Safety of pregnancy after breast cancer in young women with hormone receptor-positive disease: a systematic review and meta-analysis.

BACKGROUND: Despite increasing evidence on the safety of pregnancy after anticancer treatments in breast cancer survivors, many physicians and patients remain concerned about a potential risk of pregnancy specifically in the case of hormone receptor-positive breast cancer. MATERIALS AND METHODS: A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to 31 March 2023 was carried out. To be included, articles had to be retrospective and prospective case-control and cohort studies as well as clinical trials comparing survival outcomes of premenopausal women with or without a pregnancy after prior diagnosis of hormone receptor-positive breast cancer. Disease-free survival (DFS) and overall survival (OS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Study protocol is registered in PROSPERO (n. CRD42023394232). RESULTS: Out of 7796 screened studies, 8 were eligible to be included in the final analysis. A total of 3805 patients with hormone receptor-positive invasive early breast cancer were included in these studies, of whom 1285 had a pregnancy after breast cancer diagnosis. Median follow-up time ranged from 3.8 to 15.8 years and was similar in the pregnancy and non-pregnancy cohorts. In three studies (n = 987 patients) reporting on DFS, no difference was observed between patients with and those without a subsequent pregnancy (HR 0.96, 95% CI 0.75-1.24, P = 0.781). In the six studies (n = 3504 patients) reporting on OS, patients with a pregnancy after breast cancer had a statistically significant better OS than those without a pregnancy (HR 0.46, 95% CI 0.27-0.77, P < 0.05). CONCLUSIONS: This systematic review and meta-analysis of retrospective cohort studies provides updated evidence that having a pregnancy in patients with prior history of hormone receptor-positive invasive early breast cancer appears safe without detrimental effect on prognosis.

Clinical pregnancy in Turner syndrome following re-implantation of cryopreserved ovarian cortex.

Turner syndrome (TS) leads to a characteristic phenotype, including premature ovarian insufficiency and infertility. Ovarian tissue cryopreservation (OTC) is becoming an established fertility preservation strategy for both pre- and post-pubertal females and may offer the chance of having a biological family to selected patients with TS. To date, women with TS have had ovarian tissue cryopreserved but there are few reports of autologous re-implantation and none of pregnancy. We herein report, to our knowledge, the first clinical pregnancy in a patient with TS, conceived naturally following re-implantation of cryopreserved ovarian tissue which had been removed soon after spontaneous puberty. This provides proof of concept for OTC as a means of fertility preservation in TS.

Aedes aegypti salivary gland extract alleviates acute itching by blocking TRPA1 channels.

Aedes aegypti (Ae. aegypti) saliva induces a variety of anti-inflammatory and immunomodulatory activities. Interestingly, although it is known that mosquito bites cause allergic reactions in sensitised hosts, the primary exposure of humans to Ae. aegypti does not evoke significant itching. Whether active components in the saliva of Ae. aegypti can counteract the normal itch reaction to injury produced by a histaminergic or non-histaminergic pathway in vertebrate hosts is unknown. This study investigated the effects of Ae. aegypti mosquito salivary gland extract (SGE) on sensitive reactions such as itching and associated skin inflammation. Acute pruritus and plasma extravasation were induced in mice by the intradermal injection of either compound 48/80 (C48/80), the Mas-related G protein-coupled receptor (Mrgpr) agonist chloroquine (CQ), or the transient receptor potential ankyrin 1 (TRPA1) agonist allyl isothiocyanate (AITC). The i.d. co-injection of Ae. aegypti SGE inhibited itching, plasma extravasation, and neutrophil influx evoked by C48/80, but it did not significantly affect mast cell degranulation in situ or in vitro. Additionally, SGE partially reduced CQ- and AITC-induced pruritus in vivo, suggesting that SGE affects pruriceptive nerve firing independently of the histaminergic pathway. Activation of TRPA1 significantly increased intracellular Ca2+ in TRPA-1-transfected HEK293t lineage, which was attenuated by SGE addition. We showed for the first time that Ae. aegypti SGE exerts anti-pruriceptive effects, which are partially regulated by the histamine-independent itch TRPA1 pathway. Thus, SGE may possess bioactive molecules with therapeutic potential for treating nonhistaminergic itch.

Myrtenol Reduces Orofacial Nociception and Inflammation in Mice Through p38-MAPK and Cytokine Inhibition.

Orofacial pain is one of the commonest and most complex complaints in dentistry, greatly impairing life quality. Preclinical studies using monoterpenes have shown pharmacological potential to treat painful conditions, but the reports of the effects of myrtenol on orofacial pain and inflammation are scarce. The aim of this study was to evaluate the effect of myrtenol in experimental models of orofacial pain and inflammation. Orofacial nociceptive behavior and the immunoreactivity of the phosphorylated p38 (P-p38)-MAPK in trigeminal ganglia (TG) and spinal trigeminal subnucleus caudalis (STSC) were determined after the injection of formalin in the upper lip of male Swiss mice pretreated with myrtenol (12.5 and 25 mg/kg, i.p.) or vehicle. Orofacial inflammation was induced by the injection of carrageenan (CGN) in the masseter muscle of mice pretreated with myrtenol (25 and 50 mg/kg, i.p.) or its vehicle (0.02% Tween 80 in saline). Myeloperoxidase (MPO) activity and histopathological changes in the masseter muscle and interleukin (IL)-1ß levels in the TG and STSC were measured. The increase in face-rubbing behavior time induced by formalin and P-p38-MAPK immunostaining in trigeminal ganglia were significantly reduced by myrtenol treatment (12.5 and 25 mg/kg). Likewise, increased MPO activity and inflammatory histological scores in masseter muscle, as well as augmented levels of IL-1ß in the TG AND STSC, observed after CGN injection, were significantly decreased by myrtenol (25 and 50 mg/kg). Myrtenol has potential to treat orofacial inflammation and pain, which is partially related to IL-1ß levels in the trigeminal pathway and p38-MAPK modulation in trigeminal ganglia.

Installing oncofertility programs for breast cancer in limited versus optimum resource settings: Empirical data from 39 surveyed centers in Repro-Can-OPEN Study Part I & II.

PURPOSE: As a further step to elucidate the actual diverse spectrum of oncofertility practices for breast cancer around the globe, we present and discuss the comparisons of oncofertility practices for breast cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. METHODS: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia & Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the United States, Europe, Australia and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered to young female patients with breast cancer as well as the degree of utilization. RESULTS: In the Repro-Can-OPEN Study Part I & II, responses for breast cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings especially for established options, (2) frequent utilization of egg freezing, embryo freezing, ovarian tissue freezing, GnRH analogs, and fractionation of chemo- and radiotherapy, (3) promising utilization of oocyte in vitro maturation (IVM), (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, and stem cells reproductive technology as they are still in preclinical or early clinical research settings, (5) recognition that technical and ethical concerns should be considered when offering advanced and innovative oncofertility options. CONCLUSIONS: We presented a plausible oncofertility best practice model to guide oncofertility teams in optimizing care for breast cancer patients in various resource settings.

Prediction of premature ovarian insufficiency: foolish fallacy or feasible foresight?

Prediction of premature ovarian insufficiency (POI) would be of substantial individual benefit, but being a heterogeneous and fluctuating condition, with an extensive range of complex etiologies and arbitrary diagnostic criteria, might make this seem foolhardy. However, contemporary and complementary genetic strategies assessing consanguineous and large POI pedigrees and cohorts with age at natural menopause have shown strong enrichment in genes regulating DNA damage repair, homologous recombination, and meiosis, processes that are critical to oogenesis and folliculogenesis. Recognition of the molecular architecture of POI and its contribution to baseline genotypic risk may enable these estimates to be refined further by estimation of the residual ovarian reserve. Increasing data derived from spontaneous and gonadotoxic-induced POI cohorts demonstrate the utility of anti-Müllerian hormone (AMH) to predict POI. This review presents current understanding of how genetics in combination with AMH may facilitate the prediction of POI.

Novel approaches to fertility restoration in women with premature ovarian insufficiency.

The diagnosis of premature ovarian insufficiency (POI) brings with it the loss of fertility, an immediate concern for many affected women, and a future one for many others. While there is a low natural conception rate, for most the choice is between oocyte donation and alternative methods of family building such as adoption. There is, however, a lot of research into novel methods for increasing or restoring the fertility of women with POI, which are discussed in this review. Many approaches involve the use of mesenchymal stem cells, from a variety of sources including bone marrow, placenta and umbilical cord, and menstrual blood. These seem to have efficacy in animal models of POI, although through unclear mechanisms. Activation of remaining primordial follicles is also being explored, through physical or chemical manipulation of key regulatory pathways, notably the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Hippo pathways. Much of the clinical data are uncontrolled, and mostly in women with a reduced ovarian reserve rather than POI, as are the results thus far for administration of platelet-rich plasma. Clinical studies with appropriate controls are needed to substantiate the preliminary claims of effectiveness of these approaches.

The potential anti-inflammatory and anti-nociceptive effects of rat hemopressin (PVNFKFLSH) in experimental arthritis.

Inflammatory arthritis, such as rheumatoid arthritis (RA), stands out as one of the main sources of pain and impairment to the quality of life. The use of hemopressin (PVNFKFLSH; Hp), an inverse agonist of type 1 cannabinoid receptor, has proven to be effective in producing analgesia in pain models, but its effect on neuro-inflammatory aspects of RA is limited. In this study, antigen-induced arthritis (AIA) was evoked by the intraarticular (i.art.) injection of methylated bovine serum albumin (mBSA) in male Sprague Dawley rats. Phosphate buffered saline (PBS)-injected ipsilateral knee joints or AIA contralateral were used as control. Nociceptive and inflammatory parameters such as knee joint oedema and leukocyte influx and histopathological changes were carried out in addition to the local measurement of interleukins (IL) IL-6, IL-1ß, tumor necrosis factor-α and the immunoreactivity of the neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal cord (lumbar L3-5 segments) of AIA rats. For 4 days, AIA rats were treated daily with a single administration of saline, Hp injected (10 or 20 µg/day, i.art.), Hp given orally (20 µg/Kg, p.o.) or indomethacin (Indo; 5 mg/Kg, i.p.). In comparison to the PBS control group, the induction of AIA produced a significant and progressive mono-arthritis condition. The degree of AIA severity progressively compromised the normal walking pattern and impaired mobility over the next four days in relation to PBS-injected rats or contralateral knee joints. In AIA rats, the reduction of the distance between footprints and disturbances of gait evidenced signs of nociception. This response worsened at day 4, and a loss of footprint from the ipsilateral hind paw was evident. Daily treatment of the animals with Hp either i.art. (10 and 20 µg/knee) or p.o. (20 µg/Kg) as well as Indo (5 mg/Kg, i.p.) ameliorated the impaired mobility in a time-dependent manner (P < 0.05). In parallel, the AIA-injected ipsilateral knee joints reach a peak of swelling 24 h after AIA induction, which persisted over the next four days in relation to PBS-injected rats or contralateral knee joints. There was a significant but not dose-dependent inhibitory effect produced by all dosages and routes of Hp treatments on AIA-induced knee joint swelling (P < 0.05). In addition, the increased synovial levels of MPO activity, total leukocytes number and IL-6, but not IL-1ß, were significantly reduced by the lower i.art. dose of Hp. In conclusion, these results successfully demonstrate that Hp may represent a novel therapeutic strategy to treat RA, an effect which is unrelated to the proinflammatory actions of the neuropeptides CGRP and SP.

Premature ovarian insufficiency: an International Menopause Society White Paper.

The aim of this International Menopause Society White Paper on premature ovarian insufficiency (POI) is to provide the latest information regarding this distressing condition. The impact of POI has far-reaching consequences due to its impact on general, psychological, and sexual quality of life, fertility prospects, and long-term bone, cardiovascular, and cognitive health. Progress in fully understanding the etiology, diagnosis, and optimal management options has been slow thus far due to the complexity of the condition and fragmented research. Recent advances in epidemiological and genetic research have improved our understanding of this condition and randomized prospective trials are being planned to determine the intervention strategies, which will optimize quality of life and long-term well-being. The International Menopause Society has commissioned a number of experts at the forefront of their specialty to define the state of the art in the understanding of this condition, to advise on practical management strategies, and to propose future research strategies. It is hoped that a global task force will subsequently be convened in order to formulate a consensus statement across key societies, to accelerate date collection and analysis of a global POI registry, and to facilitate progress in the key defined areas of research.

2H-1,2,3-Triazole-chalcones as novel cytotoxic agents against prostate cancer.

Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.

Elective Egg Freezing for Non-Medical Reasons: Scientific Impact Paper No. 63.

Although a woman's fertility declines markedly in her late-30s and early-40s, gradually more and more women start a family at this stage of their lives, with the average age of childbirth progressively increasing. More women are storing their eggs (oocytes) to give them the potential opportunity to have a baby in the future. Nonetheless, the number of egg freezing cycles accounts for less than 2% of IVF cycles, and the number of cycles using stored eggs is even lower. The technology for freezing eggs changed dramatically about a decade ago with the development of a technique of rapid freezing called vitrification, which gives success rates almost as good as using fresh eggs. The growing use of this technique, and the publicity surrounding how this technique may have been promoted, has led to this paper. It is essential that women are very clearly informed about the likely success rates of egg freezing, particularly as it is entirely provided by the private sector, with the associated concerns of financial costs and inappropriate or inaccurate marketing. Its success is strongly dependent on the age of the woman at the time of freezing her eggs, with much higher success rates in those aged 35 years and under. Current legislation only allows women to store eggs for 10 years, which conflicts with the better success rates when women do so at a younger age. The reasons behind the increase in egg freezing are complex, but the most common reason given by women storing eggs is that they do not have a partner and are concerned that by the time they do find themselves in a relationship within which they wish to start a family, they may not be able to. We conclude that elective egg freezing provides women with an opportunity to take action about the drop in their fertility, but at present most women who are doing this are already in their later 30s when the success rates are limited. We strongly support the need for improved and continuing education of both women and men regarding the decline in female fertility with age.

The potential anti-inflammatory and anti-nociceptive effects of rat hemopressin (PVNFKFLSH) in experimental arthritis

Inflammatory arthritis, such as rheumatoid arthritis (RA), stands out as one of the main sources of pain and impairment to the quality of life. The use of hemopressin (PVNFKFLSH; Hp), an inverse agonist of type 1 cannabinoid receptor, has proven to be effective in producing analgesia in pain models, but its effect on neuro-inflammatory aspects of RA is limited. In this study, antigen-induced arthritis (AIA) was evoked by the intraarticular (i.art.) injection of methylated bovine serum albumin (mBSA) in male Sprague Dawley rats. Phosphate buffered saline (PBS)-injected ipsilateral knee joints or AIA contralateral were used as control. Nociceptive and inflammatory parameters such as knee joint oedema and leukocyte influx and histopathological changes were carried out in addition to the local measurement of interleukins (IL) IL-6, IL-1β, tumor necrosis factor-α and the immunoreactivity of the neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal cord (lumbar L3-5 segments) of AIA rats. For 4 days, AIA rats were treated daily with a single administration of saline, Hp injected (10 or 20 μg/day, i.art.), Hp given orally (20 μg/Kg, p.o.) or indomethacin (Indo; 5 mg/Kg, i.p.). In comparison to the PBS control group, the induction of AIA produced a significant and progressive mono-arthritis condition. The degree of AIA severity progressively compromised the normal walking pattern and impaired mobility over the next four days in relation to PBS-injected rats or contralateral knee joints. In AIA rats, the reduction of the distance between footprints and disturbances of gait evidenced signs of nociception. This response worsened at day 4, and a loss of footprint from the ipsilateral hind paw was evident. Daily treatment of the animals with Hp either i.art. (10 and 20 μg/knee) or p.o. (20 μg/Kg) as well as Indo (5 mg/Kg, i.p.) ameliorated the impaired mobility in a time-dependent manner (P < 0.05). In parallel, the AIA-injected ipsilateral knee joints reach a peak of swelling 24 h after AIA induction, which persisted over the next four days in relation to PBS-injected rats or contralateral knee joints. There was a significant but not dose-dependent inhibitory effect produced by all dosages and routes of Hp treatments on AIA-induced knee joint swelling (P < 0.05). In addition, the increased synovial levels of MPO activity, total leukocytes number and IL-6, but not IL-1β, were significantly reduced by the lower i.art. dose of Hp. In conclusion, these results successfully demonstrate that Hp may represent a novel therapeutic strategy to treat RA, an effect which is unrelated to the proinflammatory actions of the neuropeptides CGRP and SP

Kisspeptin treatment induces gonadotropic responses and rescues ovulation in a subset of preclinical models and women with polycystic ovary syndrome.

STUDY QUESTION: Can kisspeptin treatment induce gonadotrophin responses and ovulation in preclinical models and anovulatory women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Kisspeptin administration in some anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. WHAT IS KNOWN ALREADY: PCOS is a prevalent, heterogeneous endocrine disorder, characterized by ovulatory dysfunction, hyperandrogenism and deregulated gonadotrophin secretion, in need of improved therapeutic options. Kisspeptins (encoded by Kiss1) are master regulators of the reproductive axis, acting mainly at GnRH neurons, with kisspeptins being an essential drive for gonadotrophin-driven ovarian follicular maturation and ovulation. Altered Kiss1 expression has been found in rodent models of PCOS, although the eventual pathophysiological role of kisspeptins in PCOS remains unknown. STUDY DESIGN, SIZE, DURATION: Gonadotrophin and ovarian/ovulatory responses to kisspeptin-54 (KP-54) were evaluated in three preclinical models of PCOS, generated by androgen exposures at different developmental windows, and a pilot exploratory cohort of anovulatory women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three models of PCOS were generated by exposure of female rats to androgens at different periods of development: PNA (prenatal androgenization; N = 20), NeNA (neonatal androgenization; N = 20) and PWA (post-weaning androgenization; N = 20). At adulthood (postnatal day 100), rats were subjected to daily treatments with a bolus of KP-54 (100 µg/kg, s.c.) or vehicle for 11 days (N = 10 per model and treatment). On Days 1, 4, 7 and 11, LH and FSH responses were assessed at different time-points within 4 h after KP-54 injection, while ovarian responses, in terms of follicular maturation and ovulation, were measured at the end of the treatment. In addition, hormonal (gonadotrophin, estrogen and inhibin B) and ovulatory responses to repeated KP-54 administration, at doses of 6.4-12.8 nmol/kg, s.c. bd for 21 days, were evaluated in a pilot cohort of anovulatory women (N = 12) diagnosed with PCOS, according to the Rotterdam criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Deregulated reproductive indices were detected in all PCOS models: PNA, NeNA and PWA. Yet, anovulation was observed only in NeNA and PWA rats. However, while anovulatory NeNA rats displayed significant LH and FSH responses to KP-54 (P < 0.05), which rescued ovulation, PWA rats showed blunted LH secretion after repeated KP-54 injection and failed to ovulate. In women with PCOS, KP-54 resulted in a small rise in LH (P < 0.05), with an equivalent elevation in serum estradiol levels (P < 0.05). Two women showed growth of a dominant follicle with subsequent ovulation, one woman displayed follicle growth but not ovulation and desensitization was observed in another patient. No follicular response was detected in the other women. LIMITATIONS, REASONS FOR CAUTION: While three different preclinical PCOS models were used in order to capture the heterogeneity of clinical presentations of the syndrome, it must be noted that rat models recapitulate many but not all the features of this condition. Additionally, our pilot study was intended as proof of principle, and the number of participants is low, but the convergent findings in preclinical and clinical studies reinforce the validity of our conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our first-in-rodent and -human studies demonstrate that KP-54 administration in anovulatory preclinical models and women with PCOS can stimulate reproductive hormone secretion and ovulation, albeit with incomplete efficacy. As our rat models likely reflect the diversity of PCOS phenotypes, our results argue for the need of personalized management of anovulatory dysfunction in women with PCOS, some of whom may benefit from kisspeptin-based treatments. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research agreements between Ferring Research Institute and the Universities of Cordoba and Edinburgh. K.S. was supported by the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative (STMTI). Some of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. M.T.-S. is a member of CIBER Fisiopatología de la Obesidad y Nutrición, which is an initiative of Instituto de Salud Carlos III. Dr Mannaerts is an employee of Ferring International PharmaScience Center (Copenhagen, Denmark), and Drs Qi, van Duin and Kohout are employees of the Ferring Research Institute (San Diego, USA). Dr Anderson and Dr Tena-Sempere were recipients of a grant support from the Ferring Research Institute, and Dr Anderson has undertaken consultancy work and received speaker fees outside this study from Merck, IBSA, Roche Diagnostics, NeRRe Therapeutics and Sojournix Inc. Dr Skorupskaite was supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative 102419/Z/13/A. The other authors have no competing interest.

Ovarian damage from chemotherapy and current approaches to its protection.

BACKGROUND: Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage. OBJECTIVE AND RATIONALE: This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed. SEARCH METHODS: Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents. OUTCOMES: Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed. WIDER IMPLICATIONS: Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically.

Cardiovascular and renal outcomes following percutaneous coronary intervention in a population with renal disease: a case-control study.

BACKGROUND: Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes. AIM: We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD. DESIGN: Retrospective observational case-control study. METHODS: Cases were individuals with CKD (stages 1-5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan-Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression. RESULTS: We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI. CONCLUSION: Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI.

The existence and potential of germline stem cells in the adult mammalian ovary.

It has long been accepted that the complement of follicles within the ovary is formed before birth in humans, or shortly after birth in rodents, and that no follicles are formed thereafter. This follows entry of all oogonia into meiosis in fetal life, with no remaining germ stem cells in the ovary, in contrast to the presence of spermatogonia in the testis. This has been brought back into debate in recent years, following the demonstration of isolation of cells expressing both germline and stem markers from the postnatal ovary in several species, including humans. We describe these cells as putative ovarian stem cells. Isolation of these cells is challenging, adding to the debate as to their existence, and the validity of DDX4 as the main marker used for their isolation has also to be questioned. While different groups have used varying techniques and indeed terminology to describe these cells, the body of evidence regarding their initial characterization after isolation is growing. There remain very limited data regarding their developmental potential, but the demonstration of the production of functional oocytes from induced pluripotent stem cells and the advances in ovarian follicle culture techniques provide a basis for such studies.

Morphometric and gene expression analyses of stromal expansion during development of the bovine fetal ovary.

During ovarian development stroma from the mesonephros penetrates and expands into the ovarian primordium and thus appears to be involved, at least physically, in the formation of ovigerous cords, follicles and surface epithelium. Cortical stromal development during gestation in bovine fetal ovaries (n=27) was characterised by immunohistochemistry and by mRNA analyses. Stroma was identified by immunostaining of stromal matrix collagen type I and proliferating cells were identified by Ki67 expression. The cortical and medullar volume expanded across gestation, with the rate of cortical expansion slowing over time. During gestation, the proportion of stroma in the cortex and total volume in the cortex significantly increased (P<0.05). The proliferation index and numerical density of proliferating cells in the stroma significantly decreased (P<0.05), whereas the numerical density of cells in the stroma did not change (P>0.05). The expression levels of 12 genes out of 18 examined, including osteoglycin (OGN) and lumican (LUM), were significantly increased later in development (P<0.05) and the expression of many genes was positively correlated with other genes and with gestational age. Thus, the rate of cortical stromal expansion peaked in early gestation due to cell proliferation, whilst late in development expression of extracellular matrix genes increased.

The neurokinin B pathway in the treatment of menopausal hot flushes.

Hot flushes remain a debilitating aspect of menopause, disrupting daytime activities and sleep, and may last for years. Estrogen replacement is an effective treatment, but takes time to become maximally effective and is contraindicated in a significant proportion of women, most notably after breast cancer. Effective, non-hormonal therapies are therefore required. Recent years have seen substantial increases in understanding of the role of novel neuropeptides and tachykinins in hypothalamic function, particularly in the regulation of the reproductive axis through control of gonadotropin releasing hormone secretion, but with links to the control of vasomotor function. Neurokinin B, often co-expressed with kisspeptin in hypothalamic neurons, appears to be a key factor in the control of both systems. Several neurokinin B antagonists have been developed; data are emerging as to their effectiveness in the treatment of menopausal hot flushes. While data remain limited, these agents appear to have a remarkably fast onset of action, with the first 1 or 2 days of administration, and with a dramatic effect on both daytime flushes and night sleep disturbance. If safety and long-term function can be confirmed, these novel agents will be an important advance in therapy.