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One hundred and twenty postmenopausal women with osteoporosis were enrolled into an open, controlled study of 24 months' duration, with the aim of evaluating the metabolic action and the effect on bone mineral density (BMD) of calcitriol (0.5 µg/day), alendronate (10 mg/day) and combined treatment with alendronate (10 mg/day) + calcitriol (0.5 µg/day). We also studied 30 patients treated with placebo (calcium 500 mg/day). BMD was measured by total body dual-energy x-ray absorptiometry (DPX-Lunar) as total body BMD and at different sites of interest including the spine, trunk, arms, legs and pelvis. BMD appeared to be significantly higher in the group of patients receiving combined therapy compared with the group treated with alendronate or calcitriol alone. In the placebo group, BMD decreased significantly. Depending on the skeletal regions in which BMD was measured (total body or selected areas), 15 to 23% of patients treated with calcitriol, 37 to 48% of patients treated with alendronate, and 69 to 78% of patients treated with alendronate + calcitriol, respectively, had a BMD increase greater than the lowest significant densitometric difference. In patients treated with alendronate, 24-hour urinary calcium and hydroxyproline levels fell significantly after 3 months, and alkaline phosphatase levels fell significantly after 6 months; these parameters remained unchanged in all patients on combined treatment. We concluded that combined treatment with calcitriol + alendronate was more effective than therapy with alendronate alone. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nonsteroidal anti-inflammatory drugs are the most widely used agents in the symptomatic treatment of osteoarthritis (OA). No data are presently available on the medium-term management of this disease with an on-demand treatment regimen, which nevertheless reflects medical practice. OBJECTIVES: The aim of this study was to compare nimesulide-beta-cyclodextrin and naproxen in terms of short-term (2 weeks) pain control with scheduled dosing and medium-term (5.5 months) pain control with on-demand dosing in patients with OA. METHODS: In this multicenter, randomized, double-blind, controlled study, we compared 2 weeks of scheduled treatment plus 5.5 months of on-demand treatment in patients with OA of the hip and/or knee and moderate to severe pain, with no important concomitant disorders. Treatment consisted of nimesulide-beta-cyclodextrin (400 mg BID, orally = 100 mg nimesulide BID) or naproxen (500 mg BID). The primary outcome measures for scheduled dosing were pain on movement (measured by visual analog scale), morning stiffness score, Lequesne index, and adverse events. For on-demand dosing, the measures were the same as for scheduled dosing, plus duration of treatment and global assessment of efficacy and tolerability by patient and physician. RESULTS: After 2 weeks, there was equivalent reduction from baseline in pain on movement in the 2 treatment groups (nimesulide-beta-cyclodextrin, -41.5%; naproxen, -40.5%); the reduction was significant after 1 week (P < 0.001). The findings were also similar for the morning stiffness score and Lequesne index. There were no significant differences in mean duration of on-demand treatment (nimesulide-beta-cyclodextrin, 163.03 days; naproxen, 166.3 days) or in mean consumption of study drug (nimesulide-beta-cyclodextrin, 0.85 +/- 0.61 sachets/d; naproxen, 0.74 +/- 0.42 sachets/d). Withdrawal due to intolerance occurred in 8 patients given nimesulide-beta-cyclodextrin and 13 patients given naproxen, with no significant difference between groups; 3 and 12 patients, respectively, withdrew due to gastrointestinal intolerance, a finding that was significantly different between groups (P < 0.01). Global assessment of efficacy by patient and physician was similar for both drugs. Assessment of tolerability significantly favored nimesulide-beta-cyclodextrin on the physician assessments (P < 0.05) but was similar for the 2 drugs on the patient assessments (physicians, 46.9% vs 30.9%; patients, 43.5% vs 33.3%). CONCLUSIONS: The results suggest that nimesulide-beta-cyclodextrin provides similar pain relief to naproxen in the management of OA of the hip and/or knee and is associated with fewer gastrointestinal adverse reactions. On-demand dosing may be an effective and well-tolerated low-dose regimen of nonsteroidal anti-inflammatory drugs for the maintenance of pain control in OA in the medium term. [ABSTRACT FROM AUTHOR]

Study Question: Can oocyte functionality be assessed by observing changes in their intracytoplasmic lipid droplets (LDs) profiles?, Summary Answer: Lipid profile changes can reliably be detected in human oocytes; lipid changes are linked with maternal age and impaired developmental competence in a mouse model., What Is Known Already: In all cellular components, lipid damage is the earliest manifestation of oxidative stress (OS), which leads to a cascade of negative consequences for organelles and DNA. Lipid damage is marked by the accumulation of LDs. We hypothesized that impaired oocyte functionality resulting from aging and associated OS could be assessed by changes in LDs profile, hereafter called lipid fingerprint (LF)., Study Design, Size, Duration: To investigate if it is possible to detect differences in oocyte LF, we subjected human GV-stage oocytes to spectroscopic examinations. For this, a total of 48 oocytes derived from 26 young healthy women (under 33 years of age) with no history of infertility, enrolled in an oocyte donation program, were analyzed. Furthermore, 30 GV human oocytes from 12 women were analyzed by transmission electron microscopy (TEM). To evaluate the effect of oocytes' lipid profile changes on embryo development, a total of 52 C57BL/6 wild-type mice and 125 Gnpat+/- mice were also used., Participants/materials, Setting, Methods: Human oocytes were assessed by label-free cell imaging via coherent anti-Stokes Raman spectroscopy (CARS). Further confirmation of LF changes was conducted using spontaneous Raman followed by Fourier transform infrared (FTIR) spectroscopies and TEM. Additionally, to evaluate whether LF changes are associated with developmental competence, mouse oocytes and blastocysts were evaluated using TEM and the lipid dyes BODIPY and Nile Red. Mouse embryonic exosomes were evaluated using flow cytometry, FTIR and FT-Raman spectroscopies., Main Results and the Role of Chance: Here we demonstrated progressive changes in the LF of oocytes associated with the woman's age consisting of increased LDs size, area, and number. LF variations in oocytes were detectable also within individual donors. This finding makes LF assessment a promising tool to grade oocytes of the same patient, based on their quality. We next demonstrated age-associated changes in oocytes reflected by lipid peroxidation and composition changes; the accumulation of carotenoids; and alterations of structural properties of lipid bilayers. Finally, using a mouse model, we showed that LF changes in oocytes are negatively associated with the secretion of embryonic exosomes prior to implantation. Deficient exosome secretion disrupts communication between the embryo and the uterus and thus may explain recurrent implantation failures in advanced-age patients., Limitations, Reasons for Caution: Due to differences in lipid content between different species' oocytes, the developmental impact of lipid oxidation and consequent LF changes may differ across mammalian oocytes., Wider Implications of the Findings: Our findings open the possibility to develop an innovative tool for oocyte assessment and highlight likely functional connections between oocyte LDs and embryonic exosome secretion. By recognizing the role of oocyte LF in shaping the embryo's ability to implant, our original work points to future directions of research relevant to developmental biology and reproductive medicine., Study Funding/competing Interest(s): This research was funded by National Science Centre of Poland, Grants: 2021/41/B/NZ3/03507 and 2019/35/B/NZ4/03547 (to G.E.P.); 2022/44/C/NZ4/00076 (to M.F.H.) and 2019/35/N/NZ3/03213 (to Ł.G.). M.F.H. is a National Agency for Academic Exchange (NAWA) fellow (GA ULM/2019/1/00097/U/00001). K.F. is a Diamond Grant fellow (Ministry of Education and Science GA 0175/DIA/2019/28). The open-access publication of this article was funded by the Priority Research Area BioS under the program "Excellence Initiative - Research University" at the Jagiellonian University in Krakow. The authors declare no competing interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Obesity is a global epidemic that affects millions worldwide and can be a deterrent to surgical procedures in the population waiting for kidney transplantation. However, the literature on the topic is controversial. This study evaluates the impact of body mass index (BMI) on complications after renal transplantation, and identifies factors associated with major complications to develop a prognostic risk score., Methods: A correlation analysis between BMI and early and late complications was first performed, followed by a univariate and multivariate logistic regression analysis. The 302 included patients were divided into obese (BMI ≥ 30 kg/m 2 ) and non-obese (BMI ≤ 30 kg/m 2 ) groups. Correlation analysis showed that delayed graft function (DGF) was the only obesity-associated complication ( p = 0.044). Logistic regression analysis identified female sex, age ≥ 57 years, BMI ≥ 25 and ≥30 kg/m 2 , previous abdominal and/or urinary system surgery, and Charlson morbidity Score ≥ 3 as risk factors for significant complications. Based on the analyzed data, we developed a nomogram and a prognostic risk score., Results: The model's area (AUC) was 0.6457 (95% IC: 0.57; 0.72). The percentage of cases correctly identified by this model retrospectively applied to the entire cohort was 73.61%., Conclusions: A high BMI seems to be associated with an increased risk of DGF, but it does not appear to be a risk factor for other complications. Using an easy-to-use model, identification, and stratification of individualized risk factors could help to identify the need for interventions and, thus, improve patient eligibility and transplant outcomes. This could also contribute to maintaining an approach with high ethical standards.

Background: Advanced atrioventricular block (AVB), that is, higher than second-degree Mobitz-1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti-Ro/Sjögren syndrome-related antigen A (SSA) antibodies cross-reacting with L-type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti-Ro/SSA-associated advanced AVBs in a large sample of young athletes., Methods and Results: A total of 2536 consecutive athletes aged <40 years without a history of cardiac diseases/interventions were enrolled in a cross-sectional study. Resting and exercise electrocardiography was performed, and those presenting any AVB were further evaluated by 24-hour Holter ECG. Athletes with second-degree AVBs and their mothers underwent anti-Ro/SSA testing. Moreover, purified immunoglobulin G from subjects with anti-Ro/SSA-positive and anti-Ro/SSA-negative advanced AVB were tested on L-type calcium current and L-type-calcium channel expression using tSA201 cells. The global prevalence of advanced AVB in the overall sample was ≈0.1%, but the risk considerably increased (2%) when intensely trained postpubertal male subjects were selectively considered. While none of the athletes with advanced AVB showed heart abnormalities, in 100% of cases anti-Ro/SSA antibodies were detected. Ex vivo experiments showed that immunoglobulin G from anti-Ro/SSA-positive but not -negative subjects with advanced AVB acutely inhibit L-type calcium current and chronically downregulate L-type-calcium channel expression., Conclusions: Our study provides evidence that advanced AVB occurs in young athletes, in most cases associated with anti-Ro/SSA antibodies blocking L-type calcium channels. These findings may open new avenues for immunomodulating therapies to reduce the risk of life-threatening events in athletes, avoiding or delaying pacemaker implantation.

Background: Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects., Methods and Results: An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction., Conclusions: Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Background: In ∼50% of severe atrioventricular blocks (AVBs) occurring in adults <50 years, the underlying etiology remains unknown. Preliminary evidence from case reports suggests that autoimmunity, specifically the presence of circulating anti-Ro/SSA antibodies in the patient (acquired form), in the patient's mother (late-progressive congenital form), or in both (mixed form), could be involved in a fraction of idiopathic AVBs in adults by possibly targeting the L-type calcium channel (Ca v 1.2) and inhibiting the related current (I CaL )., Objectives: The purpose of this study was to evaluate whether anti-Ro/SSA antibodies are causally implicated in the development of isolated AVBs in adults., Methods: Thirty-four consecutive patients with isolated AVB of unknown origin and 17 available mothers were prospectively enrolled in a cross-sectional study. Anti-Ro/SSA antibodies were assessed by fluoroenzyme-immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified immunoglobulin-G (IgG) from anti-Ro/SSA-positive and anti-Ro/SSA-negative subjects were tested on I CaL and Ca v 1.2 expression using tSA201 and HEK293 cells, respectively. Moreover, in 13 AVB patients, the impact of a short course of steroid therapy on AV conduction was evaluated., Results: Anti-Ro/SSA antibodies, particularly anti-Ro/SSA-52kD, were found in 53% of AVB-patients and/or in their mothers, most commonly an acquired or mixed form (two-thirds of cases) without history of autoimmune diseases. Purified IgG from anti-Ro/SSA-positive but not anti-Ro/SSA-negative AVB patients acutely inhibited I CaL and chronically down-regulated Ca v 1.2 expression. Moreover, anti-Ro/SSA-positive sera showed high reactivity with peptides corresponding to the Ca v 1.2 channel pore-forming region. Finally, steroid therapy rapidly improved AV conduction in AVB-patients with circulating anti-Ro/SSA antibodies but not in those without., Conclusions: Our study points to anti-Ro/SSA antibodies as a novel, epidemiologically relevant and potentially reversible cause of isolated AVB in adults, via an autoimmune-mediated functional interference with the L-type calcium channels. These findings have significant impact on antiarrhythmic therapies by avoiding or delaying pacemaker implantation., Competing Interests: Funding Support and Author Disclosures This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN), and Bando 2017, protocollo 2017XZMBYX (to Dr Lazzerini and Dr Capecchi); a Merit Review grant I01 BX002137 from Biomedical Laboratory Research & Development Service of Veterans Affairs Office of Research and Development (to Dr Boutjdir); National Heart, Lung, and Blood Institute grant 1R01HL164415-01 (to Dr Boutjdir); and U.S. Department of Defense award number W81XWH-21-1-0424 (to Dr Boutjdir). Dr Lazzerini has received a grant from Roche Italia S.p.A. outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Lipid droplets (LDs) are intracellular structures composed of hydrophobic lipids. Their amount in oocytes and embryos varies among the mammalian species and even among different strains of the same species. Here we describe a method to stain LDs, which can be applied to previously fixed mouse oocytes and embryos. This method is based on fluorescent dyes, Nile red and BODIPY, which allow visualization and quantification of LDs using conventional and confocal fluorescence microscopy., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Conception of a child at advanced parental age (> 35 years) has been steadily increasing in recent decades, especially in developed countries. Socio-economic factors, effective contraceptives, and the availability of Assisted Reproduction Technologies (ART) have a direct impact on postponing the decision to have a baby. ART enables reproductive success for people diagnosed as infertile or with reduced possibilities of becoming pregnant due to concomitant pathologies. Epidemiological studies indicate that both advanced parental age and ART are associated with pathologies of pregnancy, such as gestational diabetes, risk of pre-eclampsia, miscarriage, placental abruption, preterm labor, stillbirth, neurodevelopmental disorders and chronic disease of the offspring. In our work, we will focus on the available information on metabolic changes that increase the risk of developing cardiovascular diseases in the offspring of parents at an advanced age and conceived through ART. Finally, we will address the sources of the observed disturbances at the gamete and embryo level, related to oxygen stress, epigenetic modifications and DNA damage, considering possible rescue actions.

Background: Heart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms., Methods: We investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro ., Results: In patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (I Kr )., Conclusion: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies., Competing Interests: PL received a grant from Roche Italia S.p.A. outside the submitted work in 2018. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lazzerini, Accioli, Acampa, Zhang, Verrengia, Cartocci, Bacarelli, Xin, Salvini, Chen, Salvadori, D’errico, Bisogno, Cevenini, Marzotti, Capecchi, Laghi-Pasini, Chen, Capecchi and Boutjdir.)

Background: DNA damage is a hazard that affects all cells of the body. DNA-damage repair (DDR) mechanisms are in place to repair damage and restore cellular function, as are other damage-induced processes such as apoptosis, autophagy and senescence. The resilience of germ cells and embryos in response to DNA damage is less well studied compared with other cell types. Given that recent studies have described links between embryonic handling techniques and an increased likelihood of disease in post-natal life, an update is needed to summarize the sources of DNA damage in embryos and their capacity to repair it. In addition, numerous recent publications have detailed novel techniques for detecting and repairing DNA damage in embryos. This information is of interest to medical or scientific personnel who wish to obtain undamaged embryos for use in offspring generation by ART., Objective and Rationale: This review aims to thoroughly discuss sources of DNA damage in male and female gametes and preimplantation embryos. Special consideration is given to current knowledge and limits in DNA damage detection and screening strategies. Finally, obstacles and future perspectives in clinical diagnosis and treatment (repair) of DNA damaged embryos are discussed., Search Methods: Using PubMed and Google Scholar until May 2021, a comprehensive search for peer-reviewed original English-language articles was carried out using keywords relevant to the topic with no limits placed on time. Keywords included 'DNA damage repair', 'gametes', 'sperm', 'oocyte', 'zygote', 'blastocyst' and 'embryo'. References from retrieved articles were also used to obtain additional articles. Literature on the sources and consequences of DNA damage on germ cells and embryos was also searched. Additional papers cited by primary references were included. Results from our own studies were included where relevant., Outcomes: DNA damage in gametes and embryos can differ greatly based on the source and severity. This damage affects the development of the embryo and can lead to long-term health effects on offspring. DDR mechanisms can repair damage to a certain extent, but the factors that play a role in this process are numerous and altogether not well characterized. In this review, we describe the multifactorial origin of DNA damage in male and female gametes and in the embryo, and suggest screening strategies for the selection of healthy gametes and embryos. Furthermore, possible therapeutic solutions to decrease the frequency of DNA damaged gametes and embryos and eventually to repair DNA and increase mitochondrial quality in embryos before their implantation is discussed., Wider Implications: Understanding DNA damage in gametes and embryos is essential for the improvement of techniques that could enhance embryo implantation and pregnancy success. While our knowledge about DNA damage factors and regulatory mechanisms in cells has advanced greatly, the number of feasible practical techniques to avoid or repair damaged embryos remains scarce. Our intention is therefore to focus on strategies to obtain embryos with as little DNA damage as possible, which will impact reproductive biology research with particular significance for reproductive clinicians and embryologists., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-β estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-β estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.

Embryonic diapause (ED) is a temporary arrest of an embryo at the blastocyst stage when it waits for the uterine receptivity signal to implant. ED used by over 100 species may also occur in normally "nondiapausing" mammals when the uterine receptivity signal is blocked or delayed. A large number of lipid droplets (LDs) are stored throughout the preimplantation embryo development, but the amount of lipids varies greatly across different mammalian species. Yet, the role of LDs in the mammalian egg and embryo remains unknown. Here, using a mouse model, we provide evidence that LDs play a crucial role in maintaining ED. By mechanical removal of LDs from zygotes, we demonstrated that delipidated embryos are unable to survive during ED. LDs are not essential for normal prompt implantation, without ED. We further demonstrated that with the progression of ED, the amount of intracellular lipid reduces, and composition changes. This decrease in lipid is caused by a switch from carbohydrate metabolism to lipid catabolism in diapausing blastocysts, which also exhibit increased release of exosomes reflecting elevated embryonic signaling to the mother. We have also shown that presence of LDs in the oocytes of various mammals positively corelates with their species-specific length of diapause. Our results reveal the functional role of LDs in embryonic development. These results can help to develop diagnostic techniques and treatment of recurrent implantation failure and will likely ignite further studies in developmental biology and reproductive medicine fields., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K + channel expression., Methods: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K + channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time., Results: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K + channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients., Conclusions: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

Background: Men normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases., Objective: To better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period., Methods and Results: We found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available)., Conclusion: We provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT., (Copyright © 2020 Lazzerini, Bertolozzi, Acampa, Cantara, Castagna, Pieragnoli, D’Errico, Rossi, Bisogno, El-Sherif, Boutjdir, Laghi-Pasini and Capecchi.)

Background: The risk of sudden cardiac death is increased in chronic inflammatory arthritis, particularly rheumatoid arthritis (RA). To evaluate the putative effect of systemic inflammation on heart rate variability (HRV) and ventricular repolarization in chronic inflammatory arthritis, we analyzed in these patients the possible relationship among HRV parameters, QT interval, and high sensitivity C-reactive protein (hsCRP)., Methods: One hundred-one patients with chronic inflammatory arthritis underwent a 15-minute ambulatory twelve-channel electrocardiogram-recording, to evaluate HRV and QT interval, as well as a venous withdrawal for hsCRP as an estimation of ongoing systemic inflammation., Results: In patients with chronic inflammatory arthritis, hsCRP is inversely correlated with HRV and directly with QTc duration, but while hsCRP is associated with HRV independently from any other investigated factor, the association between hsCRP and QTc seems to be an indirect consequence of the autonomic dysfunction itself. Within the whole cohort of patients, those subjects having elevated hsCRP levels displayed both a significant reduction in HRV and a prolongation of QTc with respect to patients with a normal hsCRP value. A similar, although less marked, degree of HRV depression and QTc prolongation was found in RA patients when compared to subjects with spondyloarthritis (SpA) and healthy controls., Conclusions: These data provide evidence of a link between systemic inflammation and the arrhythmic risk in patients with chronic inflammatory arthritis, also putatively explaining, at least in part, how the different inflammatory load characterizing RA and SpA parallels the different risks of cardiovascular death in these two conditions., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to measure the fractal dimension on x-ray images and ultrasonographic parameters of the os calcis of bone from 4 districts in osteoporotic patients and in control subjects, in order to test the hypothesis that ultrasonographic parameters correlate to the fractal dimension obtained on x-ray images., Methods: Fractal analysis on radiological images from 4 bone districts (proximal femur, calcaneus, metacarpus and 3rd phalanx) was performed in a study comparing ultrasonographic evaluation of the os calcis in severe osteoporotic patients and in control cases. We studied 86 x-ray-views from patients with severe reduction of ultrasound Stiffness Index and in healthy women. Ultrasound measurements of left os calcis were performed using the Lunar Achilles-Plus instrument. Fractal analysis was performed using the box-counting method., Results: In healthy subjects, fractal dimension, D, measure of structural complexity, resulted close to the topological dimension (no fractal structure), TD, in femur (1.99±0.03)and phalanx (1.96±0.03), D differed significantly from TD in calcaneus (D=1.90±0.02; p<0.001) and metacarpus (D=1.89±0.03, p<0.001). In osteoporotic subjects, in calcaneus and metacarpus, D was higher (1.94±0.03, 1.93±0.03, respectively) than in healthy subjects (1.90±0.02, 1.89±0.02, respectively, p<0.01). In all the subjects, fractal dimension and ultrasound broadband attenuation T-score correlated significantly in calcaneus and metacarpus (p<0.03 and p<0.02, respectively)., Conclusions: Parameters based on a combination of ultrasonic examination and fractal analysis on radiographic images may add useful structural information regarding the patients' skeleton using non invasive procedures.

Objectives: Evidence exists that the pleiotropic properties of the hydroxy-methyl-glutaryl Coenzyme A reductase inhibitors (statins) are not restricted to the cardiovascular system, as they can also favorably affect the joints, with intriguing implications for the treatment of many rheumatic diseases. In the view of the increasing interest on this topic, we here review the current state of the art., Methods: The PubMed database was searched for articles published between 1966 and 2010 for key words referring to statins and joint diseases. All relevant English-written articles were reviewed., Results: Many pivotal studies clearly demonstrated that HMG-CoA reductase inhibitors exert a wide spectrum of beneficial effects on the 3 main compartments of the joint, ie, the synovium, the cartilage, and the subchondral bone. Such (1) anti-inflammatory, (2) immunomodulating, and (3) anabolic effects strongly support a potential role of these drugs in the treatment and/or the prevention of the most important chronic joint diseases. However, although the majority of the in vivo studies with statins on animal models of inflammatory and degenerative joint diseases showed a marked protective activity substantially confirming the in vitro experiments, data arising from clinical trials are less probative and more conflicting., Conclusions: Statins display multiple joint-protective effects. Since oral administration of statins could result in a relatively low drug bioavailability to the joints, alternative routes of administration of the drug (transdermal, intra-articular) and/or specific delivery systems should be developed to establish the entire therapeutic potential of statins in this clinical setting., (Copyright © 2011 Elsevier Inc. All rights reserved.)