RESUMEN
An association between remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome and insulin or dipeptidyl peptidase-4 (DPP4) inhibitor therapy were previously reported. We encountered four cases of RS3PE syndrome with type 2 diabetes mellitus or impaired glucose tolerance (IGT) without insulin or DPP4 inhibitor medication.
Asunto(s)
Diabetes Mellitus Tipo 2/diagnóstico , Edema/diagnóstico , Intolerancia a la Glucosa/diagnóstico , Sinovitis/diagnóstico , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Edema/complicaciones , Femenino , Intolerancia a la Glucosa/complicaciones , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Síndrome , Sinovitis/complicacionesRESUMEN
Helicobacter cinaedi is the most common enterohepatic Helicobacter species that causes bacteremia in humans, but its pathogenicity is unclear. Here, we investigated the possible association of H. cinaedi with atherosclerosis in vivo and in vitro. We found that H. cinaedi infection significantly enhanced atherosclerosis in hyperlipidaemic mice. Aortic root lesions in infected mice showed increased accumulation of neutrophils and F4/80(+) foam cells, which was due, at least partly, to bacteria-mediated increased expression of proinflammatory genes. Although infection was asymptomatic, detection of cytolethal distending toxin RNA of H. cinaedi indicated aorta infection. H. cinaedi infection altered expression of cholesterol receptors and transporters in cultured macrophages and caused foam cell formation. Also, infection induced differentiation of THP-1 monocytes. These data provide the first evidence of a pathogenic role of H. cinaedi in atherosclerosis in experimental models, thereby justifying additional investigations of the possible role of enterohepatic Helicobacter spp. in atherosclerosis and cardiovascular disease.
Asunto(s)
Aterosclerosis/microbiología , Enfermedades Cardiovasculares/microbiología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Macrófagos/inmunología , Animales , Aorta/inmunología , Aorta/microbiología , Aorta/patología , Aterosclerosis/patología , Enfermedades Cardiovasculares/patología , Diferenciación Celular/inmunología , Células Cultivadas , ADN Bacteriano/análisis , Células Espumosas/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Hiperlipidemias/microbiología , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Neutrófilos/inmunología , Óxido Nítrico Sintasa de Tipo III/genética , ARN Bacteriano/análisis , Receptores de LDL/biosíntesisRESUMEN
Helicobacter cinaedi is the most frequently reported enterohepatic Helicobacter species isolated from humans. Earlier research suggested that certain patients with H. cinaedi infection may remain undiagnosed or incorrectly diagnosed because of difficulties in detecting the bacteria by conventional culture methods. Here, we report a nested PCR assay that rapidly detects the cytolethal distending toxin gene (cdt) of H. cinaedi with high specificity and sensitivity. Specificity of the assay was validated by using different species of Helicobacter and Campylobacter, as well as known H. cinaedi-positive and -negative samples. The sensitivity of detection for the cdt gene in the assay was 10(2) CFU/ml urine or 10(2) CFU/10(5) infected RAW 264.7 cells. In an H. cinaedi-infected mouse model, the cdt gene of H. cinaedi was effectively detected via the assay with urine (6/7), stool (2/3), and blood (2/6) samples. Importantly, it detected H. cinaedi in blood, urine, and stool samples from one patient with a suspected H. cinaedi infection and three patients with known infections. The assay was further used clinically to follow up two H. cinaedi-infected patients after antibiotic treatment. Stool samples from these two patients evaluated by nested PCR after antibiotic therapy showed clearance of bacterial DNA. Finally, analysis of stool specimens from healthy volunteers showed occasional positive reactions (4/30) to H. cinaedi DNA, which suggests intestinal colonization by H. cinaedi in healthy subjects. In conclusion, this nested PCR assay may be useful for the rapid diagnosis, antimicrobial treatment evaluation, and epidemiological study of H. cinaedi infection.
Asunto(s)
Técnicas Bacteriológicas/métodos , Portador Sano/diagnóstico , Infecciones por Helicobacter/diagnóstico , Helicobacter/aislamiento & purificación , Tamizaje Masivo/métodos , Reacción en Cadena de la Polimerasa/métodos , Adulto , Anciano , Animales , Toxinas Bacterianas/genética , Sangre/microbiología , Modelos Animales de Enfermedad , Heces/microbiología , Femenino , Helicobacter/clasificación , Helicobacter/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Sensibilidad y Especificidad , Orina/microbiología , Adulto JovenRESUMEN
Helicobacter cinaedi has been increasingly recognized as an emerging pathogen. Reports of recurrent bacteremia and isolation of H. cinaedi organisms from a patient with myopericarditis led us to postulate that H. cinaedi is associated with chronic inflammatory cardiovascular diseases such as atrial arrhythmias and atherosclerosis. To assess any association of H. cinaedi with atrial arrhythmias, a retrospective case-control study of patients attending Kumamoto University Hospital from 2005 to 2009 was performed. The arrhythmia status of these patients was determined from their electrocardiography and electrophysiological studies. Multiple logistic regression analysis was used to identify independent risk factors. In a comparison of case patients (n= 132) with control subjects (n= 137), H. cinaedi seropositivity was identified as an independent risk factor for atrial arrhythmia (odds ratio, 5.13; 95% confidence interval, 3.0-8.7; P < 0.001). There were no significant differences, however, between these two groups with respect to anti-H. pylori IgG concentrations, anti-Chlamydophila pneumoniae IgG concentrations, and other studied variables. IgG concentrations against H. cinaedi and H. pylori were inversely correlated, which suggests cross-immunity between these two bacteria. Also, to explore any association of H. cinaedi with atherosclerosis, immunohistochemical analysis of atherosclerotic aortic tissues collected post mortem from nine patients was performed. Immunohistochemistry of atherosclerotic aortic tissues from all nine patients detected H. cinaedi antigens inside CD68(+) macrophages. These findings provide the first evidence, to our knowledge, of a possible association of H. cinaedi with atrial arrhythmias and atherosclerosis.
Asunto(s)
Arritmias Cardíacas/epidemiología , Aterosclerosis/epidemiología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Helicobacter/patogenicidad , Anciano , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/análisis , Aorta/microbiología , Aorta/patología , Estudios de Casos y Controles , Enfermedades Transmisibles Emergentes/complicaciones , Enfermedades Transmisibles Emergentes/epidemiología , Enfermedades Transmisibles Emergentes/microbiología , Femenino , Helicobacter/clasificación , Helicobacter/aislamiento & purificación , Infecciones por Helicobacter/microbiología , Hospitales , Humanos , Inmunohistoquímica , Japón , Macrófagos/microbiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estudios SeroepidemiológicosRESUMEN
Nitric oxide (NO), produced by inducible NO synthase (iNOS) during infection, plays a crucial role in host defense mechanisms. Salmonella typhimurium infection in mice is associated with excessive production of NO from iNOS as a host defense response. An important cytoprotective and antimicrobial function of NO is mediated by induction of heme oxygenase (HO)-1. The signaling mechanism of NO-dependent HO-1 induction has remained unclear, however. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via guanine nitration with NO and reactive oxygen species. iNOS-dependent 8-nitro-cGMP formation and HO-1 induction were identified in Salmonella-infected mice. Extensive apoptosis observed with iNOS-deficient macrophages infected with Salmonella was remarkably suppressed via HO-1 induced by 8-nitro-cGMP formed in cells. This cytoprotective signaling appears to be mediated by the reaction of 8-nitro-cGMP with protein sulfhydryls to generate a novel post-translational modification named protein S-guanylation. We also found that 8-nitro-cGMP specifically S-guanylates Keap1, a negative regulator of transcription factor Nrf2, which in turn up-regulates transcription of HO-1. Here, we discuss the unique mechanism of NO-mediated host defense that operates via formation of a novel signaling molecule - 8-nitro-cGMP - during microbial infections.