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INTRODUCCIÓN: Las disecciones de arterias cervicales (DAC) son la primera causa de accidente cerebrovascular isquémico (ACVi) en personas jóvenes. Los factores asociados (FA) de ACVi y la relación temporal con la DAC no están bien caracterizados. Tampoco disponemos de una clasificación clínico-radio-lógica que permita conocer el riesgo de ACVi. OBJETIVO: Describir frecuencia y FA y temporalidad de los ACVi en pacientes con DAC. MÉTODOS: Estudio prospectivo de pacientes mayores de 18 años hospitalizados por una DAC carotidea y/o vertebral entre agosto de 2009 y junio de 2017. Las DAC se diagnosticaron clínico-radiológicamente y los ACVi con imagen con infarto. Se utilizo la Clasificación de Borgess para caracterizar radiológicamente las DAC. Se utilizaron análisis de regresión logística uni y multivariable para evaluar las características clínico-radiológicas y los FA. RESULTADOS: 163 pacientes con 182 DAC (60% vertebrales y 40% carotídeas). 73 pacientes (44,8%) tuvieron un ACVi 28 de 68 pacientes (41,2%) tuvieron simultáneamente síntomas de disección y de isquemia. 60 de 68 pacientes (88%) presentan síntomas de isquemia durante la primera semana. FR significativamente asociados a ACVi: Borgess tipo IB (p = 0,001; OR: 4,1; IC: 1,8-9,3), sexo masculino (p < 0,001; OR: 0,2; IC: 0,06-0,8) y anticonceptivos orales (p = 0,02; OR: 0,2; IC: 0,06-0,8). CONCLUSIÓN: Ocurre aproximadamente en la mitad de los pacientes, en su mayoría dentro de la primera semana, no es la forma habitual de presentación inicial y no se relaciona con el tipo de arteria disecada. El principal FA para desarrollar un ACVi fue la oclusión arterial (Borgess tipo IB).
INTRODUCTION: Cervical artery dissections (CAD) are the leading cause of ischemic stroke (CVA) in young people. The risk factors for stroke and the temporal relationship with CAD are not well characterized. Nor do we have a clinical-radiological classification that allows knowing the risk of stroke. OBJECTIVE: To describe the associated factors and temporality of ACVi in patients with CAD. METHODS: We performed a prospective study that included patients over 18 years of age, hospitalized for carotid and/or vertebral CAD between August 2009 and June 2017. CAD cases were diagnosed clinically and radiologically; ACVi was diagnosed when the imaging study demonstrated infarction. The Borgess Classification was used to characterize the CAD radiologically. For correlation studies, we used univariate and multivariate logistic regression analyses. RESULTS: We analyzed 163 patients with 182 CAD (60% vertebral and 40% carotid). 28 of 68 patients (41.2%) simultaneously had symptoms of dissection and ischemia. 60 of 68 patients (88%) presented symptoms of ischemia during the first week. CAD: Borgess type IB (p = 0.001; OR: 4.1; CI: 1.8-9.3), male (p < 0.001; OR: 0.2; CI: 0.06- 0.8) were significantly associated with ischemic strokes and oral contraceptives (p = 0.02; OR: 0.2; CI: 0.06-0.8). CONCLUSION: Stroke associated with CAD has a relatively low frequency. It is not related to the type of dissected artery. It mainly occurs not simultaneously with CAD and within the first week. The main associated factor for developing a stroke is arterial occlusion (Borgess type IB).1,8-9,3), male sex (p < 0.001; OR: 0.2; CI: 0.06-0.8) and oral contraceptives (p = 0.02; OR: 0.2; CI: 0.06-0.8).
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Infarto Cerebral/etiologia , Infarto Cerebral/diagnóstico por imagem , Dissecação da Artéria Carótida Interna/complicações , Dissecação da Artéria Carótida Interna/diagnóstico por imagem , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/diagnóstico por imagem , Fatores de Tempo , Fatores Sexuais , Estudos Prospectivos , Fatores de RiscoRESUMO
Body temperature has relevant effects on the immune response. Here, we characterized the thermal biology and health condition of the viviparous lizard Liolaemus kingii from Patagonia (Argentina), by studying field body temperatures, presence of injuries or ectoparasites, body condition (BC), and individual immune response capacity with the phytohemagglutinin (PHA) skin-swelling assay. In addition, we analyzed the effects of injections of a bacterial endotoxin (lipopolysaccharide; LPS) on the preferred temperature (Tp) and BC of adult males and newborns. The PHA treatment caused detectable thickening at 2 and 20 hours post-assay in males, indicating a significant immune response related to an increase in cellular activity. LPS-challenged lizards thermoregulated accurately and at stable body temperatures within the 50% interquartile of Tp (Tset) over the 72-hour period while the control group showed a more variable and lower Tp. Exposure to LPS negatively affected the BC of newborns, whereas it did not affect the BC of adult males. LPS challenges, used as a proxy of pathogen exposures to study lizard behavioral thermoregulation, constitute a practical approach to assess the immunological constraints lizards from high-latitude regions may face due to global warming and anthropogenic disturbances.
Assuntos
Lagartos , Recém-Nascido , Animais , Masculino , Humanos , Lagartos/fisiologia , Argentina , Lipopolissacarídeos , Regulação da Temperatura Corporal/fisiologia , TemperaturaRESUMO
INTRODUCTION: Cervical artery dissections (CAD) are the leading cause of ischemic stroke (CVA) in young people. The risk factors for stroke and the temporal relationship with CAD are not well characterized. Nor do we have a clinical-radiological classification that allows knowing the risk of stroke. OBJECTIVE: To describe the associated factors and temporality of ACVi in patients with CAD. METHODS: We performed a prospective study that included patients over 18 years of age, hospitalized for carotid and/or vertebral CAD between August 2009 and June 2017. CAD cases were diagnosed clinically and radiologically; ACVi was diagnosed when the imaging study demonstrated infarction. The Borgess Classification was used to characterize the CAD radiologically. For correlation studies, we used univariate and multivariate logistic regression analyses. RESULTS: We analyzed 163 patients with 182 CAD (60% vertebral and 40% carotid). 28 of 68 patients (41.2%) simultaneously had symptoms of dissection and ischemia. 60 of 68 patients (88%) presented symptoms of ischemia during the first week. CAD: Borgess type IB (p = 0.001; OR: 4.1; CI: 1.8-9.3), male (p < 0.001; OR: 0.2; CI: 0.06- 0.8) were significantly associated with ischemic strokes and oral contraceptives (p = 0.02; OR: 0.2; CI: 0.06-0.8). CONCLUSION: Stroke associated with CAD has a relatively low frequency. It is not related to the type of dissected artery. It mainly occurs not simultaneously with CAD and within the first week. The main associated factor for developing a stroke is arterial occlusion (Borgess type IB).1,8-9,3), male sex (p < 0.001; OR: 0.2; CI: 0.06-0.8) and oral contraceptives (p = 0.02; OR: 0.2; CI: 0.06-0.8).
Assuntos
Dissecação da Artéria Carótida Interna , Infarto Cerebral , Dissecação da Artéria Vertebral , Humanos , Masculino , Feminino , Fatores de Risco , Estudos Prospectivos , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/etiologia , Dissecação da Artéria Carótida Interna/complicações , Dissecação da Artéria Carótida Interna/diagnóstico por imagem , Fatores de Tempo , Fatores Sexuais , IdosoRESUMO
In ectotherms, the likelihood of surviving an infection is determined by the efficiency of thermoregulation, the availability of a variety of thermal microenvironments, the individual's health status, and the virulence of the infective agent. Physiological and behavioral demands related to an efficient immune response entail a series of costs that compete with other vital activities, specifically energy storage, growth, reproduction, and maintenance functions. Here, we characterize the thermal biology and health status by the presence of injuries, ectoparasites, body condition, and individual immune response capacity (using phytohemagglutinin in a skin-swelling assay) of the southernmost lizards of the world, Liolaemus sarmientoi, endemic to a sub-optimal, cold environment in Patagonia, Argentina. In particular, we study the effect of a bacterial endotoxin (lipopolysaccharide; LPS-treatment) on thermoregulation. We found that the field-active body temperature (Tb) was much lower than the preferred body temperature (Tp) obtained in the laboratory. All the individuals were in good body condition at the beginning of the experiments. The phytohemagglutinin test caused detectable thickening in sole-pads at 2 h and 24 h post-assay in males and non-pregnant females, indicating a significant innate immune response. In the experimental immune challenge, the individuals tended to prefer a low body temperature after LPS-treatment (2 h post-injection) and developed hypothermia, while the control individuals injected with phosphate buffered saline (PBS), maintained their body temperature throughout the trial. In both the LPS-treatment and PBS-control individuals, BC declined during the experiment. Hypothermia may allow this southernmost species to optimize the use of their energetic resources and reduce the costs of thermoregulation in a cold-temperate environment where they rarely attain the mean Tp (35.16 °C) obtained in laboratory.
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Aclimatação/imunologia , Lagartos/fisiologia , Aclimatação/efeitos dos fármacos , Animais , Comportamento Animal , Temperatura Corporal , Temperatura Baixa , Lipopolissacarídeos/farmacologia , Lagartos/imunologiaRESUMO
Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoromethyl group, were synthesized and their in vitro antibacterial activities assayed against fourteen bacterial strains (six Gram-positive and eight Gram-negative). A one-pot methodology was developed to obtain the 3'-(difluoromethyl)-4'-methoxycinnamoyl amides using Deoxofluor® as a fluorinating agent. The N-isopropyl, N-isopentyl, and N-(2-phenylethyl) amides 11b, 11d and 11g were the most active and selective against Mycobacterium smegmatis (MIC = 8 µg/mL) with 11b and 11g displaying negligible or no cytotoxicity against HepG2 and A549 cells. Thirteen analogs of N-isopropylamide 11b were also synthesized and their antibacterial activity assayed. Results show that the difluoromethyl moiety enhanced antibacterial activity and selectivity towards M. smegmatis, changing the microorganism inhibition profile of the parent compound. The selectivity exhibited by some of the compounds towards M. smegmatis makes them potential leads in the search for new narrow spectrum antibiotics against M. tuberculosis.
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Amidas/farmacologia , Antibacterianos/farmacologia , Mycobacterium smegmatis/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/patogenicidade , Relação Estrutura-AtividadeRESUMO
The immune state is an essential component of survival as it directly influences physiological performance and health status. Variation in the leukocyte profile, a significantly increase in body temperature, and a detriment of the eco-physiological performance are among the possible consequences of an unhealthy state. In this study we analyse and discuss how field body temperature, preferred body temperature, the speed for sprint and long runs, locomotor stamina, and body condition can be affected by the immunological state (i.e. leukocyte profile) in a wild population of Liolaemus sarmentoi. Juveniles and adult males with a high percentage of eosinophils, basophils, and a low percentage of monocytes preferred higher body temperatures in a thermal gradient, while pregnant females maintained thermal preferences independently of leukocyte profile. Although juveniles with a high percentage of heterophils showed less locomotor stamina, adult males and pregnant females showed no differences in locomotor performance in relation to leukocyte profile. This study represents a starting point in eco-immunology of a wild lizard population of Liolaemus in cold and temperate environments of Patagonia where the southward shift in the geographic ranges of pathogen populations due to global warming represents a threat to resident host populations.
Assuntos
Comportamento Animal/fisiologia , Temperatura Corporal/imunologia , Lagartos/sangue , Lagartos/imunologia , Atividade Motora/imunologia , Aclimatação , Animais , Temperatura Corporal/fisiologia , Feminino , Lagartos/fisiologia , Masculino , Atividade Motora/fisiologia , GravidezRESUMO
Global warming can significantly affect many aspects of the biology of animal species, including their thermal physiology and physiological performance. Thermal performance curves provide a heuristic model to evaluate the impacts of temperature on the ecophysiology of ectotherms. When integrated with other thermal biology parameters, they can be used to predict the impacts of climate change on individual fitness and population viability. In this study, we combine holistic measures of thermal physiology and the thermal sensitivity of locomotor performance with environmental temperatures measured at fine scale to estimate the vulnerability to global warming of the endangered Patagonian lizard Phymaturus tenebrosus. Our results indicate that this lizard exhibits its preferred temperatures and maximum locomotor performance at higher temperatures than the mean temperature it currently experiences in its habitat. In addition, it exhibits a low effectiveness of thermoregulation, being a poor thermoregulator. In view of the results obtained, we suggest that the climatic conditions of Patagonia may be advantageous for P. tenebrosus to survive future global warming, since its thermal physiology and locomotor performance may improve under increasing in environmental temperatures in its habitat.
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Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Triterpenos/farmacologia , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/toxicidade , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Tempo , Testes de Toxicidade Subcrônica , Triterpenos/toxicidade , Carga Tumoral/efeitos dos fármacos , Imagem Corporal Total , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cucurbitacins and their derivatives are triterpenoids that are found in various plant families, and are known for their pharmacological and biological activities, including anti-cancer effects. Lung cancer represents a major public health problem, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer. The objective of this work was to evaluate four cucurbitacins (CUCs) for their cytotoxic activity, effects on apoptosis induction, cell cycle progression, anti-migratory, and anti-invasive effects on the human NSCLC cell line (A549 cells). Our findings showed that these CUCs could suppress human NSCLC cell growth in vitro through their effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion. Additionally, these effects culminate in apoptosis induction and G2/M cell cycle arrest by modulating cyclin B1 expression, and in the mitigation of strategic steps of lung cancer metastasis, including migration and invasion of A549 cells. These results suggest that two natural (DDCB and CB) and two novel semisynthetic derivatives of cucurbitacin B (ACB and DBCB) could be considered as promising compounds with antitumor potential.
Assuntos
Apoptose/efeitos dos fármacos , Cucurbitacinas/farmacologia , Cucurbitacinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Células A549 , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cucurbitacinas/química , Ciclina B1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
OBJECTIVES: Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. METHODS: Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of ß-carotene bleaching, at 1-200 µm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 µm) assays. KEY FNDINGS: Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of ß-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. CONCLUSIONS: Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.