Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway.

Epidemiological studies link long term exposure to xenoestrogen Bisphenol-A to adverse cardiovascular effects. Our previous results show that BPA induces hypertension by a mechanism involving CamKII activation and increased redox stress caused by eNOS uncoupling. Recently, CamKII sustained activation has been recognized as a central mediator of programmed cell death in cardiovascular diseases, including necroptosis. However, the role of necroptosis in cardiac response to BPA had not yet been explored. Mice exposed to BPA for 16 weeks showed altered heart function, electrical conduction, and increased blood pressure. Besides, a stress test showed ST-segment depression, indicative of cardiac ischemia. The hearts exhibited cardiac hypertrophy and reduced vascularization, interstitial edema, and large hemorrhagic foci accompanied by fibrinogen deposits. BPA initiated a cardiac inflammatory response, up-regulation of M1 macrophage polarization, and increased oxidative stress, coinciding with the increased expression of CamKII and the necroptotic effector RIP3. In addition, cell death was especially evident in coronary endothelial cells within hemorrhagic areas, and Evans blue extravasation indicated a vascular leak in response to Bisphenol-A. Consistent with the in vivo findings, BPA increased the necroptosis/apoptosis ratio, the expression of RIP3, and CamKII activation in endothelial cells. Necrostatin-1, an inhibitor of necroptosis, alleviated BPA induced cardiac dysfunction and prevented the inflammatory and hemorrhagic response in mice. Mechanistically, silencing of RIP3 reversed BPA-induced necroptosis and CamKII activation in endothelial cells, while inhibition of CamKII activation by KN-93 had no effect on RIP3 expression but decreased necroptotic cell death suggesting that BPA induced necroptosis is mediated by a RIP 3/CamKII dependent pathway. Our results reveal a novel pathogenic role of BPA on the coronary circulation. BPA induces endothelial cell necroptosis, promotes the weakening of coronary vascular wall, which caused internal ventricular hemorrhages, delaying the reparative process and ultimately leading to cardiac dysfunction.post-print4043 K

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Role of testosterone and photoperiod on seasonal changes in horn growth and sperm variables in the Iberian ibex A model for polygynous wild bovids

This work examines the effect of testosterone secretion and photoperiod on seasonal changes in horn growth and sperm variables in the Iberian ibex Capra pyrenaica, here used as a model for polygynous wild bovids. The hypothesis that high levels of testosterone provide an endocrine signal that inhibits horn growth in autumn was tested by assessing the effect of cyproterone acetate CA, an anti-androgen, administered in October - coinciding with the period of natural increases in plasma testosterone concentrations - under different photoperiodic conditions natural photoperiod and artificial long days. The persistence of horn growth during autumn in all ibexes held under the long-day photoperiodic conditions clearly shows that horn growth regulation in the mating season is primarily modulated by day length and not by a fall in testosterone concentration. A retrospectively designed second experiment involving testosterone propionate TP administration in April when horns are growing was then undertaken to confirm that high levels of testosterone do not inhibit horn growth. Overall, the results strongly suggest that the rise in testosterone secretion during the autumn mating season does not act as an endocrine signal for the arrest of horn growth, although the rate of horn growth before the mating season may be related to springtime testosterone levels. A direct relationship was seen between the rate of horn growth and the incidence of sperm abnormalities. Neither CA treatment in October nor TP administration in April affected the studied sperm variables. By contrast, CA treatment plus artificial long days in autumn had a negative effect on sperm motility and sperm morphology. © 2012 Society for Endocrinology

Multidisciplinary approach to culture concept

El concepto cultura, desde el contexto occidental, se ha sustentado en axiomas de corte antropocéntrico que perduran en la actualidad. Estos paradigmas no han sido lo suficientemente atendidos; en concreto, los límites de la cultura, entre lo humano y lo no humano, que siguen generando controversia. Disciplinas que tradicionalmente no han tratado este tema, como la biología o la psicología comparada, en los últimos años han abordado el problema desde nuevas perspectivas. En el presente trabajo pretendemos seguir con esos nuevos modos de abordarlo. En este caso, desde una perspectiva multidisciplinar combinando ramas como la historia, la filosofía y la biología para contribuir a una reinterpretación del concepto “cultura”, que tradicionalmente se ha asumido como exclusivamente humanoThe concept of culture, from the western context, has always been based on anthropocentric type axioms that remain today. These paradigms are not been sufficiently questioned, in particular, the boundaries of culture, between human and non-human, that continues being controversial. Disciplines that traditionally have not considered this issue, such as biology or comparative psychology, in recent years have considered this discussion from new perspectives. In the following dissertation we aim to continue these new strategies, combining disciplines such as History, Philosophy, or Biology, from a multidisciplinary approach, in order to contribute to a reinterpretation of the concept "culture", which has traditionally been assumed to be exclusively huma

Aproximación multidisciplinar al concepto cultura

El concepto cultura, desde el contexto occidental, se ha sustentado en axiomas de corte antropocéntrico que perduran en la actualidad. Estos paradigmas no han sido lo suficientemente atendidos; en concreto, los límites de la cultura, entre lo humano y lo no humano, que siguen generando controversia. Disciplinas que tradicionalmente no han tratado este tema, como la biología o la psicología comparada, en los últimos años han abordado el problema desde nuevas perspectivas. En el presente trabajo pretendemos seguir con esos nuevos modos de abordarlo. En este caso, desde una perspectiva multidisciplinar combinando ramas como la historia, la filosofía y la biología para contribuir a una reinterpretación del concepto “cultura”, que tradicionalmente se ha asumido como exclusivamente humanoThe concept of culture, from the western context, has always been based on anthropocentric type axioms that remain today. These paradigms are not been sufficiently questioned, in particular, the boundaries of culture, between human and non-human, that continues being controversial. Disciplines that traditionally have not considered this issue, such as biology or comparative psychology, in recent years have considered this discussion from new perspectives. In the following dissertation we aim to continue these new strategies, combining disciplines such as History, Philosophy, or Biology, from a multidisciplinary approach, in order to contribute to a reinterpretation of the concept "culture", which has traditionally been assumed to be exclusively huma

Seasonal endocrine changes and breeding activity in Mediterranean wild ruminants

The methods of assisted reproduction commonly used in domestic animals are currently being applied to non-domestic species. This is because of the limitation of maintaining the genetic variability in the wild, as it occurs in wild ruminants of the Mediterranean Basin. Despite the apparent progress of the technology, success of the offspring to grow and become healthy adult individuals has remained low in wild species. Difficulties usually arise from insufficient information about basic reproductive biology, such as the seasonal changes in ovarian and testicular activity. Directional adaptive evolution involves development of specie-specific physiological reproductive patterns to cope with various environmental factors. Thus, species originating and living at the same latitude display different reproductive strategies to entrain the breeding activity at an optimal time of the year. The aim of this paper was to present current knowledge on reproductive physiology of Mediterranean wild ruminants as a basic prerequisite for the successful use of assisted reproduction methods. Special emphasis is given to seasonal endocrine changes, ovarian cycles and testicular activity of Iberian wild ruminants, together with the role of social interactions on the regulation of these events. © 2006 The Authors

Influence of age on the relationship between annual changes in horn growth rate and prolactin secretion in the European mouflon (Ovis gmelini musimon)

Annual variations in the growth of horns, and their correlation with seasonal changes of testicular size, and prolactin (PRL) and melatonin secretion were monitored in six pubertal mouflon rams living in their original latitude (40°N). Mouflons born and maintained under captive conditions were classified in two age classes sub-adult (2 years; n = 3) and adult (≥3 years; n = 3). The rate of horn growth was greater (P < 0.001) in sub-adult than in adult mouflon rams. Horn growth was influenced by season in both adult and sub-adult mouflons (P < 0.05) with largest monthly growth occurring in spring and summer. Seasonal variations of plasma PRL concentrations were correlated with horn growth in adult, but not in sub-adult mouflon rams. The rate of horn growth was inversely correlated with testicular size (r = -0.5, P = 0.07). Seasonal changes in the amplitude of the daily melatonin rhythm in solstices and equinoxes were observed, which were not correlated with variations in the rate of horn growth. These results provide support for a possible role of PRL in the control of growth of horns in the adult mouflon. © 2004 Elsevier B.V. All rights reserved

Potential impact of diseases transmissible by sperm on the establishment of Iberian ibex (Capra pyrenaica) genome resource banks

The long-term cryopreservation of the germplasm (spermatozoa and oocytes) of threatened species offers flexibility in their genetic management and security against disasters or outbreaks of disease that might seriously affect subpopulations. A wide range of infectious diseases can, however, be transmitted via artificial insemination, and the risk of infectious diseases being spread via manipulated germplasm needs to be carefully managed in order to avoid fertility problems in the dams and decreased survival of offspring. Furthermore, accidental introduction of exotic microorganisms into ecosystems remain a major threat. The aims of the present study were to assess the impact of diseases transmissible by sperm on the establishment of germplasm banks for the Iberian ibex, a wild mountain ungulate, and to determine the influence of the presence of these pathogens on sperm functionality. Blood and sperm samples were obtained from 52 mature ibex males legally shot in southern Spain. Sperm motility, morphological abnormalities, acrosome integrity and plasma membrane integrity were assessed for each sample to determine in vitro sperm quality. All serum samples underwent serological analysis for bovine herpes virus type I, bluetongue virus (BTV), bovine leukaemia virus, caprine arthritis-encephalitis virus, pestivirus, Brucella, Coxiella burnetii, Chlamydiophila abortus, Mycoplasma agalactiae and Borrelia burgdorferi. The highest prevalence (30.7%) was recorded for B. burgdorferi, followed by C. burnetii (13.4%). A total of 734 sperm doses containing approximately 200 × 106 spermatozoa each were frozen in straws. Forty-five straws (6.1% of the total number) came from animals seropositive for diseases listed in the Terrestrial Animal Code of the OIE for collection and processing of bovine and small ruminant semen (in this case, pestivirus and BTV). A total of 271 frozen straws (36.9% of the total of frozen straws) were provided by animals seropositive for pathogens potentially transmissible by semen not included in the above OIE code (in this case, B. burgdorferi and C. burnetii). The values of sperm variables were not affected by seropositivity for any of the pathogens transmissible by sperm. © 2010 Springer-Verlag