INVESTIGATION OF THE OPPOSING EFFECTS OF ENVIRONMENTAL FACTORS ON THE PREDISPOSITION TO ARTERIAL THROMBOSIS IN A MOUSE MODEL CARRYING THE HUMAN BDFNVAL66MET POLYMORPHISM

Background: Nonostante il progresso nella comprensione dei meccanismi cellulari e molecolari e gli avanzamenti nel campo della prevenzione e dei trattamenti delle malattie cardiovascolari, queste rimangono ancora la principale causa di mortalit\ue0 e morbidit\ue0 a livello mondiale. \uc8 interessante notare come fattori di rischio ambientale, quali stress, depressione e ansia, siano stati recentemente inclusi accanto ai classici fattori di rischio tradizionali data la loro capacit\ue0 di modulare l\u2019insorgere e la progressione delle malattie cardiovascolari ed influenzare la risposta alle terapie. In questo contesto si inserisce il nuovo settore della cardiologia comportamentale il cui obiettivo \ue8 quello di arrivare a comprendere e approfondire la conoscenza della patofisiologia alla base delle malattie cardiovascolari legate alla sfera comportamentale nonch\ue9 sviluppare strategie di intervento efficaci al fine di modificare gli stili di vita e i comportamenti ad alto rischio, riducendone cos\uec l\u2019impatto sui pazienti. La letteratura degli ultimi anni ha dimostrato come l\u2019esercizio fisico risulti una valida strategia di trattamento a livello clinico risultando efficace sia per il trattamento delle patologie psicosociali che di quelle cardiovascolari. In particolare, \ue8 stato osservato come la famiglia di proteine dette neurotrofine sia coinvolta nei processi patofisiologici a carico sia del sistema nervoso che di quello cardiocircolatorio. Tra le neurotrofine, il brain-derived neurotrophic factor (BDNF), ed in particolare il polimorfismo a singolo nucleotide denominato BDNFVal66Met, si sa essere associato a malattie neuropsichiatriche, ansia, maggiore suscettibilit\ue0 allo stress e recentemente ad una maggior predisposizione alla trombosi arteriosa associata a infarto acuto del miocardio, nonch\ue9 con disturbi del comportamento alimentare e obesit\ue0. Obiettivo dello studio: L\u2019obiettivo del presente studio \ue8 stato quello di mettere in evidenza l\u2019impatto che l\u2019interazione tra la presenza dell\u2019allele Met e fattori ambientali positivi, come l\u2019esercizio fisico, o negativi, come lo stress cronico, pu\uf2 avere rispetto al rischio di sviluppare trombosi arteriosa. Risultati: Il modello murino knock-in per il polimorfismo umano BDNFVal66Met rappresenta un buon modello per lo studio delle patologie che questa mutazione genera nell\u2019uomo. Topi omozigoti per l\u2019allele Met (BDNFMet/Met) sono stati da noi utilizzato per mostrare come l\u2019esercizio fisico spontaneo sia in grado di indurre cambiamenti positivi nella morfologia del tessuto adiposo e ridurre l\u2019infiammazione locale. Questi effetti positivi potrebbero essere alla base della riduzione del fenotipo pro-trombotico osservato in questo modello murino. Inoltre, dati in vitro sostengono il ruolo del Pro-BDNFMet nella capacit\ue0 di modulare l\u2019adipogenesi in linea con quanto osservato nel tessuto adiposo epididimale dei topi BDNFMet/Met. In topi eterozigoti per l\u2019allele Met (BDNFVal/Met), lo stress sub-cronico \ue8 risultato sufficiente per smascherare il fenotipo pro-trombotico portando all\u2019innalzamento del numero e della funzionalit\ue0 delle cellule del sangue e dell\u2019espressione di fattori chiave per il processo trombotico a livello arterioso. Conclusioni: Questo studio dimostra un\u2019importante interazione tra fattori ambientali positivi o negativi e l\u2019allele Met del BDNF in relazione alla modulazione della trombosi arteriosa. Studi sull\u2019uomo saranno necessari al fine di confermare questa interazione gene-ambiente e comprovare la possibilit\ue0 di prendere in considerazione l\u2019interazione al fine di mettere in atto migliori strategie di trattamento clinico del rischio trombotico in pazienti recanti il polimorfismo in oggetto.Background: Despite the growing knowledge and the advances in the prevention and treatment of cardiovascular disease (CVD), this pathology is still the leading cause of morbidity and mortality worldwide. Of note, environmental factors such as stress, depression, and anxiety, were recently included in the category of risk factors alongside the canonical ones since their ability to modulate the onset and progression of CVD and to influence the response to therapies. In this context, the new field of behavioral cardiology aims to reach a deeper understanding of the pathophysiology of behavior-related CVDs and the development of effective interventions both to modify high-risk lifestyles and behaviors and to reduce psychosocial risk factors for patients. Among the non-pharmacological treatments, growing amount of literature shows that physical exercise (PE) takes hold as a clinical management strategy for its positive effect on both psychological pathologies and CVD. Interestingly, the family of proteins named neurotrophins was found to be involved in the patho-physiology of both cardiovascular and nervous system. Among them, the human BDNF Val66Met polymorphism is known to be associated to neuro-psychiatric disorders, anxiety and to higher susceptibility to stress, and recently to the individual predisposition to arterial thrombosis related to acute myocardial infarction (AMI) and to eating disorders and obesity. Aim of the study: The aim of this study was to highlight the impact of the interplay between BDNF Met allele and positive (physical exercise) and negative (chronic stress) environmental factors on the risk of arterial thrombosis. Results: Taking advantage of a knock-in mouse carrying the human BDNF Val66Met polymorphism that represents a good model of the pathologies observed in human, we showed that spontaneous physical exercise is able to induce positive morphological changes and reduce the inflammatory profile of the adipose tissue in homozygous BDNF Met/Met mice. These beneficial effects might be at the bases of the observed reduction in the pro-thrombotic phenotype detected in this animal model. In addition, our in vitro data well support the role of Pro-BDNFMet in modulating adipogenesis in line with what observed in the epididymal white adipose tissue of BDNF Met/Met mice. In addition, sub-chronic stress is sufficient to unveil the pro-thrombotic phenotype in heterozygous BDNF Val/Met mice affecting the number and functionality of blood circulating cells, and the expression of key thrombotic molecules in arterial tissue. Conclusions: This study supports the important interaction between both positive and negative environmental factors and Met allele of the BDNF gene in relation to the modulation of arterial thrombosis. Human studies will be crucial to confirm this possible gene-environment interaction and to assess the necessity of taking this interaction into account to deploy better strategies of clinical management of the arterial thrombosis risk in patients carrying this polymorphism

Almotriptan in the treatment of migraine

Almotriptan is an orally administered, highly selective serotonin 5-HT(1B/1D) receptor agonist that is effective in the acute treatment of moderate to severe migraine attacks. Since its introduction on to the market in 2001, several studies involving a large number of migraine patients have confirmed its efficacy and tolerability profile. Almotriptan, was found to be among the best-responding triptans in terms of pain relief and pain-free rate at 2 h. It has been reported that almotriptan has the best sustained pain-free (SPF) rate and the lowest adverse events (AEs) rate of all the triptans. When these clinical characteristics were combined to form the composite endpoint SPF and no AEs (SNAE), almotriptan emerged as the triptan with the best efficacy and tolerability profile. It also showed a good efficacy profile during the early treatment (within 1 h of onset) of migraine attacks characterized by moderate pain intensity. On the basis of these findings, almotriptan may be considered a therapeutic option for the acute treatment of migraine attacks

Zoneamento para a fruticultura em Mato Grosso do Sul.

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Physical Exercise Affects Adipose Tissue Profile and Prevents Arterial Thrombosis in BDNF Val66Met Mice

Adipose tissue accumulation is an independent and modifiable risk factor for cardiovascular disease (CVD). The recent CVD European Guidelines strongly recommend regular physical exercise (PE) as a management strategy for prevention and treatment of CVD associated with metabolic disorders and obesity. Although mutations as well as common genetic variants, including the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, are associated with increased body weight, eating and neuropsychiatric disorders, and myocardial infarction, the effect of this polymorphism on adipose tissue accumulation and regulation as well as its relation to obesity/thrombosis remains to be elucidated. Here, we showed that white adipose tissue (WAT) of humanized knock-in BDNFVal66Met (BDNFMet/Met) mice is characterized by an altered morphology and an enhanced inflammatory profile compared to wild-type BDNFVal/Val. Four weeks of voluntary PE restored the adipocyte size distribution, counteracted the inflammatory profile of adipose tissue, and prevented the prothrombotic phenotype displayed, per se, by BDNFMet/Met mice. C3H10T1/2 cells treated with the Pro-BDNFMet peptide well recapitulated the gene alterations observed in BDNFMet/Met WAT mice. In conclusion, these data indicate the strong impact of lifestyle, in particular of the beneficial effect of PE, on the management of arterial thrombosis and inflammation associated with obesity in relation to the specific BDNF Val66Met mutation

Lasting deficit in inhibitory control with mild traumatic brain injury

Abstract Being able to focus on a complex task and inhibit unwanted actions or interfering information (i.e., inhibitory control) are essential human cognitive abilities. However, it remains unknown the extent to which mild traumatic brain injury (mTBI) may impact these critical functions. In this study, seventeen patients and age-matched healthy controls (HC) performed a variant of the Stroop task and attention-demanding 4-choice response tasks (4CRT) with identical stimuli but two contexts: one required only routine responses and the other with occasional response conflicts. The results showed that mTBI patients performed equally well as the HC when the 4CRT required only routine responses. However, when the task conditions included occasional response conflicts, mTBI patients with even a single concussion showed a significant slow-down in all responses and higher error rates relative to the HC. Results from event-related functional magnetic resonance imaging (efMRI) revealed altered neural activity in the mTBI patients in the cerebellum-thalamo-cortical and the fronto-basal-ganglia networks regulating inhibitory control. These results suggest that even without apparent difficulties in performing complex attention-demanding but routine tasks, patients with mTBI may experience long-lasting deficits in regulating inhibitory control when situations call for rapid conflict resolutions

Avaliação da qualidade física e da matéria orgânica de um argissolo vermelho derivado de arenito da fronteira Oeste do Rio Grande do Sul.

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Impact of BDNF Val66Met Polymorphism on Myocardial Infarction: Exploring the Macrophage Phenotype

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family, well known for its role in the homeostasis of the cardiovascular system. Recently, the human BDNF Val66Met single nucleotide polymorphism has been associated with the increased propensity for arterial thrombosis related to acute myocardial infarction (AMI). Using cardiac magnetic resonance imaging and immunohistochemistry analyses, we showed that homozygous mice carrying the human BDNF Val66Met polymorphism (BDNFMet/Met) undergoing left anterior descending (LAD) coronary artery ligation display an adverse cardiac remodeling compared to wild-type (BDNFVal/Val). Interestingly, we observed a persistent presence of pro-inflammatory M1-like macrophages and a reduced accumulation of reparative-like phenotype macrophages (M2-like) in the infarcted heart of mutant mice. Further qPCR analyses showed that BDNFMet/Met peritoneal macrophages are more pro-inflammatory and have a higher migratory ability compared to BDNFVal/Val ones. Finally, macrophages differentiated from circulating monocytes isolated from BDNFMet/Met patients with coronary heart disease displayed the same pro-inflammatory characteristics of the murine ones. In conclusion, the BDNF Val66Met polymorphism predisposes to adverse cardiac remodeling after myocardial infarction in a mouse model and affects macrophage phenotype in both humans and mice. These results provide a new cellular mechanism by which this human BDNF genetic variant could influence cardiovascular disease

Effect of clotting duration and temperature on BDNF measurement in human serum

Brain-derived neurothrophic factor (BDNF) is a neurotrophin expressed in different tissues and cells, including neurons, endothelial cells, leukocytes, megakaryocytes and platelets. Modifications of BDNF in plasma and/or in serum are associated with neurodegenerative and psychiatric disorders, cardiovascular diseases, metabolic syndrome and with mortality risk. Indeed, changes in blood levels of BDNF may reflect those of its tissue of origin and/or promote pathological dysfunctions. The measurement of BDNF amount in plasma or in serum has been characterized with particular attention in the impact of different anti-coagulants, clotting duration, temperature (\ue2\u89\ua421 \ue2\u97\ua6C) and delay in blood sample centrifugation as well as in stability of storage. However, the influences of normothermic conditions (37 \ue2\u97\ua6C) and of clotting duration on BDNF levels in human serum have not been investigated yet. Here, we showed that time and temperature during serum preparation could be taken into consideration to assess the association and/or impact of BDNF levels in the occurrence of pathological conditions

Patho- physiological role of BDNF in fibrin clotting

Circulating levels of Brain Derived Neurotrophic Factor (BDNF) are lower in coronary heart disease (CHD) than in healthy subjects and are associated with coronary events and mortality. However, the mechanism(s) underling this association is not fully understood. We hypothesize that BDNF may influence fibrin fiber structure and clot stability, favoring clot lysis and thrombus resolution. We showed that recombinant BDNF (rh-BDNF) influenced with clot formation in a concentration-dependent manner in both purified fibrinogen and plasma from healthy subjects. In particular, rh-BDNF reduced the density of fibrin fibers, the maximum clot firmness (MCF) and the maximum clot turbidity, and affected the lysis of clot. In addition, both thrombin and reptilase clotting time were prolonged by rh-BDNF, despite the amount of thrombin formed was greater. Intriguingly, CHD patients had lower levels of BDNF, greater fibrin fibers density, higher MCF than control subjects, and a negative correlation between BDNF and MCF was found. Of note, rh-BDNF markedly modified fibrin clot profile restoring physiological clot morphology in CHD plasma. In conclusion, we provide evidence that low levels of BDNF correlate with the formation of bigger thrombi (in vitro) and that this effect is mediated, at least partially, by the alteration of fibrin fibers formation

Apocynin Prevents Abnormal Megakaryopoiesis and Platelet Activation Induced by Chronic Stress

Environmental chronic stress (ECS) has been identified as a trigger of acute coronary syndromes (ACS). Changes in redox balance, enhanced reactive oxygen species (ROS) production, and platelet hyperreactivity were detected in both ECS and ACS. However, the mechanisms by which ECS predisposes to thrombosis are not fully understood. Here, we investigated the impact of ECS on platelet activation and megakaryopoiesis in mice and the effect of Apocynin in this experimental setting. ECS induced by 4 days of forced swimming stress (FSS) treatment predisposed to arterial thrombosis and increased oxidative stress (e.g., plasma malondialdehyde levels). Interestingly, Apocynin treatment prevented these alterations. In addition, FSS induced abnormal megakaryopoiesis increasing the number and the maturation state of bone marrow megakaryocytes (MKs) and affecting circulating platelets. In particular, a higher number of large and reticulated platelets with marked functional activation were detected after FSS. Apocynin decreased the total MK number and prevented their ability to generate ROS without affecting the percentage of CD42d+ cells, and it reduced the platelet hyperactivation in stressed mice. In conclusion, Apocynin restores the physiological megakaryopoiesis and platelet behavior, preventing the detrimental effect of chronic stress on thrombosis, suggesting its potential use in the occurrence of thrombosis associated with ECS