67% of patients in the study were insufficient, and 33% deficient, in Vitamin D, although they were considered together for the analysis. Women received a single dose of 600,000 IU 25-hydroxyvitamin D or placebo from 2 to 12 weeks before oocyte retrieval. Inclusion criteria were female age 18-39 years, with a BMI between 18 and 25 Kg/m2. Serum 25-hydroxyvitamin D was assessed at the time of hCG administration. Uterine fluid samples were collected during the secretory phase of the menstrual cycle preceding oocyte retrieval. The quantitative determination of 27 cytokines in endometrial secretion samples was performed by using a multiplex immunoassay. MAIN RESULTS AND THE ROLE OF CHANCE Uterine fluid samples were collected after a median (range) of 21 (12–41) days after the oral Vitamin D supplementation. Both the supplemented and placebo groups had Vitamin D serum levels below 30 ng/ml at baseline/time of randomization ((median 23.4 ng/ml (IQR 19.5–28.4) and 23.4 ng/ml (17.8–25.9), respectively). At time of hCG administration, serum Vitamin D in supplemented subjects was significantly raised compared to the placebo group ((median 52.9 ng/ml (interquartile range 40.7–64.1) and 24.6 ng/ml (19.3–29.2), respectively, p < 0.001). Our data revealed no significant differences in uterine fluid cytokine/chemokine composition of Vitamin D-supplemented women compared with the placebo group. This finding remained when the concentrations of all mediators studied were normalized to total protein. In a further analysis, no significant differences were found in the content of cytokines/chemokines in uterine fluid from women who conceived (n = 19) compared with the non-pregnant group (n = 30). LIMITATIONS, REASONS FOR CAUTION Using a randomized study design (a single dose of 600,000 IU 25-hydroxyvitamin D versus placebo), we found no significant differences between groups. However, we cannot exclude that any benefit of Vitamin D supplementation may be specific for some subgroups of patients, such as those with an imbalance of T-helper 1 and T-helper 2 cell populations. The uterine secretions were collected during the menstrual cycle that preceded oocyte retrieval, therefore it is possible the uterine fluid collection and analysis in the same cycle as the embryo transfer might have resulted in different conclusions. Moreover, the small sample size could limit the power of the study. WIDER IMPLICATIONS OF THE FINDINGS Our analysis of the uterine secretome profiling failed to show any significant difference in endometrial cytokine/chemokine patterns between women with oral Vitamin D supplementation and the placebo group. Vitamin D may act on the uterine environment through a different mechanism. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Italian Ministry of Health following peer review in the competitive “Bando di Ricerca Finalizzata e Giovani Ricercatori 2013” with reference code RF-2013-02358757. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER EudraCT registration number: 2015-004233-27.
Background In women scheduled for cancer treatment, oocytes cryopreservation is a well-established procedure. Random start protocols have been a substantial improvement in this setting, allowing to prevent delay in the initiation of cancer treatments. However, there is still the need to optimize the regimen of ovarian stimulation, to make treatments more patient-friendly and to reduce costs. Methods This retrospective study compares two periods (2019 and 2020), corresponding to two different ovarian stimulation regimens. In 2019, women were treated with corifollitropin, recombinant FSH and GnRH antagonists. Ovulation was triggered with GnRH agonists. In 2020, the policy changed, and women were treated with a progestin-primed ovarian stimulation (PPOS) protocol with human menopausal gonadotropin (hMG) and dual trigger (GnRH agonist and low dose hCG) Continuous data are reported as median [Interquartile Range]. To overcome expected changes in baseline characteristics of the women, the primary outcome was the ratio between the number of mature oocytes retrieved and serum anti-mullerian hormone (AMH) in ng/ml. Results Overall, 124 women were selected, 46 in 2019 and 78 in 2020. The ratio between the number of mature oocytes retrieved and serum AMH in the first and second period was 4.0 [2.3–7.1] and 4.0 [2.7–6.8], respectively (p = 0.80). The number of scans was 3 [3–4] and 3 [2–3], respectively (p<0.001). The total costs of the drugs used for ovarian stimulation were 940 € [774–1,096 €] and 520 € [434–564 €], respectively (p<0.001). Conclusions Random start PPOS with hMG and dual trigger represents an easy and affordable ovarian stimulation protocol for fertility preservation in women with cancer, showing similar efficacy and being more friendly and economical.
21Globoid Cell Leukodystrophy (GLD, or Krabbe disease) is a rare lysosomal storage disease caused 22 by inherited deficiency of β-galactocerebrosidase (GALC). The build-up of psychosine and other 23 undegraded galactosylsphingolipids in the nervous system causes serious demyelination and 24 neurodegeneration. The molecular mechanisms of GLD are poorly elucidated in neural cells and whether 25 murine systems faithfully recapitulate critical aspects of the human disease is still to be defined. 26Here, we established a collection of GLD patient-specific induced pluripotent stem cell (iPSC) 27 lines. We differentiated iPSCs from two patients -bearing different disease-causing mutations -into 28 neural progenitors cells (NPCs) and their neuronal/glial progeny, assessing the impact of GALC deficiency 29 and lentiviral vector-mediated GALC rescue/overexpression by means of phenotypic, biochemical, 30 molecular, and lipidomic analysis. We show a progressive increase of psychosine during the 31 differentiation of GLD NPCs to neurons and glia. We report an early and persistent impairment of glial 32 and neuronal differentiation in GLD cultures, with peculiar differences observed in the two GLD lines. 33GLD cells display a global unbalance of lipid composition during the iPSC to neural differentiation and 34 early activation of cellular senescence, depending on the disease-causing mutation. Restoration of GALC 35 activity normalizes the primary pathological hallmarks and partially rescues the differentiation program 36 of GLD NPCs. 37Our results show that multiple mechanisms besides psychosine toxicity concur to CNS pathology 38 in GLD and highlight the need of a timely regulated GALC expression for proper lineage commitment and 39 differentiation of human NPCs. These findings have important implications for establishing tailored 40 cell/gene therapy strategies to enhance disease correction in GLD. 41 42
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