ABSTRACT
La enfermedad de Chagas es una enfermedad parasitaria (Trypanosoma cruzi), endémica en 21 países de América y que las migraciones la han dispersado en distintos continentes. Una de las manifestaciones más precoces de esta enfermedad son las alteraciones disautonómicas o disfunción autonómica. La severidad de este inadecuado funcionamiento del sistema nervioso autónomo resulta mensurable, de modo que la evolución y/o progresión de la enfermedad puede constatarse mediante la alteración de estudios clínicos y detección de anticuerpos antimuscarínicos. Estos anticuerpos están presentes en un 30% de los infectados y aparecen muy precozmente una vez instalada la parasitosis; además otros estudios, como la dispersión del QT (>65 mseg) y la variabilidad de la frecuencia cardíaca (<100 mseg) presentan valores anormales. La utilización de nuevos paradigmas de atención, diagnóstico y tratamientos adecuados son imprescindibles para prevenir el desarrollo de esta cardiopatía.
Chagas disease is a parasitic disease (Trypanosoma cruzi), endemic in 21 countries of America and that migrations have dispersed it in different continents. One of the earliest manifestations of this disease is dysautonomic alterations or autonomic dysfunction. The severity of this inadequate functioning of the autonomic nervous system is measurable, so that the evolution and/or progression of the disease can be verified by altering clinical studies and detecting antimuscarinic antibodies. These antibodies are present in 30% of those infected and appear very early once the parasitosis is installed; In addition, other studies, such as QT dispersion (> 65 ms) and heart rate variability (<100 ms) show abnormal values. The use of new paradigms of care, diagnosis and appropriate treatments are essential to prevent the development of this heart disease.
A doença de Chagas é uma doença parasitária (Trypanosoma cruzi), endêmica em 21 países da América e que as migrações a dispersaram em diferentes continentes. Uma das primeiras manifestações desta doença são as alterações disautonômicas ou disfunção autonômica. A gravidade desse funcionamento inadequado do sistema nervoso autônomo é mensurável, de modo que a evolução e/ou progressão da doença pode ser verificada alterando os estudos clínicos e detectando anticorpos antimuscarínicos. Esses anticorpos estão presentes em 30% dos infectados e aparecem muito cedo, uma vez instalada a parasitose; Além disso, outros estudos, como a dispersão do QT (> 65 mseg) e a variabilidade da freqüência cardíaca (<100 mseg), mostram valores anormais. A utilização de novos paradigmas de atendimento, diagnóstico e tratamentos adequados são essenciais para prevenir o desenvolvimento desta doença cardíaca.
ABSTRACT
Previous studies showed that circulating autoantibodies against M2 muscarinic receptors (anti-M2R Ab) are associated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD). Here we investigated whether the exposure of M2R to such antibodies could impair agonist-induced receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced Gi protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2R internalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation. Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.
Subject(s)
Autoantibodies/immunology , Autonomic Nervous System Diseases/immunology , Chagas Disease/immunology , Receptor, Muscarinic M2/immunology , Adult , Aged , Allosteric Regulation , Autoantibodies/metabolism , Autoantibodies/pharmacology , Autonomic Nervous System Diseases/etiology , Autonomic Nervous System Diseases/metabolism , Autonomic Nervous System Diseases/physiopathology , Carbachol/pharmacology , Chagas Disease/complications , Chagas Disease/metabolism , Chagas Disease/physiopathology , Cholinergic Agonists/pharmacology , Female , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , HEK293 Cells , Heart Rate , Humans , Male , Middle Aged , Receptor, Muscarinic M2/drug effects , Receptor, Muscarinic M2/metabolism , beta-Arrestin 1/metabolismABSTRACT
BACKGROUND: Emergence of extended-spectrum beta-lactamases (ESBLs) in Shigella species imparting resistance to third-generation cephalosporins is a growing concern worldwide. The aim of this study is to molecularly characterize the newly emerging beta-lactam resistant Shigella sonnei, specifically ESBLs in Lebanon, and compare them to beta-lactam sensitive isolates. METHODOLOGY: We compared five beta-lactam-resistant S. sonnei isolates to six isolates susceptible to beta-lactams. Presence of ESBLs was established by the combination disk method. PCR amplification and sequence analysis of the beta-lactamase-encoding genes, along with other antimicrobial resistance genes, were performed. The localization of beta-lactamase genes was established by conjugation experiments. Beta-lactamase gene transcription levels were determined by real-time RT-PCR. Molecular typing was performed by pulsed-field gel electrophoresis (PFGE). RESULTS: Four of five beta-lactam resistant isolates were extended spectrum beta-lactamase producers. These harbored the bla-CTX-M-15 gene borne on a 70 Kb plasmid and class 2 integron genes on their chromosomes. The bla-CTX-M-15 gene was flanked by an insertion element ISEcp1. A chromosomal bla-TEM-1 gene was detected in one beta-lactam resistant Shigella isolate and two of the ESBL producing isolates. The bla-CTX-M-15 gene transcription levels were increased in EBSL isolates exposed to subinhibitory concentrations of ceftazidime. PFGE analysis revealed that the four bla-CTX-M-15 positive isolates were nonclonal but two of them shared genotypes with -lactam susceptible isolates. CONCLUSION: Dissemination of broad-spectrum beta-lactam resistance in Shigella sonnei is mediated by bla-CTX-M-15 through horizontal plasmid transfer rather than by clonal spread of the resistant isolates. Expression of this gene is further induced in the presence of ceftazidime.
