Multiresistance to Nonazole Fungicides in Aspergillus fumigatus TR34/L98H Azole-Resistant Isolates.

Drug resistance is a worldwide problem affecting all pathogens. The human fungal pathogen Aspergillus fumigatus coexists in the environment with other fungi targeted by crop protection compounds, being unintentionally exposed to the selective pressure of multiple antifungal classes and leading to the selection of resistant strains. A. fumigatus azole-resistant isolates are emerging in both clinical and environmental settings. Since their approval, azole drugs have dominated clinical treatment for aspergillosis infections and the agriculture fungicide market. However, other antifungal classes are used for crop protection, including benzimidazoles (methyl benzimidazole carbamates [MBCs]), strobilurins (quinolone oxidation inhibitors [QoIs]), and succinate dehydrogenase inhibitors (SDHIs). Mutations responsible for resistance to these fungicides have been widely researched in plant pathogens, but resistance has not been explored in A. fumigatus. In this work, the genetic basis underlying resistance to MBCs, QoIs, and SDHIs was studied in azole-susceptible and -resistant A. fumigatus strains. E198A/Q and F200Y mutations in ß-tubulin conferred resistance to MBCs, G143A and F129L substitutions in cytochrome b conferred resistance to QoIs, and H270R/Y mutations in SdhB conferred resistance to SDHIs. Characterization of susceptibility to azoles showed a correlation between strains resistant to these fungicides and the ones with tandem-repeat (TR)-based azole resistance mechanisms. Whole-genome sequencing analysis showed a genetic relationship among fungicide multiresistant strains, which grouped into subclusters that included only strains carrying the TR-based azole resistance mechanisms, indicating a common ancestor/evolution pattern and confirming the environmental origin of this type of azole-resistant A. fumigatus.

Parámetros asociados al desarrollo de fibrilación auricular en unidad de cuidados críticos / Parameters associated with the development of atrial fibrillation in a critical care unit

A pesar de los avances en el manejo de los pacientes con fibrilación auricular (FA), esta arritmia es responsable de accidente cerebrovascular, insuficiencia cardíaca, muerte súbita y morbilidad cardiovascular en el mundo. El objetivo de este trabajo fue determinar la frecuencia de fibrilación auricular y analizar las cardiopatías subyacentes y predictores de fibrilación auricular en el servicio de Unidad Coronaria del Instituto de Cardiología de la Ciudad de Corrientes. Estudio observacional y descriptivo donde ingresaron 412 pacientes consecutivos en unidad Coronaria de instituto de Cardiología Juana Francisca Cabral, desde el 1 de enero al 30 de junio de 2018. Del total de la población el 24,51% presentó fibrilación auricular, 80,2% FA paroxística y 19,8% permanente. El 94% de los pacientes con FA paroxística fueron hipertensos. La edad media fue de 71,60±12,19 años, el índice de masa corporal fue de 28,33±6,13, el tamaño de la aurícula izquierda fue de 47,91±7,06 mm y la fracción de eyección de 50,41±17,9%. La presencia de insuficiencia cardiaca estuvo presente en 69% de los pacientes con FA paroxística. Las cardiopatías subyacentes fueron: infarto agudo de miocardio 50,5%, valvulopatías 50,5%, hipertrófica 5%. Más de dos tercios de los pacientes tuvieron FA paroxística. La cardiopatía isquémica fue la más frecuente

SUMMARY Despite the advances in the management of patients with atrial fibrillation (AF), this arrhythmia causes stroke, heart failure, sudden death and cardiovascular morbidity. The aim of this work was to determine the frequency of atrial fibrillation and to analyze the underlying heart diseases and predictors of atrial fibrillation in the Coronary Unit Service of the Institute of Cardiology from Corrientes City. This is a descriptive and observational study. There were admitted 412 consecutive patients to the Coronary unit of "Juana Francisca Cabral Institute of Cardiology", from January 1st to June 30th, 2018. From the total population, 24.51% patients presented atrial fibrillation, 80.2% presented paroxysmal AF and 19.8% permanent AF. The 94% of the patients with paroxysmal AF were hypertensive. The mean age was 71.60 ± 12.19 years, the body mass index was 28.33 ± 6,13, the size of the left atrium was 47.91 ± 7.06 mm and the ejection fraction 50.41 ± 17.9%. Heart failure was present in 69% of patients with paroxysmal AF. The underlying heart diseases were: acute myocardial infarction 50.5%, valvulopathies 50.5%, hypertrophic cardiomyopathy 5%. More than two thirds of the patients had paroxysmal AF. Ischemic heart disease was the most frequent

RESUMO Apesar dos avanços na manipulação de pacientes com fibrilação atrial (FA), essa arritmia é responsável por acidente vascular cerebral, insuficiência cardíaca, morte súbita e morbilidade cardiovascular no mundo. O objetivo deste trabalho foi determinar a frequência de fibrilação atrial e analisar as cardiopatias subjacentes e os preditores de fibrilação atrial no serviço de unidade coronariana do Instituto de Cardiologia da cidade de Corrientes. Estudo observacional descritivo em que 412 pacientes consecutivos foram internados na Unidade Coronariana do Instituto Juana Francisca Cabral de Cardiologia, do día 1º de janeiro a 30 de junho de 2018. Do total da população, 24,51% apresentaram fibrilação atrial, 80,2% AF paroxística e permanente 19,8%. 94% dos pacientes com FA paroxística eram hipertensos. A média de idade foi de 71,60 ± 12,19 anos, o índice de massa corpórea foi de 28,33 ± 6,13, o tamanho do átrio esquerdo foi de 47,91 ± 7,06 mm e a fração de ejeção 50,41 ± 17,9%. A presença de insuficiência cardíaca esteve presente em 69% dos pacientes com FA paroxística. As doenças cardíacas subjacentes foram: infarto agudo do miocárdio 50,5%, valvopatias 50,5%, hipertrófica 5%. Mais de dois terços dos pacientes apresentavam FA paroxística. A doença isquêmica do coração foi a mais frequente.

EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma.

Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.

Y155H amino acid substitution in influenza A(H1N1)pdm09 viruses does not confer a phenotype of reduced susceptibility to neuraminidase inhibitors.

The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1) pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1) pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients.

Correlation between Chenopodiacea/Amaranthacea pollen counts and allergic symptoms in Salsola kali monosensitized patients.

UNLABELLED: We performed a prospective observational study to establish a relationship between pollen counts of Chenopodiacea/Amaranthacea and clinical symptoms of rhinoconjunctivitis and asthma in a group of monosensitised patients. MATERIAL AND METHODS: A total of 60 patients (19 with asthma) were included in the study. All patients collected daily symptom scores during the summer months of 1999, 2000 and 2001. The questionnaire included ocular, nasal and pulmonary symptoms. Pollen counts were expressed as pollen grains/m3. Symptom scores and pollen counts were correlated using correlation coefficients and Log transformed variables. RESULTS: In the 3 seasons studied we identified a peak of pollen and clinical symptoms in the second half of August and first half of September. In 1999, there was a significant positive correlation between total symptoms and daily pollen grains/m3 (p<0.005, r = 0.347). This correlation was not significant for the summers of 2000 and 2001. After further analysis, and by displacing one of both variables between 11 to 17 days, the correlation coefficients for total symptoms, improved for 1999 (r = 0. 744; p < 0.0001) and became significant for 2000 (r = 0. 521; p < 0.0001) and 2001 (r = 0.635; p < 0.0001). CONCLUSION: We identified a significant time lag between pollen counts and symptom scores in S. kali monosensitized patients.