Neoadjuvant chemotherapy modifies serum pyrrolidone carboxypeptidase specific activity in women with breast cancer and influences circulating levels of GnRH and gonadotropins.

PURPOSE: Functional studies have demonstrated that gonadotropin-releasing hormone (GnRH) regulates cell proliferation, apoptosis, and tissue remodeling. GnRH is metabolized by the proteolytic regulatory enzyme pyrrolidone carboxypeptidase (Pcp) (E.C. 3.4.19.3), which is an omega peptidase widely distributed in fluids and tissues. We previously reported a decrease in both rat and human Pcp activity in breast cancer, suggesting that GnRH may be an important local hormonal factor in the pathogenesis of breast cancer. Recently, we have described that postmenopausal women with breast cancer show lower levels of serum Pcp activity than control postmenopausal women. To determine the effect of neoadjuvant chemotherapy (NACT) on serum Pcp specific activity and circulating levels of GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and steroid hormones 17-ß-estradiol and progesterone in pre- and postmenopausal women diagnosed with infiltrating ductal carcinoma. METHODS: Serum Pcp activity was measured fluorometrically using pyroglutamyl-ß-naphthylamide. Circulating GnRH levels were dosed using a commercial RIA kit. Circulating LH and FSH levels were measured by enzyme immunoassays. Levels of steroid hormones were measured in serum samples by dissociation-enhanced lanthanide fluorescence immunoassay. RESULTS AND CONCLUSION: Our results show the effect of NACT on the hypothalamic-pituitary axis, with the consequent alteration of circulating gonadotropins in premenopausal women with breast cancer. However, the results obtained in postmenopausal women with breast cancer treated with NACT, that is, the significant decrease in the concentration of GnRH and FSH compared to control postmenopausal women, differ from those obtained for premenopausal women. The only difference between pre- and postmenopausal women is their hormonal profile at the beginning of the study, that is, the presence of menopause and the consequent alteration of the hypothalamic-pituitary-gonadal axis.

The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons.

BACKGROUND: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a CXCR4 antagonist, member of bicyclam family) may affect neuronal survival in the absence of insult. Thus, we have measured the mitochondrial membrane potential (MMP), Bax and Bcl-2 protein translocation, and cytochrome c release in AMD3100-treated brain cortical neurons at 7 DIV (days in vitro). METHODS: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. RESULTS: CXCR4 blockade by AMD3100 (200 nM, 24 h) induces mitochondrial hyperpolarization and increases caspase-3/9 hyperpolarization without affecting LDH release as compared to untreated controls. AMD3100 also increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. CONCLUSION: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult.

Organic silicon protects human neuroblastoma SH-SY5Y cells against hydrogen peroxide effects.

BACKGROUND: Hydrogen peroxide (H2O2) is a toxic agent that induces oxidative stress and cell death. Silicon (Si) is a biological element involved in limiting aluminium (Al) absorption with possible preventive effects in Alzheimer's disease. However, Si has not yet been associated with other neuroprotective mechanisms. METHODS: The present experiments evaluated in the SH-SY5Y human neuroblastoma cell line the possible role of different Si G5 (50-1000 ng/mL) concentrations in preventing cellular death induced by H2O2 (400 µM, 24 hours). RESULTS: Our findings showed that H2O2 promoted cell death in the human SH-SY5Y cell cultures and this could be prevented by Si treatment. The loss in cell viability mediated by H2O2 was due to an apoptotic and necrotic process. Apoptotic death was incurred by regulating caspase-8 activity in the extrinsic pathway. The apoptotic and necrotic cell death induced by H2O2 was almost totally reversed by Si (50-500 ng/mL), indicating that it down-regulates both processes in H2O2 treated cells. CONCLUSIONS: According to our data, Si is able to increase SH-SY5Y cell survival throughout partially blocking cellular damage related to oxidative stress through a mechanism that would affect H2O2/ROS elimination.

Antioxidant and protective mechanisms against hypoxia and hypoglycaemia in cortical neurons in vitro.

In the present work, we have studied whether cell death could be induced in cortical neurons from rats subjected to different period of O2 deprivation and low glucose (ODLG). This "in vitro" model is designed to emulate the penumbra area under ischemia. In these conditions, cortical neurons displayed loss of mitochondrial respiratory ability however, nor necrosis neither apoptosis occurred despite ROS production. The absence of cellular death could be a consequence of increased antioxidant responses such as superoxide dismutase-1 (SOD1) and GPX3. In addition, the levels of reduced glutathione were augmented and HIF-1/3α overexpressed. After long periods of ODLG (12-24 h) cortical neurons showed cellular and mitochondrial membrane alterations and did not recuperate cellular viability during reperfusion. This could mean that therapies directed toward prevention of cellular and mitochondrial membrane imbalance or cell death through mechanisms other than necrosis or apoptosis, like authophagy, may be a way to prevent ODLG damage.

Structural and functional alterations under stress conditions by contamination: A multi-species study in a non-forced multi-compartmented mesocosm.

Despite the existing connectivity and heterogeneity of aquatic habitats, the concept of interconnected landscapes has been frequently overlooked in ecotoxicological risk assessment studies. In this study, a novel mesocosm system, the HeMHAS (Heterogeneous Multi-Habitat Assay System), was constructed with the potential to assess structural and functional changes in a community resulting from exposure to contaminants, while also considering the complex ecological scenarios. Fish (Sparus aurata), shrimp (Palaemon varians) and three species of marine microalgae (Isochrysis galbana, Nannochloropsis gaditana and Tetraselmis chuii) were used as test organisms. Other species, such as Artemia sp. and macroalgae were also introduced into the system as environmental enrichment. All the species were distributed in five interconnected mesocosm compartments containing a copper gradient (0, 1, 10, 100 and 250 µg/L). The mobile fish avoided the copper contaminants from 1 µg/L (24 h-AC50: 4.88 µg/L), while the shrimp avoided from 50 µg/L (24 h-AC50: 136.58 µg/L). This finding suggests interspecies interactions influence habitat selection in contaminated environments, potentially jeopardizing population persistence. Among the non-motile organisms, the growth and chlorophyll content of the microalgae were concentration dependent. The growth of I. galbana was more sensitive (growth inhibition of 50 % at the highest concentration) in contrast to N. gaditana (30 % inhibition at the highest concentration) and T. chuii (25 % inhibition at the last two highest concentrations). In summary, the mesocosm HeMHAS showed how contamination-driven responses can be studied at landscape scales, enhancing the ecological relevance of ecotoxicological research.

Ecological consequences when organisms avoid a contaminated environment: A study evaluating the toxicity of fipronil.

The ability of aquatic organisms to sense the surrounding environment chemically and interpret these signals correctly is crucial to their survival and ecological niche. This study applied the Heterogenous Multi-Habitat Assay System - HeMHAS to evaluate the avoidance potential of Daphnia magna to detect fipronil-contaminated habitats in a connected landscape after a short (48 h), previous, forced exposure to an environmentally relevant concentration of the same insecticide. The swimming of daphnids was also analyzed by recording the total distance covered. D. magna preferred areas with less contamination, although the effect of fipronil on their swimming ability (a decrease) was observed for all the concentrations tested. The application of non-forced multi-compartment exposure methodologies is a recent trend and is ecologically relevant as it is based on how contamination can really produce changes in an organism's habitat selection. Finally, we consider the importance of more non-forced exposure approaches where Stress Ecology can be aggregated to improve systemic understanding of the risk that contaminants pose to aquatic ecosystems from a broader landscape perspective.

Multi-level biological responses of Daphnia magna exposed to settleable atmospheric particulate matter from metallurgical industries.

Metallurgical industries are a continuous source of air pollution due to the amount of settleable particulate matter (SePM) they release. This SePM is a complex mixture formed by metallic nanoparticles and metals, which reach terrestrial and aquatic ecosystems and can be a significant source of contamination. The aim of this study was to evaluate the adverse effects of SePM at different levels of biological organization in order to estimate its ecological impacts on aquatic ecosystems. For this purpose, the crustacean Daphnia magna was exposed to different concentrations of SePM (0.01, 0.1, 1, 5, 10 g/L) using a multi-level response approach. The endpoints studied were: avoidance throughout 24 h in a non-forced exposure system, reproduction (total number of neonates per female after 21 days of exposure), acetylcholinesterase activity (AChE) after 48 h, and finally, the feeding rates during a short-term exposure (48 h) and a long-term exposure (21 day + 48 h). There was a negative effect of SePM on all responses measured at high concentrations. The avoidance was concentration-dependent and represented 88 % and 100 % at the two highest concentrations. The AChE activity was significantly inhibited at 5 and 10 g/L. The total number of neonates increased from 1 g/L of SePM and the first brood occurred earlier as of 5 g/L compared to control. The post-exposure feeding rates were lower during long-term exposure at the highest concentration. Chemical analyses were performed to characterize the metals present in this SePM, but this study did not report any direct relationship with toxicity, due to the chemical heterogeneity of the particles. The emission of compounds caused by anthropogenic activity may have significant ecological consequences, so it is important to consider these possible effects on aquatic biota generated by the mixture of metals present in SePM originated from metallurgical activities. Environmental and sectorial regulations are needed to prevent contamination and ecological disturbances.

Physiopathology of Osteoporosis: Nursing Involvement and Management.

Osteoporosis is a major public health problem today. We are facing an aging society where the average life expectancy continues to increase. Osteoporosis affects more than 30% of postmenopausal women due to hormonal changes that occur during this time. Postmenopausal osteoporosis is therefore of particular concern. The aim of this review is to identify the etiology, pathophysiology, diagnosis and treatment of this disease and lay the foundation for the role nurses should play in preventing postmenopausal osteoporosis. Several risk factors are associated with osteoporosis. In addition to age and sex, genetics, ethnicity, diet, or the presence of other disorders determine the development of this disease. The key factors include exercise, a balanced diet, and high levels of vitamin D. This is primarily from a solar source, and infancy is the time when future bone formation is greatest. There are now medications that can complement these preventive measures. The work of nursing staff is not only prevention, but also early detection and early treatment. In addition, imparting information and knowledge about the disease to the population is key to preventing an osteoporosis epidemic. In this study, a detailed description is provided of the biological and physiological disease, the preventive measures currently being researched, the information currently available to the population, and how health professionals address osteoporosis from a preventive perspective.

Glutathione Peroxidase gpx1 to gpx8 Genes Expression in Experimental Brain Tumors Reveals Gender-Dependent Patterns.

Extensive research efforts in the field of brain tumor studies have led to the reclassification of tumors by the World Health Organization (WHO) and the identification of various molecular subtypes, aimed at enhancing diagnosis and treatment strategies. However, the quest for biomarkers that can provide a deeper understanding of tumor development mechanisms, particularly in the case of gliomas, remains imperative due to their persistently incurable nature. Oxidative stress has been widely recognized as a key mechanism contributing to the formation and progression of malignant tumors, with imbalances in antioxidant defense systems being one of the underlying causes for the excess production of reactive oxygen species (ROS) implicated in tumor initiation. In this study, we investigated the gene expression patterns of the eight known isoforms of glutathione peroxidase (GPx) in brain tissue obtained from male and female control rats, as well as rats with transplacental ethyl nitrosourea (ENU)-induced brain tumors. Employing the delta-delta Ct method for RT-PCR, we observed minimal expression levels of gpx2, gpx5, gpx6, and gpx7 in the brain tissue from the healthy control animals, while gpx3 and gpx8 exhibited moderate expression levels. Notably, gpx1 and gpx4 displayed the highest expression levels. Gender differences were not observed in the expression profiles of these isoforms in the control animals. Conversely, the tumor tissue exhibited elevated relative expression levels in all isoforms, except for gpx4, which remained unchanged, and gpx5, which exhibited alterations solely in female animals. Moreover, except for gpx1, which displayed no gender differences, the relative expression values of gpx2, gpx3, gpx6, gpx7, and gpx8 were significantly higher in the male animals compared to their female counterparts. Hence, the analysis of glutathione peroxidase isoforms may serve as a valuable approach for discerning the behavior of brain tumors in clinical settings.

Peritoneal ultrafiltration in older adult patients with advanced heart failure.

Advanced heart failure (HF) with congestive symptoms refractory to diuretic treatment worsens the patient's prognosis and quality of life. Peritoneal ultrafiltration (PUF) attempts to improve symptoms and reduce HF-related events. This study analyzes the impact of PUF on older adult patients with significant comorbidity and advanced HF. Eighteen patients with advanced HF attended to in the Internal Medicine HF Unit of the Lucus Augusti University Hospital of Lugo, Spain, who started PUF between 2014 and 2021 were analyzed. The number of admissions and instances in which diuretic rescue treatment was used in the year before and after starting PUF were compared. The evolution of renal function, complications secondary to the technique, and survival were also analyzed. The median age was 80 (SD 5.8) years and 72.2% were men. Comparing the year after starting PUF to the year before starting PUF, hospital admissions due to HF (4 vs 20, p = 0.01) and the use of intravenous diuretic rescue treatment declined (4 vs 118, p < 0.001). There was no significant deterioration in renal function during the first year of follow-up or major complications associated with the technique. Survival was 72% at 1 year. In older adult patients with comorbidity, advanced HF, and refractory congestive symptoms, PUF reduced hospital admissions and the use of intravenous diuretic rescue treatment, without major complications.

Hypothalamus-pituitary-thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system.

Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-ß-naphthylamide as the substrate, in the hypothalamus-pituitary-thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.

Circulating levels of ß-endorphin and cortisol in breast cancer.

Neurobehavioral stress can promote the growth and progression of different types of cancer because psychological factors can alter immune and endocrine function. ß-endorphin is one of the hormones involved in the bidirectional connection between the immune and neuroendocrine systems that explains the effects of stress on the immune capacity against cancer. Breast cancer (BC) is the most common type of cancer in women and one of the best known to influence the different stressors involved in coping with the disease. Here we evaluated the circulating levels of ß-endorphin and cortisol in premenopausal and postmenopausal women with BC treated or not with neoadjuvant chemotherapy, to understand the neuroendocrine basis that explain the relationship between stress and the development of the disease. In our hands, healthy women show elevated levels of ß-endorphin, levels that are even higher in postmenopausal women. In women with BC, however, significantly lower levels appear, with no differences between premenopausal and postmenopausal women. These data correlate with cortisol levels, which are much higher in women with BC regardless of their hormonal status. Neoadjuvant chemotherapy treatment only improves ß-endorphin levels in postmenopausal women, without recovering the levels of healthy women. In women treated with neoadjuvant chemotherapy, both premenopausal and postmenopausal maintain elevated cortisol levels that are indicative of the stressful situation. Regulation of stress levels by modulation with ß-endorphin could be an alternative pharmacological therapy against tumor growth and development, as well as its ability to promote in patients feelings of well-being that improve the development of their disease.

Transient focal cerebral ischemia significantly alters not only EAATs but also VGLUTs expression in rats: relevance of changes in reactive astroglia.

The involvement of plasma membrane glutamate transporters (EAATs - excitatory aminoacid transporters) in the pathophysiology of ischemia has been widely studied, but little is known about the role of vesicular glutamate transporters (VGLUTs) in the ischemic process. We analyzed the expression of VGLUT1-3 in the cortex and caudate-putamen of rats subjected to transient middle cerebral artery occlusion. Western blot and immunohistochemistry revealed an increase of VGLUT1 signal in cortex and caudate-putamen until 3 days of reperfusion followed by a reduction 7 days after the ischemic insult. By contrast, VGLUT2 and 3 were drastically reduced. Confocal microscopy revealed an increase in VGLUT2 and 3 immunolabelling in the reactive astrocytes of the ischemic corpus callosum and cortex. Changes in VGLUTs and EAATs expression were differently correlated to neurological deficits. Interestingly, changes in VGLUT1 and EAAT2 expression showed a significant positive correlation in caudate-putamen. Taken together, these results suggest a contribution of VGLUTs to glutamate release in these structures, which could promote neuroblast migration and neurogenesis during ischemic recovery, and a possible interplay with EAATs in the regulation of glutamate levels, at least in the first stages of ischemic recovery.

Interregional inequality and road accident rates in Spain.

The aim of this study was to determine whether interregional inequality in Spain had the same impact on the risks of fatality and injury across the different provinces of Spain, in the period from 1999 to 2015. This allows us to map fatality and injury rates in Spanish provinces depending on their level of economic development. Provinces were divided in two large groups according to the mean weight of their per capita GDP on the national GDP from 2000 to 2015. Using fixed effects data panel models, estimations were obtained for each group of the impact of the relationships between per capita GDP, unemployment rate and other control variables on their risks of fatality and injury. The models reveal that economic conditions and education are explanatory factors with greater significance and impact on the risks of fatality and injury in provinces with higher levels of economic development. In this group, the penalty-points driving licence was found have a greater impact, although its effectiveness is now being questioned. In contrast, to reduce the risks of fatality and injury in less developed provinces, it is imperative to invest in road infrastructure, increasing the proportion of high capacity roads and investing more in road replacement and maintenance. The geographical distribution generated in this study allows us to better identify the areas with a higher risk of fatality or injury. This, in turn, confirms the need to improve the configuration of road safety policy, taking into account the different fatality or injury rates across provinces, the origins of which lie in the specific provincial conditions.

[Provincial savings of costs in road accidents in Spain (2000-2014)]. / Ahorros de costes provinciales en los accidentes viales en España (2000-2014).

OBJECTIVE: To quantify cost savings obtained before and after the implementation of the penalty-points driving licence on the interurban roads in Spain. METHOD: Descriptive study through the construction of three indicators that expressed the cost savings by the number of victims avoided. We defined two periods according to the objective and collected data on fatalities, serious injuries and slight injuries on interurban roads in 1999-2014 for each Spanish province. Thus, data for its population, GDP or number of vehicles-kilometres travelled on its roads (MVKT) were used for each province. The quantification of savings was obtained using official figures of costs for each type of victim in 2014 prices. RESULTS: The cost savings per inhabitant on fatalities in the period of validity of the penalty-points driving licence was between ⿬ 3.89 and ⿬ 19.65 per year. Savings on serious injuries by MVKT were reduced by 15%-66% between 2006 and 2014, being from ⿬ 449.15 to 1707.88 ⿬ annually. CONCLUSIONS: During the period of validity of the penalty-points driving licence, the Spanish provinces have achieved significant cost savings.

2-D organization of silica nanoparticles on gold surfaces: CO2 marker detection and storage.

A single layer of silica nanoparticles with an average size of ∼200 nm was deposited over the surface of pristine gold wafers, aided by (3-mercaptopropyl)trimethoxysilane. The nanoparticle immobilization was driven by covalent bonding rather than a self-assembly process, leading to a cluster-assembled material which has CO2 sensing features. Here, we show how this device can be used for CO2 physisorption and chemisorption. We analyse the device, both spectroscopically and morphologically, before and after exposure to an atmosphere of 7 mbar of CO2, inside a planetary atmospheres and surfaces simulation chamber, (PASC) mimiking Martian atmospheric conditions. Our studies demonstrate that these clusters are suitable for CO2 detection and storage, under well controlled experimental Martian conditions. Their high sensitivity at a very low concentration of CO2, 12.4 ppm, makes them ideal candidates in the nanosensor field.

Insulin-Regulated Aminopeptidase in Women with Breast Cancer: A Role beyond the Regulation of Oxytocin and Vasopressin.

Insulin-regulated aminopeptidase (IRAP) is the only enzyme known to cleave oxytocin and vasopressin; however, it is also the high-affinity binding site for angiotensin IV (AngIV) receptor type 4 (AT4) ligands and it is related to insulin-dependent glucose transporters through the translocation of the glucose transporter type 4 (GLUT4). Previous studies have demonstrated an association between IRAP activity and the number and size of mammary tumors in an animal model of breast cancer (BC). Also, a highly significant increase in IRAP activity has been found in BC tissue from women patients. Here, we found no changes in circulating IRAP in premenopausal (preMP) women, but it increased significantly in postmenopausal (postMP) women not treated with neoadjuvant chemotherapy (NACH). However, in women treated with NACH, IRAP activity increased in both preMP and postMP women. Two years of follow-up indicated lower levels of IRAP activity in untreated preMP women, but a return to control levels in untreated postMP women, while IRAP activity returned to control levels in women treated with NACH. Circulating oxytocin decreased in both preMP and postMP women during the follow-up period. Differences in Oxytocin appeared between preMP and postMP women treated with NACH, but not in women who were not treated with NACH. On the contrary, circulating vasopressin increased in untreated and treated preMP and postMP women, with most of the differences related to the hormonal status as well as the neoadjuvant treatment during the two year follow-up We propose that IRAP is involved in mechanisms related not only to oxytocin and/or vasopressin regulation, but also to the local mammary RAS through AngIV and its role in glucose transportation through the IRAP/GLUT4 system.

Signaling mechanisms of interferon gamma induced apoptosis in chromaffin cells: involvement of nNOS, iNOS, and NFkappaB.

Previous work of our group stated that exogenously added and endogenous nitric oxide (NO) generated by cytokines induce apoptosis in chromaffin cells. In this work, we investigate the specific regulation of the NO synthase (NOS) isoforms, inducible NOS (iNOS) and neuronal NOS (nNOS), and their particular participation in cell death induced by interferon gamma (IFNgamma). Lipopolysaccharide (LPS) and IFNgamma increase iNOS expression, with no effect on nNOS expression. On the other hand, dexamethasone increases basal nNOS expression but decreases LPS + IFNgamma-induced iNOS expression. IFNgamma-induced cell death was abolished by W-1400, a specific iNOS inhibitor, but only partially by nNOS inhibitors [N-omega-propyl- L-arginine (N-PLA), 3-Bromo-7-nitroindazol (7-NI), L-methyl thiocitrulline and N-methyl L-arginine], indicating the main iNOS participation in chromaffin cell death. IFNgamma and LPS induce nuclear factor kappaB (NFkappaB) translocation to the nucleus, a process implicated in activation of iNOS expression, as inhibition of NFkappaB translocation, by SN50, decreased iNOS expression. In addition, IFNgamma and LPS induce (847)SernNOS phosphorylation, inhibiting nNOS activity. Both processes, nNOS phosphorylation and iNOS expression induced by LPS + IFNgamma, are regulated by Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, as IFNgamma increases (727)STAT-3 phosphorylation and specific inhibitors of JAK/STAT pathway, such as AG490, inhibited both processes. Taken together, these results support the hypothesis of an inactivating phosphorylation of nNOS by IFNgamma, via JAK/STAT, in bovine chromaffin cells. Low NO concentrations achieved by this event, would activate NFkappaB translocation, increasing iNOS expression and generating, this last, high apoptotic NO concentrations.

[Analysis of the determinants of cost savings in traffic accidents on interurban roads in Spain]. / Análisis de los factores determinantes del ahorro de costes en accidentes de tráfico en la red de carreteras de España.

OBJECTIVE: The increase in traffic accidents depends on multiple factors; it generates an economic and public health problem that must be analyzed jointly by agents involved in road safety. The aim of the work was to quantify the effect of various factors in the cost savings due to traffic accidents on interurban roads in Spain. METHODS: It was analyzed, through a lineal regression with panel data model and in the period 2000-2017, how different factors affected cost savings due to the risk of mortality or injury avoided on Spanish interurban roads. RESULTS: A 1% increase in traffic volume led to a reduction in costs per MVKT (million vehiclekilometres travelled) of €162.46 referring to the risk of mortality, €115.32 for serious injuries and €10.10 for mild injuries. This increase in unemployment caused a cost reduction of €31.43, €10.76 and €0.98, respectively. The same increase in the investment in replacement implied a reduction of these costs of €11 for any risk. A 1% increase in the ageing index led to an increase in costs of €276.83 in terms of mortality risk and €257.49 in terms of injury. Foreign tourism generated a cost of more than €40 for any risk. A 1% increase in GDP per capita led to an increase in costs of €155.50, €138.09 and €8.21 for defined risks. The points driving license led to an increase in costs of €785.50 per MVKR when referring to mortality risks. CONCLUSIONS: Determining factors for cost savings: motorization rate, unemployment rate and investment in replacement interurban roads. Determining factors that increased costs: expiry of the effect of the penalty - points driving licence, ageing index of the population, increase in GDP or proportion of foreign travelers.

OBJETIVO: El incremento de los accidentes de tráfico depende de múltiples factores, generando un problema económico y de salud pública que debe ser analizado conjuntamente por los agentes intervinientes en la seguridad vial. El objetivo del trabajo fue cuantificar el efecto de diversos factores determinantes en el ahorro de costes por accidentes de tráfico en vías interurbanas en España. METODOS: Se analizó, a través de un análisis de regresión mediante datos de panel referidos al período 2000-2017, cómo afectaban diferentes factores al ahorro de costes por cada riesgo de mortalidad o lesividad evitado en las vías interurbanas españolas. RESULTADOS: El aumento del 1% del volumen de tráfico conllevó una reducción de costes por MVKR (millón de vehículos-kilómetros recorridos) de 162,46€ refiriéndonos al riesgo de mortalidad, 115,32€ para lesividad grave y 10,10€ para leve. El aumento en el desempleo supuso una reducción de costes de 31,43€, 10,76€ y 0,98€, respectivamente. Idéntico incremento de la inversión en la reposición implicó una reducción de estos costes de 11€ para cualquier riesgo. El aumento del 1% del índice de envejecimiento comportó un aumento de costes de 276,83€ hablando del riesgo de mortalidad y de 257,49€ si hablamos de lesividad. El turismo extranjero generó un coste superior a los 40€ para cualquier riesgo. El aumento del 1% del Producto Interior Bruto (PIB) per cápita conllevó un aumento de costes de 155,50€, 138,09€ y 8,21€ para los riesgos anteriormente definidos. El permiso de conducción por puntos condujo a un incremento de costes de 785,50€ por MVKR al referirnos a los riesgos de mortalidad. CONCLUSIONES: Los factores condicionantes del ahorro de costes son el volumen de tráfico, la tasa de paro y la inversión en reposición. Los factores condicionantes del incremento de costes son la caducidad del efecto del permiso de conducción por puntos, el índice de envejecimiento, el incremento del PIB y la proporción de conductores extranjeros.

Gender Differences in the Antioxidant Response to Oxidative Stress in Experimental Brain Tumors.

BACKGROUND: Brain tumorigenesis is related to oxidative stress and a decreased response of antioxidant defense systems. As it is well known that gender differences exist in the incidence and survival rates of brain tumors, it is important to recognize and understand the ways in which their biology can differ. OBJECTIVE: To analyze gender differences in redox status in animals with chemically-induced brain tumors. METHODS: Oxidative stress parameters, non-enzyme and enzyme antioxidant defense systems are assayed in animals with brain tumors induced by transplacental N-ethyl-N-nitrosourea (ENU) administration. Both tissue and plasma were analyzed to know if key changes in redox imbalance involved in brain tumor development were reflected systemically and could be used as biomarkers of the disease. RESULTS: Several oxidative stress parameters were modified in tumor tissue of male and female animals, changes that were not reflected at plasma level. Regarding antioxidant defense system, only glutathione (GSH) levels were decreased in both brain tumor tissue and plasma. Superoxide dismutase (SOD) and catalase (CAT) activities were decreased in brain tumor tissue of male and female animals, but plasma levels were only altered in male animals. However, different protein and mRNA expression patterns were found for both enzymes. On the contrary, glutathione peroxidase (GPx) activity showed increased levels in brain tumor tissue without gender differences, being protein and gene expression also increased in both males and female animals. However, these changes in GPx were not reflected at plasma level. CONCLUSION: We conclude that brain tumorigenesis was related to oxidative stress and changes in brain enzyme and non-enzyme antioxidant defense systems with gender differences, whereas plasma did not reflect the main redox changes that occur at the brain level.