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Notwithstanding the fact that streptomycetes are overlooked in clinical laboratories, studies describing their occurrence in disease and potential pathogenicity are emerging. Information on their species diversity in clinical specimens, aetiology and appropriate therapeutic treatment is scarce. We identified and evaluated the antibiotic susceptibility profile of 84 Streptomyces clinical isolates from the Czech Republic. In the absence of appropriate disk diffusion (DD) breakpoints for antibiotic susceptibility testing (AST) of Streptomyces spp., we determined DD breakpoints by correlation with the broth microdilution method and by the distribution of zone diameters among isolates. Correlation accuracy was high for 9 antibiotics, leading to the establishment of the most valid DD breakpoints for Streptomyces antibiotic susceptibility evaluation so far. Clinical strains belonged to 17 different phylotypes dominated by a cluster of strains sharing the same percentage of 16S rRNA gene sequence identity with more than one species (S. albidoflavus group, S. hydrogenans, S. resistomycificus, S. griseochromogenes; 70% of isolates). AST results showed that Streptomyces exhibited intrinsic resistance to penicillin, general susceptibility to amikacin, gentamycin, vancomycin and linezolid, and high percentage of susceptibility to tetracyclines and clarithromycin. For the remaining antibiotics, AST showed inter- and intra-species variations when compared to available literature (erythromycin, trimethoprim-sulfamethoxazole), indicating a region-dependent rather than species-specific patterns.
Závažnost a zvyšující se výskyt mykotických infekcí spolu s rozšiřujícím se armamentáriem antifungálních léků sebou nese zvýšenou potřebu a nároky na hodnocení antimycetární citlivosti houbových izolátů. Během posledního desetiletí byl zaznamenán podstatný pokrok na poli testování citlivosti na antimykotika v podmínkách in vitro a byly předloženy standardní protokoly pro testování kvasinek (M27-A) i vláknitých hub (M38-P). Vedle toho bylo vypracováno několik testů kompatibilních s navrženými standardy, které jsou vhodnými kandidáty pro rutinní testování patogenních hub v mikrobiologické laboratoři. V případě kvantitativního stanovení citlivosti na antimykotika se jedná zejména o gradientovou difúzní metodu E-test a mikrodiluční formát standardu M27-A, včetně jeho kolorimetrické varianty. Ve vývoji je diskový test jako skríninková metoda k prozatímnímu ohodnocení antimycetární citlivosti houbových izolátů. Hlavní pozornost je zaměřena na stanovení hraničních koncentrací nezbytných k predikci klinického účinku antifungální látky. Doposud byla stanovena interpretační kritéria pro hodnocení výsledku testování flukonazolu, itrakonazolu a flucytosinu, ale chybí pro amfotericin B. Předpověď výsledku antifungální terapie na základě in vitro testování je obecně spolehlivější pro seIhání terapie než její úspěch, avšak vychází především ze studia terapie orofaryngeální kandidózy u pacientů s AIDS. Do budoucna je potřebné vyhodnotit korelaci in vitro-in vivo u dalších rizikových skupin pacientů a v prvé řadě s ohledem na systémové formy houbových infekcí. V případě antifungálních léků je výsledný terapeutický efekt významně ovlivněn nemikrobiologickými aspekty, zejména imunologickým statutem pacienta a farmakologickým profilem antimykotika. Informace o citlivosti houbového agens se tak stává jen jednou, ale ne jedinou, která rozhoduje o výběru racionální terapie pacienta v riziku mykotické infekce.
Substantial progress has been achieved in the field of in vitro antifungal susceptibilitv testing and the interpretation of the test results towards clinical practice. Reference methods for antifungal testing of yeasts (M27-A) and filamentous fungi (M38-P) are available. There are several alternative tests to these standards as potential candidates for routine laboratory testing of antifungal drugs. Microdilution format of M27-A standard including colorimetric tests and gradient diffusion method (E test) seem to be suitable for the determinativ of miminum inhibitory concentration (MIC). Disk diffusion test is promising for tentative evaluation of antifungal susceptibility of fungal isolates, but this test has not been standardized yet. The development of the standard techniques M27-A and M38-P has improved the reproducibility of MICs, and made possible the establishment of interpretce breakpoints for fluconazole, itraconazole and flucytosine. As the majority of in vitro-in vivo studies described involved AIDS patiens with oropharyngeal candidiasis treated with fluconazole, main effort has been focused on definic interpretce kriteria for amphotericin B and predicting therapy of systemic mycoses caused by yeasts and molds. The prediction of the clinical response to antifungal therapy based on susceptibility testing data is komplex due to a number of non-microbiology factors, especially immunological status of the host and the pharmacological profile of an antifungal drug, which affect the therapeutic outcome. Hence, a number of therapeutic failures in patiens with systemic mycoses results rather from the clinical resistence than the resistence of the fungal strain to the antifungal drug. Information on antifungal susceptibility (MIC) of a fungal strain i sone, but not the only factor which influences the choice of the antifungal therapy of patiens at risk of a fungal infection.
Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
- MeSH
- celogenomová asociační studie MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- nehodgkinský lymfom * genetika MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- zárodečné buňky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
Among the co-infectious agents in COVID-19 patients, Aspergillus species cause invasive pulmonary aspergillosis (IPA). IPA is difficult to diagnose and is associated with high morbidity and mortality. This study is aimed at identifying Aspergillus spp. from sputum and tracheal aspirate (TA) samples of COVID-19 patients and at determining their antifungal susceptibility profiles. A total of 50 patients with COVID-19 hospitalized in their intensive care units (ICU) were included in the study. Identification of Aspergillus isolates was performed by phenotypic and molecular methods. ECMM/ISHAM consensus criteria were used for IPA case definitions. The antifungal susceptibility profiles of isolates were determined by the microdilution method. Aspergillus spp. was detected in 35 (70%) of the clinical samples. Among the Aspergillus spp., 20 (57.1%) A. fumigatus, six (17.1%) A. flavus, four (11.4%) A. niger, three (8.6%) A. terreus, and two (5.7%) A. welwitschiae were identified. In general, Aspergillus isolates were susceptible to the tested antifungal agents. In the study, nine patients were diagnosed with possible IPA, 11 patients were diagnosed with probable IPA, and 15 patients were diagnosed with Aspergillus colonization according to the used algorithms. Serum galactomannan antigen positivity was found in 11 of the patients diagnosed with IPA. Our results provide data on the incidence of IPA, identification of Aspergillus spp., and its susceptibility profiles in critically ill COVID-19 patients. Prospective studies are needed for a faster diagnosis or antifungal prophylaxis to manage the poor prognosis of IPA and reduce the risk of mortality.
- MeSH
- antifungální látky farmakologie terapeutické užití MeSH
- Aspergillus MeSH
- COVID-19 * komplikace MeSH
- invazivní plicní aspergilóza * diagnóza farmakoterapie komplikace MeSH
- lidé MeSH
- plicní aspergilóza * diagnóza farmakoterapie komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations. METHODS: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines. RESULTS: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166. CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.
- MeSH
- celogenomová asociační studie MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- represorové proteiny genetika MeSH
- RNA MeSH
- transkriptom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Differences in biological responses to exposure to hazardous airborne substances between children and adults have been reported, suggesting children to be more susceptible. Aim of this study was to improve our understanding of differences in susceptibility in cancer risk associated with air pollution by comparing genome-wide gene expression profiles in peripheral blood of children and their parents. Gene expression analysis was performed in blood from children and parents living in two different regions in the Czech Republic with different levels of air pollution. Data were analyzed by two different approaches: one method first selected significantly differentially expressed genes and analyzed these gene lists for overrepresented biological processes, whereas the other applied the T-profiler tool to directly perform pathway analyses on the total gene set without preselection of significantly modulated gene expressions. In addition, gene expressions in both children and adults were investigated for associations with micronuclei frequencies. Both analysis approaches returned considerably more genes or gene groups and pathways that significantly differed between children from both regions than between parents. Very little overlap was observed between children and adults. The two most important biological processes or molecular functions significantly modulated in children, but not in adults, are nucleosome and immune response related. Our study suggests differences between children and adults in relation to air pollution exposure at the transcriptome level. The findings underline the necessity of implementing environmental health policy measures specifically for protecting children's health.
- MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- nukleární rodina MeSH
- receptory chemokinů genetika MeSH
- regulace genové exprese MeSH
- RNA genetika MeSH
- rodiče MeSH
- sestřih RNA genetika MeSH
- stanovení celkové genové exprese * MeSH
- znečištění ovzduší * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
- MeSH
- Asijci * genetika MeSH
- běloši * genetika MeSH
- celogenomová asociační studie * MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus * MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- lokus kvantitativního znaku * MeSH
- mapování chromozomů MeSH
- sekvenování exomu MeSH
- studie případů a kontrol MeSH
- transkriptom MeSH
- východní Asiaté MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
OBJECTIVES: This study examined the antimicrobial susceptibility and resistance mechanisms of Clostridium difficile recovered in Greek hospitals during 2012-2015. METHODS: C. difficile isolates (n=88) were collected from clinically-confirmed C. difficile infection from symptomatic patients in 10 Greek hospitals. Minimum inhibitory concentrations (MICs) of various antimicrobial agents were determined by Etest. Isolates were typed by multilocus sequence typing (MLST). Toxin and resistance genes were detected by PCR. Chromosomal mutations in gyrA, gyrB and rpoB were identified by PCR and sequencing. The genetic environment of resistance genes was characterised by Illumina sequencing. RESULTS: The 88 C. difficile isolates comprised 27 sequence types (STs), with ST37 (n=26) and ST11 (n=21) being the most prevalent. All isolates were susceptible to vancomycin and metronidazole, with variable resistance rates to other antimicrobials. Of the 88 isolates, 45.5% were multidrug-resistant and the majority belonged to ST11 and ST37. The presence of chromosomal mutations in gyrA, gyrB and rpoB was mainly observed in high-risk clones such as ST11 and ST37. The antimicrobial resistance genes ermB, mefA, msrA and tetM were identified at different prevalences and combinations. Additionally, cfrB and cfrC were identified for the first time in Greece and were carried by a Tn6218 transposon and a novel plasmid, respectively. CONCLUSIONS: To our knowledge, this is the first study examining the resistance profiles and respective mechanisms of C. difficile recovered in Greek hospitals. Gut commensals such as C. difficile may serve as hubs for further transfer of antimicrobial resistance genes.
- MeSH
- antibakteriální látky farmakologie MeSH
- bakteriální proteiny genetika MeSH
- Clostridioides difficile klasifikace účinky léků genetika MeSH
- klostridiové infekce mikrobiologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mnohočetná bakteriální léková rezistence genetika MeSH
- multilokusová sekvenční typizace MeSH
- mutace MeSH
- nemocnice MeSH
- techniky typizace bakterií MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Řecko MeSH
Bacterial ocular infections represent a common public health problem affecting people of all age groups. These infections can lead to damage of ocular structures or even a loss of vision. The spectrum of isolated bacteria and their susceptibilities to antibiotics, however, shows geographical variabilities, which can affect the success of most empirically-administered antimicrobial therapies. The aim of this study was thus to analyse bacterial aetiology in culture-positive acute and chronic ocular infections and its antimicrobial susceptibility profile in a large cohort of patients in the Czech Republic. The study also focused on corynebacteria identification, particularly on the prevalence of Corynebacterium macginleyi. A total of 2500 bacterial isolates obtained from 2015 to 2020 in University Hospital Hradec Kralove were included in the study. A total of 2320 (92.8%) bacterial isolates were Gram-positive and 180 (7.2%) were Gram-negative. Staphylococcus aureus was the predominant pathogen, isolated from 15.3% of ocular infections, followed by Enterobacterales, Streptococcus pneumoniae and Haemophilus influenzae, isolated in 2.9%, 1.6% and 1.0%, respectively. Corynebacterium macginleyi was confirmed as the most prevalent species of corynebacteria. Most bacteria showed good susceptibility to fluoroquinolones, chloramphenicol, and aminoglycosides. Gram-positive bacteria were also susceptible to tetracycline. To conclude, this study presents a 5-year assessment of bacterial aetiology of ocular infections in the East Bohemian region. The survey showed clear differences in the susceptibilities of several bacteria to select antibiotics compared to studies from other geographical regions in Europe. This clearly shows that local surveillance of the aetiology and antimicrobial susceptibility of bacteria is essential for adequate empirical therapy of ocular infections.
- MeSH
- antibakteriální látky * farmakologie MeSH
- Bacteria * účinky léků izolace a purifikace klasifikace MeSH
- bakteriální léková rezistence MeSH
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- mladiství MeSH
- mladý dospělý MeSH
- oční infekce bakteriální mikrobiologie farmakoterapie epidemiologie MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
The growth adaptability to increasing concentration of the biocide 2-phenoxyethanol (PE) was determined in Pseudomonas aeruginosa PAO1 (P.a.) as part of efforts to understand and control the biocide tolerance and its effect on cross-resistance to other biocides and resistance to antibiotics. After repeated subculturing in media containing increasing sub-minimum-inhibitory PE concentration, P.a. exhibited an adaptive resistance indicated by two-fold increase in MIC at the 10th passage. The resistance was stable and remained after passaging the strain in further 7 successive passages in PE-free growth media. The strain showed cross-resistance towards dissimilar biocides and displayed increased susceptibility to antibiotics, which was not influenced by the presence of the efflux inhibitor 'carbonyl cyanide m-chlorophenyl hydrazone'. Outer membranes of adapted strain showed altered protein profile when examined by SDS-PAGE.
- MeSH
- antibakteriální látky farmakologie MeSH
- biologická adaptace MeSH
- dezinficiencia metabolismus toxicita MeSH
- elektroforéza v polyakrylamidovém gelu MeSH
- ethylenglykoly metabolismus toxicita MeSH
- financování organizované MeSH
- mikrobiální testy citlivosti MeSH
- proteiny vnější bakteriální membrány analýza MeSH
- proteom analýza MeSH
- Pseudomonas aeruginosa fyziologie MeSH
- sériové pasážování MeSH
- tolerance léku MeSH
