Abstract
Meiotic divisions in oocytes are extremely asymmetric and require pre- and post-anaphase-onset phases of spindle migration. The latter induces membrane protrusion that is moulded around the ...spindle thereby reducing cytoplasmic loss. Here, we find that depleting the NAD biosynthetic enzyme, nicotinamide phosphoribosyl-transferase (
Nampt
), in mouse oocytes results in markedly longer spindles and compromises asymmetry. By analysing spindle speed in live oocytes, we identify a striking and transient acceleration after anaphase-onset that is severely blunted following Nampt-depletion. Slow-moving midzones of elongated spindles induce cortical furrowing deep within the oocyte before protrusions can form, altogether resulting in larger oocyte fragments being cleaved off. Additionally, we find that Nampt-depletion lowers NAD and ATP levels and that reducing NAD using small molecule Nampt inhibitors also compromises asymmetry. These data show that rapid midzone displacement is critical for extreme asymmetry by delaying furrowing to enable protrusions to form and link metabolic status to asymmetric division.
Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte ...quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.
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•Declining NAD(P)H is associated with oocyte dysfunction during reproductive aging•Oocyte quality and fertility can be restored by NMN treatment in aged mice•Supplementation of embryo media with NMN improves developmental milestones•SIRT2 overexpression mimics benefits of NMN but is unlikely to mediate its effects
Declining oocyte quality is considered an irreversible feature of aging and is rate limiting for human fertility. Bertoldo et al. show that reversing an age-dependent decline in NAD(P)H restores oocyte quality, embryo development, and functional fertility in aged mice. These findings may be relevant to reproductive medicine.
Introduction
Non‐tubal ectopic pregnancy (NTEP) is a rare but significant early pregnancy complication which can result in maternal morbidity and mortality. There is however a lack of evidence‐based ...guidelines for the management of NTEP.
Purpose
To evaluate the success rates of expectant, medical and surgical management in the treatment of NTEP at our tertiary centre.
Methods
Retrospective cohort study from 2010 to 2020. All NTEP were classified by ectopic sites. Primary management was classified by expectant, medical systemic methotrexate (Sys‐MTX) and/or local ultrasound‐guided injection of MTX and/or KCl intra‐sac (L‐MTX, L‐MTX/KCl) or surgical. Primary management was considered successful if no change in intervention was required. Treatment complications were compared.
Results
Twenty‐four NTEP were identified, which included 14 interstitial pregnancies (IP), 9 caesarean scar pregnancies (CSP) and 1 ovarian pregnancy (OP), which gave NTEP an incidence of 7.12% among all EP (4.15% for IP, 2.67% for CSP and 0.30% for OP). The success of primary surgical management was 100% (7/7), primary medical management was 76.9% (10/13) and primary expectant management was 33.3% (1/3). Primary medical management had a non‐statistically significant greater mean time to serum ß‐human Chorionic Gonadotrophin <5 IU/L, mean length of hospitalisation, mean number of follow‐up visits and hospital re‐presentation/readmissions compared to primary surgical management. There was no other difference in complication rates between the treatment management groups.
Conclusion
Surgery remains the most effective way to manage NTEP. However, medical management can be a safe and effective alternative option in carefully selected cases.
Endometriosis in adolescents is often underrecognized and is a contributing factor to significant delays in its diagnosis and management. Extraovarian endometrioma is uncommon, especially in the ...adolescent age range. We report on a rare case of a large extraovarian endometrioma involving the terminal ileum in an adolescent who presented with abdominal pain and a pelvic mass and its subsequent surgical management. It emphasizes the importance of having a broad differential diagnosis and considers endometriosis in any adolescent with pelvic pain and mass, especially in an atypical context. Increased awareness, education, and research on endometriosis in this young population are essential in order to overcome existing challenges in the early diagnosis and optimal management of this chronic gynaecological condition and avoid morbidity associated with advanced disease.
Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating ...long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.
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