AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation.

AMP-activated protein kinase (AMPK) is a metabolic sensor in mammals that is activated when ATP levels in the cell decrease. AMPK is a heterotrimeric protein that comprises 3 subunits, each of which has multiple phosphorylation sites that play critical roles in the regulation of either anabolism or catabolism by directly phosphorylating proteins or modulating gene transcription in multiple pathways, such as synthesis, oxidation and lipolysis of lipid. Research focused on the phosphorylation sites that are involved in lipid metabolism will lead to a better recognition of the role of AMPK in therapeutics for several common diseases. In this review, close attention is paid to the recent research on the structure, and multisite phosphorylation of AMPK subunits, as well as AMPK regulation of lipid metabolism via phosphorylation of related molecules.

Erratum to rhinovirus is associated with severe adult community-acquired pneumonia in China.

[This corrects the article DOI: 10.21037/jtd.2017.10.107.].

Rhinovirus is associated with severe adult community-acquired pneumonia in China.

BACKGROUND: Human rhinovirus (HRV) is one of the most common viral etiologies detected in community-acquired pneumonia (CAP) adult cases. However, few is known about the characteristics of HRV-associated CAP. To describe the clinical features of HRV-associated CAP in immunocompetent adults admitted to multiple medical centers in mainland China over a 2-year period. METHODS: A total of 383 patients admitted to hospitals for CAP were enrolled from 46 medical centers in mainland China between January 2013 and December 2014. Multiplex real-time polymerase chain reaction (RT-PCR) assays for viral detection and DNA-based quantitative loop-mediated isothermal amplification (qLAMP) assays for bacterial detection were implemented to all lower respiratory tract specimens obtained from the patients. Twenty-eight cases (28/383, 7.3%) revealed HRV-positive PCR results. Patients with bronchoalveolar lavage (BAL) HRV-positive PCR results (n=20) were further enrolled and divided into two groups depending on the status of bacterial co-infection (viral group, n=12; viral-Bacterial group, n=8). Demographic, clinical and microbiological data were reviewed and compared in detail. RESULTS: Cases with HRV-infection were remarkably correlated with respiratory failure (14/20) and most of them (13/14) received mechanical ventilation. Fever (17/20), productive cough (15/20) and dyspnea (6/20) were common symptoms while flu-like symptoms were rarely observed in the cohort. Streptococcus pneumoniae (3/8), Klebsiella pneumoniae (3/8) and Mycoplasma pneumoniae (2/8) were most frequently identified bacterium in the viral-bacterial group. Compared with the viral group, higher incidence of septic shock (3/8 vs. 1/12, P=0.255), longer ICU length of stay (LOS) (10.0 vs. 6.5 days, P=0.686), longer hospital LOS (18.5 vs. 13.0 days, P=0.208) and higher 28-day mortality (2/8 vs. 2/12, P=1) were observed in the Viral-Bacterial group, although without statistically significant difference. CONCLUSIONS: HRV is a common etiology in CAP among China adults, especially in severe CAP. Clinicians should be vigilant considering of the poor outcome. Highly qualified multiplex PCR techniques with invasive sampling are needed to increase the detection rate.

A randomized, open, multicenter clinical study on the short course of intravenous infusion of 750 mg of levofloxacin and the sequential standard course of intravenous infusion/oral administration of 500 mg of levofloxacin for treatment of community-acquired pneumonia.

BACKGROUND: To compare 5-day regimen of levofloxacin 750 mg IV daily with 7-14-day conventional regimen of levofloxacin 500 mg intravenous to oral (IV/PO) daily for treatment of community-acquired pneumonia (CAP) in Chinese population. METHODS: This was a non-inferiority study to assess the difference of clinical efficacy at the end of treatment (EOT) between two regimens. Adult CAP patients with CURB-65 score 0-2 were enrolled from 17 hospitals in China from November 2012 to July 2014. The subjects were randomized into levofloxacin 750 or 500 mg group and the clinical data were collected. Sputum and blood specimens were sent for bacterial culture. The urinary antigen of Streptococcus pneumoniae (S. pneumoniae) was detected as well. At EOT, the clinical efficacy (primary endpoint), microbiological efficacy and safety were evaluated. RESULTS: A total of 457 patients were enrolled. Intent-to-treat (ITT) for primary endpoint analysis and per-protocol set (PPS) populations were 448 and 427 patients respectively. The therapeutic durations were 4.86 and 10.35 days and the mean drug exposure was 3,641.4 and 5,169.6 mg in 750 and 500 mg groups respectively. The clinical efficacy rate was 91.40% (202/221) in 750 mg group and 94.27% (214/227) in 500 mg group (ITT, P=0.2449). The difference in clinical efficacy rate was -2.87 (95% CI: -7.64, 1.90) between the two groups. The non-inferiority hypothesis of two groups was tenable (Δ=10%). The bacterial eradication rate was 100.00% in both groups. The most common drug-related clinical adverse events were injection site and gastrointestinal reactions. The most common drug-related laboratory abnormalities were WBC decrease and ALT/AST elevation. No statistical difference was found between two groups (P>0.05). CONCLUSIONS: The 5-day regimen of levofloxacin 750 mg daily is non-inferior to 7-14-day conventional regimen of 500 mg daily in clinical efficacy for treatment of mild to moderate Chinese CAP population. The short course regimen allows the reduction of antimicrobial drug exposure and is well tolerated.

The link between mold sensitivity and asthma severity in a cohort of northern Chinese patients.

BACKGROUND: Mold sensitivity in asthmatic patients has recently attracted clinical interest; however the links between mold sensitivity and asthma severity in the Chinese population have been poorly characterized. In this study, we assess the relationship between asthma severity and airborne mold sensitivity in a cohort of northern Chinese patients. METHODS: Ninety-three non-smoking adult outpatients with asthma completed a questionnaire and underwent skin prick testing with five aeroallergens. For all patients, eosinophil cell counts, total serum IgE (sIgE) levels, and pulmonary function were measured. An asthma severity score was calculated based on the patient's forced expiratory volume in one second (FEV1), number of asthma attacks, number of hospital admissions, and use of inhaled or oral corticosteroids in the past year. RESULTS: Ninety-three patients were divided into three groups based on the results of their allergy tests: negative results for all tested allergens (group A, n=32); positive reactions to aeroallergens including mold antigens (group B, n=41); and positive reactions to aeroallergens other than molds (group C, n=20). Patients in group B had a lower FEV1 (74.46%±23.09% predicted) compared with group A (85.52%±19.53%, P=0.023). Patients in both group B and C had elevated absolute eosinophil count (AEC) (group A: 3.12%±2.71%, group B: 5.41%±2.85%, group C: 6.1%±4.49%; group A vs. group B, P=0.008; group A vs. group C, P=0.002), and total sIgE values (group A: 117.36±144.90 IU/mL, group B: 195.86±155.87 IU/mL, group C: 253.31±152.41 IU/mL; group A vs. group B, P=0.031; group A vs. group C, P=0.002) compared with patients in group A. Asthma severity scores were higher in patients in group B compared to patients in group C (7 vs. 5.5, P<0.05). Patients allergic to molds were more likely to have severe asthma [odds ratio 3.636, 95% confidence interval (CI): 1.394 to 9.484; for severe versus mild asthma, P<0.05]. There was no association between asthma severity and sensitisation to house mites or weeds. CONCLUSIONS: Mold sensitivity is positively correlated with asthma severity in our cohort of northern Chinese patients.

Pulmonary function abnormalities in adult patients with acute exacerbation of bronchiectasis: A retrospective risk factor analysis.

Lung function impairments, especially airflow obstruction, are important features during acute exacerbation in patients with bronchiectasis. Recognition of the risk factors associated with airflow obstruction is important in the management of these exacerbations. The medical records of adult patients admitted to the Peking University People's Hospital, Beijing, China, from 2004 to 2011 with a diagnosis of bronchiectasis were reviewed retrospectively. Univariate and multivariate analyses were used to evaluate the risk factors associated with airflow obstruction. Airflow obstruction was found in 55.6% of 156 patients hospitalized with acute exacerbation of bronchiectasis, and the risk factors associated with airflow obstruction included young age (≤14 years old) at diagnosis (odds ratio (OR) = 3.454, 95% confidence interval (CI) 1.709-6.982, p = 0.001) as well as the presence of chronic obstructive pulmonary disease (COPD; OR = 14.677, 95% CI 5.696-37.819, p = 0.001), asthma (OR = 3.063, 95% CI 1.403-6.690, p = 0.005), and wheezing on auscultation (OR = 3.279, 95% CI 1.495-7.194, p = 0.003). The C-reactive protein (13.9 mg/dl vs. 6.89 mg/dl, p = 0.005), partial pressure of arterial oxygen (66.7 ± 8.57 mmHg vs. 89.56 ± 12.80 mmHg, p < 0.001), and partial pressure of arterial carbon dioxide (40.52 ± 2.77 mmHg vs. 42.87 ± 5.39 mmHg, p = 0.02) profiles were different between patients with or without airflow obstruction. In addition, patients colonized with potential pathogenic microorganisms had a decreased diffusing capacity (56.0% vs. 64.7%, p = 0.04). Abnormal pulmonary function was common in hospitalized patients with bronchiectasis exacerbations. Airflow obstruction was correlated with the patient's age at diagnosis, as well as the presence of combined COPD and asthma, and wheezing on auscultation, which also resulted in more severe systemic inflammation and hypoxemia.

Etiologic diagnosis of lower respiratory tract bacterial infections using sputum samples and quantitative loop-mediated isothermal amplification.

UNLABELLED: Etiologic diagnoses of lower respiratory tract infections (LRTI) have been relying primarily on bacterial cultures that often fail to return useful results in time. Although DNA-based assays are more sensitive than bacterial cultures in detecting pathogens, the molecular results are often inconsistent and challenged by doubts on false positives, such as those due to system- and environment-derived contaminations. Here we report a nationwide cohort study on 2986 suspected LRTI patients across P. R. China. We compared the performance of a DNA-based assay qLAMP (quantitative Loop-mediated isothermal AMPlification) with that of standard bacterial cultures in detecting a panel of eight common respiratory bacterial pathogens from sputum samples. Our qLAMP assay detects the panel of pathogens in 1047(69.28%) patients from 1533 qualified patients at the end. We found that the bacterial titer quantified based on qLAMP is a predictor of probability that the bacterium in the sample can be detected in culture assay. The relatedness of the two assays fits a logistic regression curve. We used a piecewise linear function to define breakpoints where latent pathogen abruptly change its competitive relationship with others in the panel. These breakpoints, where pathogens start to propagate abnormally, are used as cutoffs to eliminate the influence of contaminations from normal flora. With help of the cutoffs derived from statistical analysis, we are able to identify causative pathogens in 750 (48.92%) patients from qualified patients. In conclusion, qLAMP is a reliable method in quantifying bacterial titer. Despite the fact that there are always latent bacteria contaminated in sputum samples, we can identify causative pathogens based on cutoffs derived from statistical analysis of competitive relationship. TRIAL REGISTRATION: ClinicalTrials.gov NCT00567827.

Preliminary molecular epidemiology of the Staphylococcus aureus in lower respiratory tract infections: a multicenter study in China.

BACKGROUND: Staphylococcus aureus (S. aureus) remains as an important microbial pathogen resulting in community and nosocomial acquired infections with significant morbidity and mortality. Few reports for S. aureus in lower respiratory tract infections (LRTIs) have been documented. The aim of this study was to explore the molecular epidemiology of S. aureus in LRTIs in China. METHODS: A multicenter study of the molecular epidemiology of S. aureus in LRTIs was conducted in 21 hospitals in Beijing, Shanghai and twelve other provinces from November 2007 to February 2009. All the collected S. aureus strains were classified as minimum inhibitory concentration (MIC), mecA gene, virulence genes Panton-Valentine Leukocidin (PVL) and γ-hemolysin (hlg), staphylococcal cassette chromosome mec (SCCmec) type, agr type, and Multilocus Sequence Typing (MLST). RESULTS: Totally, nine methicillin-sensitive S. aureus (MSSA) and 29 methicillin-resistant S. aureus (MRSA) strains were isolated after culture from a total of 2829 sputums or bronchoalveolar lavages. The majority of MRSA strains (22/29) had a MIC value of ≥ 512 µg/ml for cefoxitin. The mecA gene acting as the conservative gene was carried by all MRSA strains. PVL genes were detected in only one S. aureus strain (2.63%, 1/38). The hlg gene was detected in almost the all S. aureus (100% in MSSA and 96.56% in MRSA strains). About 75.86% of MRSA strains carried SCCmec III. Agr type 1 was predominant (78.95%) among the identified three agr types (agr types 1, 2, and 3). Totally, ten sequence type (ST) of S. aureus strains were detected. A new sequence type (ST1445) was found besides confirming ST239 as the major sequence type (60.53%). A dendrogram generated from our own MLST database showed all the bootstrap values ≤ 50%. CONCLUSION: Our preliminary epidemiology data show SCCmec III, ST239 and agr type 1 of S. aureus as the predominant strains in LRTIs in Mainland of China.

Drug-resistant genes carried by Acinetobacter baumanii isolated from patients with lower respiratory tract infection.

BACKGROUND: Acinetobacter baumanii (A. baumanii ) remains an important microbial pathogen resulting in nosocomial acquired infections with significant morbidity and mortality. The mechanism by which nosocomial bacteria, like A. baumanii, attain multidrug resistance to antibiotics is of considerable interest. The aim in this study was to investigate the spread status of antibiotic resistance genes, such as multiple ß-lactamase genes and aminoglycoside-modifying enzyme genes, from A. baumanii strains isolated from patients with lower respiratory tract infections (LRTIs). METHODS: Two thousand six hundred and ninety-eight sputum or the bronchoalveolar lavage samples from inpatients with LRTIs were collected in 21 hospitals in the mainland of China from November 2007 to February 2009. All samples were routinely inoculated. The isolated bacterial strains and their susceptibility were analyzed via VITEK-2 expert system. Several kinds of antibiotic resistant genes were further differentiated via polymerase chain reaction and sequencing methods. RESULTS: Totally, 39 A. baumanii strains were isolated from 2698 sputum or bronchoalveolar lavage samples. There was not only a high resistant rate of the isolated A. baumanii strains to ampicillin and first- and second-generation cephalosporins (94.87%, 100% and 97.44%, respectively), but also to the third-generation cephalosporins (ceftriaxone at 92.31%, ceftazidine at 51.28%) and imipenem (43.59%) as well. The lowest antibiotic resistance rate of 20.51% was found to amikacin. The OXA-23 gene was identified in 17 strains of A. baumanii, and the AmpC gene in 23 strains. The TEM-1 gene was carried in 15 strains. PER-1 and SHV-2 genes were detected in two different strains. Aminoglycoside-modifying enzyme gene aac-3-Ia was found in 23 strains, and the aac-6'-Ib gene in 19 strains. aac-3-Ia and aac-6'-Ib genes hibernated in three A. baumanii strains that showed no drug-resistant phenotype. CONCLUSIONS: A. baumanii can carry multiple drug-resistant genes at the same time and result in multi-drug resistance. Aminoglycoside-modifying enzyme genes could be hibernating in aminoglycoside sensitive strains without expressing their phenotype.

[Atypical pathogens in adult patients admitted with community-acquired pneumonia].

OBJECTIVE: To investigate the current status of atypical pathogen associated infections in community-acquired pneumonia (CAP) in adults, and their clinical attributes. METHODS: Clinical data, sputum specimens from acute phase, and paired sera from acute- and convalescent-phases of CAP in 153 adult patients were collected from May 2005 to May 2008 in multiple medical centers. Chlamydia pneumoniae (Cpn) IgG antibody, and Legionella pneumophila (LP) mixed IgG, IgA and IgM antibodies were determined by indirect immuno-fluorescent assay. Mycoplasma pneumoniae (Mpn) mixed IgG, IgA and IgM antibodies were determined by passive agglutination assay. All the sputum specimens were routinely cultured for bacterial isolation. RESULTS: Fifty-two (34%) out of the 153 cases were diagnosed as atypical CAP per the paired serum-antibody assay. Forty-seven of the 52 atypical CAP cases were infected by one atypical pathogen, 38 with Cpn, 4 with Mpn, and 5 with LP, while 5 out of the 52 atypical CAP cases were infected by 2 pathogens, Cpn and Mpnin 2, Cpn and LP in 3 cases. Eleven cases (21.2%) out of the 52 patients with atypical pneumonia were complicated with bacterial infection. Except peripheral white blood count was significant increased in the group of typical (bacterial only) pneumonia (WBC > 10 × 109)/L, P = 0.03), all the other clinical parameters did not show statistically significant difference between the typical and the atypical pneumonia groups. CONCLUSIONS: Our data suggest that Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila are common pathogens of adult CAP. Chlamydia pneumoniae might be the most frequent atypical pathogen associated with atypical CAP.

[Effects of injection of Huangqi injectio into Zusanli (ST 36) on immune function in the patient of schizophrenia].

OBJECTIVE: To study on effects of injection of Huangqi Injectio into Zusanli (ST 36) on the hospital infection and immune function in the patient of schizophrenia. METHODS: Thirty inpatients of chronic schizophrenia were treated with injection of Huangqi Injectio into bilateral Zusanli (ST 36), 2 mL each point, thrice each week, for 8 weeks. Relative immune indexes and the hospital infection were investigated. RESULTS: The hospital infection and the sub-infection were 4 cases (13.3%), 7 cases-times (23.3%) in the injection group; and 9 cases (15.0%), 19 cases-times (31.7%) in the control group, respectively, with no significant difference between the two groups (P>0.05). The drug-administration duration was 7.77 days/case and 11.87 days/case in the two groups, respectively (P<0.01). In the injection group, as compared with that of last 3 years the duration was 7.77 days/case and 14.08 days/case (P<0.01). IgG, IgA, IgM and T-cell subgroups did not have significant changes, but there was the most different value before and after injection in SIL-2R of the no-infection group, and the longer the drug administration duration, the smaller the different values. CONCLUSION: Injection of Huangqi Injectio into Zusanli (ST 36) has definite effect for prevention of the hospital infection in inpatients of chronic schizophrenia, and SIL-2R is a valuable index for investigation of the hospital of infection.

[The effect of murine interferon-gamma transgene expression on bleomycin-induced pulmonary fibrosis in mice].

OBJECTIVE: To investigate the effect of murine interferon-gamma (IFN-gamma) transgene expression on bleomycin-induced pulmonary fibrosis in mice. METHODS: 6 - 8 week aged pathogen-free male ICR mice were treated with bleomycin (3 mg/kg weight in 70 micro l) by intranasal instillation on day 0 in the model group. Adenoviral vector with murine IFN-gamma cDNA (AdCMVmIFN-gamma) 5 x 10(8) plague forming unit (pfu) was administrated via nastril instillation 48 h before bleomycin treatment in the preventive therapeutic group, but 72 h after bleomycin treatment in the therapeutic group. Mice treated with a same volume of normal saline (NS) and a same dosage of sham recombinant adenoviruses (AdCMVNull) served as controls. The animals were weighted on day 0, 7, 14, and sacrificed on day 14. Bronchial alveolar lavage fluid (BALF) and lungs were recovered. The right lung was stained with either hematoxylin-eosin or masson. The left lung was weighted, and its content of hydroxyproline (HYP) was measured by HCl acid hydrosis method. The IFN-gamma concentration in BALF was determined with enzyme-linked immunosorbent assay. RESULTS: The concentrations of IFN-gamma in BALF from the AdCMVmIFN-gamma treated groups were remarkably increased, (21,250 +/- 6,497) pg/ml and (21,000 +/- 5,451) pg/ml in the IFN-gamma transgenetic preventive therapeutic group and the therapeutic group respectively. IFN-gamma was undetectable in BALF from other groups. Mice in the two groups treated with AdCMVmIFN-gamma had statistically significant weight loss (P < 0.05), higher HYP content (P < 0.05), and tended to have more severe alveolitis and pulmonary fibrosis (P = 0.07) as compared with those in other groups. CONCLUSIONS: (1) mIFN-gamma could be overexpressed in airway and alveolar epithelium by locally administrated AdCMVmIFN-gamma. (2) Early mIFN-gamma transgene expression via adenoviral vector in this bleomycin model aggravated alveolitis and fibrosis to some degree.