RESUMEN
OBJECTIVES: To evaluate the feasibility of the autoinflammatory disease activity index (AIDAI) as a tool to assess disease activity in patients with hereditary recurrent fever syndromes (HRFs) treated with canakinumab. METHODS: Patients with active colchicine-resistant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), or tumor necrosis factor receptor-associated periodic syndrome (TRAPS) were enrolled in the phase III CLUSTER study and asked to complete the AIDAI questionnaire daily. All patients included in the analysis were treated with canakinumab, but regimens and periods of treatment varied per study protocol. The AIDAI for each patient was calculated weekly over the first 40 weeks of study, based on the diaries completed over 30 days. Disease-specific cut-off AIDAI values for inactive disease were calculated in a ROC analysis by comparing AIDAI scores with the occurrence of clinically inactive disease, based on the physician global assessments of disease activity and the occurrence of flares. RESULTS: Sixty patients with crFMF, 70 with MKD, and 43 with TRAPS were included in the analysis. Median AIDAI scores were high during the first 4 weeks for the three disease cohorts, and decreased afterwards, with some differences between disease cohorts. AIDAI values of 12.0, 9.6 and 15.5 were obtained as the most optimal thresholds to discriminate patients with inactive disease, with sensitivity and specificity values mostly over 75%. CONCLUSIONS: The AIDAI allows to discriminate between patients with active and inactive HRFs, and can be used in clinical practice to monitor the disease course of patients and the effect of medications.
Asunto(s)
Fiebre Mediterránea Familiar , Enfermedades Autoinflamatorias Hereditarias , Deficiencia de Mevalonato Quinasa , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colchicina/uso terapéutico , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Deficiencia de Mevalonato Quinasa/tratamiento farmacológico , Deficiencia de Mevalonato Quinasa/inducido químicamenteRESUMEN
Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.
Asunto(s)
Descubrimiento de Drogas , Gasotransmisores/farmacología , Sulfuro de Hidrógeno/farmacología , Animales , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/metabolismo , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Química Farmacéutica , Gasotransmisores/administración & dosificación , Gasotransmisores/metabolismo , Gasotransmisores/uso terapéutico , Humanos , Sulfuro de Hidrógeno/administración & dosificación , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/uso terapéutico , Morfolinas/administración & dosificación , Morfolinas/metabolismo , Morfolinas/farmacología , Morfolinas/uso terapéutico , Naproxeno/administración & dosificación , Naproxeno/análogos & derivados , Naproxeno/metabolismo , Naproxeno/farmacología , Naproxeno/uso terapéutico , Compuestos Organotiofosforados/administración & dosificación , Compuestos Organotiofosforados/metabolismo , Compuestos Organotiofosforados/farmacología , Compuestos Organotiofosforados/uso terapéuticoRESUMEN
Kidney injury may be a severe complication of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and contributes to worsen the prognosis. Various pathophysiological mechanisms can contribute to organ damage and impair renal function, proving the complexity of the virus activity and the resulting immunity response. We summarized the evidence of the literature on the prevalence of kidney involvement, on the pathogenic pathways and on its management.
RESUMEN
The actual Coronavirus Disease (COVID 19) pandemic is due to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the coronavirus family. Besides the respiratory involvement, COVID 19 patients frequently develop a pro-coagulative state caused by virus-induced endothelial dysfunction, cytokine storm and complement cascade hyperactivation. It is common to observe diffuse microvascular thrombi in multiple organs, mostly in pulmonary microvessels. Thrombotic risk seems to be directly related to disease severity and worsens patients' prognosis. Therefore, the correct understanding of the mechanisms underlying COVID-19 induced prothrombotic state can lead to a thorough assessment of the possible management strategies. Hence, we review the pathogenesis and therapy of COVID 19-related thrombosis disease, focusing on the available evidence on the possible treatment strategies and proposing an algorithm for the anticoagulation strategy based on disease severity.
Asunto(s)
Anticoagulantes/uso terapéutico , Tratamiento Farmacológico de COVID-19 , COVID-19/complicaciones , SARS-CoV-2/fisiología , Trombofilia/virología , Algoritmos , Interacciones Huésped-Patógeno , HumanosRESUMEN
As of January 2020, a new pandemic has spread from Wuhan and caused thousands of deaths worldwide. Several studies have observed a relationship between coronavirus disease (COVID-19) infection and the cardiovascular system with the appearance of myocardial damage, myocarditis, pericarditis, heart failure and various arrhythmic manifestations, as well as an increase in thromboembolic risk. Cardiovascular manifestations have been highlighted especially in older and more fragile patients and in those with multiple cardiovascular risk factors such as cancer, diabetes, obesity and hypertension. In this review, we will examine the cardiac involvement associated with SARS-CoV-2 infection, focusing on the pathophysiological mechanism underlying manifestations and their clinical implication, taking into account the main scientific papers published to date.
Asunto(s)
Lesión Renal Aguda , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Lesión Renal Aguda/virología , Anciano de 80 o más Años , COVID-19 , Prueba de COVID-19 , Deterioro Clínico , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Femenino , Humanos , Pruebas de Función Renal , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Terapia por Inhalación de Oxígeno/métodos , Manejo de Atención al Paciente/métodos , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , SARS-CoV-2 , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
17beta-Hydroxysteroid dehydrogenases (17beta-HSD) regulate the intracellular concentration of active sex steroid hormones in target tissues. To date, at least 14 different isozymes have been identified. The type 8 17beta-hydroxysteroid dehydrogenase (17beta-HSD8) selectively catalyzes the conversion of estradiol (E2) to estrone (E1). To map the promoter region and to investigate its regulation, we cloned and fused a 1600 bp DNA fragment upstream of the 17beta-HSD8 transcriptional start site to a luciferase reporter gene. After transient transfection in HepG2 cells, this fragment was shown to possess promoter activity. Deletion constructs of the 5' flanking region of the 17beta-HSD8 gene led to the identification of the minimal promoter region within the first 75 bp upstream of the transcriptional start site. This region included two CCAAT boxes and sequences closely resembling the consensus Sp1 and NF-kappaB motifs. Site directed mutagenesis revealed that the CCAAT boxes were essential for transcription in HepG2. EMSA, supershift and chromatin immunoprecipitation reflected that these sequences were binding sites for C/EBPbeta. Furthermore, promoter activity was increased by the co-transfection of a C/EBPbeta expression vector, and this transactivation was through both CCAAT boxes. Our studies indicate that C/EBPbeta is essential for the transcription of the 17beta-HSD8 gene in the liver.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Proteína beta Potenciadora de Unión a CCAAT/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Transcripción Genética/fisiología , Animales , Secuencia de Bases , Línea Celular , Inmunoprecipitación de Cromatina , ADN , Ensayo de Cambio de Movilidad Electroforética , Humanos , Hígado/metabolismo , Ratones , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Regiones Promotoras Genéticas , Homología de Secuencia de Ácido NucleicoRESUMEN
In human somatic cells, including T lymphocytes, telomeres progressively shorten with each cell division, eventually leading to a state of cellular senescence. Ectopic expression of telomerase results in the extension of their replicative life spans without inducing changes associated with transformation. However, it is yet unknown whether somatic cells that overexpress telomerase are physiologically indistinguishable from normal cells. Using CD8+ T lymphocyte clones overexpressing telomerase, we investigated the molecular mechanisms that regulate T cell proliferation. In this study, we show that early passage T cell clones transduced or not with human telomerase reverse transcriptase displayed identical growth rates upon mitogenic stimulation and no marked global changes in gene expression. Surprisingly, reduced proliferative responses were observed in human telomerase reverse transcriptase-transduced cells with extended life spans. These cells, despite maintaining high expression levels of genes involved in the cell cycle progression, also showed increased expression in several genes found in common with normal aging T lymphocytes. Strikingly, late passage T cells overexpressing telomerase accumulated the cyclin-dependent inhibitors p16Ink4a and p21Cip1 that have largely been associated with in vitro growth arrest. We conclude that alternative growth arrest mechanisms such as those mediated by p16Ink4a and p21Cip1 still remained intact and regulated the growth potential of cells independently of their telomere status.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/enzimología , Proliferación Celular , Expresión Génica/inmunología , Telomerasa/biosíntesis , Telomerasa/genética , Células Cultivadas , Cromosomas Humanos , Células Clonales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Cariotipificación , Mitosis/genética , Mitosis/inmunología , Telomerasa/metabolismo , Transducción GenéticaRESUMEN
Human Ag-specific CD8(+) T lymphocytes are heterogeneous and include functionally distinct populations. In this study, we report that at least two distinct mechanisms control the expansion of circulating naive, memory, and effector CD8(+) T lymphocytes when exposed to mitogen or Ag stimulation. The first one leads to apoptosis and occurs shortly after in vitro stimulation. Susceptibility to cell death is prominent among primed T cell subsets, and it is inversely correlated with the size of the ex vivo Bcl-2(high) population within these subsets. Importantly, the Bcl-2(high) phenotype is associated to the proportion of responsive CD8(+) T cells, independently of their differentiation stage. The second one depends on the expression of newly synthesized cyclin-dependent kinase inhibitor p16(INK4a) that occurs in a significant fraction of T cells that had been actively cycling, leading to their cell cycle arrest upon stimulation. Strikingly, accumulation of p16(INK4a) protein preferentially occurs in naive as opposed to primed derived T lymphocytes and is not related to apoptosis. Significant levels of p16 are readily detectable in a small number of ex vivo CD8(+) T cells. Our observations reveal that activation-induced p16 expression represents an alternative process to apoptosis, limiting the proliferation potential of activated naive derived T lymphocytes.
Asunto(s)
Antígenos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Adulto , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , Cinética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Human T lymphocytes can be numerically expanded in vitro only to a limited extent. The cyclin-dependent kinase inhibitor p16(INK4a) is essential in the control of cellular proliferation, and its expression, in epithelial cells, is associated with irreversible growth arrest. Using long-term cultured CD8+ T lymphocytes, we have investigated the role of the p16/pRb pathway in the regulation of T cell proliferation and senescence. In this study, we describe at least two mechanisms that cause replicative growth arrest in cultured lymphocytes. The first one depends on the expression of p16(INK4a) and is directly responsible for the exit of a significant proportion of CD8+ T cells from the proliferative population. This induced p16 expression pattern is observed during each round of mitogen stimulation and is not related to activation-induced cell death. Importantly, knocking down p16(INK4a) expression allows increased proliferation of T cells. The second one is a phenomenon that resembles human fibroblast senescence, but is independent of p16(INK4a) and of telomere attrition. Interestingly, virtually all pRb proteins in the senescent population are found in the active form. Our data indicate that newly synthesized p16(INK4a) limits the proliferation of T lymphocytes that respond to mitogen, but is not required for the loss of mitogen responsiveness called senescence.