Endocarditis caused by methicillin-susceptible Staphylococcus aureus with reduced susceptibility to vancomycin: a case report

Staphylococcus aureus is the most common cause of acute infective endocarditis. Recent reports have described heteroresistance to vancomycin associated with methicillin-resistant Staphylococcus aureus. We present the first case report in Argentina of the failure of treatment with vancomycin in endocarditis caused by methicillin-susceptible Staphylococcus aureus containing subpopulations with reduced susceptibility to vancomycin. Case presentation: We report the case of a 66-year-old Hispanic man with infective endocarditis complicated by septic emboli in the lumbosacral spine and the left iliopsoas muscle. This disease was caused by methicillin susceptible Staphylococcus aureus containing subpopulations with reduced susceptibility to vancomycin. He was initially treated with cephalothin and gentamicin but developed a rash caused by beta-lactams and interstitial nephritis. For that reason, the treatment was subsequently switched to vancomycin but he failed to respond. The infection resolved after administration of vancomycin in combination with gentamicin and rifampin. Conclusion: Our case report provides important evidence for the existence of subpopulations of methicillin susceptible Staphylococcus aureus that have reduced susceptibility to vancomycin which would account for treatment failure. Our case raises an alert about the existence of these strains and highlights the need to determine the vancomycin minimum inhibitory concentration of Staphylococcus aureus to screen for the presence of strains that have reduced vancomycin susceptibility at different infection sites.Fil: Perazzi, Beatriz. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Bello, Natalia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Mollerach, Marta Eugenia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Vay, Carlos. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Lasala, María Beatriz. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Famiglietti, Angela. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentin

Clinical, Microbiological, and Genetic Characteristics of Heteroresistant Vancomycin-Intermediate Staphylococcus aureus Bacteremia in a Teaching Hospital

The emergence of vancomycin intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) is of major concern worldwide. Our objective was to investigate the prevalence, phenotypic and molecular features of hVISA strains isolated from bacteremic patients and to determine the clinical significance of the hVISA phenotype in patients with bacteremia. A total of 104 S. aureus blood isolates were collected from a teaching hospital of Argentina between August 2009 and November 2010. No VISA isolate was recovered, and 3 out of 92 patients (3.3%) were infected with hVISA, 2 of them methicillin-resistant S. aureus (MRSA) (4.5% of MRSA). Macro Etest and prediffusion method detected 3/3 and 2/3 hVISA respectively. Considering the type of bacteremia, the three cases were distributed as follows: two patients had suffered multiple episodes of bacteremia (both hVISA strains recovered in the second episode), while only one patient had suffered a single episode of bacteremia with hVISA infection. MRSA bloodstream isolates exhibiting the hVISA phenotype were related to HA-MRSA Cordobes clone (ST5-SCCmec I-spa t149) and MRSA Argentinean pediatric clone (ST100-SCCmec IVNV-spa t002), but not to CA-MRSA-ST30-SCCmec IV-spa t019 clone that was one of the most frequent in our country. Although still relatively infrequent in our hospital, hVISA strains weresignificantly associated with multiple episodes of bacteremia ( p = 0.037) and genetically unrelated.Fil: Di Gregorio, Sabrina Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Perazzi, Beatriz Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Martinez Ordoñez, Andrea. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: de Gregorio, Stella. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Focoli, Mónica. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Lasala, María Beatriz. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Garcia, Susana. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Vay, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Famiglietti, Angela María Rosa. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Mollerach, Marta Eugenia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Hantavirus pulmonary syndrome in Southern Argentina

Fil: Resa, Amanda J. Hospital de Area El Bolsón; Argentina.Fil: Barclay, Carlos M. Sanatorio San Carlos; Argentina.Fil: Calanni, Liliana. Hospital Provincial de Neuquén; Argentina.Fil: Samengo, Luis. Hospital Zonal Bariloche; Argentina.Fil: Lazaro, María Ester. Hospital Zonal Bariloche; Argentina.Fil: Martinez, Lucia. Hospital Zonal Bariloche; Argentina.Fil: Padula, Paula. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Pini, Noemi. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina,Fil: Lasala, María Beatriz. Universidad de Buenos Aires. Hospital de Clínicas José de San Martín; Argentina.Fil: Elsner, Boris. Universidad de Buenos Aires. Hospital de Clínicas José de San Martín; Argentina.Fil: Enria, Delia. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas; Argentina,Fil: Resa, Amanda J. Hospital de Area El Bolsón; Argentina.Fil: Barclay, Carlos M. Sanatorio San Carlos; Argentina.Fil: Calanni, Liliana. Hospital Provincial de Neuquén; Argentina.Fil: Samengo, Luis. Hospital Zonal Bariloche; Argentina.Fil: Lazaro, María Ester. Hospital Zonal Bariloche; Argentina.Fil: Martinez, Lucia. Hospital Zonal Bariloche; Argentina.Fil: Padula, Paula. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Pini, Noemi. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.Fil: Lasala, María Beatriz. Universidad de Buenos Aires. Hospital de Clínicas José de San Martín; Argentina.Fil: Elsner, Boris. Universidad de Buenos Aires. Hospital de Clínicas José de San Martín; Argentina.Fil: Enria, Delia. Instituto Nacional de Enfermedades Virales Humanas Dr. Julio Maiztegui; Argentina.El virus Andes fue identificado en 1995 como el agente etiológico del Síndrome Pulmonar por Hantavirus (SPH) en la región surandina argentina. En este trabajo describimos la presentación clínica de 25 casos de SPH confirmados adquiridos en la zona entre 1993 y septiembre de 1999. La edad media fue de 34 años (rango 11-70) y el 72% eran varones. Las características clínicas fueron similares a las referidas para el virus Sin Nombre (VSN), con algunas diferencias: se presentó inyección conjuntival en 10 casos (42%), rubicundez facial en 8 (33%), fauces congestivas en 7 (29%) y petequias en 3 casos (12%). El laboratorio mostró urea plasmática elevada en 83% de los casos (media 0.77 g/l; rango 0.31-2.01) y en el 56% la creatininemia superó 20 mg/l (media 26.8 mg/l; rango: 9.6-110); en 12/12 pacientes el sedimento urinario fue patológico con proteinuria, hematuria y cilindros granulosos. Las transaminasas, elevadas en el 90% de los casos, superaron 5-10 veces su valor normal en el 50% de los pacientes. La creatinfosfoquinasa estuvo elevada en 11/14 casos. Dos pacientes requirieron hemodiálisis. Se observó miocarditis mononuclear en dos casos, un hallazgo no descripto para VSN. La letalidad fue del 44% y diez pacientes fallecieron dentro de los primeros 10 días de enfermedad. Durante el brote de SPH por virus Andes en 1996 hubo evidencias epidemiológicas y moleculares de transmisión interpersonal no demostrada hasta entonces para otros miembros del género hantavirus. Estos datos muestran algunas diferencias clínicas del SPH por virus Andes con mayor frecuencia de compromiso renal que el descripto para el VSN

HLA-Driven Convergence of HIV-1 Viral Subtypes B and F Toward the Adaptation to Immune Responses in Human Populations

BACKGROUND: Cytotoxic T-Lymphocyte (CTL) response drives the evolution of HIV-1 at a host-level by selecting HLA-restricted escape mutations. Dissecting the dynamics of these escape mutations at a population-level would help to understand how HLA-mediated selection drives the evolution of HIV-1. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a study of the dynamics of HIV-1 CTL-escape mutations by analyzing through statistical approaches and phylogenetic methods the viral gene gag sequenced in plasma samples collected between the years 1987 and 2006 from 302 drug-naive HIV-positive patients. By applying logistic regression models and after performing correction for multiple test, we identified 22 potential CTL-escape mutations (p-value<0.05; q-value<0.2); 10 of these associations were confirmed in samples biologically independent by a Bayesian Markov Chain Monte-Carlo method. Analyzing their prevalence back in time we found that escape mutations that are the consensus residue in samples collected after 2003 have actually significantly increased in time in one of either B or F subtype until becoming the most frequent residue, while dominating the other viral subtype. Their estimated prevalence in the viral subtype they did not dominate was lower than 30% for the majority of samples collected at the end of the 80's. In addition, when screening the entire viral region, we found that the 75% of positions significantly changing in time (p<0.05) were located within known CTL epitopes. CONCLUSIONS: Across HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic in our setting was related to an association with an HLA allele. The fact that these mutations accumulated in one of either B or F subtypes have also dominated the other subtype shows how this selection might be causing a convergence of viral subtypes to variants which are more likely to evade the immune response of the population where they circulate

Molecular function of α7 nicotinic receptors as drug targets

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation. Its diverse physiological actions and associated disorders have made of α7 an attractive novel target for drug modulation. Potentiation of the α7 receptor has emerged as a novel therapeutic strategy for several neurological diseases, such as Alzheimer's and Parkinson's diseases, and inflammatory disorders. In contrast, increased α7 activity has been associated with cancer cell proliferation. The presence of different drug target sites offers a great potential for α7 modulation in different pathological contexts. In particular, compounds that target allosteric sites offer significant advantages over orthosteric agonists due to higher selectivity and a broader spectrum of degrees and mechanisms of modulation. Heterologous expression of α7, together with chaperone proteins, combined with patch clamp recordings have provided important advances in our knowledge of the molecular basis of α7 responses and their potential modulation for pathological processes. This review gives a synthetic view of α7 and its molecular function, focusing on how its unique activation and desensitization features can be modified by pharmacological agents. This fundamental information offers insights into therapeutic strategies.Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Nielsen, Beatriz Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Esandi, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentin

Endocarditis caused by methicillin-susceptible <it>Staphylococcus aureus</it> with reduced susceptibility to vancomycin: a case report

Abstract Introduction Staphylococcus aureus is the most common cause of acute infective endocarditis. Recent reports have described heteroresistance to vancomycin associated with methicillin-resistant Staphylococcus aureus. We present the first case report in Argentina of the failure of treatment with vancomycin in endocarditis caused by methicillin-susceptible Staphylococcus aureus containing subpopulations with reduced susceptibility to vancomycin. Case presentation We report the case of a 66-year-old Hispanic man with infective endocarditis complicated by septic emboli in the lumbosacral spine and the left iliopsoas muscle. This disease was caused by methicillin-susceptible Staphylococcus aureus containing subpopulations with reduced susceptibility to vancomycin. He was initially treated with cephalothin and gentamicin but developed a rash caused by beta-lactams and interstitial nephritis. For that reason, the treatment was subsequently switched to vancomycin but he failed to respond. The infection resolved after administration of vancomycin in combination with gentamicin and rifampin. Conclusion Our case report provides important evidence for the existence of subpopulations of methicillin-susceptible Staphylococcus aureus that have reduced susceptibility to vancomycin which would account for treatment failure. Our case raises an alert about the existence of these strains and highlights the need to determine the vancomycin minimum inhibitory concentration of Staphylococcus aureus to screen for the presence of strains that have reduced vancomycin susceptibility at different infection sites.</p

A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries

The cholinergic 7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric 7 receptor, involved in learning and memory. In humans, exons 5–10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A. Its product, dup7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dup7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected cells expressed dup7 protein, but they exhibited neither surface binding of the 7 antagonist -bungaro-toxin nor responses to acetylcholine (ACh) or to an allosteric agonist that binds to the conserved transmembrane region. To determine whether dup7 assembles with 7, we generated receptors comprising 7 and dup7 subunits, one of which was tagged with conductance substitutions that report subunit stoichiometry and monitored ACh-elicited channel openings in the presence of a positive allosteric 7 modulator. We found that 7 and dup7 subunits co-assemble into functional heteromeric receptors, which require at least two 7 subunits for channel opening, and that dup7’s presence in the pentameric arrangement does not affect the duration of the potentiated events compared with that of 7. Using an 7 subunit mutant, we found that activation of (7) 2 (dup7) 3 receptors occurs through ACh binding at the 7/7 interfacial binding site. Our study contributes to the understanding of the modulation of 7 function by the human specific, duplicated subunit, associated with human disorders.Fil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Bruzzone, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Esandi, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentin

A human truncated α7 subunit coassembles with the full-length α7 to form functional nicotinic receptors

The α7 nicotinic receptor subunit gene, CHRNA7, codes for a subunit that forms the homomeric α7 receptor, which is involved in learning and memory. In humans, exons 5-10 of CHRNA7 were duplicated and fused to the FAM7A gene, given rise to the CHRFA M7A gene. The product of the resulting chimeric gene, dupα7, is a truncated subunit that lacks part of the ACh binding site. We here combined cell expression, confocal microscopy, western blot, and electrophysiological recordings in HEK cells to understand the func tional role of the dupα7 subunit. We found that cells transfected with dupα7 cDNA express the dupα7 protein but show neither surface binding of an α7 specific antagonist nor agonist-elicited currents. To determine if dupα7 assembles with α7 into functional receptors, we used an α7 subunit carrying mutations in determinants of conduct ance (α7LC) as a reporter of receptor stoichiometry. Co-expression of α7LC with dupα7 or the reverse combination, α7 with dupα7LC, allowed detection of single-channel openings elicited by ACh, indi cating that α7 and dupα7 subunits co-assemble into functional het eromeric receptors. The analysis revealed that a minimum of two α7 subunits is required for forming functional receptors and that activa tion of the heteromeric receptors occurs through the α7/α7 interface. Our results contribute to the understanding of the functional signifi cance of the partial duplication of the α7 gene.Fil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bruzzone, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Esandi, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaReunión Conjunta de Sociedades de BiocienciasBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de Investigación Bioquímica y Biología MolecularSociedad Argentina de InmunologíaSociedad Argentina de AndrologiaSociedad Argentina de BiofísicaSociedad Argentina de BiologiaSociedad Argentina de Farmacología ExperimentalSociedad Argentina de FisiologiaSociedad Argentina de Hematologi