RESUMO
OBJECTIVE: To evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19. METHODS: We present a post hoc analysis from a double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products-active caspase-1 (Casp1p20), IL-1ß, and IL-18-were assessed at enrollment and after 48-72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days. RESULTS: Thirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2-3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1ß. CONCLUSION: Treatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the 'cytokine storm' in COVID-19. TRIAL REGISTRATION NUMBERS: RBR-8jyhxh.
Assuntos
COVID-19 , Inflamassomos , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-18 , Proteínas NLR , Colchicina/uso terapêutico , Interleucina-1beta/metabolismoRESUMO
AIMS: Allergic asthma is a chronic inflammatory lung disease characterized by a Th2-type immune response pattern. The development of nonspecific immunotherapy is one of the primary goals for the control of this disease. METHODS AND RESULTS: In this study, we evaluated the therapeutic effects of Lactococcus lactis-producing mycobacterial heat shock protein 65 (LLHsp65) in an ovalbumin (OVA)-induced allergic asthma model. OVA-challenged BALB/c mice were orally administrated with LLHsp65 for 10 consecutive days. The results demonstrate that LLhsp65 attenuates critical features of allergic inflammation, like airway hyperresponsiveness and mucus production. Likewise, the treatment decreases the pulmonary eosinophilia and the serum level of OVA-specific IgE. In addition to deviating immune responses towards Th1-cytokine profile, increase regulatory T cells, and cytokine levels, such as IL-6 and IL-10. CONCLUSIONS: Our results reveal that the mucosal immunotherapy of LLHsp65 significantly reduces the overall burden of airway allergic inflammation, suggesting a promising therapeutic strategy for allergic asthma treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: This research reveals new perspectives on nonspecific immunotherapy based on the delivery of recombinant proteins by lactic acid bacteria to treat of allergic disorders.
Assuntos
Asma/tratamento farmacológico , Proteínas de Bactérias/farmacologia , Chaperonina 60/farmacologia , Inflamação/tratamento farmacológico , Lactococcus lactis/imunologia , Administração Oral , Animais , Asma/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hipersensibilidade/tratamento farmacológico , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunoterapia , Lactococcus lactis/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Linfócitos T Reguladores/imunologiaRESUMO
Background and Aims: The substantial reduction in adiponectin concentration among obese individuals seems to depend on fat distribution and is a marker of metabolic and adipose tissue dysfunction. We aimed to: (i) address whether abdominal fat from different compartments (visceral, deep subcutaneous abdominal and superficial subcutaneous abdominal) and gluteofemoral fat are independently associated with blood adiponectin concentration; and (ii) investigate whether abdominal (proxied by waist circumference) and gluteofemoral fat (proxied by hip circumference) accumulation causally determine blood adiponectin concentration. Methods: To investigate the independent association of abdominal and gluteofemoral fat with adiponectin concentration, we used multivariable regression and data from 30-year-old adults from the 1982 Pelotas Birth Cohort (n = 2,743). To assess the causal role of abdominal and gluteofemoral fat accumulation on adiponectin concentration, we used Mendelian randomization and data from two consortia of genome-wide association studies-the GIANT (n > 210 000) and ADIPOGen consortia (n = 29 347). Results: In the multivariable regression analysis, all abdominal fat depots were negatively associated with adiponectin concentration, specially visceral abdominal fat [men: ß = -0.24 standard unit of log adiponectin per standard unit increase in abdominal fat; 95% confidence interval (CI) = -0.31, -0.18; P = 8*10-13; women: ß = -0.31; 95% CI = -0.36, -0.25; P = 7*10-27), whereas gluteofemoral fat was positively associated with adiponectin concentration (men: ß = 0.13 standard unit of log adiponectin per standard unit increase in gluteofemoral fat; 95% CI = 0.03, 0.22; P = 0.008; women: ß = 0.24; 95% CI = 0.17, 0.31; P = 7*10-11). In the Mendelian randomization analysis, genetically-predicted waist circumference was inversely related to blood adiponectin concentration (ß = -0.27 standard unit of log adiponectin per standard unit increase in waist circumference; 95% CI = -0.36, -0.19; P = 2*10-11), whereas genetically-predicted hip circumference was positively associated with blood adiponectin concentration (ß = 0.17 standard unit of log adiponectin per standard unit increase in hip circumference; 95% CI = 0.11, 0.24; P = 1*10-7). Conclusions: These results support the hypotheses that there is a complex interplay between body fat distribution and circulating adiponectin concentration, and that whereas obesity-induced hypoadiponectinaemia seems to be primarily attributed to abdominal fat accumulation, gluteofemoral fat accumulation is likely to exert a protective effect.
Assuntos
Adiponectina/sangue , Adiponectina/deficiência , Gordura Intra-Abdominal , Erros Inatos do Metabolismo/genética , Obesidade/complicações , Adiponectina/genética , Adiposidade , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Brasil , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Análise Multivariada , Obesidade/sangue , Análise de Regressão , Fatores Sexuais , Circunferência da CinturaRESUMO
BACKGROUND/OBJECTIVES: Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. SUBJECTS/METHODS: The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. RESULTS: Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers (⩾15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction <0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction <0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction <0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. CONCLUSIONS: In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future.
Assuntos
Interação Gene-Ambiente , Homocisteína/sangue , Estilo de Vida , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Alelos , Brasil , Estudos de Coortes , Feminino , Ácido Fólico/sangue , Deficiência de Ácido Fólico , Genótipo , Humanos , Masculino , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Allergic asthma is a chronic pulmonary disease characterized by a Th2 inflammatory response. The modulation of a Th2 immune response based on immune deviation to a Th1 pattern or induction and migration of regulatory T cells to the lungs constitutes one of the major therapeutic approaches that is being investigated for the treatment of allergic asthma. The potentials of Mycobacterium leprae 65-kD heat-shock protein or Toll-like receptor 9 ligand (CpG oligodeoxynucleotides) as immune modulators for the treatment of airway allergic disease have been studied individually. OBJECTIVE: Mycobacterial protein combined with CpG was used as immunotherapy for airway allergy. METHODS: Using an ovalbumin-induced asthma model, mice were sensitized and challenged, and then treated with mycobacterial heat-shock protein (Hsp65) combined with CpG. RESULTS: The treatment of mice with established allergy led to the attenuation of eosinophilia, Th2 cytokines and airway hyperresponsiveness. Hsp65 plus CpG treatment also induced an increase in OVA-specific IFN-γ levels and in the frequency of lung inflammatory monocytes. Moreover, we show that the reduction of eosinophilia and the recruitment of inflammatory monocytes to the lungs required early triggering of TLR9, IFN-γ and CCR2 by immunotherapy components. CONCLUSION: In addition to immune deviation to a Th1 response in the modulation of Th2 allergic inflammation, our findings also attribute an important role to the innate response mediated by TLR9, associated with the recruitment of CCR2-dependent monocytes. CLINICAL RELEVANCE: Our findings show that the Hsp65/CpG treatment is a promising strategy for consideration in translational studies.
Assuntos
Asma/tratamento farmacológico , Proteínas de Bactérias/farmacologia , Chaperonina 60/farmacologia , Interferon gama/imunologia , Mycobacterium leprae , Oligodesoxirribonucleotídeos/farmacologia , Receptores CCR2/imunologia , Transdução de Sinais/efeitos dos fármacos , Receptor Toll-Like 9/imunologia , Animais , Asma/genética , Asma/imunologia , Imunoterapia , Interferon gama/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores CCR2/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Receptor Toll-Like 9/genéticaRESUMO
HIV patients frequently have opportunistic oesophageal infections. We report Haemophilus ducreyi genetic material detected by polymerase chain reaction in biopsies of oesophageal lesions in three HIV-1-infected patients. This finding may be an indication of its aetiopathological role in oesophageal lesions of HIV patients.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Cancroide/diagnóstico , Doenças do Esôfago/diagnóstico , Infecções por HIV/complicações , HIV-1 , Haemophilus ducreyi/isolamento & purificação , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/patologia , Adulto , Idoso , Cancroide/microbiologia , Cancroide/patologia , DNA Bacteriano/análise , Doenças do Esôfago/microbiologia , Doenças do Esôfago/patologia , Feminino , Haemophilus ducreyi/genética , Haemophilus ducreyi/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Inhalation of hypertonic saline (HS) causes bronchoconstriction in asthmatic subjects. Repeated inhalation of HS leads to substantially reduced bronchoconstriction, known as the refractory period. Refractoriness due to different stimuli has also been described (cross-refractoriness). Nocturnal asthma is defined as an increase in symptoms, need for medication, airway responsiveness, and/or worsening of lung function that usually occurs from 4 to 6 am. Our objective was to determine the effect of refractoriness on nocturnal asthma. The challenge test consisted of inhalations of 4.5% saline with increasing durations until a reduction of 20% in forced expiratory volume in 1 s (FEV1) (PD20HS) or total time of 15.5 min. Twelve subjects with nocturnal asthma were challenged with HS at 16:00 and 18:00 h and FEV1 was measured at 4:00 h. One to 2 weeks later, FEV1 was determined at 16:00 and 4:00 h. LogPD20HS at 18:00 h was significantly greater than logPD20HS at 16:00 h, 0.51 +/- 0.50 and 0.69 +/- 0.60 mg, respectively (P = 0.0033). When subjects underwent two HS challenges in the afternoon, mean (+/- SD) FEV1 reduction was 206 +/- 414 mL or 9.81 +/- 17.42%. On the control day (without challenge in the afternoon) FEV1 reduction was 523 +/- 308 mL or 22.75 +/- 15.40% (P = 0.021). Baseline FEV1 values did not differ significantly between the control and study days, 2.48 +/- 0.62 and 2.36 +/- 0.46 L, respectively. The refractory period following HS challenges reduces the nocturnal worsening of asthma. This new concept may provide beneficial applications to asthmatic patients.
Assuntos
Asma/prevenção & controle , Testes de Provocação Brônquica/métodos , Solução Salina Hipertônica/administração & dosagem , Administração por Inalação , Adulto , Ritmo Circadiano , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pico do Fluxo ExpiratórioRESUMO
Inhalation of hypertonic saline (HS) causes bronchoconstriction in asthmatic subjects. Repeated inhalation of HS leads to substantially reduced bronchoconstriction, known as the refractory period. Refractoriness due to different stimuli has also been described (cross-refractoriness). Nocturnal asthma is defined as an increase in symptoms, need for medication, airway responsiveness, and/or worsening of lung function that usually occurs from 4 to 6 am. Our objective was to determine the effect of refractoriness on nocturnal asthma. The challenge test consisted of inhalations of 4.5 percent saline with increasing durations until a reduction of 20 percent in forced expiratory volume in 1 s (FEV1) (PD20HS) or total time of 15.5 min. Twelve subjects with nocturnal asthma were challenged with HS at 16:00 and 18:00 h and FEV1 was measured at 4:00 h. One to 2 weeks later, FEV1 was determined at 16:00 and 4:00 h. LogPD20HS at 18:00 h was significantly greater than logPD20HS at 16:00 h, 0.51 ± 0.50 and 0.69 ± 0.60 mg, respectively (P = 0.0033). When subjects underwent two HS challenges in the afternoon, mean (± SD) FEV1 reduction was 206 ± 414 mL or 9.81 ± 17.42 percent. On the control day (without challenge in the afternoon) FEV1 reduction was 523 ± 308 mL or 22.75 ± 15.40 percent (P = 0.021). Baseline FEV1 values did not differ significantly between the control and study days, 2.48 ± 0.62 and 2.36 ± 0.46 L, respectively. The refractory period following HS challenges reduces the nocturnal worsening of asthma. This new concept may provide beneficial applications to asthmatic patients.
Assuntos
Adulto , Feminino , Humanos , Masculino , Asma/prevenção & controle , Testes de Provocação Brônquica/métodos , Solução Salina Hipertônica/administração & dosagem , Administração por Inalação , Ritmo Circadiano , Volume Expiratório Forçado , Pico do Fluxo ExpiratórioRESUMO
Os autores relatam o caso de uma paciente de 57 anos que passou a apresentar bloqueio atrioventricular total (BAVT) em conseqüência de um coice desferido por cavalo (trauma cardíaco fechado). O impacto de coice do animal foi de tal intensidade que arremessou a paciente a vários metros, fraturando-lhe uma costela e provocando o transtorno de conduçäo atrioventricular. Realizado com sucesso o implante de marcapasso provisório, a paciente mostrou boa evoluçäo. O ritmo sinusal com conduçäo AV 1:1 foi restabelecido no dia seguinte ao traumatismo e avaliaçöes posteriores confirmaram o desaparecimento do transtorno.
Assuntos
Feminino , Pessoa de Meia-Idade , Bloqueio Cardíaco , Traumatismos Cardíacos , Marca-Passo Artificial/classificaçãoRESUMO
A total of 150 patients were submitted to in-vitro fertilization (IVF) and endometrial pattern and thickness were assessed on the day of administration of human chorionic gonadotrophin (HCG). Ovarian stimulation was performed with gonadotrophins [human menopausal (HMG) or follicle stimulating hormone (FSH)] after down-regulation with leuprolide acetate. The endometrium was evaluated by vaginal ultrasound and classified into two groups: pattern I (a 'triple line' multilayer) and pattern II (fully homogeneous and hyperechogenic in relation to myometrial tissue). Pattern I was detected in 129 cycles (86%) and pattern II in 21 cycles (14%). The clinical pregnancy rates per cycle were similar (P = 0.79) for pattern I (29.4%) and pattern II (33.3%). There was no significant difference (P = 0.40) in the number of miscarriages between patients with pattern I and those with pattern II. Endometrial thicknesses were similar (10.3 +/- 2.0 mm and 11.2 +/- 3.1 mm) (P = 0.25). The thicknesses were similar (P = 0.14) for pregnant (10.8 +/- 2.1 mm) and non-pregnant (10.2 +/- 2.2 mm) women, but no pregnancies occurred when thickness was <7.0 mm. However, there was a significant difference (P = 0.04) between pregnant (10.8 +/- 1.9 mm) and non-pregnant (10.0 +/- 1.9 mm) women who showed pattern I. The conclusions from these data are that endometrial ultrasound in terms of pattern and thickness is of no prognostic value in IVF cycles on the day of administration of HCG. However, a minimum thickness has to be achieved for pregnancy to occur (7.0 mm). The presence of pattern I appears more likely to favour pregnancy.
Assuntos
Endométrio/diagnóstico por imagem , Fertilização in vitro , Hormônio Liberador de Gonadotropina/administração & dosagem , Gonadotropinas/administração & dosagem , Indução da Ovulação , Adulto , Endométrio/fisiologia , Feminino , Humanos , Ovário/fisiologia , Valor Preditivo dos Testes , Gravidez , Taxa de Gravidez , UltrassonografiaRESUMO
Os autores relatam o caso em que uma criança de 48 horas de vida, portadora de bloqueio atrioventricular (BAV) de grau avançado, bradicardia acentuada e insuficiência cardíaca importante foi submetida com sucesso a um implante de marcapasso endocárdico. Como via de acesso foi utilizada a veia jugular interna, o cabo-eletrodo de fixaçäo passiva foi posicionado no ventrículo direito e uma alça foi efetuada no interior do átrio direito. Com o crescimento da criança, observou-se o progressivo desenrolar do cabo-eletrodo. A freqüência inicial do marcapasso com que se obteve melhor débito cardíaco foi de 120 ppm, valor definido através de ecocardiograma bidimensional. Após 28 meses a criança vem apresentando ótima evoluçäo clínica. O marcapasso atualmente demonstra bom funcionamento, tanto no comando como na sensibilidade, e o cabo-eletrodo apresenta desenrolar suave, acompanhando o crescimento da criança.
Assuntos
Recém-Nascido , Masculino , Humanos , Bloqueio Cardíaco/patologia , Bradicardia/diagnóstico , Cirurgia Torácica/instrumentação , Recém-Nascido , Bloqueio Cardíaco/cirurgiaAssuntos
Coração/fisiologia , Hemodinâmica , Adulto , Função Atrial , Ecocardiografia , Processamento Eletrônico de Dados , Feminino , Humanos , Contração Isométrica , Masculino , DescansoRESUMO
Foram estudados pela ecocardiografia, com analise computadorizada dos dados obtidos, 40 individuos sadios, 20 de cada sexo, com idades variando entre 20 e 40 anos. Visando a avaliar o efeito do exercicio isometrico sobre a dinamica do atrio esquerdo (AE), os individuos foram estudados em repouso e durante esforco realizado em dinamometro manual de pressao ("handgrip").Foram estudados as seguintes variaveis:velocidade de enchimento do AE (VE), velocidade de esvaziamento rapido do AE (VR), velocidade de esvaziamento lento do AE (VL) e velocidade de esvaziamento sistolitico AE (VS). O tratamento estatistico das variaveis obtidas permitiu as seguintes conclusoes: 1 - O valor medio da VE em repouso foi 33 mm/s nao havendo diferenca entre os sexos ou entre as condicoes de repouso e esforco. 2 - O valor medio da VR em repouso foi 68 mm/s, nao havendo diferenca entre os sexos ou entre o exercicio e repouso. 3 - O valor medio da VS em repouso foi 59 mm/s nao havendo diferenca entre os sexos sendo maior durante o exercicio
Assuntos
Humanos , Masculino , Feminino , Adulto , Ecocardiografia , Átrios do Coração , Contração IsométricaAssuntos
Humanos , Masculino , Infarto do Miocárdio , Pressão Arterial , Teste de Esforço , Ventrículos do CoraçãoRESUMO
Com a finalidade de contribuir para o esclarecimento dos mecanismos da morte subita na forma cronica da tripanossomose cruzi, foram analisados, de modo sistematico, os seguintes aspectos em 116 chagasicos falecidos subitamente: o sexo, a idade em que ocorreu o obito, a profissao, o papel da emocao e do esforco fisico no momento do desenlace fatal e a epoca da morte em relacao as estacoes do ano. Todos estes tripanossomoticos, aparentemente, nao manifestaram, em vida, sintomas e/ou sinais de insuficiencia cardiaca. Para analise comparativa utilizou-se um grupo constituido por chagasicos cronicos falecidos com ou apos manifestacoes de insuficiencia cardiaca. Os resultados demonstraram que o obito acomete (tanto nos chagasicos falecidos subitamente como naqueles com insuficiencia cardiaca) mais frequentemente o homem que a mulher e que nos chagasicos do sexo masculino falecidos subitamente a morte ocorre mais cedo do que em triponossomoticos cujo desenlace esta associado ou e precedido por quadro de insuficiencia cardiaca. Finalmente, nossos dados sugerem que o esforco fisico, os fatores emotivos e as variacoes sazonais nao exercem papel essencial no desencadeamento do obito do chagasico cronico