The (endo)cannabinoid signaling in female reproduction: What are the latest advances?

Cannabis extracts like marijuana have the highest consumption rate worldwide. Yet, their societal acceptance as recreational and therapeutic drugs could represent a serious hazard to female human reproduction, because cannabis ingredients [termed (phyto)cannabinoids] can perturb an endogenous system of lipid signals known as endocannabinoids. Accumulated evidence on animal models and humans has demonstrated a crucial role of these endogenous signals on different aspects of female reproduction, where they act through an ensamble of proteins that synthesize, transport, degrade and traffic them. Several reports have recently evidenced the potential role of endocannabinoids as biomarkers of female infertility for disease treatment and prevention, as well as their possible epigenetic effects on pregnancy. The purpose of this review is to provide an update of data collected in the last decade on the effects of cannabinoids and endocannabinoids on female reproductive events, from development and maturation of follicles and oocytes, to fertilization, oviductal transport, implantation and labor. In this context, a particular attention has ben devoted to the ovary and the production of fertilizable oocytes, because recent studies have addressed this hot topic with conflicting results among species

Heat Sensing Receptor TRPV1 Is a Mediator of Thermotaxis in Human Spermatozoa

The molecular bases of sperm thermotaxis, the temperature-oriented cell motility, are currently under investigation. Thermal perception relies on a subclass of the transient receptor potential [TRP] channels, whose member TRPV1 is acknowledged as the heat sensing receptor. Here we investigated the involvement of TRPV1 in human sperm thermotaxis. We obtained semen samples from 16 normozoospermic subjects attending an infertility survey programme, testis biopsies from 6 patients with testicular germ cell cancer and testis fine needle aspirates from 6 patients with obstructive azoospermia undergoing assisted reproductive technologies. Expression of TRPV1 mRNA was assessed by RT-PCR. Protein expression of TRPV1 was determined by western blot, flow cytometry and immunofluorescence. Sperm motility was assessed by Sperm Class Analyser. Acrosome reaction, apoptosis and intracellular-Ca2+ content were assessed by flow cytometry. We found that TRPV1 mRNA and protein were highly expressed in the testis, in both Sertoli cells and germ-line cells. Moreover, compared to no-gradient controls at 31°C or 37°C (Ctrl 31°C and Ctrl 37°C respectively), sperm migration towards a temperature gradient of 31-37°C (T gradient) in non-capacitated conditions selected a higher number of cells (14,9 ± 4,2×106 cells T gradient vs 5,1± 0,3×106 cells Ctrl 31°C and 5,71±0,74×106 cells Ctrl 37°C; P = 0,039). Capacitation amplified the migrating capability towards the T gradient. Sperms migrated towards the T gradient showed enriched levels of both TRPV1 protein and mRNA. In addition, sperm cells were able to migrate toward a gradient of capsaicin, a specific agonist of TRPV1, whilst capsazepine, a specific agonist of TRPV1, blocked this effect. Finally, capsazepine severely blunted migration towards T gradient without abolishing. These results suggest that TRPV1 may represent a facilitating mediator of sperm thermotaxis

Anthropogenic sinkholes of the city of Naples, Italy: an update

In recent years, the study of anthropogenic sinkholes in densely urbanized areas has attracted the attention of both researchers and land management entities. The city of Naples (Italy) has been frequently affected by processes generating such landforms in the last decades: for this reason, an update of the sinkhole inventory and a preliminary susceptibility estimation are proposed in this work. Starting from previous data, not modified since 2010, a total of 270 new events occurred in the period February 2010–June 2021 were collected through the examination of online newspapers, local daily reports, council chronicle news and field surveys. The final consistence of the updated inventory is of 458 events occurred between 1880 and 2021, distributed through time with an increasing trend in frequency. Spatial analysis of sinkholes indicates a concentration in the central sector of the city, corresponding to its ancient and historic centre, crossed by a dense network of underground tunnels and cavities. Cavity-roof collapse is confirmed as one of the potential genetic types, along with processes related to rainfall events and service lines damage. A clear correlation between monthly rainfall and the number of triggered sinkholes was identified. Finally, a preliminary sinkhole susceptibility assessment, carried out by Frequency Ratio method, confirms the central sector of city as that most susceptible to sinkholes and emphasizes the predisposing role of service lines, mostly in the outermost areas of the city

Effects of Obesity and Thrombophilia on the Risk of Abortion in Women Undergoing In Vitro Fertilization.

Introduction Obesity is associated with a higher risk of abortion in women undergoing in vitro fertilization (IVF). Whether thrombophilia amplifies this risk is currently unclear. The aim of this study was to evaluate the effects of thrombophilia on the risk of abortion in obese women treated with IVF. Methods Patient characteristics, presence of inherited or acquired thrombophilia, and comorbidities were prospectively collected before the procedure in consecutive women undergoing IVF. The primary outcome was the incidence of abortion among women who achieved a clinical pregnancy. Results A total of 633 non-obese and 49 obese Caucasian women undergoing IVF were included. 204 (32%) women achieved clinical pregnancy, of whom six had an ectopic pregnancy and 63 experienced an abortion. The incidence of abortion was higher in obese women compared to non-obese women after adjusting for age (64.3% vs. 29.3%, odds ratio [OR] 4.41; 95% CI 1.41 to 13.81). Women with one or more thrombophilia were at increased risk of abortion relative to those without thrombophilia (OR 2.70; 95% CI 1.34 to 5.45), and the risk seemed to be higher with hereditary (OR 5.12; 95% CI 1.77 to 14.8) than acquired thrombophilia (OR 1.92; 95% CI 0.52 to 5.12; p for interaction 0.194). Among obese women, the presence of one or more thrombophilia seemed associated with a substantially increased risk of abortion (unadjusted OR 14.00; 95% CI 0.94 to 207.6). Conclusions Obese women undergoing IVF have a high risk of abortion which seems further amplified by the concomitant presence of thrombophilia

Increased Cardiovascular Risk Associated with Chemical Sensitivity to Perfluoro-Octanoic Acid: Role of Impaired Platelet Aggregation

Perfluoro\u2013alkyl substances (PFAS), particularly perfluoro\u2013octanoic acid (PFOA), are persisting environmental chemicals showing bioaccumulation in human tissues. Recently, exposure to PFAS has been associated with increased prevalence of cardiovascular diseases (CVDs). However, a causal role of PFAS in atherosclerosis pathogenesis is under-investigated. Here, we investigated the effect of PFOA exposure on platelets\u2019 function, a key player in atherosclerosis process. PFOA accumulation in platelets was evaluated by liquid chromatography-mass spectrometry. Changes in platelets\u2019 membrane fluidity and activation after dose-dependent exposure to PFOA were evaluated by merocyanine 540 (MC540) and anti P-Selectin immune staining at flow cytometry, respectively. Intracellular calcium trafficking was analyzed with Fluo4M probe, time-lapse live imaging. Platelets\u2019 aggregation state was also evaluated with Multiplate\uae aggregometry analyzer in 48 male subjects living in a specific area of the Veneto region with high PFAS environmental pollution, and compared with 30 low-exposure control subjects. Platelets\u2019 membrane was the major target of PFOA, whose dose-dependent accumulation was associated in turn with increased membrane fluidity, as expected by a computational model; increased activation at resting condition; and both calcium uptake and aggregation upon activation. Finally, exposed subjects had higher serum and platelets levels of PFOA, together with increased aggregation parameters at Multiplate\uae, compared with controls. These data help to explain the emerging association between PFAS exposure and CVD

Computerised cognitive training for 12 or more weeks for maintaining cognitive function in cognitively healthy people in late life

Background: Increasing age is associated with a natural decline in cognitive function and is the greatest risk factor for dementia. Cognitive decline and dementia are significant threats to independence and quality of life in older adults. Therefore, identifying interventions that help to maintain cognitive function in older adults or that reduce the risk of dementia is a research priority. Cognitive training uses repeated practice on standardised exercises targeting one or more cognitive domains and may be intended to improve or maintain optimal cognitive function. This review examines the effects of computerised cognitive training interventions lasting at least 12 weeks on the cognitive function of healthy adults aged 65 or older and has formed part of a wider project about modifying lifestyle to maintain cognitive function. We chose a minimum 12 weeks duration as a trade-off between adequate exposure to a sustainable intervention and feasibility in a trial setting. Objectives: To evaluate the effects of computerised cognitive training interventions lasting at least 12 weeks on cognitive function in cognitively healthy people in late life. Search methods: We searched to 31 March 2018 in ALOIS (www.medicine.ox.ac.uk/alois), and we performed additional searches of MEDLINE, Embase, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP (www.apps.who.int/trialsearch), to ensure that the search was as comprehensive and as up-to-date as possible to identify published, unpublished, and ongoing trials. Selection criteria: We included randomised controlled trials (RCTs) and quasi-RCTs, published or unpublished, reported in any language. Participants were cognitively healthy people, and at least 80% of the study population had to be aged 65 or older. Experimental interventions adhered to the following criteria: intervention was any form of interactive computerised cognitive intervention - including computer exercises, computer games, mobile devices, gaming console, and virtual reality - that involved repeated practice on standardised exercises of specified cognitive domain(s) for the purpose of enhancing cognitive function; the duration of the intervention was at least 12 weeks; cognitive outcomes were measured; and cognitive training interventions were compared with active or inactive control interventions. Data collection and analysis: We performed preliminary screening of search results using a 'crowdsourcing' method to identify RCTs. At least two review authors working independently screened the remaining citations against inclusion criteria. At least two review authors also independently extracted data and assessed the risk of bias of included RCTs. Where appropriate, we synthesised data in random-effects meta-analyses, comparing computerised cognitive training (CCT) separately with active and inactive controls. We expressed treatment effects as standardised mean differences (SMDs) with 95% confidence intervals (CIs). We used GRADE methods to describe the overall quality of the evidence for each outcome. Main results: We identified eight RCTs with a total of 1183 participants. The duration of the interventions ranged from 12 to 26 weeks; in five trials, the duration of intervention was 12 or 13 weeks. The included studies had moderate risk of bias, and the overall quality of evidence was low or very low for all outcomes. We compared CCT first against active control interventions, such as watching educational videos. Negative SMDs favour CCT over control. Trial results suggest slight improvement in global cognitive function at the end of the intervention period (12 weeks) (standardised mean difference (SMD) -0.31, 95% confidence interval (CI) -0.57 to -0.05; 232 participants; 2 studies; low-quality evidence). One of these trials also assessed global cognitive function 12 months after the end of the intervention; this trial provided no clear evidence of a persistent effect (SMD -0.21, 95% CI -0.66 to 0.24; 77 participants; 1 study; low-quality evidence). CCT may result in little or no difference at the end of the intervention period in episodic memory (12 to 17 weeks) (SMD 0.06, 95% CI -0.14 to 0.26; 439 participants; 4 studies; low-quality evidence) or working memory (12 to 16 weeks) (SMD -0.17, 95% CI -0.36 to 0.02; 392 participants; 3 studies; low-quality evidence). Because of the very low quality of the evidence, we are very uncertain about the effects of CCT on speed of processing and executive function. We also compared CCT to inactive control (no interventions). We found no data on our primary outcome of global cognitive function. At the end of the intervention, CCT may lead to slight improvement in episodic memory (6 months) (mean difference (MD) in Rivermead Behavioural Memory Test (RBMT) -0.90 points, 95% confidence interval (CI) -1.73 to -0.07; 150 participants; 1 study; low-quality evidence) but can have little or no effect on executive function (12 weeks to 6 months) (SMD -0.08, 95% CI -0.31 to 0.15; 292 participants; 2 studies; low-quality evidence), working memory (16 weeks) (MD -0.08, 95% CI -0.43 to 0.27; 60 participants; 1 study; low-quality evidence), or verbal fluency (6 months) (MD -0.11, 95% CI -1.58 to 1.36; 150 participants; 1 study; low-quality evidence). We could not determine any effects on speed of processing because the evidence was of very low quality. We found no evidence on quality of life, activities of daily living, or adverse effects in either comparison. Authors' conclusions: We found low-quality evidence suggesting that immediately after completion of the intervention, small benefits of CCT may be seen for global cognitive function when compared with active controls, and for episodic memory when compared with an inactive control. These benefits are of uncertain clinical importance. We found no evidence that the effect on global cognitive function persisted 12 months later. Our confidence in the results was low, reflecting the overall quality of the evidence. In five of the eight trials, the duration of the intervention was just three months. The possibility that more extensive training could yield larger benefit remains to be more fully explored. We found substantial literature on cognitive training, and collating all available scientific information posed problems. Duration of treatment may not be the best way to categorise interventions for inclusion. As the primary interest of older people and of guideline writers and policymakers involves sustained cognitive benefit, an alternative would be to categorise by length of follow-up after selecting studies that assess longer-term effects

Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis

Background: Venous thromboembolism (VTE) may complicate the course of Coronavirus Disease 2019 (COVID-19). Objectives: To evaluate the incidence of VTE in patients with COVID-19. Methods: MEDLINE, EMBASE, and PubMed were searched up to 24th June 2020 for studies that evaluated the incidence of VTE, including pulmonary embolism (PE) and/or deep vein thrombosis (DVT), in patients with COVID-19. Pooled proportions with corresponding 95% confidence intervals (CI) and prediction intervals (PI) were calculated by random-effect meta-analysis. Results: 3487 patients from 30 studies were included. Based on very low-quality evidence due to heterogeneity and risk of bias, the incidence of VTE was 26% (95% PI, 6%–66%). PE with or without DVT occurred in 12% of patients (95% PI, 2%–46%) and DVT alone in 14% (95% PI, 1%–75%). Studies using standard algorithms for clinically suspected VTE reported PE in 13% of patients (95% PI, 2%–57%) and DVT in 6% (95% PI, 0%–60%), compared to 11% (95% PI, 2%–46%) and 24% (95% PI, 2%–85%) in studies using other diagnostic strategies or patient sampling. In patients admitted to intensive care units, VTE occurred in 24% (95% PI, 5%–66%), PE in 19% (95% PI, 6%–47%), and DVT alone in 7% (95% PI, 0%–69%). Corresponding values in general wards were respectively 9% (95% PI, 0%–94%), 4% (95% PI, 0%–100%), and 7% (95% CI, 1%–49%). Conclusions: VTE represents a frequent complication in hospitalized COVID-19 patients and often occurs as PE. The threshold for clinical suspicion should be low to trigger prompt diagnostic testing

An Optimal Execution Problem with Market Impact

We study an optimal execution problem in a continuous-time market model that considers market impact. We formulate the problem as a stochastic control problem and investigate properties of the corresponding value function. We find that right-continuity at the time origin is associated with the strength of market impact for large sales, otherwise the value function is continuous. Moreover, we show the semi-group property (Bellman principle) and characterise the value function as a viscosity solution of the corresponding Hamilton-Jacobi-Bellman equation. We introduce some examples where the forms of the optimal strategies change completely, depending on the amount of the trader's security holdings and where optimal strategies in the Black-Scholes type market with nonlinear market impact are not block liquidation but gradual liquidation, even when the trader is risk-neutral.Comment: 36 pages, 8 figures, a modified version of the article "An optimal execution problem with market impact" in Finance and Stochastics (2014