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1.
J Intern Med ; 294(1): 21-46, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37106509

RESUMO

In acute coronavirus disease 19 (COVID-19) patients, effective clinical risk stratification has important implications on treatment and therapeutic resource distribution. This article reviews the evidence behind a wide range of biomarkers with prognostic value in COVID-19. Patient characteristics and co-morbidities, such as cardiovascular and respiratory diseases, are associated with increased mortality risk. Peripheral oxygen saturation and arterial oxygenation are predictive of severe respiratory compromise, whereas risk scores such as the 4C-score enable multi-factorial prognostic risk estimation. Blood tests such as markers of inflammation, cardiac injury and d-dimer and abnormalities on electrocardiogram are linked to inpatient prognosis. Of the imaging modalities, lung ultrasound and echocardiography enable the bedside assessment of prognostic abnormalities in COVID-19. Chest radiograph (CXR) and computed tomography (CT) can inform about prognostic pulmonary pathologies, whereas cardiovascular CT detects high-risk features such as coronary artery and aortic calcification. Dynamic changes in biomarkers, such as blood tests, CXR, CT and electrocardiogram findings, can further inform about disease severity and prognosis. Despite the vast volumes of existing evidence, several gaps exist in our understanding of COVID-19 biomarkers. First, the pathophysiological basis on which these markers can foretell prognosis in COVID-19 remains poorly understood. Second, certain under-explored tests such as thoracic impedance assessment and cardiovascular magnetic resonance imaging deserve further investigation. Lastly, the prognostic values of most biomarkers in COVID-19 are derived from retrospective analyses. Prospective studies are required to validate these markers for guiding clinical decision-making and to facilitate their translation into clinical management pathways.


Assuntos
COVID-19 , Humanos , Prognóstico , Estudos Retrospectivos , Biomarcadores , Medição de Risco
2.
Clin Exp Allergy ; 50(4): 508-519, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31845415

RESUMO

BACKGROUND: We have previously demonstrated that Mycobacteria tuberculosis chaperonin 60.1 inhibits leucocyte diapedesis and bronchial hyperresponsiveness in a murine model of allergic lung inflammation. METHODS: In the present study, we have investigated the effect of a shorter peptide sequence derived from Cpn 60.1, named IRL201104, on allergic lung inflammation induced by ovalbumin (OVA) in mice and by house dust mite (HDM) in guinea pigs, as well as investigating the action of IRL201104 on human cells in vitro. RESULTS: Pre-treatment of mice or guinea pigs with IRL201104 inhibits the infiltration of eosinophils to the lung, cytokine release, and in guinea pig skin, inhibits allergen-induced vascular permeability. The protective effect of intranasal IRL201104 against OVA-induced eosinophilia persisted for up to 20 days post-treatment. Moreover, OVA-sensitized mice treated intranasally with 20 ng/kg of IRL201104 show a significant increase in the expression of the anti-inflammatory molecule ubiquitin A20 and significant inhibition of the activation of NF-κB in lung tissue. Our results also show that A20 expression was significantly reduced in blood leucocytes and ASM obtained from patients with asthma compared to cells obtained from healthy subjects which were restored after incubation with IRL201104 in vitro, when added alone, or in combination with LPS or TNF-α in ASM. CONCLUSIONS: Our results suggest that a peptide derived from mycobacterial Cpn60.1 has a long-lasting anti-inflammatory and immunomodulatory activity which may help explain some of the protective effects of TB against allergic diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Asma/imunologia , Proteínas de Bactérias/farmacologia , Chaperonina 60/farmacologia , Mycobacterium tuberculosis/química , Peptídeos/farmacologia , Animais , Anti-Inflamatórios/química , Asma/tratamento farmacológico , Asma/patologia , Proteínas de Bactérias/química , Líquido da Lavagem Broncoalveolar , Chaperonina 60/química , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Cobaias , Humanos , Pulmão , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/química
3.
J Pharmacokinet Pharmacodyn ; 47(5): 421-430, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32488575

RESUMO

Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure-response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated based on bacterial cultures grown with and without drug exposure using CFU alone or CFU plus MPN data. Phenotypic resistance and total bacterial number in in vitro natural growth observations, i.e. without drug, was well predicted by the MTP model using only CFU data. Capturing the murine in vivo total bacterial number and persisters during natural growth did however require re-estimation of model parameter using both the CFU and MPN observations implying that the ratio of persisters to total bacterial burden is different in vitro compared to murine in vivo. The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using CFU and MPN compared to CFU alone although drug effects on the other bacterial populations were well predicted using only CFU data. The ratio of persistent bacteria to total bacteria was predicted to be different between in vitro and murine in vivo. This difference could have implications for subsequent translational efforts in tuberculosis drug development.


Assuntos
Antituberculosos/farmacocinética , Modelos Biológicos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/administração & dosagem , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana , Humanos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/administração & dosagem , Rifampina/farmacocinética , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
4.
J Antimicrob Chemother ; 73(7): 1750-1754, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29528413

RESUMO

A low pH was assumed to be required for the activity of pyrazinoic acid (the active form of pyrazinamide) against Mycobacterium tuberculosis, but recently activity has been demonstrated at neutral pH. Renewed interest in pyrazinamide has led to an increasing number of potential targets and the suspicion that pyrazinamide is a 'dirty drug'. However, it is our opinion that the recent demonstration that pyrazinoic acid is active against PanD provides an alternative explanation for the secret of pyrazinamide's unusual activity. In this article we propose that PanD is the primary target of pyrazinoic acid but expression of pyrazinoic acid susceptibility requires an intact stress response. As the mycobacterial stress response requires the interaction of a number of genes, disruption of any could result in an inability to enter the susceptible phenotype. We believe this model can explain most of the recent observations of the seemingly diverse spectrum of activity of pyrazinamide.


Assuntos
Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/análogos & derivados , Pirazinamida/farmacologia , Farmacorresistência Bacteriana , Humanos , Concentração de Íons de Hidrogênio , Pirazinamida/química
5.
Biochemistry ; 56(8): 1163-1174, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28156093

RESUMO

HT61 is a quinoline-derived antimicrobial, which exhibits bactericidal potency against both multiplying and quiescent methicillin resistant and sensitive Staphylococcus aureus, and has been proposed as an adjunct for other antimicrobials to extend their usefulness in the face of increasing antimicrobial resistance. In this study, we have examined HT61's effect on the permeability of S. aureus membranes and whether this putative activity can be attributed to an interaction with lipid bilayers. Using membrane potential and ATP release assays, we have shown that HT61 disrupts the membrane enough to result in depolarization of the membrane and release of intercellular constituents at concentrations above and below the minimum inhibitory concentration of the drug. Utilizing both monolayer subphase injection and neutron reflectometry, we have shown that increasing the anionic lipid content of the membrane leads to a more marked effect of the drug. In bilayers containing 25 mol % phosphatidylglycerol, neutron reflectometry data suggest that exposure to HT61 increases the level of solvent in the hydrophobic region of the membrane, which is indicative of gross structural damage. Increasing the proportion of PG elicits a concomitant level of membrane damage, resulting in almost total destruction when 75 mol % phosphatidylglycerol is present. We therefore propose that HT61's primary action is directed toward the cytoplasmic membrane of Gram-positive bacteria.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Membrana Celular/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Anti-Infecciosos/metabolismo , Membrana Celular/metabolismo , Bicamadas Lipídicas/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Quinolinas/metabolismo , Staphylococcus aureus/citologia , Staphylococcus aureus/efeitos dos fármacos
6.
J Antimicrob Chemother ; 71(4): 964-74, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26702921

RESUMO

OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states. METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships. RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively. CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/microbiologia , Algoritmos , Proteínas de Bactérias/biossíntese , Contagem de Colônia Microbiana , Relação Dose-Resposta a Droga , Humanos , Metionina/metabolismo , Testes de Sensibilidade Microbiana , Modelos Biológicos , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/metabolismo , Rifampina/farmacologia
7.
BMC Infect Dis ; 15: 473, 2015 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-26503434

RESUMO

BACKGROUND: Molecular resistance detection (MRD) of resistance to second-line anti-tuberculous drugs provides faster results than phenotypic tests, may shorten treatment and allow earlier separation among patients with and without second-line drug resistance. METHODS: In a decision-analytical model we simulated a cohort of patients diagnosed with TB in a setting where drug resistant TB is highly prevalent and requires initial hospitalization, to explore the potential benefits of a high-throughput MRD-assay for reducing potential nosocomial transmission of highly resistant strains, and total costs for diagnosis of drug resistance, treatment and hospitalization. In the base case scenario first-line drug resistance was diagnosed with WHO-endorsed molecular tests, and second-line drug resistance with culture and phenotypic methods. Three alternative scenarios were explored, each deploying high-throughput MRD allowing either detection of second-line mutations in cultured isolates, directly on sputum, or MRD with optimized markers. RESULTS: Compared to a base case scenario, deployment of high-throughput MRD reduced total costs by 17-21 %. The period during which nosocomial transmission may take place increased by 15 % compared to the base case if MRD had currently reported suboptimal sensitivity and required cultured isolates; increased by 7 % if direct sputum analysis were possible including in patients with smear-negative TB, and reduced by 24 % if the assay had improved markers, but was still performed on cultured isolates. Improved clinical sensitivity of the assay (additional markers) by more than 35 % would be needed to avoid compromising infection control. CONCLUSIONS: Further development of rapid second-line resistance testing should prioritize investment in optimizing markers above investments in a platform for direct analysis of sputum.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Ensaios de Triagem em Larga Escala/métodos , Mutação , Tuberculose Resistente a Múltiplos Medicamentos/genética , Antituberculosos/uso terapêutico , Custos e Análise de Custo , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/prevenção & controle , Diagnóstico Precoce , República da Geórgia , Ensaios de Triagem em Larga Escala/economia , Humanos , Controle de Infecções , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Escarro/microbiologia , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/economia
8.
J Antimicrob Chemother ; 68(2): 374-84, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23042813

RESUMO

OBJECTIVES: Previously, we described a small quinoline-derived compound that exhibited selective bactericidal activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). It depolarizes the bacterial cell membrane. In this study, we investigated if HT61 was able to enhance the potency of other antibiotics, namely neomycin, gentamicin and mupirocin, and an antiseptic, namely chlorhexidine, against clinical isolates of MSSA and MRSA in vitro and in vivo. METHODS: The MICs were determined by the broth microdilution method. The effect of combinations was examined using the chequerboard method and time-kill curves. A murine skin infection model was used to evaluate the enhancement by HT61 of other antimicrobials. RESULTS: Using the fractional inhibitory concentration index, no interaction was seen in both MSSA and MRSA for the pair HT61 and gentamicin or the pair HT61 and neomycin. Synergism was seen for 65% of both MSSA and MRSA when HT61 was combined with chlorhexidine. There was also no interaction between HT61 and mupirocin. Time-kill analysis demonstrated significant synergistic activities when a low level of HT61 was combined with neomycin, gentamicin or chlorhexidine. The effect was more dramatic against non-multiplying bacteria against which the antimicrobials used were inactive on their own. Significant synergistic effects were also seen on mouse infected skin. CONCLUSIONS: We demonstrate that HT61, developed as a topical agent, acts as an enhancer that accelerates the activities of other antimicrobial agents against both MSSA and MRSA.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Sinergismo Farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Administração Tópica , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/microbiologia , Resultado do Tratamento
9.
Microbiol Spectr ; 11(1): e0224422, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36475728

RESUMO

Here, we report the development and key features of the first external quality assessment (EQA) scheme for Mycobacterium tuberculosis whole-genome sequencing (WGS). The results of four rounds (2017 to 2020) of implementation within the European tuberculosis reference laboratories network (ERLTB-Net-2) are presented and discussed. EQA panels comprising 10 genomic DNAs were distributed to ERLTB-Net 2 laboratories volunteering to participate in this exercise. Since 2018, five FASTQ files were added to better assess the dry WGS processes, and in 2020, three of the five files were replaced by synthetic files (providing additional flexibility for the mutations included in the panels). Ten National tuberculosis reference laboratories participated in all four EQA rounds, and seven participated in at least one. High-confidence resistance mutations were correctly identified by all laboratories, but challenges remained with respect to the identification of mixed loci and interpretation of rare mutations. M. tuberculosis genotyping and clustering analysis was >90% accurate for pure samples with the main challenges being related to the analysis of mixed genotypes and DNA FASTQ files. The development and implementation of this WGS EQA scheme has contributed to the continuous improvement in performance of participating laboratories in M. tuberculosis WGS and data analysis. This scheme can serve as a model of comprehensive quality assessment for M. tuberculosis WGS that can be replicated in different settings worldwide. IMPORTANCE The wider availability of whole-genome sequencing (WGS) coupled to new developments in bioinformatic tools and databases to interpret Mycobacterium tuberculosis complex WGS data has accelerated the adoption of this method for the routine prediction of antimycobacterial drug resistance and genotyping, thus necessitating the establishment of a comprehensive external quality control system. Here, we report 4 years of development and results from such a panel.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/genética , União Europeia , Tuberculose/diagnóstico , Tuberculose/microbiologia , Sequenciamento Completo do Genoma , Antibacterianos
10.
Biomedicines ; 11(9)2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37760863

RESUMO

Background: CRB-65 (Confusion; Respiratory rate ≥ 30/min; Blood pressure ≤ 90/60 mmHg; age ≥ 65 years) is a risk score for prognosticating patients with COVID-19 pneumonia. However, a significant proportion of COVID-19 patients have normal chest X-rays (CXRs). The influence of CXR abnormalities on the prognostic value of CRB-65 is unknown, limiting its wider applicability. Methods: We assessed the influence of CXR abnormalities on the prognostic value of CRB-65 in COVID-19. Results: In 589 study patients (71 years (IQR: 57-83); 57% males), 186 (32%) had normal CXRs. On ROC analysis, CRB-65 performed similarly in patients with normal vs. abnormal CXRs for predicting inpatient mortality (AUC 0.67 ± 0.05 vs. 0.69 ± 0.03). In patients with normal CXRs, a CRB-65 of 0 ruled out mortality, NIV requirement and critical illness (intubation and/or ICU admission) with negative predictive values (NPVs) of 94%, 98% and 99%, respectively. In patients with abnormal CXRs, a CRB-65 of 0 ruled out the same endpoints with NPVs of 91%, 83% and 86%, respectively. Patients with low CRB-65 scores had better inpatient survival than patients with high CRB-65 scores, irrespective of CXR abnormalities (all p < 0.05). Conclusions: CRB-65, CXR and CRP are independent predictors of mortality in COVID-19. Adding CXR findings (dichotomised to either normal or abnormal) to CRB-65 does not improve its prognostic accuracy. A low CRB-65 score of 0 may be a good rule-out test for adverse clinical outcomes in COVID-19 patients with normal or abnormal CXRs, which deserves prospective validation.

11.
Biomedicines ; 11(10)2023 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-37893192

RESUMO

Introduction: The ferritin-lymphocyte ratio (FLR) is a novel inflammatory biomarker for the assessment of acute COVID-19 patients. However, the prognostic value of FLR for predicting adverse clinical outcomes in COVID-19 remains unclear, which hinders its clinical translation. Methods: We characterised the prognostic value of FLR in COVID-19 patients, as compared to established inflammatory markers. Results: In 217 study patients (69 years [IQR: 55-82]; 60% males), FLR was weakly correlated with CRP (R = 0.108, p = 0.115) and white cell count (R = -0.144; p = 0.034). On ROC analysis, an FLR cut-off of 286 achieved a sensitivity of 86% and a specificity of 30% for predicting inpatient mortality (AUC 0.60, 95% CI: 0.53-0.67). The negative predictive values of FLR for ruling out mortality, non-invasive ventilation requirement and critical illness (intubation and/or ICU admission) were 86%, 85% and 93%, respectively. FLR performed similarly to CRP (AUC 0.60 vs. 0.64; p = 0.375) for predicting mortality, but worse than CRP for predicting non-fatal outcomes (all p < 0.05). On Kaplan-Meier analysis, COVID-19 patients with FLR values > 286 had worse inpatient survival than patients with FLR ≤ 286, p = 0.041. Conclusions: FLR has prognostic value in COVID-19 patients, and appears unrelated to other inflammatory markers such as CRP and WCC. FLR exhibits high sensitivity and negative predictive values for adverse clinical outcomes in COVID-19, and may be a good "rule-out" test. Further work is needed to improve the sensitivity of FLR and validate its role in prospective studies for guiding clinical management.

12.
J Pers Med ; 13(6)2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37373898

RESUMO

Background: In COVID-19 patients, lymphocyte-CRP ratio (LCR) is a promising biomarker for predicting adverse clinical outcomes. How well LCR performs compared to conventional inflammatory markers for prognosticating COVID-19 patients remains unclear, which hinders the clinical translation of this novel biomarker. Methods: In a cohort of COVID-19 inpatients, we characterised the clinical applicability of LCR by comparing its prognostic value against conventional inflammatory markers for predicting inpatient mortality and a composite of mortality, invasive/non-invasive ventilation and intensive care unit admissions. Results: Of the 413 COVID-19 patients, 100 (24%) patients suffered inpatient mortality. On Receiver Operating Characteristics analysis, LCR performed similarly to CRP for predicting mortality (AUC 0.74 vs. 0.71, p = 0.049) and the composite endpoint (AUC 0.76 vs. 0.76, p = 0.812). LCR outperformed lymphocyte counts (AUC 0.74 vs. 0.66, p = 0.002), platelet counts (AUC 0.74 vs. 0.61, p = 0.003) and white cell counts (AUC 0.74 vs. 0.54, p < 0.001) for predicting mortality. On Kaplan-Meier analysis, patients with a low LCR (below a 58 cut-off) had worse inpatient survival than patients with other LCR values (p < 0.001). Conclusion: LCR appears comparable to CRP, but outperformed other inflammatory markers, for prognosticating COVID-19 patients. Further studies are required to improve the diagnostic value of LCR to facilitate clinical translation.

13.
PLoS One ; 18(4): e0284523, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37083886

RESUMO

INTRODUCTION: Assessment of inpatient mortality risk in COVID-19 patients is important for guiding clinical decision-making. High sensitivity cardiac troponin T (hs-cTnT) is a biomarker of cardiac injury associated with a worse prognosis in COVID-19. We explored how hs-cTnT could potentially be used in clinical practice for ruling in and ruling out mortality in COVID-19. METHOD: We tested the diagnostic value of hs-cTnT in laboratory-confirmed COVID-19 patients (≥18 years old) admitted to the Royal Berkshire Hospital (UK) between 1st March and 10th May 2020. A normal hs-cTnT was defined as a value within the 99th percentile of healthy individuals (≤14 ng/L), and an elevated hs-cTnT was defined as >14 ng/L. Adverse clinical outcome was defined as inpatient mortality related to COVID-19. RESULTS: A total of 191 COVID-19 patients (62% male; age 66±16 years) had hs-cTnT measured on admission. Of these patients, 124 (65%) had elevated hs-cTnT and 67 (35%) had normal hs-cTnT. On a group level, patients with elevated hs-cTnT had worse inpatient survival (p = 0.0014; Kaplan-Meier analysis) and higher risk of inpatient mortality (HR 5.84 [95% CI 1.29-26.4]; p = 0.02; Cox multivariate regression) compared to patients with normal hs-cTnT. On a per-patient level, a normal hs-cTnT had a negative predictive value of 94% (95% CI: 85-98%) for ruling out mortality, whilst an elevated hs-cTnT had a low positive predictive value of 38% (95% CI: 39-47%) for ruling in mortality. CONCLUSIONS: In this study cohort of COVID-19 patients, the potential clinical utility of hs-cTnT appears to rest in ruling out inpatient mortality. This finding, if prospectively validated in a larger study, may allow hs-cTnT to become an important biomarker to facilitate admission-avoidance and early safe discharge.


Assuntos
COVID-19 , Troponina , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adolescente , Feminino , Pacientes Internados , COVID-19/diagnóstico , Biomarcadores , Prognóstico , Troponina T
14.
Am J Respir Cell Mol Biol ; 47(2): 245-52, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22447969

RESUMO

Chaperonin 60.1 from Mycobacterium tuberculosis suppressed allergic lung inflammation and bronchial hyperresponsiveness in mice by a mechanism that is yet to be clarified. To investigate the possible antiinflammatory mechanism(s) of action of Cpn60.1 in a model of allergic lung inflammation, ovalbumin (OVA)-allergic mice were pretreated with Cpn60.1 intranasally 20 minutes before each OVA aerosol challenge in a total of three treatments. Readouts were performed 24 hours after last challenge. Pretreatment with Cpn60.1 (1.0-0.001 µg) significantly inhibited the number of eosinophils in bronchoalveolar lavage fluid (OVA, 49.2 ± 12.3 versus Cpn60.1 [1 µg dose], 90.4 ± 2.3 × 10(4) cells/ml) and IL-5 release (OVA, 43 ± 8.5 versus Cpn60.1 [1 µg dose], 3 ± 11 pg/ml) but increased IL-12 levels (OVA, 50 ± 24 versus Cpn60.1 [1 µg dose], 103 ± 13 pg/ml). The effect of Cpn60.1 on cell recruitment and IL-5, but not IL-12, release was abolished in TLR-4 knockout mice. Intravital microscopy demonstrated that Cpn60.1 reduced chemokine-mediated leukocyte rolling and transmigration across the vessel wall (rolling cells: eotaxin, 11.7 ± 1.1 versus Cpn60.1 [1 µg dose], 2.8 ± 1 cells in 30 s). Similarly, Cpn60.1 reduced eotaxin-induced leukocyte migration in vitro (eotaxin, 17.3 ± 3.3 versus Cpn60.1 [0.1 µg dose], 3.3 ± 0.4 cells × 10(4)/ml). Immunostaining demonstrated that Cpn60.1 inhibits VCAM-1 and increases vascular endothelial-cadherin expression in lung vascular tissue, suggesting that the antiinflammatory effect of Cpn60.1 is partly mediated by altering the expression of adhesion molecules. This study shows that Cpn60.1 inhibits leukocyte diapedesis by a TLR-4 and an adhesion molecule-dependent mechanism in allergic inflammation in mice.


Assuntos
Chaperonina 60/farmacologia , Leucócitos/imunologia , Mycobacterium tuberculosis/imunologia , Pneumonia/imunologia , Animais , Anti-Inflamatórios , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Chaperonina 60/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-5/imunologia , Interleucina-5/metabolismo , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/metabolismo , Ovalbumina/imunologia , Pneumonia/metabolismo , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
16.
Antimicrob Agents Chemother ; 56(5): 2420-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22330913

RESUMO

The global emergence of multidrug-resistant tuberculosis has highlighted the need for the development of rapid tests to identify resistance to second-line antituberculosis drugs. Resistance to fluoroquinolones and aminoglycosides develops through nonsynonymous single nucleotide polymorphisms in the gyrA and gyrB genes and the rrs gene, respectively. Using DNA sequencing as the gold standard for the detection of mutations conferring resistance, in conjunction with spoligotyping, we demonstrated heteroresistance in 25% and 16.3% of Mycobacterium tuberculosis isolates resistant to ofloxacin and amikacin, respectively. Characterization of follow-up isolates from the same patients showed that the population structure of clones may change during treatment, suggesting different phases in the emergence of resistance. The presence of underlying mutant clones was identified in isolates which failed to show a correlation between phenotypic resistance and mutation in the gyrA or rrs gene. These clones harbored previously described mutations in either the gyrA or rrs gene, suggesting that rare mutations conferring resistance to ofloxacin or amikacin may not be as important as was previously thought. We concluded that the absence of a correlation between genotypic and phenotypic resistance implies an early phase in the emergence of resistance within the patient. Thus, the diagnostic utility of genetics-based drug susceptibility tests will depend on the proportion of patients whose bacilli are in the process of acquiring resistance in the study setting. These data have implications for the interpretation of molecular and microbiological diagnostic tests for patients with drug-susceptible and drug-resistant tuberculosis who fail to respond to treatment and for those with discordant results.


Assuntos
Amicacina/uso terapêutico , Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Ofloxacino/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Amicacina/administração & dosagem , Antituberculosos/administração & dosagem , Técnicas de Tipagem Bacteriana , Sequência de Bases , DNA Girase/genética , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Ofloxacino/administração & dosagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
17.
Rapid Commun Mass Spectrom ; 26(6): 679-85, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22328222

RESUMO

RATIONALE: Several mycobacterial species can produce serious infections in humans, and the treatment required depends on the infecting species. Fast identification, ideally with minimal manipulation of the infecting species, is therefore critical; here, we propose a method potentially allowing cultures to be identified by headspace analysis and use it to screen for differences between mycobacterial species based on the volatiles released during growth. METHODS: Short-chain volatile organic compound emissions from two non-tuberculosis slow growing mycobacterial species, Mycobacterium avium and Mycobacterium kansasii, and a non-pathogenic fast growing species, Mycobacterium smegmatis, in Middlebrook M7H9 culturing media were followed online with a proton transfer reaction quadrupole mass spectrometer. RESULTS: Measurable differences between the headspace of the two slow growing mycobacteria M. kansasii and M. avium were found, as well as differences with respect to the faster growing mycobacteria M. smegmatis. Three compounds, attributed to sulfur-containing volatiles--dimethyl sulfide, propanethiol and dimethyl disulfide--were found to be specific to M. avium. CONCLUSIONS: Clear differences were detected in the low molecular weight volatile emissions compounds of the mycobacterial species under study, without the need for sample manipulation. Further studies with other mycobacterial species will reveal if the differences observed are specific to the species studied here. Furthermore, the use of an ion trap as a mass analyzer with the same ionization technique, allowing molecular detection over a wider molecular range, could allow the detection of additional biomarkers thus capturing a wider molecular range.


Assuntos
Espectrometria de Massas/métodos , Mycobacterium/isolamento & purificação , Compostos Orgânicos Voláteis/análise , Humanos , Mycobacterium/química , Infecções por Mycobacterium/diagnóstico , Mycobacterium avium/química , Mycobacterium avium/isolamento & purificação , Mycobacterium kansasii/química , Mycobacterium kansasii/isolamento & purificação , Mycobacterium smegmatis/química , Mycobacterium smegmatis/isolamento & purificação , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/isolamento & purificação , Prótons
18.
Handb Exp Pharmacol ; (211): 167-83, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23090602

RESUMO

There are 19 compounds in late-stage clinical trials, of which ten may be suitable for Gram-positive infections. However, there are only five compounds in development for Gram-negative infections, in addition to four broad-spectrum ones. There are two new classes in late-stage clinical development. This chapter discusses in some detail each of the antibiotics in Phase II and Phase III clinical trials. Only those that appear in the literature are covered. The shortage of compounds in development for Gram-negatives and the small number of new classes in the pipeline is of serious concern; this matter needs to be addressed by governments, the regulatory authorities, the pharmaceutical industry and academia urgently.


Assuntos
Antibacterianos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Farmacorresistência Bacteriana , Quimioterapia Combinada , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos
19.
Public Health Action ; 12(2): 64-67, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35734008

RESUMO

OBJECTIVE: To compare the clinical characteristics and laboratory results of pulmonary TB (PTB) patients with and without diabetes mellitus (DM) and the relationship between haemoglobin A1C (HbA1c) concentration and mycobacterial load at county level area in Sichuan Province, China. METHODS: A retrospective study was performed from January 2018 to July 2019 inJianyang People's Hospital, Sichuan Province. Clinical characteristics and laboratory results of newly diagnosed TB patients were collected. Univariable and multivariable logistic regression analyses were performed. The Kruskal-Wallis test was used to compare HbA1c level and mycobacterial load. RESULTS: The final sample included 415 patients with TB, of whom 45 were diagnosed with DM (10.8%). Uni-variable logistic regression showed that PTB patients with concomitant DM were more likely to present with haemoptysis, positive acid-fast bacilli (AFB) smear, cavity, higher erythrocyte sedimentation rate (ESR), higher serum C-reactive protein (CRP), lower serum albumin (ALB), or higher fasting blood glucose (FBG). Multivariate logistic regression analyses showed that AFB smear positivity (OR 15.81, 95% CI 3.09-80.95) and FBG (OR 1.88, 95% CI 1.53-2.31) were independent risk factors of DMPTB. The mycobacterial load was heaviest when the HbA1c was 7.9 mmol/L (95% CI 7.35-11.1) and declined along with HbA1c rising up. But it has not been significantly associated with HbA1c. CONCLUSIONS: Patients with PTB over 45 years old, with haemoptysis, positive AFB, cavity, higher ESR, higher CRP, lower ALB or higher FBG are more likely to present with concomitant DM. Patients with PTB with these factors need to be targeted for DM screening. The mycobacterial load has not been significantly associated with HbA1c.


OBJECTIF: Comparer les caractéristiques cliniques et les résultats de laboratoire des patients atteints de TB pulmonaire (PTB) avec et sans diabète sucré (DM), et le lien entre le taux d'hémoglobine glyquée (HbA1c) et la charge mycobactérienne dans une zone de la province du Sichuan, Chine. MÉTHODES: Nous avons réalisé une étude rétrospective de janvier 2018 à juillet 2019 au Jianyang People's Hospital dans la province du Sichuan. Les caractéristiques cliniques et les résultats de laboratoire des patients ayant récemment reçu un diagnostic de TB ont été recueillis. Des analyses de régression logistique univariables et multivariables ont été réalisées. Le test de Kruskal-Wallis a été utilisé pour comparer le taux d'HbA1c avec la charge mycobactérienne. RÉSULTATS: L'échantillon final comprenait 415 patients atteints de TB, dont 45 avaient un diagnostic de DM (10,8%). La régression logistique univariable a démontré que les patients atteints de PTB étaient plus susceptibles de présenter un DM-PTB avec hémoptysie, une TB à microscopie positive, une TB cavitaire, une vitesse de sédimentation (ESR) plus élevée, un taux sérique de protéine C-réactive (CRP) plus élevé, un taux sérique d'albumine (ALB) plus bas ou une glycémie à jeun (FBG) plus élevée. Les analyses de régression logistique multivariables ont démontré que la microscopie positive (OR 15,81 ; IC 95% 3,09­80,95) et la FBG (OR 1,88 ; IC 95% 1,53­2,31) étaient des facteurs de risque indépendants de DM-PTB. La charge mycobactérienne était plus élevée lorsque le taux d'HbA1c était de 7,9 mmol/L (IC 95% 7,35­11,1) et baissait à mesure que le taux d'HbA1c augmentait. Aucune association significative avec le taux d'HbA1c n'a cependant été démontrée. CONCLUSIONS: Les patients atteints de PTB de plus de 45 ans, avec hémoptysie, microscopie positive, TB cavitaire, ESR élevée, CRP élevée, ALB basse ou FBG élevée sont plus susceptibles de présenter également un DM. Les patients atteints de PTB présentant ces facteurs de risque doivent faire l'objet d'un dépistage du DM. La charge mycobactérienne n'a pas été associée de manière significative avec le taux d'HbA1c.

20.
Biomolecules ; 12(9)2022 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-36139158

RESUMO

Ruthenium complexes are at the forefront of developments in metal-based anticancer drugs, but many questions remain open regarding their reactivity in biological media, including the role of transferrin (Tf) in their transport and cellular uptake. A well-known anticancer drug, KP1019 ((IndH)[RuIIICl4(Ind)2], where Ind = indazole) and a reference complex, [RuIII(nta)2]3- (nta = nitrilotriacetato(3-)) interacted differently with human apoTf, monoFeTf, or Fe2Tf. These reactions were studied by biolayer interferometry (BLI) measurements of Ru-Fe-Tf binding to recombinant human transferrin receptor 1 (TfR1) in conjunction with UV-vis spectroscopy and particle size analysis. Cellular Ru uptake in human hepatoma (HepG2) cells was measured under the conditions of the BLI assays. The mode of Tf binding and cellular Ru uptake were critically dependent on the nature of Ru complex, availability of Fe(III) binding sites of Tf, and the presence of proteins that competed for metal binding, particularly serum albumin. Cellular uptake of KP1019 was not Tf-mediated and occurred mostly by passive diffusion, which may also be suitable for treatments of inoperable cancers by intratumoral injections. High cellular Ru uptake from a combination of [RuIII(nta)2]3- and Fe2Tf in the absence of significant Ru-Tf binding was likely to be due to trapping of Ru(III) species into the endosome during TfR1-mediated endocytosis of Fe2Tf.


Assuntos
Antineoplásicos , Compostos Organometálicos , Rutênio , Antineoplásicos/química , Compostos Férricos/metabolismo , Humanos , Indazóis/química , Compostos Organometálicos/química , Receptores da Transferrina/metabolismo , Rutênio/química , Rutênio/farmacologia , Compostos de Rutênio , Albumina Sérica , Transferrina/metabolismo
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