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1.
Artigo em Inglês | MEDLINE | ID: mdl-35546215

RESUMO

Coccidioidomycosis is caused by the dimorphic fungi Coccidioides species which is endemic in the Western hemisphere. Reports on the characteristics of travel-related disseminated coccidioidomycosis in immunocompetent patients are rare, especially in non-endemic regions. The multifaceted symptoms of this condition present a diagnostic challenge to clinicians. This study aimed to review immunocompetent patients diagnosed with disseminated coccidioidomycosis in a tertiary hospital in Eastern China and other non-endemic areas, and to emphasize the importance of combining travel history with clinical manifestations and proper diagnostic examinations. This study retrospectively reviewed a case series of disseminated coccidioidomycosis diagnosed in an academic hospital in Eastern China. We conducted a global literature review of disseminated coccidioidomycosis in immunocompetent patients with travel history. We identified six patients in our case series and reviewed 42 cases in the literature. Travel history included Mexico, Arizona, California, and regions of low endemicity. Extrapulmonary sites of infection, which presented with diverse signs and symptoms, involved the skin and soft tissue, musculoskeletal system, lymph nodes, and central nervous system. Misdiagnoses and diagnostic delays were common. Next-generation sequencing substantially promoted precise diagnosis in our series. The overall prognosis for immunocompetent individuals was positive, mainly benefited from long-term azole therapies. The patients that succumbed had either central nervous system involvement or multiorgan dissemination. Progressive pneumonia with varied symptoms and travel history should alert healthcare professionals in non-endemic areas to consider the possibility of Coccidioides species infection. We recommend detailed history-taking and hypothesis-free detection of pathogens for cases with diagnostic delay.

2.
mSphere ; : e0014322, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35546482

RESUMO

Carbapenemase-producing Klebsiella pneumoniae (CP-Kpn) are a major concern for nosocomial infections. We previously reported an intensive care unit (ICU) outbreak of CP-Kpn. This study investigated the transmission pattern and genetic characteristic of CP-Kpn in the hospital during the outbreak period. Whole-genome sequencing was retrospectively performed on 173 CP-Kpn isolates. Pairwise single-nucleotide polymorphism (SNP) distances were calculated to determine SNP thresholds for clustering. Plasmids and mobile genome elements (MGEs) were identified through short- and long-read sequencing. Strains were classified into three groups, sequence type 11 (ST11) (86.12%), ST15 (9.83%), and other ST. An SNP threshold of 16 revealed a 66.47% clustering rate. ICU admission and meropenem use proportions were significantly higher in clustered patients than in unique patients. MGE distribution was consistent with the phylogenetic tree. Of the isolates, 53.18% were CP-Kpn with hypervirulence genes. We identified five plasmids carrying virulence genes, and four of them have not been previously reported. Clonal transmission was the main cause of CP-Kpn infections in the hospital. Multidrug resistance genes and MGE variations were correlated with clustering. Finally, four novel plasmids carrying virulence genes were identified. The findings highlight the control of CR-Kpn transmission through prevention measures to reduce nosocomial infections. IMPORTANCE In this study, we combined genomic and epidemiological analyses and defined an optimal cutoff value for SNP difference that could be used to aid investigation in tertiary hospital in China. We revealed clonal transmission was the main cause of CP-Kpn infections in the hospital and identified four novel plasmids carrying virulence genes. Our results strongly suggested that dominant CP K. pneumoniae strains lead to outbreaks and described different evolutionary patterns of plasmids carrying multidrug resistance and virulence genes.

3.
Neuron ; 110(9): 1483-1497.e7, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35263617

RESUMO

Vesicular transporters (VTs) define the type of neurotransmitter that synaptic vesicles (SVs) store and release. While certain mammalian neurons release multiple transmitters, it is not clear whether the release occurs from the same or distinct vesicle pools at the synapse. Using quantitative single-vesicle imaging, we show that a vast majority of SVs in the rodent brain contain only one type of VT, indicating specificity for a single neurotransmitter. Interestingly, SVs containing dual transporters are highly diverse (27 types) but small in proportion (2% of all SVs), excluding the largest pool that carries VGLUT1 and ZnT3 (34%). Using VGLUT1-ZnT3 SVs, we demonstrate that the transporter colocalization influences the SV content and synaptic quantal size. Thus, the presence of diverse transporters on the same vesicle is bona fide, and depending on the VT types, this may act to regulate neurotransmitter type, content, and release in space and time.


Assuntos
Proteínas de Transporte de Neurotransmissores , Vesículas Sinápticas , Animais , Mamíferos , Proteínas de Membrana Transportadoras , Neurotransmissores , Sinapses , Vesículas Sinápticas/fisiologia , Proteína Vesicular 1 de Transporte de Glutamato
4.
BMJ Open ; 11(8): e048891, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452962

RESUMO

INTRODUCTION: Chronic heart failure (CHF) is a common disease worldwide, and imposes a substantial burden to the healthcare system. In CHF, limited exercise capacity and affected mental well-being leads to a reduced quality of life (QOL). How to improve the QOL and exercise endurance is critical for patients with CHF. Exercise therapy, such as some traditional Asian exercises (TAEs) including Taichi, Baduanjin and Yoga, plays an important role in the rehabilitation of patients with CHF. TAE is suitable for the rehabilitation of patients with CHF because of its soft movements and can relax the body and mind. Studies have shown that TAE can regulate the overall health status of the body and exercise tolerance, improve QOL and reduce rehospitalisation rate in patients with CHF. However, the difference in efficacy of TAE in patients with CHF is not yet clear. The main purpose of this study is to conduct a network meta-analysis (NMA) of randomised trials to determine the impact of TAE on patients with CHF of different types, different causes and different New York Heart Association (NYHA) heart function classifications and to provide references for different types of patients with CHF to choose appropriate exercise rehabilitation therapy. METHODS AND ANALYSIS: The literature search will be retrieved from PubMed, the Cochrane Library, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang database, Chinese biomedical literature service system (SinoMed) and Chinese Scientific Journals Database (VIP) from the date of their inception until 1 August 2021. All randomised controlled trials that evaluated the effects of three different TAE therapies (Taichi, Baduanjin and Yoga) on patients with CHF will be included. The primary outcomes are peak oxygen uptake (peak VO2), exercise capacity (6-min walking distance) and QOL tested with the Minnesota Living with Heart Failure Questionnaire. Secondary outcomes include the levels of N-terminal pro brain natriuretic peptide, left ventricular ejection fraction, systolic blood pressure and diastolic blood pressure. For included articles, two reviewers will independently extract the data, and Cochrane Collaboration's tool will be used to assess risk of bias. We will perform the Bayesian NMA to pool all treatment effects. The ranking probabilities for the optimal intervention of various treatments (Taichi, Baduanjin or Yoga) will be estimated by the mean ranks and surface under the cumulative ranking curve. Subgroup analysis for different types, different causes and different NYHA heart function classifications of CHF will be performed. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence contributing to each network estimate. ETHICS AND DISSEMINATION: The results will be disseminated through peer-reviewed publications. They will provide useful information to inform clinicians on the potential functions of TAE in CHF, and to provide consolidated evidence for clinical practice and further research of TAE. PROSPERO REGISTRATION NUMBER: CRD42020179304.


Assuntos
Insuficiência Cardíaca , Meditação , Teorema de Bayes , Insuficiência Cardíaca/terapia , Humanos , Metanálise como Assunto , Metanálise em Rede , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Volume Sistólico , Função Ventricular Esquerda
5.
Front Cardiovasc Med ; 8: 792592, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35252368

RESUMO

Percutaneous coronary intervention (PCI) is one of the most effective reperfusion strategies for acute myocardial infarction (AMI) despite myocardial ischemia/reperfusion (I/R) injury, causing one of the causes of most cardiomyocyte injuries and deaths. The pathological processes of myocardial I/R injury include apoptosis, autophagy, and irreversible cell death caused by calcium overload, oxidative stress, and inflammation. Eventually, myocardial I/R injury causes a spike of further cardiomyocyte injury that contributes to final infarct size (IS) and bound with hospitalization of heart failure as well as all-cause mortality within the following 12 months. Therefore, the addition of adjuvant intervention to improve myocardial salvage and cardiac function calls for further investigation. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in Chinese herbal medicine. Great effort has been put into phytochemicals because they are often in line with the expectations to improve myocardial I/R injury without compromising the clinical efficacy or to even produce synergy. We summarized the previous efforts, briefly outlined the mechanism of myocardial I/R injury, and focused on exploring the cardioprotective effects and potential mechanisms of all phytochemical types that have been investigated under myocardial I/R injury. Phytochemicals deserve to be utilized as promising therapeutic candidates for further development and research on combating myocardial I/R injury. Nevertheless, more studies are needed to provide a better understanding of the mechanism of myocardial I/R injury treatment using phytochemicals and possible side effects associated with this approach.

6.
Emerg Microbes Infect ; 9(1): 1864-1868, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32757712

RESUMO

Infective endocarditis caused by Neisseria macacae in humans is extremely rare. We presented here a case of N. macacae infective endocarditis in a 61-year-old man with a native aortic valve infection. N. macacae was isolated from blood culture and was detected by nanopore-based metagenomic sequencing in the vegetations. Finally, the patient recovered completely after surgery and antibiotic therapy.


Assuntos
Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/terapia , Neisseria/isolamento & purificação , Análise de Sequência de DNA/métodos , Antibacterianos/uso terapêutico , Hemocultura , Endocardite Bacteriana/sangue , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Sequenciamento por Nanoporos , Neisseria/genética , Neisseria/crescimento & desenvolvimento , Resultado do Tratamento
7.
Proc Natl Acad Sci U S A ; 117(24): 13468-13479, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32467162

RESUMO

The functions of nervous and neuroendocrine systems rely on fast and tightly regulated release of neurotransmitters stored in secretory vesicles through SNARE-mediated exocytosis. Few proteins, including tomosyn (STXBP5) and amisyn (STXBP6), were proposed to negatively regulate exocytosis. Little is known about amisyn, a 24-kDa brain-enriched protein with a SNARE motif. We report here that full-length amisyn forms a stable SNARE complex with syntaxin-1 and SNAP-25 through its C-terminal SNARE motif and competes with synaptobrevin-2/VAMP2 for the SNARE-complex assembly. Furthermore, amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane of neurosecretory cells by binding to phospholipid PI(4,5)P2 However, unlike synaptrobrevin-2, the SNARE motif of amisyn is not sufficient to account for the role of amisyn in exocytosis: Both the pleckstrin homology domain and the SNARE motif are needed for its inhibitory function. Mechanistically, amisyn interferes with the priming of secretory vesicles and the sizes of releasable vesicle pools, but not vesicle fusion properties. Our biochemical and functional analyses of this vertebrate-specific protein unveil key aspects of negative regulation of exocytosis.


Assuntos
Exocitose , Fosfatidilinositol 4,5-Difosfato/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Membrana Celular/metabolismo , Células Cultivadas , Células Cromafins/metabolismo , Humanos , Lipossomos/metabolismo , Fusão de Membrana , Células PC12 , Domínios de Homologia à Plecstrina , Ligação Proteica , Ratos , Proteínas SNARE/metabolismo , Proteína 25 Associada a Sinaptossoma/metabolismo , Sintaxina 1/metabolismo , Vertebrados , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
8.
J Antimicrob Chemother ; 75(4): 890-895, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003793

RESUMO

BACKGROUND: The pandemics caused by MDR Klebsiella pneumoniae are mostly due to the global dissemination of high-risk clonal complex 258 (CC258) and related IncF epidemic plasmids. However, the factors leading to the epidemiological advantages of CC258-IncF linkage remain obscure. The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) and CRISPR-associated protein (CRISPR-Cas) systems, providing adaptive immunity against invading DNA, play an important role in the interactions between plasmids and hosts. OBJECTIVES: To investigate the relationship between CRISPR-Cas systems and the high-risk linkage CC258-IncF. METHODS: CRISPR-Cas loci were detected among 381 collected K. pneumoniae clinical isolates and 207 K. pneumoniae complete genomes available in GenBank. MLST was used to determine the genetic relatedness of these isolates. Nucleotide BLAST was used to search for protospacers on K. pneumoniae plasmids. RESULTS: We observed an epidemic correlation between CRISPR-Cas loci, CC258 and IncF plasmids. Interestingly, most type I-E CRISPR-Cas systems identified carried spacers matching the backbone regions of IncF plasmids. CONCLUSIONS: Our results suggest that the absence of type I-E CRISPR-Cas systems in K. pneumoniae CC258 is strongly associated with the dissemination of IncF epidemic plasmids, contributing to the global success of the international high-risk linkage CC258-IncF. Our findings provide new information regarding the dissemination and evolution of the high-risk linkage of K. pneumoniae CC258-IncF and pave the way for new strategies to address the problem of antibiotic resistance.


Assuntos
Epidemias , Klebsiella pneumoniae , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Klebsiella pneumoniae/genética , Tipagem de Sequências Multilocus , Plasmídeos/genética
9.
Influenza Other Respir Viruses ; 14(2): 142-149, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31786832

RESUMO

BACKGROUND: In this study, we evaluated the diagnostic potential and clinical impact of an automated multiplex PCR platform (the FilmArray Respiratory Panel; FA-RP), specially designed for pathogen detection in respiratory tract infections in adults with unexplained pneumonia (UP). METHODS: A total of 112 UP patients in Shanghai, China, were enrolled prospectively and assessed using the FA-RP from October 2016 to March 2018. We examined the test results and their influence on clinical decisions. Furthermore, as a control group, we retrospectively obtained the clinical data of 70 UP patients between October 2014 and March 2016 (before the FA-RP was available). The two patient groups were compared with respect to factors, including general antimicrobial use and defined daily dose (DDD) numbers. RESULTS: Between October 2016 and March 2018, the positive rate obtained using FA-RP for UP was 76.8%. The primary pathogens in adults with UP were Influenza A/B (47.3%, 53/112). Compared with the patients before FA-RP was available, patients who underwent FA-RP testing had higher rates of antiviral drug use and antibiotic de-escalation during clinical treatment. FA-RP significantly decreased the total DDDs of antibiotic or antifungal drugs DDDs by 7 days after admission (10.6 ± 2.5 vs 14.1 ± 8.8, P < .01). CONCLUSIONS: The FA-RP is a rapid and sensitive nucleic acid amplification test method for UP diagnosis in adults. The application of FA-RP may lead to a more accurately targeted antimicrobial treatment and reduced use of antibiotic/antifungal drugs.


Assuntos
Reação em Cadeia da Polimerase Multiplex/métodos , Pneumonia/virologia , Infecções Respiratórias/diagnóstico , Adulto , Idoso , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , China , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/métodos , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , RNA Viral/genética , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Vírus/genética , Vírus/isolamento & purificação
10.
Front Cell Infect Microbiol ; 10: 567615, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33585263

RESUMO

Pulmonary infections are among the most common and important infectious diseases due to their high morbidity and mortality, especially in older and immunocompromised individuals. However, due to the limitations in sensitivity and the long turn-around time (TAT) of conventional diagnostic methods, pathogen detection and identification methods for pulmonary infection with greater diagnostic efficiency are urgently needed. In recent years, unbiased metagenomic next generation sequencing (mNGS) has been widely used to detect different types of infectious pathogens, and is especially useful for the detection of rare and newly emergent pathogens, showing better diagnostic performance than traditional methods. There has been limited research exploring the application of mNGS for the diagnosis of pulmonary infections. In this study we evaluated the diagnostic efficiency and clinical impact of mNGS on pulmonary infections. A total of 100 respiratory samples were collected from patients diagnosed with pulmonary infection in Shanghai, China. Conventional methods, including culture and standard polymerase chain reaction (PCR) panel analysis for respiratory tract viruses, and mNGS were used for the pathogen detection in respiratory samples. The difference in the diagnostic yield between conventional methods and mNGS demonstrated that mNGS had higher sensitivity than traditional culture for the detection of pathogenic bacteria and fungi (95% vs 54%; p<0.001). Although mNGS had lower sensitivity than PCR for diagnosing viral infections, it identified 14 viral species that were not detected using conventional methods, including multiple subtypes of human herpesvirus. mNGS detected viruses with a genome coverage >95% and a sequencing depth >100× and provided reliable phylogenetic and epidemiological information. mNGS offered extra benefits, including a shorter TAT. As a complementary approach to conventional methods, mNGS could help improving the identification of respiratory infection agents. We recommend the timely use of mNGS when infection of mixed or rare pathogens is suspected, especially in immunocompromised individuals and or individuals with severe conditions that require urgent treatment.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica , Idoso , China , Humanos , Filogenia , Sensibilidade e Especificidade
11.
Artigo em Inglês | MEDLINE | ID: mdl-31440476

RESUMO

The presence of carbapenem-producing Klebsiella pneumoniae (CP-Kp) is a serious threat to the control of nosocomial infections. Plasmid-mediated horizontal transfer of the resistance gene makes it difficult to control hospital-acquired CP- Kp infections. Nine CP- Kp strains were isolated during an outbreak in the intensive care unit of Shanghai Huashan hospital in east China. We conducted a retrospective study to identify the origin and route of transmission of this CP-Kp outbreak. Whole-genome sequencing (WGS) analysis was performed on 9 clinical isolates obtained from 8 patients, and the results were compared to clinical and epidemiological records. All isolates were ST11 CP-Kp. Single-nucleotide polymorphisms and the presence and structure of plasmids indicated that this CP-Kp outbreak had different origins. These 9 isolates were partitioned into two clades according to genetic distance. Four plasmids, CP002474.1, CP006799.1, CP018455.1, and CP025459.1, were detected among the 9 isolates. The plasmid phylogeny and antibiotic resistance (AR) gene profile results were consistent with the sequencing results. We found that two clades of CP-Kp were responsible for this nosocomial outbreak and demonstrated the transmission route from two index patients. Plasmid carriage and phylogeny are a useful tool for identifying clades involved in disease transmission.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos/classificação , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Farmacorresistência Bacteriana , Infecções por Klebsiella/epidemiologia , Klebsiella pneumoniae/classificação , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , China/epidemiologia , Infecção Hospitalar/microbiologia , Feminino , Genótipo , Hospitais , Humanos , Unidades de Terapia Intensiva , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Tipagem Molecular , Filogenia , Plasmídeos/análise , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos
12.
Biochem Biophys Res Commun ; 517(2): 297-302, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31353087

RESUMO

The electrical membrane potential (Vm) is a key dynamical variable of excitable membranes. Despite the tremendous success of optogenetic methods to modulate Vm with light, there are some shortcomings, such as the need of genetic manipulation and limited time resolution. Direct optical stimulation of gold nanoparticles targeted to cells is an attractive alternative because the absorbed energy heats the membrane and, thus, generates capacitive current sufficient to trigger action potentials [1, Carvalho-de-Souza et al., 2015]. However, focused laser light is required and precise location and binding of the nanoparticles cannot be assessed with a conventional microscope. We therefore examined a complementary method to manipulate Vm in a spatio-temporal fashion by non-focused visible flashlight stimulation (Xenon discharge lamp, 385-485 nm, ∼500 µs) of superparamagnetic microbeads. Flashlight stimulation of single beads targeted to cells resulted in transient inward currents under whole-cell patch-clamp control. The waveform of the current reflected the first time derivative of the local temperature induced by the absorbed light and subsequent heat dissipation. The maximal peak current as well as the temperature excursion scaled with the proximity to the plasma membrane. Transient illumination of light-absorbing beads, targeted to specific cellular sites via protein-protein interaction or direct micromanipulation, may provide means of rapid and spatially confined heating and electrical cell stimulation.


Assuntos
Iluminação/instrumentação , Imãs/química , Potenciais da Membrana/efeitos da radiação , Células HEK293 , Humanos , Luz , Técnicas de Patch-Clamp , Temperatura
13.
Ann Clin Microbiol Antimicrob ; 18(1): 15, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922382

RESUMO

BACKGROUND: Prosthetic valve endocarditis (PVE) is a rare but severe complication of valve replacement surgery, with an incidence rate of 0.3-1.2% per patient-year. At present, staphylococci are the predominant causative microorganism of PVE. Herein, we report a confirmed case of late PVE in a mechanical aortic valve caused by Mycobacterium tuberculosis. CASE PRESENTATION: A 32-year-old immunocompetent man with recurrent fever and 5-kg weight loss had a history of having undergone the Bentall procedure due to congenital heart disease. Nine years after the operation, he developed a paravalvular abscess in the mechanical aortic valve, presented with evidence of pulmonary tuberculosis on CT scan and was diagnosed with tuberculous endocarditis. This case report highlights a rare and non-negligible example of tuberculous endocarditis involving a mechanical valve. CONCLUSIONS: Tuberculous PVE should be considered in patients with a history of valve replacement, recurrent fever, unexplained weight loss, pulmonary tuberculosis and meaningful valvular findings on echocardiogram.


Assuntos
Valva Aórtica/cirurgia , Endocardite Bacteriana/microbiologia , Cardiopatias/cirurgia , Próteses Valvulares Cardíacas/microbiologia , Mycobacterium tuberculosis/fisiologia , Complicações Pós-Operatórias/microbiologia , Adulto , Valva Aórtica/diagnóstico por imagem , Endocardite Bacteriana/diagnóstico por imagem , Cardiopatias/congênito , Cardiopatias/diagnóstico por imagem , Próteses Valvulares Cardíacas/efeitos adversos , Humanos , Masculino , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
14.
J Transl Med ; 16(1): 206, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30029650

RESUMO

BACKGROUND: The early and accurate diagnosis of tuberculosis (TB) is critical for controlling the global TB epidemic. Although early studies have supported the potential role of cytokine biomarkers in blood for the diagnosis of TB, this method requires further investigation and validation in different populations. A set of biomarkers that can discriminate between active TB (ATB) and latent TB infection (LTBI) remains elusive. METHODS: In the current study, we organized two retrospective cohorts and one prospective cohort to investigate the immune responses at different clinical stages of TB infection, as determined by candidate cytokine biomarkers detected with a multiplex cytokine platform. Using a pre-established diagnostic algorithm, participants were classified as ATB, LTBI, and TB uninfected controls (CON). Based on our multiplex cytokine assay, a multi-cytokine biosignature was modelled for the optimal recognition of the different TB infection status. RESULTS: Our analysis identified a six-cytokine biosignature of TB-antigen stimulated IFN-γ, IP-10, and IL-1Ra, and unstimulated IP-10, VEGF, and IL-12 (p70) for a biomarker screening group (n = 88). The diagnostic performance of the biosignature was then validated using a biomarker validation cohort (n = 216) and resulted in a sensitivity of 88.2% and a specificity of 92.1%. In a prospectively recruited clinical validation cohort (n = 194), the six-cytokine biosignature was further evaluated, and displayed a sensitivity of 85.7%, a specificity of 91.3% and an overall accuracy of 88.7%. CONCLUSIONS: We have identified a six-cytokine biosignature for accurately differentiating ATB patients from subjects with LTBI and CON. This approach holds promise as an early and rapid diagnostic test for ATB.


Assuntos
Citocinas/sangue , Tuberculose Latente/sangue , Tuberculose Latente/diagnóstico , Programas de Rastreamento , Adulto , Idoso , Antígenos/metabolismo , Biomarcadores , Estudos de Coortes , Árvores de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
15.
BMC Gastroenterol ; 18(1): 45, 2018 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-29625557

RESUMO

BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment. CASE PRESENTATION: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 µmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range. CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.


Assuntos
Acidose Láctica/induzido quimicamente , Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Rabdomiólise/induzido quimicamente , Tenofovir/efeitos adversos , Timidina/análogos & derivados , Antivirais/uso terapêutico , DNA Polimerase gama/antagonistas & inibidores , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Telbivudina , Tenofovir/uso terapêutico , Timidina/efeitos adversos , Timidina/uso terapêutico
16.
Artigo em Inglês | MEDLINE | ID: mdl-29527517

RESUMO

Klebsiella pneumoniae bacteremia biofilm traits and distribution characteristics have not been clarified. This study aimed to determine the prevalence and characteristics of K. pneumoniae bacteremia biofilm formation (BF) and to explore the virulence factors associated with K. pneumoniae BF. A total of 250 K. pneumoniae bacteremia isolates were collected from patients in Shenzhen and Shanghai, China. Virulence genes in their genomes were detected by PCR. The isolates were subjected to multilocus sequence typing (MLST) and clonal complex (CC) classification based on housekeeping genes. Biofilms were detected by crystal violet staining. Greater BF was observed in isolates from young adults (<40 years old) than in those from seniors (≥65 years old; P = 0.002). MLST yielded 65 different sequence types (STs), with the most represented STs being ST11, ST23, and ST65, and the main CCs were CC23 and CC65; CC23 isolates exhibited greater BF than CC65 or ST11 isolates (both P < 0.001). BF was more pronounced among magA(K1), aero+, rmpA+, rmpA2+, allS+, wcaG+, and iutA+ isolates than in isolates that were negative for these virulence factors. Multivariate regression analysis revealed only wcaG as an independent risk factor for BF (odds ratio 11.426, P < 0.001), and BF was decreased when wcaG was silenced by antisense RNA. In conclusion, BF in K. pneumoniae bacteremia isolates was found to be associated with CC23 classification and the presence of the wcaG virulence factor gene.


Assuntos
Bacteriemia/microbiologia , Biofilmes , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/fisiologia , Fatores de Virulência/genética , Adulto , Antibacterianos/farmacologia , Feminino , Inativação Gênica , Humanos , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Virulência/genética , Fatores de Virulência/metabolismo , Adulto Jovem
17.
Int J Infect Dis ; 70: 1-9, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29410147

RESUMO

OBJECTIVES: The serological antibody detection tests offer several advantages for the rapid diagnosis of tuberculosis (TB). The Mycobacterium tuberculosis-specific antibody responses associated with different stages of TB infection remain to be investigated. METHODS: The Pathozyme-Myco IgG (Myco G), Pathozyme TB Complex Plus (TB Complex), IBL M. tuberculosis IgG ELISA (IBL), Anda Biologicals TB IgG (Anda-TB), and T-SPOT.TB (T-SPOT) tests were performed for 133 active TB patients (ATB group), 131 controls (CON group), and 95 subjects with latent TB infection (LTBI group). RESULTS: The four serological tests all showed relatively low sensitivity in the ATB group but high specificity in the LTBI and CON groups. The antibody levels of the four serological tests were significantly higher in the ATB group than in the LTBI group. The same trend was observed between the LTBI and CON groups. The four serological tests demonstrated potential diagnostic value in discriminating ATB from LTBI. A combination of the Anda-TB and TB Complex tests exhibited the best diagnostic potential in discriminating ATB from LTBI, with a sensitivity of 89.4% and a specificity of 94.7%. Further, the diagnostic value of Anda-TB and TB Complex were validated in a prospective cohort including 106 patients with suspected ATB. Combined with the T-SPOT test, the tests showed a sensitivity of 87.2% and a specificity of 92.5% for discriminating ATB patients from all ATB suspected cases in the validation group. CONCLUSIONS: The antibody responses of the serological tests all showed significant differences between the ATB and LTBI groups. A combination of Anda-TB and the TB Complex test demonstrated high diagnostic potential in discriminating ATB from LTBI and may be an additional diagnostic tool in the diagnosis of M. tuberculosis infection.


Assuntos
Anticorpos Antibacterianos/imunologia , Especificidade de Anticorpos , Mycobacterium tuberculosis/imunologia , Testes Sorológicos , Tuberculose/diagnóstico , Tuberculose/imunologia , Latência Viral/imunologia , Adulto , Idoso , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Teste Tuberculínico , Tuberculose/fisiopatologia
18.
Biomed Res Int ; 2018: 4902941, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30687747

RESUMO

Objective: Nontuberculous mycobacteria (NTM) cause various diseases in humans and animals. Recently, the prevalence of NTM-related disease has been on the rise, becoming an emerging public health problem. The aim of this study was to determine the antibiotic susceptibility profiles of clinical isolates of Mycobacterium abscessus and Mycobacterium fortuitum. Methods. We performed susceptibility tests on 37 clinical NTM isolates to 30 antibiotics with the microdilution method recommended by the Clinical and Laboratory Standards Institute. Results: Both M. abscessus and M. fortuitum were highly resistant to antitubercular drugs such as isoniazid, rifampin, ethambutol, clofazimine, ethionamide, and rifabutin. M. abscessus showed the lowest resistant rates to cefoxitin (10%), azithromycin (10%), amikacin (10%), and clarithromycin (20%) and very high resistant to sulfamethoxazole, vancomycin, oxacillin, clindamycin, and all fluoroquinolones. M. fortuitum showed low resistance to tigecycline (0%), tetracycline (0%), cefmetazole (12%), imipenem (12%), linezolid (18%), and the aminoglycosides amikacin (0%), tobramycin (0%), neomycin (0%), and gentamycin (24%). Conclusion: Amikacin, cefoxitin, and azithromycin have the highest in vitro activity against M. abscessus. Isolates of M. fortuitum need to be individually evaluated for drug susceptibility before choosing an effective antimicrobial regimen for treatment of infections.


Assuntos
Antibacterianos/farmacologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium fortuitum/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana
19.
PLoS One ; 12(2): e0171339, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28152085

RESUMO

The global emergence of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae poses a major public health threat requiring immediate and aggressive action. Some older generation antibiotics, such as trimethoprim, serve as alternatives for treatment of infections. Here, we determined the complete nucleotide sequence of plasmid pHS091147, which co-harbored the carbapenemase (blaKPC-2) and trimethoprim resistance genes (dfrA25) from a Klebsiella pneumoniae sequence type (ST) 11 clone recovered in Shanghai, China. pHS091147 had three replication genes, several plasmid-stability genes and an intact type IV secretion system gene cluster. Besides blaKPC-2 and dfrA25, pHS091147 carried several other resistance genes, including ß-lactamase genes blaTEM-1 and blaCTX-M-14, sulphonamide resistance gene sul1, a quinolone resistance gene remnant (ΔqnrB2), and virulence associated gene iroN. Notably, the multidrug-resistance region was a chimeric structure composed of three subregions, which shared strong sequence homology with several plasmids previously assigned in Genbank. To our knowledge, this is the first report of the co-localization of blaKPC-2 and dfrA25 on a novel putative multi-replicon plasmid in a Klebsiella pneumoniae ST11 clone.


Assuntos
Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/genética , Plasmídeos/genética , Resistência a Trimetoprima/genética , Trimetoprima/farmacologia , Resistência beta-Lactâmica/genética , China/epidemiologia , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Filogenia , Replicon/genética
20.
Emerg Microbes Infect ; 5: e12, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26905025

RESUMO

Moxifloxacin (MOX) and gatifloxacin (GAT) have exhibited promising mycobactericidal activity, and a number of clinical trials have been conducted in recent decades to compare the treatment efficacy of MOX-containing and/or GAT-containing regimens with the standard regimen. The aim of this meta-analysis for clinical trials of MOX- or GAT-containing regimens was to evaluate their treatment efficacy and safety in initial therapy for drug-sensitive tuberculosis (TB). Databases were searched for randomized controlled trials, and nine studies with 6980 patients were included. We found that fluoroquinolone substitution for isoniazid or ethambutol in short-course regimens might result in more frequent unfavorable treatment outcomes compared with the standard regimen-in particular, an increased incidence of relapse. In a per-protocol analysis, MOX-containing regimens had slightly higher rates of sputum culture conversion at two months than the standard regimen (RR 1.08, 95% CI 1.04-1.11, P <0.001); there was no significant difference in the rate of sputum conversion between the GAT-containing regimens and the standard regimen (RR 1.13, 95% CI 0.96-1.33, P = 0.13). There were no significant differences in the incidence of death from any cause, including TB, nor were there serious adverse events between the MOX- or GAT-containing regimens and the standard regimen. In conclusion, MOX or GAT might not have the ability to shorten treatment duration in the initial therapy for tuberculosis despite the non-inferiority or even slightly better efficacy in the early phase of treatment compared with the standard regimen. Furthermore, it is safe to include MOX or GAT in initial TB treatment.


Assuntos
Antituberculosos/uso terapêutico , Fluoroquinolonas/uso terapêutico , Tuberculose/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Quimioterapia Combinada , Feminino , Fluoroquinolonas/efeitos adversos , Gatifloxacina , Humanos , Masculino , Moxifloxacina , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Tuberculose/mortalidade , Tuberculose/enfermagem
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