Platelet-activating factor receptor (PAFR) regulates neuronal maturation and synaptic transmission during postnatal retinal development.

Introduction: Platelet-activating factor (PAF), PAF receptor (PAFR), and PAF- synthesis/degradation systems are involved in essential CNS processes such as neuroblast proliferation, differentiation, migration, and synaptic modulation. The retina is an important central nervous system (CNS) tissue for visual information processing. During retinal development, the balance between Retinal Progenitor Cell (RPC) proliferation and differentiation is crucial for proper cell determination and retinogenesis. Despite its importance in retinal development, the effects of PAFR deletion on RPC dynamics are still unknown. Methods: We compared PAFR knockout mice (PAFR-/-) retinal postnatal development proliferation and differentiation aspects with control animals. Electrophysiological responses were analyzed by electroretinography (ERG). Results and discussion: In this study, we demonstrate that PAFR-/- mice increased proliferation during postnatal retinogenesis and altered the expression of specific differentiation markers. The retinas of postnatal PAFR-/- animals decreased neuronal differentiation and synaptic transmission markers, leading to differential responses to light stimuli measured by ERG. Our findings suggest that PAFR signaling plays a critical role in regulating postnatal RPC cell differentiation dynamics during retinal development, cell organization, and neuronal circuitry formation.

Platelet-Activating Factor Receptor (PAFR) Regulates Retinal Progenitor/Stem Cells Profile in Ciliary Epithelium Cells.

The retina is a central nervous tissue essential to visual perception and highly susceptible to environmental damage. Lower vertebrate retinas activate intrinsic regeneration mechanisms in response to retinal injury regulated by a specialized population of progenitor cells. The mammalian retina does not have populations of progenitor/stem cells available to activate regeneration, but contains a subpopulation of differentiated cells that can be reprogrammed into retinal stem cells, the ciliary epithelium (CE) cells. Despite the regenerative potential, stem cells derived from CE exhibit limited reprogramming capacity probably associated with the expression of intrinsic regulatory mechanisms. Platelet-activating factor (PAF) is a lipid mediator widely expressed in many cells and plays an important role in stem cell proliferation and differentiation. During mammalian development, PAF receptor signaling showed important effects on retinal progenitors' cell cycle regulation and neuronal differentiation that need to be further investigated. In this study, our findings suggested a dynamic role for PAF receptor signaling in CE cells, impacting stem cell characteristics and neurosphere formation. We showed that PAF receptors and PAF-related enzymes are downregulated in retinal progenitor/stem cells derived from PE cells. Blocking PAFR activity using antagonists increased the expression of specific progenitor markers, revealing potential implications for retinal tissue development and maintenance.

Characterization of extracellular trap production and release by equine neutrophils in response to different stimuli.

This study explores Neutrophil Extracellular Trap (NET) formation in equine neutrophils, which is crucial for eliminating infections and is implicated in various equine inflammatory diseases. We investigated the molecular pathways involved in NET release by equine neutrophils in response to stimuli. We use PMA, A23187, LPS, PAF, OZ, and cytokines, observing NET release in response to PMA, PAF, and A23187. In contrast, LPS, OZ, and the cytokines tested did not induce DNA release or did not consistently induce citrullination of histone 4. Peptidyl-arginine deiminase inhibition completely halted NET release, while NADPH oxidase and mitochondrial reactive oxygen species only played a role in PMA-induced NETs. Neutrophil elastase inhibition modestly affected PAF-induced NET liberation but not in PMA or A23187-induced NET, while myeloperoxidase did not contribute to NET release. We expect to provide a foundation for future investigations into the role of NETs in equine health and disease and the search for potential therapeutic targets.

Methodology for the prediction of paroxysmal atrial fibrillation based on heart rate variability feature analysis.

Atrial fibrillation (AF) is the most clinically diagnosed arrhythmia, as its prevalence increases with age, and its initial stage is paroxysmal atrial fibrillation (PAF). This pathology usually triggers hemodynamic disorders that can generate cerebrovascular accidents (CVA), causing morbidity and even death. The aim of this study is to predict the occurrence of PAF episodes in order to take precautions to prevent PAF episodes. The PhysioNet AFPDB prediction database was used to extract 77 heart rate variability (HRV) features using time domain, geometrical analysis, Poincaré plot, nonlinear analysis, detrended fluctuation analysis, autoregressive modeling, fast Fourier transform (FFT), Lomb-Scargle periodogram, wavelet packet transform (WPT) and bispectrum measurements. The number of features was reduced using the near-zero value, correlation, and recursive feature elimination (RFE) methods for time windows of 1, 2, 5, 10, and 30 min. Feature selection was performed using backwards selection, genetic algorithm, analysis of variance (ANOVA), and non-dominated sorting genetic algorithm (NSGA-III) methods, and then random forest, conditional random forest, k-nearest neighbor (KNN), and support vector machine (SVM) classification algorithms were applied and evaluated using 10-fold cross-validation. The proposed method achieved a precision of 93.24% with a 5-minute window and 89.21% with a 2-minute window, improving performance in predicting PAF when compared with similar studies in the literature.

The burden of excessive saturated fatty acid intake attributed to ultra-processed food consumption: a study conducted with nationally representative cross-sectional studies from eight countries.

Cross-sectional nutritional survey data collected in eight countries were used to estimate saturated fatty acid intakes. Our objective was to estimate the proportion of excessive saturated fatty acid intakes (>10 % of total energy intake) that could be avoided if ultra-processed food consumption was reduced to levels observed in the first quintile of each country. Secondary analysis was performed of 24 h dietary recall or food diary/record data collected by the most recently available nationally representative cross-sectional surveys carried out in Brazil (2008-9), Chile (2010), Colombia (2005), Mexico (2012), Australia (2011-12), the UK (2008-16), Canada (2015) and the US (2015-16). Population attributable fractions estimated the impact of reducing ultra-processed food consumption on excessive saturated fatty acid intakes (above 10 % of total energy intake) in each country. Significant relative reductions in the percentage of excessive saturated fatty acid intakes would be observed in all countries if ultra-processed food consumption was reduced to levels observed in the first quintile's consumption. The reductions in excessive intakes ranged from 10⋅0 % (95 % CI 6⋅2-13⋅6 %) in Canada to 35⋅0 % (95 % CI 28⋅7-48⋅0 %) in Mexico. In all eight studied countries, all presenting more than 30 % of intakes with excessive saturated fatty acids, lowering the dietary contribution of ultra-processed foods to attainable, context-specific levels was shown to be a potentially effective way to reduce the percentage of intakes with excessive saturated fatty acids, which may play an important role in the prevention of non-communicable diseases, particularly cardiovascular diseases.

Relationships Between Cardiovascular Autonomic Profile and Work Ability in Patients With Pure Autonomic Failure.

Pure autonomic failure (PAF) is a rare disorder belonging to the group of synucleinopathies, characterized by autonomic nervous system degeneration. Severe orthostatic intolerance with recurrent syncope while standing are the two most disabling manifestations. Symptoms may start at middle age, thus affecting people at their working age. The aims of this study were to evaluate the autonomic and work ability impairment of a group of PAF patients and assess the relationships between cardiovascular autonomic control and work ability in these patients. Eleven PAF patients (age 57.3 ± 6.7 years), engaged in work activity, participated in the study. They completed the Composite Autonomic Symptom Score (COMPASS-31, range 0 no symptom-100 maximum symptom intensity) and Work Ability questionnaires (Work Ability Index, WAI, range 7-49; higher values indicate better work ability and lower values indicating unsatisfactory or jeopardized work ability). Electrocardiogram, blood pressure and respiratory activity were continuously recorded for 10 min while supine and during 75° head-up tilt (HUT). Autoregressive spectral analysis of cardiac cycle length approximated as the time distance between two consecutive R-wave peaks (RR) and systolic arterial pressure (SAP) variabilities provided the power in the high frequency (HF, 0.15-0.40 Hz) and low frequency (LF, 0.04-0.15 Hz) bands of RR and SAP variabilities. Cardiac sympatho-vagal interaction was assessed by LF to HF ratio (LF/HF), while the LF power of SAP (LFSAP) quantified the vascular sympathetic modulation. Changes in cardiovascular autonomic indexes induced by HUT were calculated as the delta (Δ) between HUT and supine resting positions. Spearman correlation analysis was applied. PAF patients were characterized by a moderate autonomic dysfunction (COMPASS-31 total score 47.08 ± 20.2) and by a reduction of work ability (WAI 26.88 ± 10.72). Direct significant correlations were found between WAI and ΔLFRR (r = 0.66, p = 0.03) and ΔLF/HFRR (r = 0.70, p = 0.02). Results indicate that patients who were better able to modulate heart rate, as revealed by a greater cardiac sympathetic increase and/or vagal withdrawal during the orthostatic stimulus, were those who reported higher values of WAI. This finding could be relevant to propose new strategies in the occupational environment to prevent early retirement or to extend the working life of these patients.

Platelet activating factor in the eye: Physiological roles, diseases and future perspectives.

Platelet Activating Factor (PAF) is a known phospholipid mediator of inflammation. Since its first description in 1972, it has emerged as a key regulator of vital cellular signaling functions, as proliferation, cell adhesion, and apoptosis. Evidence suggests that interactions between PAF and its receptor (PAFR) play a critical role in nervous system tissues, including the retina. The retina is a very important constituent of the visual system, along with the cornea, sclera, choroid, iris, and ciliary body, that acts synergistically to provide vision and to maintain optical homeostasis. There is evidence that PAF may regulate a wide range of physiological functions in the visual system tissues, such as eye development, inflammation, epithelial wound healing, and synapsis. Due to their multiple functions, PAF and PAFR also have important pathological and clinical implications in ocular disorders such as Choroidal Neovascularization (CNV), Age Macular Degeneration, (AMD), Diabetic Retinopathy (DR), transplant responses, and pharmacological interactions. Studies with PAFR antagonists have shown promising results such as inhibition of neovascularization and chloroquine-induced retinopathies, as well as reducing inflammation and retinal cell death. Due to the importance of PAFR signaling in the visual system and ophthalmology research, this review aims to provide a general overview of current and future perspectives about PAF in eye biology.

Chronic urticaria and thyroid pathology.

Urticaria is defined as the sudden appearance of erythematous, itchy wheals of variable size, with or without angioedema (AE) (swelling of the deeper layers of the skin). Its classification depends on time course of symptoms and the presence of eliciting factors. When it lasts less than 6 weeks it is classified as acute urticaria (AU), and if the symptoms persist for more than 6 weeks, it is classified as chronic urticaria (CU). Current International Guidelines also classify CU as chronic spontaneous urticaria (CSU) and inducible urticarial, according to the absence or presence of environmental triggering factors. CSU is defined as urticaria and/or angioedema in which there is no evidence of a specific eliciting factor. CSU is associated with autoimmunity in 30-45% of the cases, sharing some immunological mechanisms with other autoimmune diseases, and is associated with autoimmune thyroid disease (ATD) in about 4.3%-57.4% patients. Several studies suggest that adequate therapy with anti-thyroid drugs or levothyroxine in early stages of ATD and CSU, may help to remit the latter; but there is still a lack of double-blind, placebo-controlled studies that support this hypothesis in patients without abnormal thyroid hormone levels. The objective of this review is to describe the pathophysiology of chronic spontaneous urticaria and its association with autoimmune thyroid disease.

Mechanisms underlying fat pad remodeling induced by fasting: role of PAF receptor.

OBJECTIVES: Fasting has long been practiced for political and religious reasons and to lose weight. However, biological responses during fasting have yet to be fully understood. Previous studies have shown that cytokines may control fat pad expansion, at least in part, owing to the induction of lipolysis. Indeed, we have previously shown that mice with a lower inflammatory response, such as platelet-activating factor receptor knockout mice (PAFR-/-), are prone to gain weight and adiposity. The aims of this study were to determine whether adipose tissue becomes inflamed after fasting and to evaluate whether the PAF signaling is a factor in the fat loss induced by fasting. METHODS: Wild-type (WT) and PAFR-/- mice were fasted for 24 h. Adiposity, leukocyte recruitment, and cytokine levels were evaluated. Multiple comparisons were performed using two-way analysis of variance and post hoc Fisher exact test. RESULTS: After fasting, male WT mice showed lower adiposity (P < 0.001), higher recruitment of immune cells (P < 0.001), and increased cytokine levels (P < 0.05) in adipose tissue. Although WT mice lost ~79% of their adipose tissue mass, PAFR-/- mice lost only 36%. Additionally, PAFR-/- mice did not show enhanced cytokine and chemokine levels after fasting (P > 0.05). CONCLUSION: Despite low-grade inflammation being associated with metabolic syndrome, at least in part, the inflammatory milieu is also important to induce proper fat mobilization and remodeling of adipose tissue.

[Associated risk factors for infection in open fractures by firearms]. / Factores de riesgo asociados a infección de fracturas expuestas por proyectil de arma de fuego.

BACKGROUND: The introduction of firearms has increased deaths, assassinations and suicides. Firearm projectile injuries (PAF) increasingly affect civilian populations (500,000 injuries annually), it is the second cause of death in young people. Half required fracture treatment (45%), accompanied by reports of 6% who developed a deep infection. MATERIAL AND METHODS: Retrospective, observational, cross-sectional study in four hospitals of the Secretary of Health of CDMX of the frequency of infection in fractures exposed by PAF and if there is any other factor that is associated with the infection. RESULTS: In the review of the files of the four hospitals, 67 patients were found, men, with an incidence of infections of 4.5%, when analyzing the risk factors these did not present a significant association. DISCUSSION: No risk factor has statistical significance for any infectious process to occur, probably due to a good initial treatment.

ANTECEDENTES: La introducción de armas de fuego ha incrementado las muertes, asesinatos y suicidios. Las lesiones por proyectil de arma de fuego (PAF) afectan cada vez más a poblaciones civiles (500,000 lesiones anualmente) y es la segunda causa de muerte en jóvenes. La mitad requiere tratamiento de fracturas (45%), acompañado de reportes de 6% que desarrollaron una infección profunda. MATERIAL Y MÉTODOS: Estudio retrospectivo, observacional y transversal en cuatro hospitales de la Secretaría de Salud de la CDMX de la frecuencia de infección en fracturas expuestas por PAF y si existe algún otro factor que acompañe a la infección. RESULTADOS: Se encontraron en la revisión de los expedientes de los cuatro hospitales a 67 pacientes, hombres, con una incidencia de infecciones de 4.5%, al analizar los factores de riesgo éstos no presentaron asociación significativa. DISCUSIÓN: Ningún factor de riesgo posee significancia estadística de que se presente algún proceso infeccioso, probablemente por un buen tratamiento inicial.

Factores de riesgo asociados a infección de fracturas expuestas por proyectil de arma de fuego / Associated risk factors for infection in open fractures by firearms

Resumen: Antecedentes: La introducción de armas de fuego ha incrementado las muertes, asesinatos y suicidios. Las lesiones por proyectil de arma de fuego (PAF) afectan cada vez más a poblaciones civiles (500,000 lesiones anualmente) y es la segunda causa de muerte en jóvenes. La mitad requiere tratamiento de fracturas (45%), acompañado de reportes de 6% que desarrollaron una infección profunda. Material y métodos: Estudio retrospectivo, observacional y transversal en cuatro hospitales de la Secretaría de Salud de la CDMX de la frecuencia de infección en fracturas expuestas por PAF y si existe algún otro factor que acompañe a la infección. Resultados: Se encontraron en la revisión de los expedientes de los cuatro hospitales a 67 pacientes, hombres, con una incidencia de infecciones de 4.5%, al analizar los factores de riesgo éstos no presentaron asociación significativa. Discusión: Ningún factor de riesgo posee significancia estadística de que se presente algún proceso infeccioso, probablemente por un buen tratamiento inicial.

Abstract: Background: The introduction of firearms has increased deaths, assassinations and suicides. Firearm projectile injuries (PAF) increasingly affect civilian populations (500,000 injuries annually), it is the second cause of death in young people. Half required fracture treatment (45%), accompanied by reports of 6% who developed a deep infection. Material and methods: Retrospective, observational, cross-sectional study in four hospitals of the Secretary of Health of CDMX of the frequency of infection in fractures exposed by PAF and if there is any other factor that is associated with the infection. Results: In the review of the files of the four hospitals, 67 patients were found, men, with an incidence of infections of 4.5%, when analyzing the risk factors these did not present a significant association. Discussion: No risk factor has statistical significance for any infectious process to occur, probably due to a good initial treatment.

Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

Platelet activating factor is a lipid mediator of inflammation, and in recent decades, it has emerged as an important factor in tumor outcomes. Platelet activating factor acts by specific binding to its receptor, which is present in both tumor cells and cells that infiltrate tumors. Pro-tumorigenic effects of platelet activating factor receptor in tumors includes promotion of tumor cell proliferation, production of survival signals, migration of vascular cells and formation of new vessels and stimulation of dendritic cells and macrophages suppressor phenotype. In experimental models, blocking of platelet activating factor receptor reduced tumor growth and increased animal survival. During chemotherapy and radiotherapy, tumor cells that survive treatment undergo accelerated proliferation, a phenomenon known as tumor cell repopulation. Work from our group and others showed that these treatments induce overproduction of platelet activating factor-like molecules and increase expression of its receptor in tumor cells. In this scenario, antagonists of platelet activating factor markedly reduced tumor repopulation. Here, we note that combining chemo- and radiotherapy with platelet activating factor antagonists could be a promising strategy for cancer treatment.

Risk perception in subjects at-risk for Familial Amyloidotic Polyneuropathy / Percepción del riesgo en sujetos con riesgo de Polineuropatía Amiloide Familiar

Abstract The aims of this study are to know if subjects at-risk were aware of their 50% risk for Familial Amyloidotic Polyneuropathy (FAP); to know the value of the subjective risk; to understand the association between sociodemographic characteristics and risk perception, and between the risk status and the subjective perception of risk. 174 subjects 50% at-risk for FAP were tested. 52.9% subjects at-risk were aware of their 50% risk condition. The mean value of the subjective risk was higher and closer to 50% when the subjects were aware of their 50% risk condition. Education was associated to a higher awareness of being at 50% risk. It seems that information on previous knowledge before performing the genetic counselling increases the subjective risk.

Resumen Los objetivos de este estudio son saber si los sujetos en riesgo eran conscientes de su riesgo del 50% para la polineuropatía amiloide familiar (PAF); conocer el valor del riesgo subjetivo; y comprender la asociación entre las características sociodemográficas y la percepción del riesgo y entre el riesgo real y la percepción subjetiva del riesgo. Se examinaron 174 sujetos con riesgo de PAF del 50%. 52,9% de los sujetos en riesgo eran conscientes de su condición de riesgo del 50%. El valor medio del riesgo subjetivo fue mayor y más cercano al 50% cuando los sujetos eran conscientes de su condición de riesgo del 50%. La educación se asoció a una mayor conciencia de estar al 50% de riesgo. Parece que la información sobre los conocimientos previos antes de realizar el asesoramiento genético aumenta el riesgo subjetivo.

Motivation to perform presymptomatic testing in portuguese subjects at-risk for late-onset genetic diseases

El papel del psicólogo clínico en el contexto del consejo genético incluye brindar apoyo a los sujetos en riesgo en el proceso de toma de decisiones, independientemente de la decisión adoptada por el sujeto (conociendo o no el resultado de las pruebas genéticas). El estudio que se informa aborda la motivación para realizar las pruebas pre-sintomáticas (PPS) de sujetos en situación de riesgo para tres enfermedades: polineuropatía amiloide familiar (PAF), la enfermedad de Huntington (EH) y la enfermedad de Machado-Joseph (EMJ) y comparar con la motivación para realizar las PPS para hemocromatosis (HH). La muestra consistió en 213 sujetos portugueses que tenían riesgo genético para contraer las tres enfermedades y 31 sujetos en situación de riesgo genético para contraer hemocromatosis. Ellos fueron evaluados con una entrevista para obtener datos sociodemográficos y debían responder a una pregunta sobre la motivación para llevar a cabo las pruebas pre-sintomáticas. Se obtuvieron siete categorías principales y las siguientes son las más significativas para PAF, EH y EMJ: razones relacionadas con el futuro, razones relacionadas con los demás y razones relacionadas con la curiosidad y la necesidad de conocer. Para hemocromatosis, las más importantes resultaron ser razones relacionadas con los demás y las relacionadas con las características de la enfermedad. La motivación para realizar el test pre-sintomático (PST) de la PAF, EH y EMJ es externa y sin relación con la enfermedad, mientras que la motivación de los sujetos en situación de riesgo para la HH está relacionada con la enfermedad. Las razones relacionadas con los demás es una motivación común en ambos grupos. A los sujetos también les preocupa la posibilidad de transmitir la enfermedad a sus hijos.

The role of the clinical psychologist in the context of genetic counseling includes support for the process of decision-making for subjects at-risk, regardless of the decision that was made. For this, it is important to know the motivations behind these decisions. What may be considered advant-ageous and justifiable reasons to perform the PST for genetic diseases from the medical and public point of view, i.e., planning for the future, helping in the choice of a profession, family planning, improving quality of life and contributing to health, may not be recognized as such by the individual seeking the PST. This study addresses the motivation to perform the presymptomatic testing (PST) of subjects at-risk for three diseases, Familial Amyloid Polyneuro pathy (FAP), Huntington's disease (HD), and Machado-Joseph disease (MJD), compared with the motivation to perform the PST for Hemochromatosis (HH). FAP, HD and MJD are three genetic (monogenic) autosomal dominant late-onset diseases (LON-Ds) with no cure. FAP is a progressive sensorimotor and autonomic neuropathy of adult hood. HD is characterized by a triad of clinical symptoms of chorea (motor, cognitive and psychiatric symptoms), emotional distress and cognitive decline. MJD is characterized by slowly progressive clumsiness in the arms and legs, a staggering lurching gait, sometimes mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements, and may be accompanied by double vision or bulging eyes, and lower limb spasticity. HH is a disease in which too much iron accumulates in parenchymal organs, leading to iron overload and subsequent organ toxicity and failure. The study participants consisted in 213 subjects at genetic risk for FAP, HD, and MJD and 31 subjects at genetic risk for HH, that were assessed through an interview to obtain sociodemographic data and the answer to one question about motivation to perform PST: "Which were the reasons that led you to perform the predictive test? "This study was carried out in Center for Predictive and Preventive Genetics (CGPP), Institute for Molecular and Cell Biology (IBMC), Porto (Portugal). This research used a mixed-method, since qualitative and quantitative techniques of data analysis were used. Before deciding to seek genetic counseling and to know their genetic status, subjects at-risk have naturally considered their motives and it was probably the pro-counseling reasons the ones dictating the motivation to perform the PST. This may suggest that in fact there is a prior self-selection to the test, i.e. only those considering to have emotional skills to go through the process, performing the test. Seven major categories were obtained. The most significant ones for FAP, HD and MJD were reasons related to the future, reasons related to others and reasons related to curiosity and to the need to know. For HH, the most important ones were reasons related to others and reasons related to the characteristics of the disease. The motivation of subjects at-risk to perform the PST for FAP, HD and MJD is external and unrelated to the disease, while the motivation of subjects at-risk to perform the PST for HH is related to the disease. Reasons related to others area common motivation: as subjects at-risk for FAP, HD and MJD, subjects at-risk for HH also chose reasons related to others as one of the most important motivations to carry out the PST. These subjects also care about the fact that they can transmit the disease to their children and care about other family members which are already ill. The category reasons related to others includes sub-categories that identify the person and the situation that led to the decision to perform a PST. Subjects at-risk are also concerned about the fact that they have to decide whether or not to have children and its economic implications.

Reporte de cáncer colorrectal atendido en el Hospital Metropolitano de Quito, 2013-2016 / Colorectal cancer report treated in the Metropolitan Hospital of Quito, 2013-2016

Resumen: En la revisión retrospectiva se contabilizó un total de 57 casos de cáncer colorrectal (CCR) atendidos en esta casa de salud: 32 (56%) hombres y 25 (44 %) mujeres; el grupo etario con mayor frecuencia es de >40 años; el sitio predominante es el recto (15 casos = 26%). Según el tipo histológico son: adenocarcinomas 47 casos (82%); de acuerdo a la diferenciación histológica la mayoría son moderadamente diferenciados: 24 casos (42%) y, finalmente, según el estadiaje de piezas quirúrgicas, la mayoría son CCR avanzados en estadio T4 (48%).

Abstract: In the retrospective review, a total of 57 cases of RCC attended in this health home were counted, of which 32 (56%) men and 25 (44%) women; The age group is most often 40 years or older. The predominant site is the rectum with 15 cases corresponding to 26%. According to the histological type, adenocarcinomas with 47 cases (82%); according to the histological differentiation of the most moderately differentiated cases with 24 cases (42%); and finally in relation to the set of surgical pieces, most of their children CCR advanced stage T4 (48%).

Opportunities for the development of novel therapies based on host-microbial interactions.

Immune responses are fundamental for protecting against most infectious agents. However, there is now much evidence to suggest that the pathogenesis and tissue damage after infection are not usually related to the direct action of the replication of microorganisms, but instead to altered immune responses triggered after the contact with the pathogen. This review article discusses several mechanisms necessary for the host to protect against microbial infection and focuses in aspects that cause altered inflammation and drive immunopathology. These basic findings can ultimately reveal pathways amenable to host-directed therapy in adjunct to antimicrobial therapy for future improved control measures for many infectious diseases. Therefore, modulating the effects of inflammatory pathways may represent a new therapy during infection outcome and disease.

Emerging targets for combination therapy in melanomas.

Cutaneous melanomas are often difficult to treat when diagnosed in advanced stages. Melanoma cells adapt to survive in extreme environmental conditions and are among the tumors with larger genomic instability. Here we discuss some intrinsic and extrinsic mechanisms of resistance of melanoma cells to both conventional and target therapies, such as autophagy, adaptation to endoplasmic reticulum stress, metabolic reprogramming, mechanisms of tumor repopulation and the role of extracellular vesicles in this later phenomenon. These biological processes are potentially targetable and thus provide a platform for research and discovery of new drugs for combination therapy to manage melanoma patient treatment.

Contribution of the platelet activating factor signaling pathway to cerebral microcirculatory dysfunction during experimental sepsis by ExoU producing Pseudomonas aeruginosa.

Intravital microscopy was used to assess the involvement of ExoU, a Pseudomonas aeruginosa cytotoxin with phospholipase A2 activity, in dysfunction of cerebral microcirculation during experimental pneumosepsis. Cortical vessels from mice intratracheally infected with low density of the ExoU-producing PA103 P. aeruginosa strain exhibited increased leukocyte rolling and adhesion to venule endothelium, decreased capillar density and impaired arteriolar response to vasoactive acetylcholine. These phenomena were mediated by the platelet activating factor receptor (PAFR) pathway because they were reversed in mice treated with a PAFR antagonist prior to infection. Brains from PA103-infected animals exhibited a perivascular inflammatory infiltration that was not detected in animals infected with an exoU deficient mutant or in mice treated with the PAFR antagonist and infected with the wild type bacteria. No effect on brain capillary density was detected in mice infected with the PAO1 P. aeruginosa strain, which do not produce ExoU. Finally, after PA103 infection, mice with a targeted deletion of the PAFR gene exhibited higher brain capillary density and lower leukocyte adhesion to venule endothelium, as well as lower increase of systemic inflammatory cytokines, when compared to wild-type mice. Altogether, our results establish a role for PAFR in mediating ExoU-induced cerebral microvascular failure in a murine model of sepsis.

Blood cells and endothelial barrier function.

The barrier properties of endothelial cells are critical for the maintenance of water and protein balance between the intravascular and extravascular compartments. An impairment of endothelial barrier function has been implicated in the genesis and/or progression of a variety of pathological conditions, including pulmonary edema, ischemic stroke, neurodegenerative disorders, angioedema, sepsis and cancer. The altered barrier function in these conditions is often linked to the release of soluble mediators from resident cells (e.g., mast cells, macrophages) and/or recruited blood cells. The interaction of the mediators with receptors expressed on the surface of endothelial cells diminishes barrier function either by altering the expression of adhesive proteins in the inter-endothelial junctions, by altering the organization of the cytoskeleton, or both. Reactive oxygen species (ROS), proteolytic enzymes (e.g., matrix metalloproteinase, elastase), oncostatin M, and VEGF are part of a long list of mediators that have been implicated in endothelial barrier failure. In this review, we address the role of blood borne cells, including, neutrophils, lymphocytes, monocytes, and platelets, in the regulation of endothelial barrier function in health and disease. Attention is also devoted to new targets for therapeutic intervention in disease states with morbidity and mortality related to endothelial barrier dysfunction.

Papel do fator de ativação de plaquetas na infecção de macrófagos por leishmania infantum e identificação de uma Paf-Acetilhidrolase no parasita / Role of platelet-activating factor in macrophage infection by Leishmania infantum and identification of the parasite PAF acetylhydrolase

A leishmaniose visceral é causada pelo parasita Leishmania infantum. A infecção ocorre quando flebótomos infectados se alimentam na derme do hospedeiro vertebrado, inoculando o parasita. A infecção produz uma resposta com diversas moléculas inflamatórias, como os mediadores lipídicos. O fator de ativação de plaquetas (PAF) é um potente mediador lipídico derivado de um lisofosfolipídio. PAF participa da fisiologia normal da célula e possui um perfil pró-inflamatório. A participação de mediadores lipídicos, como eicosanóides e PAF, já foi identificada na imunopatogênese das leishmanioses. PAF gerado pelo hospedeiro tem efeito leishmanicida e de controle da infecção por L. amazonensis. PAF-acetilhidrolases (PAF-AH) são fosfolipases A2 que hidrolisam PAF e foi demonstrado que PAF-AH podem ser um fator de virulência devido a essa habilidade. O objetivo desse estudo foi avaliar o papel do PAF e de uma PAF-AH na infecção de macrófagos por L. infantum. Foi observado que PAF 1μM, quando adicionado durante e após a infecção, foi capaz de diminuir 50% da infecção após 72 horas, bem como a viabilidade dos parasitas dentro dos macrófagos num mecanismos independente do seu receptor PAFR e da produção de óxido nítrico. PAF 10μM interrompeu o crescimento de promastigotas de L. infantum em cultura axênica. Uma PAFAH, com elevada identidade e semelhança com PLA2/PAF-AH de outros tripanossomatídeos, foi identificada no genoma de L. infantum. A clonagem e expressão recombinante produziu uma proteína de cerca de 69kDa, com atividade PAF-AH. Frações celulares do parasita, enriquecidas com estruturas de membrana também apresentaram atividade PAF-AH. Os resultados indicam que PAF é capaz de diminuir a infecção de macrófagos por L. infantum e que o parasita possui uma PAF-AH funcional possivelmente envolvida com sua virulência.

Visceral leishmaniasis is caused by Leishmania infantum parasites. Infection occurs when infected sandflies feed on vertebrate host skin delivering the parasite which survive, multiply and spread on the parasitophorous vacuoles of macrophages. The inflammatory response during the infection leads to the production of diverse bioactive molecules, as lipid mediators. The platelet activating factor (PAF) is a lipid mediator derived from a lysophospholipid. PAF has a role in normal cellular physiology, acting as proinflamatory molecule. The participation of some lipid mediators, as eicosanoids and PAF has been identified in leishmaniasis. PAF produced by the host is able to kill the parasite and control the infection by L. amazonensis. PAF-acetylhydrolases (PAF-AH) are phospholipases A2 (PLA2) that hydrolyse PAF, and possibly involved in pathogen virulence. The aim of this study was to evaluate the role of PAF on macrophages infection by L. infantum and identify a PAF-AH expressed by the parasite. PAF 1μM, added during and after the infection, was able to reduce approximately 50% of infection, as well as, the viability of parasites inside macrophages. Apparently this reduction occurs by an classical PAF receptor and nitric oxide production independent mechanism. PAF 10μM inhibited L. infantum promastigotes growing in axenic culture. A PAF-AH with high identity to PLA2/PAF-AH of others trypanosomatids was identified in L. infantum genome. The cloning and recombinant expression produced a 69kDa protein with PAF-AH activity. Cellular fractions from parasites, with membrane structures also presented PAF-AH activity. The results suggest that PAF is able to decrease machophage infection by L. infantum witch has a functional PAFAH possibly related to its virulence.