Publications by authors named "I Ramis"

78 Publications

Tuberculosis cases in a prison in the extreme south of Brazil.

J Med Microbiol 2021 Mar 8;70(3). Epub 2021 Feb 8.

Medical Microbiology Research Center, Faculty of Medicine, Federal University of Rio Grande (FURG), Rio Grande, Rio Grande do Sul, Brazil.

Tuberculosis (TB) control is a challenge, especially in vulnerable populations, such as prisoners. In prison houses, the transmission of micro-organisms that cause infectious diseases can occur due to the susceptibility and immune compromise of prisoners, and due to the precarious physical conditions of the prison houses. However, strategies such as monitoring by health professionals, can mitigate the transmission of these micro-organisms, as well as, reduce the number of coinfections and antimicrobials resistance. This study attempted to analyse the dynamics of transmission and the antimicrobial resistance profile of strains obtained from prisoners and to characterize the epidemiological, clinical and laboratory profiles of prisoners diagnosed with TB. A cross-sectional and retrospective study was conducted with sputum samples collected from 228 distinct prisoners who were treated at the Health Unit located in the Regional Penitentiary of Rio Grande, Rio Grande do Sul, Brazil. The antimicrobial resistance profile of the strains was evaluated using the Resazurin Microtiter Assay and the transmission dynamics was investigated using 15- MIRU-VNTR. Thirty-five patients (15.4 %) were diagnosed with TB, and when a TB/HIV coinfection was assessed, 8.6 % (3/35) of the patients were positive. In addition, all patients with results available for HBV, HCV, syphilis and diabetes mellitus were negative. Based on the genotypic profile, 55.9 % of the clinical isolates were grouped into five groups. One isolate with mono-resistance to isoniazid and two with mono-resistance to streptomycin were found. The presence of a Health Unit may have influenced the low numbers of TB/HIV, TB/HBV, TB/HCV, TB/syphilis coinfections and TB cases resistant to antimicrobials. Recent transmission can be inferred based on the high percentage of formatting of clusters. This situation stresses the need to improve active and passive detection, the screening of individuals for TB upon entrance into prison for early detection, and the implementation of prophylactic measures to reduce transmission.
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http://dx.doi.org/10.1099/jmm.0.001319DOI Listing
March 2021

Laboratory diagnosis for Covid-19: A mini-review.

Rev Soc Bras Med Trop 2020 26;53:e20200451. Epub 2020 Aug 26.

Programa de Pós-Graduação em Ciências da Saúde, Núcleo de Pesquisa em Microbiologia Médica, Universidade Federal do Rio Grande, Rio Grande, RS, Brasil.

Coronavirus disease (COVID-19) is a pandemic caused by a new coronavirus, called SARS-CoV-2. This disease was first identified in December 2019 and rapidly developed into a challenge to the public health systems around the world. In the absence of a vaccine and specific therapies, disease control and promotion of patient health are strongly dependent on a rapid and accurate diagnosis. This review describes the main laboratory approaches to making a diagnosis of COVID-19 and identifying those previously infected with SARS-CoV-2.
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http://dx.doi.org/10.1590/0037-8682-0451-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451498PMC
September 2020

Nontuberculous mycobacteria in patients with suspected tuberculosis and the genetic diversity of Mycobacterium avium in the extreme south of Brazil.

J Bras Pneumol 2020;46(2):e20190184. Epub 2020 May 11.

Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil.

Objective: Nontuberculous mycobacteria (NTM) are a heterogeneous group of bacteria that are widely distributed in nature and associated with opportunistic infections in humans. The aims of this study were to identify NTM in patients with suspected tuberculosis who presented positive cultures and to evaluate the genetic diversity of strains identified as Mycobacterium avium.

Methods: We studied pulmonary and extrapulmonary samples obtained from 1,248 patients. The samples that tested positive on culture and negative for the M. tuberculosis complex by molecular identification techniques were evaluated by detection of the hsp65 and rpoB genes and sequencing of conserved fragments of these genes. All strains identified as M. avium were genotyped using the eight-locus mycobacterial interspersed repetitive unit-variable-number tandem-repeat method.

Results: We found that NTM accounted for 25 (7.5%) of the 332 mycobacteria isolated. Of those 25, 18 (72%) were M. avium, 5 (20%) were M. abscessus, 1 (4%) was M. gastri, and 1 (4%) was M. kansasii. The 18 M. avium strains showed high diversity, only two strains being genetically related.

Conclusions: These results highlight the need to consider the investigation of NTM in patients with suspected active tuberculosis who present with positive cultures, as well as to evaluate the genetic diversity of M. avium strains.
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http://dx.doi.org/10.36416/1806-3756/e20190184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462694PMC
August 2020

and co-infection in an immunocompromised patient: Case report and literature review.

Med Mycol Case Rep 2020 Jun 6;28:29-32. Epub 2020 Apr 6.

Faculdade de Medicina, Universidade Federal do Rio Grande (FAMED-FURG), Rio Grande do Sul, RS, Brazil.

We report a case of fungal and mycobacterial co-infection in an immunosuppressed patient from Southern Brazil. Histoplasmosis was diagnosed in an AIDS patient admitted to the hospital with nonspecific respiratory signs. However, 4 months post hospital discharge, the patient worsened and a co-infection with was detected. Physicians must consider and investigate a broad spectrum of diseases which can occur as co-infections and which share the same clinical symptoms and signs in immunosuppressed patients.
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http://dx.doi.org/10.1016/j.mmcr.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171255PMC
June 2020

Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.

J Med Chem 2019 10 14;62(20):9045-9060. Epub 2019 Oct 14.

Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone , a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00533DOI Listing
October 2019

Laboratory tools for tuberculosis control in a setting with a high burden of HIV/AIDS.

J Med Microbiol 2019 Nov;68(11):1622-1628

Rede TB (TB Research Network in Brazil), Rio de Janeiro, RJ, Brazil.

Nosocomial transmission of is an important health issue and the detection of tuberculosis (TB) cases is the main tool for controlling this disease. We aimed to assess the possible occurrence of nosocomial transmission of in a reference hospital for HIV/AIDS patients and evaluate both the performance of the Xpert MTB/RIF (Xpert) platform and drug resistance profiles. We evaluated the performance of the Xpert platform. Samples that tested positive on the BACTEC MGIT 320 (MGIT320) platform were submitted for genotyping and drug susceptibility testing. In this study, pulmonary and extrapulmonary samples from 407 patients were evaluated, and among these, 15.5 % were diagnosed with TB by the MGIT320 platform, with a TB/HIV coinfection rate of 52.4 %. The Xpert platform gave positive results for TB for 11 samples with negative results on the MGIT320 platform. In the genotyping results, 53.3 % of the strains clustered; of these strains, half were in two of the four clusters formed, and the patients had visited the hospital on the same day. Drug resistance was observed in 11.7 % of the strains. Putative nosocomial transmission of was detected, showing that genotyping is a powerful approach for understanding the dynamics of transmission, especially in a high-burden TB and HIV landscape.
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http://dx.doi.org/10.1099/jmm.0.001089DOI Listing
November 2019

The Contribution of Efflux Pumps in Complex Resistance to Clarithromycin.

Antibiotics (Basel) 2019 Sep 18;8(3). Epub 2019 Sep 18.

Núcleo de Pesquisas em Microbiologia Médica, Universidade Federal de Rio Grande, Rua Visconde de Paranaguá, 102, Rio Grande 96200-190, RS, Brazil.

The basis of drug resistance in is still poorly understood. Nevertheless, as seen in other microorganisms, the efflux of antimicrobials may also play a role in drug resistance. Here, we investigated the role of efflux pumps in clarithromycin resistance using nine clinical isolates of complex belonging to the T28 (41) sequevar responsible for the inducible resistance to clarithromycin. The strains were characterized by drug susceptibility testing in the presence/absence of the efflux inhibitor verapamil and by genetic analysis of drug-resistance-associated genes. Efflux activity was quantified by real-time fluorometry. Efflux pump gene expression was studied by RT-qPCR upon exposure to clarithromycin. Verapamil increased the susceptibility to clarithromycin from 4- to ≥64-fold. The efflux pump genes and were found consistently overexpressed. The results obtained demonstrate that the T28 (41) polymorphism is not the sole cause of the inducible clarithromycin resistance in subsp. or with efflux activity providing a strong contribution to clarithromycin resistance. These data highlight the need for further studies on efflux response to antimicrobial stress in order to implement more effective therapeutic regimens and guidance in the development of new drugs against these bacteria.
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http://dx.doi.org/10.3390/antibiotics8030153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784190PMC
September 2019

In silico and in vitro evaluation of tetrahydropyridine compounds as efflux inhibitors in Mycobacterium abscessus.

Tuberculosis (Edinb) 2019 09 23;118:101853. Epub 2019 Jul 23.

Núcleo de Pesquisa Em Microbiologia Médica, Universidade Federal de Rio Grande, Rua General Osório s/n, Rio Grande, RS, Brazil.

Herein, we evaluated tetrahydropyridine (THP) compounds (NUNM) as antimicrobials and inhibitors of the efflux mechanism in M. abscessus. subsp. abscessus. The modulation factor (MF) of efflux inhibitors was calculated from the minimum inhibitory concentrations (MICs) of amikacin (AMI), ciprofloxacin (CIP) and clarithromycin (CLA) in the absence and presence of subinhibitory concentrations of the NUNM compounds and canonical inhibitors carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and verapamil (VP). The kinetics of the intracellular accumulation of the fluorimetric substrate ethidium bromide (EtBr) was evaluated and calculated by the relative final fluorescence (RFF). In addition, molecular modeling simulations for the MmpL5 and Tap efflux transporters with ligands (CLA, NUNM, CCCP, VP and EtBr) were performed to better understand the efflux mechanism. We highlight the NUNM01 compound because it reduced the MICs of AMI, CIP and CLA by 4-, 4- and 16-fold, respectively, had the highest effect on EtBr accumulation (RFF = 3.1) and showed a significant in silico affinity for the evaluated proteins in docking simulations. Based on the analyses performed in vitro and in silico, we propose that NUNM01 is a potential pharmacophore candidate for the development of a therapeutic adjuvant for M. abscessus infections.
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http://dx.doi.org/10.1016/j.tube.2019.07.004DOI Listing
September 2019

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats.

J Pharmacol Exp Ther 2019 08 13;370(2):137-147. Epub 2019 May 13.

Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.
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http://dx.doi.org/10.1124/jpet.119.256263DOI Listing
August 2019

Mycobacterium avium: an overview.

Tuberculosis (Edinb) 2019 01 4;114:127-134. Epub 2019 Jan 4.

Núcleo de Pesquisa em Microbiologia Médica, Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil. Electronic address:

Mycobacterium avium is an environmental microorganism found in soil and water sources worldwide. It is the most prevalent species of nontuberculous mycobacteria that causes infectious diseases, especially in immunocompromised individuals. This review discusses and highlights key topics about M. avium, such as epidemiology, pathogenicity, glycopeptidolipids, laboratory identification, genotyping, antimicrobial therapy and antimicrobial resistance. Additionally, the main comorbidities associated with M. avium infection are discussed.
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http://dx.doi.org/10.1016/j.tube.2018.12.004DOI Listing
January 2019

Tetrahydropyridine derivative as efflux inhibitor in Mycobacterium abscessus.

J Glob Antimicrob Resist 2019 06 7;17:296-299. Epub 2019 Jan 7.

Núcleo de Pesquisa em Microbiologia Médica, Universidade Federal de Rio Grande, Rio Grande, RS, Brazil.

Objectives: This study aimed to evaluate a tetrahydropyridine derivative (THP) as a potential inhibitor of the efflux mechanism and modulator of the high level of antimicrobial resistance usually observed in members of the Mycobacterium abscessus (M. abscessus) group.

Methods: The strain M. abscessus subsp. abscessus (ATCC 19997) was used as reference, in addition to three clinical isolates: M. abscessus subsp. abscessus (AT 07), and two M. abscessus subsp. bolletii (AT 46 and AT 52). The minimum inhibitory concentration (MIC) of amikacin (AMI), ciprofloxacin (CIP), clarithromycin (CLA), verapamil (VP), and THP derivative (NUNL02) was determined.

Results: The NUNL02 showed activity against M. abscessus; the MIC of AMI against ATCC 19997 was reduced more than 16-fold, and the MIC of CIP against AT 52 was reduced four-fold. When combined with CLA, the MIC was reduced against all tested strains. In addition, to detect and quantify the activity of the efflux mechanism, the intracellular accumulation kinetics of the fluorometric substrate ethidium bromide in the presence and absence of VP and NUNL02 were evaluated. The NUNL02 was found to be a more effective efflux inhibitor than VP, which is the classical inhibitor.

Conclusions: The tetrahydropyridine derivative, NUNL02, is a promising adjuvant in the treatment of infections caused by M. abscessus.
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http://dx.doi.org/10.1016/j.jgar.2018.12.020DOI Listing
June 2019

Antimicrobial Resistance and Molecular Characterization of Extended-Spectrum β-Lactamases of Escherichia coli and Klebsiella spp. Isolates from Urinary Tract Infections in Southern Brazil.

Microb Drug Resist 2019 Mar 22;25(2):173-181. Epub 2018 Aug 22.

1 Faculdade de Medicina, Medical Microbiology Research Center (NUPEMM), Universidade Federal do Rio Grande-FURG , Rio Grande, Brazil .

The objective of this study was to evaluate the frequency of different extended-spectrum β-lactamases (ESBL) as well as to associate these ESBL with antimicrobial (ATM) resistance in Escherichia coli and Klebsiella spp. isolates from outpatients and inpatients with urinary tract infections. The study included 435 consecutive nonduplicate clinical isolates, including 362 E. coli isolates, 62 Klebsiella pneumoniae isolates, and 11 K. oxytoca isolates. Isolates were obtained from patients who were treated in a University Hospital between August 2012 and July 2013. Three multiplex PCR were performed to identify the ESBL groups. A total of 48 (11%) ESBL-producing isolates were found. The risk for the ESBL presence was significantly higher in males (26.4%) than females (8%), from hospital-acquired infections (29.1%) than community-acquired infections (7.0%) and in Klebsiella spp. (27.4%) than in E. coli (7.7%). ESBL-producing isolates presented a significantly higher percentage of resistance in 21 of the 23 ATMs analyzed. The CTX-M-1 group was the most predominant ESBL identified. The bla gene was found in 56% of the total ESBL producers from community and in 42.4% from hospital origins; it was followed in frequency by the bla, also found in both environments. Klebsiella spp. presented the largest variety of β-lactamase enzyme combinations and a higher level of resistance to cefotaxime. These findings contribute to better knowledge of the epidemiology of ESBL enzymes and are alarming for the reduced therapeutic options available for the risk groups identified in the studied populations.
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http://dx.doi.org/10.1089/mdr.2018.0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441284PMC
March 2019

The interplay between mutations in cagA, 23S rRNA, gyrA and drug resistance in Helicobacter pylori.

Rev Inst Med Trop Sao Paulo 2018 28;60:e25. Epub 2018 Jun 28.

Núcleo de Pesquisas em Microbiologia Médica, Universidade Federal de Rio Grande, Rio Grande, Rio Grande do Sul, Brazil.

In this study, we evaluated the mutations of Helicobacter pylori associated with resistance to clarithromycin and levofloxacin. Furthermore, based on the proposed interaction between antimicrobial resistance and pathogenicity, we correlated the mutation profiles of the strains with the presence of the pathogenicity gene cagA. We analyzed 80 gastric biopsy specimens from H. pylori-infected patients for point mutations in the 23S rRNA gene region and in the gyrA gene, which are related to clarithromycin and levofloxacin resistance, respectively, and investigated the presence of the cagA gene in these strains. We observed that in the assayed biopsies, 8.7% (7/80) had mutations in the 23S rRNA gene region at positions 2143 and 2142, while 22.5% (18/80) had mutations in gyrA at codons 87 and 91. Moreover, absence of the CagA-EPIYA pathogenicity factor was observed in 68% (17/25) of resistant samples. The knowledge of the local profile of antimicrobial resistance and the complex interplay involving resistance and pathogenicity can contribute to an appropriate clinical approach.
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http://dx.doi.org/10.1590/s1678-9946201860025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029892PMC
July 2018

Antifungal activity of diphenyl diselenide alone and in combination with itraconazole against Sporothrix brasiliensis.

Med Mycol 2019 Apr;57(3):328-331

Mycology Lab, Faculty of Medicine, Federal University of Rio Grande (FaMed-FURG), Rio Grande do Sul, Brazil.

Sporothrix brasiliensis is the main agent of feline and zoonotic sporotrichosis. Given the scarcity of options for sporotrichosis treatment and the promising activity of diphenyl diselenide (PhSe)2 against a diversity of fungal pathogens, this study aimed to evaluate the in vitro susceptibility of Sporothrix brasiliensis to (PhSe)2 alone and in combination with itraconazole (ITC). Forty clinical isolates of S. brasiliensis were subjected to broth microdilution method to evaluate their susceptibility to (PhSe)2 in concentrations ranging between 0.25 and 128 μg/ml, and to ITC (0.0313-16 μg/ml) following the protocol of the Clinical and Laboratory Standards Institute (CLSI, 2008). All of these isolates were also used to evaluate the interaction between these drugs by checkerboard technique. Geometric mean of (PhSe)2 MIC values was 12.12 μg/ml, ranging from 4 to 32 μg/ml, and for ITC was 0.37 μg/ml (0.125 to 1 μg/ml). Benefic effect (additive or synergistic) in the interaction test between (PhSe)2 and ITC occurs in 73% (29/40) of the isolates. The promising (PhSe)2in vitro activity against S. brasiliensis suggests that it may not only be a potential alternative therapy but also be used as a combination with ITC, which is the first choice of therapy to sporotrichosis.
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http://dx.doi.org/10.1093/mmy/myy044DOI Listing
April 2019

Antimicrobial and Efflux Inhibitor Activity of Usnic Acid Against Mycobacterium abscessus.

Planta Med 2018 Nov 18;84(17):1265-1270. Epub 2018 Jun 18.

Núcleo de Pesquisa em Microbiologia Médica, Universidade Federal de Rio Grande, Rio Grande, RS, Brazil.

New drugs are needed to treat infections with antimicrobial-resistant ; therefore, we evaluated usnic acid as an antimicrobial agent and efflux inhibitor (EI) against . Usnic acid showed antimicrobial activity, and synergistically, the EI verapamil increased this activity. In addition, when we evaluated the interaction of antimicrobials with usnic acid, the increase of their activity was observed. Finally, usnic acid showed an efflux inhibitory effect between the classical EIs verapamil and carbonyl cyanide m-chlorophenylhydrazine. In conclusion, usnic acid showed both antimicrobial and EI activity, indicating that this natural compound may be a promising scaffold for new drugs against this difficult-to-treat microorganism.
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http://dx.doi.org/10.1055/a-0639-5412DOI Listing
November 2018

PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge.

Biomark Res 2018 11;6:14. Epub 2018 Apr 11.

1Division of Infection, Immunity & Respiratory Medicine, The Medicines Evaluation Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.

Background: Inhaled allergen challenges are often used to evaluate novel asthma treatments in early phase clinical trials. Current novel therapeutic targets in asthma include phosphoinositide 3-kinases (PI3K) delta and gamma, p38 mitogen-activated protein kinase (p38) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathways. The activation of these pathways following allergen exposure in atopic asthma patients it is not known.

Methods: We collected bronchial biopsies from 11 atopic asthma patients at baseline and after allergen challenge to investigate biomarkers of PI3K, p38 MAPK and JAK/STAT activation by immunohistochemistry. Cell counts and levels of eosinophil cationic protein and interleukin-5 were also assessed in sputum and bronchoalvelar lavage.

Results: Biopsies collected post-allergen had an increased percentage of epithelial cells expressing phospho-p38 (17.5 vs 25.6%,  = 0.04), and increased numbers of sub-epithelial cells expressing phospho-STAT5 (122.2 vs 540.6 cells/mm,  = 0.01) and the PI3K marker phospho-ribosomal protein S6 (180.7 vs 777.3 cells/mm = 0.005). Type 2 inflammation was increased in the airways post allergen, with elevated levels of eosinophils, interleukin-5 and eosinophil cationic protein.

Conclusions: Future clinical trials of novel kinase inhibitors could use the allergen challenge model in proof of concept studies, while employing these biomarkers to investigate pharmacological inhibition in the lungs.
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http://dx.doi.org/10.1186/s40364-018-0128-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896031PMC
April 2018

High frequency of aac(6')-Ib-cr gene associated with double mutations in gyrA and parC in Escherichia coli isolates from patients with urinary tract infections.

J Glob Antimicrob Resist 2018 06 4;13:180-183. Epub 2018 Jan 4.

Medical Microbiology Research Center (NUPEMM), Faculdade de Medicina, Universidade Federal do Rio Grande - FURG, Rio Grande, Rio Grande do Sul, Brazil. Electronic address:

Objectives: The aims of this study were (i) to determine the frequency of plasmid-mediated resistance to fluoroquinolones (FQs) in Escherichia coli isolated from patients with urinary tract infections (UTIs) of nosocomial and community origin and (ii) to determine the relationships between the presence of extended-spectrum β-lactamases (ESBLs), mutations in the gyrA and parC genes, and resistance to FQs.

Methods: A total of 71 E. coli isolates, including 38 ESBL-producers and 33 non-ESBL-producers, were analysed. The aac(6')-Ib gene was amplified using PCR and was subsequently digested with the BtsCI restriction enzyme to identify aac(6')-Ib-cr, a variant associated with FQ resistance. Detection of qnr genes was performed by multiplex PCR. In isolates that tested positive for these genes, the gyrA and parC genes were sequenced and the modulation factor of an efflux pump inhibitor was determined on the minimum inhibitory concentration (MIC) of norfloxacin.

Results: The frequencies of qnrS, qnrB and qnrA were 4.2%, 2.8% and 0%, respectively. The frequency of aac(6')-Ib-cr was 40.8% and this variant was associated with double mutations in gyrA and parC as well as resistance to FQs and ESBL production. Modulation of efflux pump activity was more frequent in resistant isolates that had a wild-type parC gene.

Conclusion: An interplay of resistance mechanisms increased the level of resistance to FQs, and the high frequency of putative plasmid-mediated quinolone resistance genes associated with ESBL-producing isolates reduced therapeutic options to treat UTIs in the affected population.
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http://dx.doi.org/10.1016/j.jgar.2017.12.013DOI Listing
June 2018

Activity of Rifabutin and Hemi-synthetic Derivatives Against Mycobacterium abscessus.

Med Chem 2018 ;14(4):394-399

Nucleo de Pesquisa em Microbiologia Medica (NUPEMM), Faculdade de Medicina, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil.

Background: Mycobacterium abscessus causes a wide range of clinical diseases that are difficult to treat. This microorganism is resistant not only to the classical antituberculosis agents but also to most of the antimicrobials that are currently available, resulting in limited therapeutic options and treatment failure. This scenario stresses the need to search for new drugs with activity against M. abscessus.

Objective: To evaluate in vitro the antimycobacterial activity and cytotoxicity of rifabutin (RFB 1) and ten derivatives (2-11) against M. abscessus ATCC 19977.

Method: The minimum inhibitory concentration (MIC) of the molecules was determined by the microdilution broth method according to the guideline described in CLSI. The toxicity evaluation was carried in 96-well microplates, using the cell line J774A.1 (ATCC TIB-67).

Result: From the eleven molecules tested, RFB 1 and RFB 4 were the compounds showing higher activities against M. abscessus, with MICs of 0.9 and 1.0 µM, respectively. The R1 and R2 moieties seem to have deciding influence over the final activity. Furthermore, N-oxide derivatives 9, 10, and 11 were also active against M. abscessus, with MICs of 7.2 µM, 1.8 µM and 3.8 µM, respectively. An explanatory hypothesis for the better activities of compounds RFB 1, RFB 4, RFB 10 and RFB 11 considers the likely hydrogen bonding between ligands and receptor, balancing the global flexibility and interaction energies. RFB 1 and its most effective derivatives were found to be not toxic.

Conclusion: Besides RFB 1, its derivatives 4, 10 and 11 show potential for clinical development in the M. abscessus treatment.
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http://dx.doi.org/10.2174/1573406414666171204102633DOI Listing
August 2018

Tofacitinib ameliorates inflammation in a rat model of airway neutrophilia induced by inhaled LPS.

Pulm Pharmacol Ther 2017 04 10;43:60-67. Epub 2017 Jan 10.

Almirall R+D Centre, Almirall S.A., Laureà Miró 408, 08980 Sant Feliu de Llobregat, Barcelona, Spain.

Background And Purpose: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model.

Experimental Approach: Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o.

Key Results: Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue.

Conclusions And Implications: In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.
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http://dx.doi.org/10.1016/j.pupt.2017.01.002DOI Listing
April 2017

Anti-inflammatory potential of PI3Kδ and JAK inhibitors in asthma patients.

Respir Res 2016 10 4;17(1):124. Epub 2016 Oct 4.

The University of Manchester; Division of Infection, Immunity & Respiratory Medicine; Manchester Academic Health Science Centre; University Hospital South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.

Background: Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression.

Method: Cells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry.

Results: JAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells.

Conclusions: Targeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051065PMC
http://dx.doi.org/10.1186/s12931-016-0436-2DOI Listing
October 2016

DRUG RESISTANCE IN HELICOBACTER PYLORI.

Arq Gastroenterol 2016 Oct-Dec;53(4):215-223

Núcleo de Pesquisas em Microbiologia Médica, Universidade Federal do Rio Grande, RS, Brasil.

Background: Helicobacter pylori has a worldwide distribution and is associated with the pathogenesis of various diseases of the digestive system. Treatment to eradicate this microorganism involves the use of a combination of antimicrobials, such as amoxicillin, metronidazole, clarithromycin, and levofloxacin, combined with proton pump inhibitors. Although the current therapy is effective, a high rate of treatment failure has been observed, mainly because of the acquisition of point mutations, one of the major resistance mechanisms developed by H. pylori. This phenomenon is related to frequent and/or inappropriate use of antibiotics.

Conclusion: This review reported an overview of the resistance to the main drugs used in the treatment of H. pylori, confirming the hypothesis that antibacterial resistance is a highly local phenomenon and genetic characteristics of a given population can influence which therapy is the most appropriate.
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http://dx.doi.org/10.1590/S0004-28032016000400002DOI Listing
January 2017

Relationship of interleukin-1B gene promoter region polymorphism with Helicobacter pylori infection and gastritis.

J Infect Dev Ctries 2015 Sep 29;9(10):1108-16. Epub 2015 Sep 29.

Universidade Federal de Pelotas (UFPel), Pelotas, Rio Grande do Sul, Brasil.

Introduction: Helicobacter pylori infection is associated with gastritis, peptic ulcer disease and gastric carcinoma. The severity of damage is determined by the interplay between environmental/behavioral factors, bacterial pathogenicity genes and host genetic polymorphisms that can influence the secretion levels of inflammatory cytokines. Accordingly, this study aimed to identify polymorphisms in the IL-1B and IL-1RN genes and their associations with H. pylori infection, cagA gene of H. pylori, and gastroduodenal diseases.

Methodology: Gastric biopsy samples from 151 patients infected with H. pylori and 76 uninfected individuals were analyzed. H. pylori infection was diagnosed by histology and PCR. Polymorphisms at positions -511, -31 and +3954 of the IL-1B gene were detected by PCR-RFLP, and an analysis of the VNTR polymorphism of the IL-1RN gene was performed by PCR.

Results: It was observed that the presence of the T/T genotype at position -511 and the C/C genotype at position -31 were associated with H. pylori infection and with an increased risk of gastritis in H. pylori-positive patients. Additionally, strains from patients H. pylori-positive carrying the cagA gene was significantly related with the T/T genotype at position -511 of IL-1B.  No association of polymorphisms at position +3954 of IL-1B and in the IL-1RN with H. pylori infection and with risk of severe gastric diseases was found.

Conclusions: We demonstrated that polymorphisms in the promoter region of the IL-1B gene (at positions -511 and -31) are associated with an enhanced risk of H. pylori infection as well as gastritis in H. pylori-positive patients.
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http://dx.doi.org/10.3855/jidc.6123DOI Listing
September 2015

Detection of Helicobacter pylori CagA EPIYA in gastric biopsy specimens and its relation to gastric diseases.

Diagn Microbiol Infect Dis 2015 Oct 10;83(2):89-92. Epub 2015 Jun 10.

Núcleo de Pesquisas em Microbiologia Médica, Universidade Federal do Rio Grande (FURG), Rua General Osório, S/N, Rio Grande, Rio Grande do Sul, Brazil.

CagA of Helicobacter pylori undergoes tyrosine phosphorylation in a region containing differing numbers of repeat sequences (EPIYAs), which can result in a modulation of the inflammatory response. This study investigated whether the presence of CagA EPIYA variations in strains of H. pylori that are positive for this region contributes to differing degrees of disease severity in the gastric mucosa. In this study, 157 H. pylori-positive patients were included, and of those, 40.8% (64/157) were infected with cagA-positive strains, which were assayed for the presence of CagA EPIYA-ABC, EPIYA-ABCC, and EPIYA-ABCCC. Peptic ulcers were significantly more prevalent in patients infected with strains containing CagA EPIYA-ABCC/ABCCC than in those with CagA EPIYA ABC strains (P=0.044). This suggests that the number of repetitions of EPIYA-C influences the development of gastroduodenal lesions, highlighting the importance and usefulness of evaluating the cagA gene sequence when making therapeutic intervention decisions in patients infected with H. pylori.
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http://dx.doi.org/10.1016/j.diagmicrobio.2015.05.017DOI Listing
October 2015

A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response.

Pharmacol Res 2015 Sep 4;99:116-24. Epub 2015 Jun 4.

Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address:

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.
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http://dx.doi.org/10.1016/j.phrs.2015.05.011DOI Listing
September 2015

Polymorphisms of the IL-6, IL-8 and IL-10 genes and the risk of gastric pathology in patients infected with Helicobacter pylori.

J Microbiol Immunol Infect 2017 Apr 24;50(2):153-159. Epub 2015 Mar 24.

Centro de Desenvolvimento Tecnológico-Universidade Federal de Pelotas (UFPel), Pelotas, Rio Grande do Sul, Brazil; Núcleo de Pesquisa em Microbiologia Médica-Universidade Federal do Rio Grande (FURG), Rio Grande, Rio Grande do Sul, Brazil.

Background/purpose: Helicobacter pylori-induced gastric mucosal inflammation is mediated by proinflammatory and anti-inflammatory cytokines. Polymorphisms in genes that code cytokines influence cytokine secretion levels and appear to contribute to the risk of gastric diseases. In this sense, we performed this study to identify the polymorphisms in the IL-6, IL-8, and IL-10 genes and their associations with H. pylori infection and gastric pathologies.

Methods: Gastric biopsy samples of 151 patients infected with H. pylori and 76 uninfected individuals were used. Helicobacter pylori infection was diagnosed by histological examination and the detection of the ureA and glmM genes. The polymorphisms in the IL-6 (at position -174), IL-8 (at position -251), and IL-10 (at position -819) were detected by polymerase chain reaction-restriction fragment length polymorphism.

Results: Among the genetic polymorphisms studied, we observed that only the presence of the A allele at position -251 of the IL-8 gene was significantly associated with H. pylori infection. In addition, patient carriers of the A/A genotype at position -251 of the IL-8 gene and carriers of the T allele at position -819 of the IL-10 gene had an increased risk of peptic ulcer disease in the presence of H. pylori infection. We did not find a correlation between polymorphisms in the IL-6, IL-8, and IL-10 genes and a higher risk of gastric carcinoma.

Conclusion: We demonstrated that polymorphisms in the IL-8 gene was significantly associated with H. pylori infection. Furthermore, polymorphisms in the IL-8 and IL-10 genes were associated with an enhanced risk of peptic ulcer disease in H. pylori-positive patients.
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http://dx.doi.org/10.1016/j.jmii.2015.03.002DOI Listing
April 2017

Antimicrobial susceptibility of rapidly growing mycobacteria using the rapid colorimetric method.

Eur J Clin Microbiol Infect Dis 2015 Jul 29;34(7):1403-13. Epub 2015 Mar 29.

Centro de Desenvolvimento Tecnológico (CDTec), Universidade Federal de Pelotas, Pelotas, Brazil,

Drug susceptibility testing (DST) of rapidly growing mycobacteria (RGM) are recommended for guiding the antimicrobial therapy. We have evaluated the use of resazurin in Mueller-Hinton medium (MHR) for MIC determination of RGM and compared the results with those obtained with the reference standard broth microdilution in Mueller-Hinton (MH) and with the resazurin microtiter assay (REMA) in 7H9 broth. The MIC of eight drugs: amikacin (AMI), cefoxitin (FOX), ciprofloxacin (CIP), clarithromycin (CLA), doxycycline (DOX), linezolid (LZD), moxifloxacin (MXF) and trimethoprim-sulfamethoxazole (TMP-SMX) were evaluated against 76 RGM (18 species) using three methods (MH, MHR, and REMA) in a 96-well plate format incubated at 37 °C over 3-5 days. Results obtained in the MH plates were interpreted by the appearance of turbidity at the bottom of the well before adding the resazurin. MHR and 7H9-REMA plates were read by visual observation for a change in color from blue to pink. The majority of results were obtained at day 5 for MH and 1 day after for MHR and 7H9-REMA. However, the preliminary experiment on time to positivity results using the reference strain showed that the resazurin can be added to the MH at day 2 to produce the results at day 3, but future studies with large sets of strains are required to confirm this suggestion. A high level of agreement (kappa 1.000-0.884) was obtained between the MH and the MHR. Comparison of results obtained with 7H9-REMA, on the other hand, revealed several discrepancies and a lower level of agreement (kappa 1.000-0.111). The majority of the strains were resistant to DOX and TMP-SMX, and the most active antimicrobials for RGM were AMI and FOX. In the present study, MHR represented an excellent alternative for MIC determination of RGM. The results could be read reliably, more easily, and more quickly than with the classical MH method.
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http://dx.doi.org/10.1007/s10096-015-2365-2DOI Listing
July 2015

Evaluation of the Speed-Oligo Mycobacteria assay for the identification of nontuberculous mycobacteria.

J Med Microbiol 2015 Mar 16;64(Pt 3):283-287. Epub 2015 Jan 16.

Laboratory of Microbiology, Department of Biochemistry and Microbiology, Ghent University, Gent, Belgium.

Nontuberculous mycobacteria (NTM) causing human infectious disease have become increasingly common. Rapid and accurate identification to the species level is, therefore, critical. The Speed-Oligo Mycobacteria assay is an oligochromatographic method that was made available recently for the identification and differentiation of mycobacteria. The present study aimed to evaluate the performance of the Speed-Oligo Mycobacteria assay for the identification of NTM. We examined a total of 62 strains (9 type strains, 19 reference strains and 34 clinical isolates) belonging to 13 different species (Mycobacterium intracellulare, M. fortuitum, M. gordonae, M. kansasii, M. marinum, M. peregrinum, M. scrofulaceum, M. abscessus, M. bovis BCG, M. chelonae, M. avium, M. malmoense and M. xenopi). The Speed-Oligo Mycobacteria assay was performed according to the manufacturer's instructions. Discrepant results between Speed-Oligo Mycobacteria and the original identification were reassessed by the Speed-Oligo Mycobacteria assay and resolved by the GenoType Mycobacterium CM assay and by sequencing of 16S rRNA and protein-encoding genes. We found 93.5 % (58/62) concordance for the identification of NTM as compared with the original identification. Three strains were erroneously identified by Speed-Oligo Mycobacteria: one M. kansasii strain was identified as Mycobacterium tuberculosis complex, and one M. chelonae strain and one M. peregrinum strain were both identified as Mycobacterium abscessus. Moreover, one M. chelonae strain was not identified by Speed-Oligo Mycobacteria since it did not react with any species-specific probe. For these strains, sequencing of the genes hsp65, 16S rRNA and rpoB and the GenoType Mycobacterium CM assay were performed. The Speed-Oligo Mycobacteria assay can be a useful tool for the rapid and easy identification of the most common NTM. If applied in clinical practice it could reduce diagnostic delays and contribute to correct clinical and better management of infections caused by NTM.
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http://dx.doi.org/10.1099/jmm.0.000025DOI Listing
March 2015

Authors reply: cagE as a biomarker of the pathogenicity of Helicobacter pylori.

Rev Soc Bras Med Trop 2014 May-Jun;47(3):404

Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, BRAZIL.

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http://dx.doi.org/10.1590/0037-8682-0261-2013DOI Listing
October 2014

cagE as a biomarker of the pathogenicity of Helicobacter pylori.

Rev Soc Bras Med Trop 2013 Mar-Apr;46(2):185-9

Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brasil.

Introduction: Helicobacter pylori infection is associated with gastro-duodenal diseases. Genes related to pathogenicity have been described for H. pylori and some of them appear to be associated with more severe clinical outcomes of the infection. The present study investigates the role of cagE as a pathogenicity biomarker of H. pylori compare it to cagA, vacA, iceA and babA2 genes and correlate with endoscopic diagnoses.

Methods: Were collected biopsy samples of 144 dyspeptic patients at the Hospital of the Federal University of Rio Grande, Rio Grande do Sul, Brazil. After collection, the samples were sent for histological examination, DNA extraction and detection of all putative pathogenicity genes by PCR.

Results: Of the 144 patients undergoing endoscopy, 57 (39.6%) presented H. pylori by histological examination and PCR by detection of the ureA gene. Based on the endoscopic diagnoses, 45.6% (26/57) of the patients had erosive gastritis, while 54.4% (31/57) had enanthematous gastritis. The genes cagA, cagE, vacAs1/m1, vacAs1/m2 and iceA1 were related to erosive gastritis, while the genes vacAs2/m2, iceA2 and babA2 were associated to enanthematous gastritis. We found a statistically significant association between the presence of cagE and the endoscopic diagnosis. However, we detect no statistically significant association between the endoscopic diagnosis and the presence of cagA, vacA, iceA and babA2, although a biological association has been suggested. Conclusions Thus, cagE could be a risk biomarker for gastric lesions and may contribute to a better evaluation of the H. pylori pathogenic potential and to the prognosis of infection evolution in the gastric mucosa.
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http://dx.doi.org/10.1590/0037-8682-0054-2012DOI Listing
October 2013

Highly potent aminopyridines as Syk kinase inhibitors.

Bioorg Med Chem Lett 2012 Sep 20;22(17):5419-23. Epub 2012 Jul 20.

Almirall-Barcelona Science Park Unit, Barcelona Science Park, 08028 Barcelona, Spain.

A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.
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http://dx.doi.org/10.1016/j.bmcl.2012.07.045DOI Listing
September 2012