Efflux pump effects on levofloxacin resistance in Mycobacterium abscessus.

Mycobacterium abscessus (M. abscessus) inherently displays resistance to most antibiotics, with the underlying drug resistance mechanisms remaining largely unexplored. Efflux pump is believed to play an important role in mediating drug resistance. The current study examined the potential of efflux pump inhibitors to reverse levofloxacin (LFX) resistance in M. abscessus. The reference strain of M. abscessus (ATCC19977) and 60 clinical isolates, including 41 M. abscessus subsp. abscessus and 19 M. abscessus subsp. massilense, were investigated. The drug sensitivity of M. abscessus against LFX alone or in conjunction with efflux pump inhibitors, including verapamil (VP), reserpine (RSP), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), or dicyclohexylcarbodiimide (DCC), were determined by AlarmarBlue microplate assay. Drug-resistant regions of the gyrA and gyrB genes from the drug-resistant strains were sequenced. The transcription level of the efflux pump genes was monitored using qRT-PCR. All the tested strains were resistant to LFX. The drug-resistant regions from the gyrA and gyrB genes showed no mutation associated with LFX resistance. CCCP, DCC, VP, and RSP increased the susceptibility of 93.3% (56/60), 91.7% (55/60), 85% (51/60), and 83.3% (50/60) isolates to LFX by 2 to 32-fold, respectively. Elevated transcription of seven efflux pump genes was observed in isolates with a high reduction in LFX MIC values in the presence of efflux pump inhibitors. Efflux pump inhibitors can improve the antibacterial activity of LFX against M. abscessus in vitro. The overexpression of efflux-related genes in LFX-resistant isolates suggests that efflux pumps are associated with the development of LFX resistance in M. abscessus.

A metric for quantitative evaluation of glioma margin changes in magnetic resonance imaging.

BACKGROUND: Gliomas differ from meningiomas in their margins, most of which are not separated from the surrounding tissue by a distinct interface. PURPOSE: To characterize the margins of gliomas quantitatively based on the margin sharpness coefficient (MSC) is significant for clinical judgment and invasive analysis of gliomas. MATERIAL AND METHODS: The data for this study used magnetic resonance image (MRI) data from 67 local patients and 15 open patients to quantify the intensity of changes in the glioma margins of the brain using MSC. The accuracy of MSC was assessed by consistency analysis and Bland-Altman test analysis, as well as invasive correlations using receiver operating characteristic (ROC) and Spearman correlation coefficients for subjects. RESULTS: In grading the tumors, the mean MSC values were significantly lower for high-grade gliomas (HGG) than for low-grade gliomas (LGG). The concordance correlation between the measured gradient and the actual gradient was high (HGG: 0.981; LGG: 0.993), and the Bland-Altman mean difference at the 95% confidence interval (HGG: -0.576; LGG: 0.254) and the limits of concordance (HGG: 5.580; LGG: 5.436) indicated no statistical difference. The correlation between MSC and invasion based on the margins of gliomas showed an AUC of 0.903 and 0.911 for HGG and LGG, respectively. The mean Spearman correlation coefficient of the MSC versus the actual distance of invasion was -0.631 in gliomas. CONCLUSION: The relatively low MSC on the blurred margins and irregular shape of gliomas may help in benign-malignant differentiation and invasion prediction of gliomas and has potential application for clinical judgment.

Medical and nursing students' satisfaction with e-learning platforms during the COVID-19 pandemic: Initial findings of an experimental project in China.

Satisfaction with learning management systems (LMSs) is an essential indicator of students' e-learning experiences and reflects the quality of e-learning. Applying the technology satisfaction model, the present study aimed to investigate medical and nursing students' satisfaction with LMSs and its predictors. We conducted our survey at a medical university located in East China and received a total of 329 effective responses. Structural equation modelling was used to analyse the data. Our findings confirmed that perceived ease of use and perceived usefulness were two direct predictors of medical and nursing students' satisfaction with LMSs. Furthermore, the influence of perceived usefulness on satisfaction was more powerful than that of perceived ease of use. This study also substantiated that computer self-efficacy and perceived ease of use can indirectly impact medical and nursing students' satisfaction with LMSs. Our research effectively links the theoretical hypotheses with empirical findings, highlighting the central role of Computer Self-Efficacy (CSE), perceived ease of use, and perceived usefulness in shaping medical and nursing students' satisfaction with LMSs. Our findings contributed to the understanding of the technology satisfaction model and medical and nursing students' e-learning during the COVID-19 pandemic.

Tuberculosis-targeted next-generation sequencing and machine learning: An ultrasensitive diagnostic strategy for paucibacillary pulmonary tuberculosis and tuberculous meningitis.

BACKGROUND: Existing diagnostic approaches for paucibacillary tuberculosis (TB) are limited by the low sensitivity of testing methods and difficulty in obtaining suitable samples. METHODS: An ultrasensitive TB diagnostic strategy was established, integrating efficient and specific TB targeted next-generation sequencing and machine learning models, and validated in clinical cohorts to test plasma cfDNA, cerebrospinal fluid (CSF) DNA collected from tuberculous meningitis (TBM) and pediatric pulmonary TB (PPTB) patients. RESULTS: In the detection of 227 samples, application of the specific thresholds of CSF DNA (AUC = 0.974) and plasma cfDNA (AUC = 0.908) yielded sensitivity of 97.01 % and the specificity of 95.65 % in CSF samples and sensitivity of 82.61 % and specificity of 86.36 % in plasma samples, respectively. In the analysis of 44 paired samples from TBM patients, our strategy had a high concordance of 90.91 % (40/44) in plasma cfDNA and CSF DNA with both sensitivity of 95.45 % (42/44). In the PPTB patient, the sensitivity of the TB diagnostic strategy yielded higher sensitivity on plasma specimen than Xpert assay on gastric lavage (28.57 % VS. 15.38 %). CONCLUSIONS: Our TB diagnostic strategy provides greater detection sensitivity for paucibacillary TB, while plasma cfDNA as an easily collected specimen, could be an appropriate sample type for PTB and TBM diagnosis.

Efficacy of clofazimine-containing regimens for treatment of Mycobacterium avium complex-pulmonary disease in patients unsuitable for standard treatment regimen.

OBJECTIVES: Patients with Mycobacterium avium complex-pulmonary disease (MAC-PD) can exhibit contraindications in applying the recommended treatment regimens by the guidelines. Clofazimine (CFZ) is considered a promising drug for MAC-PD treatment and is frequently included in alternative regimens; however, its efficacy remains unclear. METHODS: MAC-PD patients, unsuitable for standard regimens, were enrolled continuously in a prospective study at Beijing Chest Hospital. The treatment response of the CFZ-containing regimen was monitored. RESULTS: Fifty patients were enrolled in the initial treatment, and 25 patients had a history of anti-TB treatment. Nodular bronchiectasis was observed in 34 patients, while 8 patients exhibited fibrocavitary changes. Additionally, eight patients displayed a combination of both patterns. In a multivariate analysis, MAC-PD patients with CFZ MIC < 0.25 mg/L were significantly associated with culture conversion [OR 8.415, 95% CI (1.983-35.705); P = 0.004]. Among patients who had previous TB treatment history, patients with CFZ MIC < 0.25 mg/L had a higher chance of acquiring culture conversion outcomes [(OR 7.737, 95% CI 1.032-57.989); P = 0.046]. In contrast, among patients with no previous TB treatment history, the RIF-containing regimen had a higher chance of acquiring culture conversion outcomes [(OR 11.038, 95%CI 1.008-120.888); P = 0.049]. CONCLUSION: MAC-PD patients unsuitable for standard regimens could benefit from a CFZ-containing regimen, especially for patients with previous TB treatment history and baseline CFZ MIC values lower than 0.25 mg/L.

STMP-Net: A Spatiotemporal Prediction Network Integrating Motion Perception.

This article proposes a video prediction network called STMP-Net that addresses the problem of the inability of Recurrent Neural Networks (RNNs) to fully extract spatiotemporal information and motion change features during video prediction. STMP-Net combines spatiotemporal memory and motion perception to make more accurate predictions. Firstly, a spatiotemporal attention fusion unit (STAFU) is proposed as the basic module of the prediction network, which learns and transfers spatiotemporal features in both horizontal and vertical directions based on spatiotemporal feature information and contextual attention mechanism. Additionally, a contextual attention mechanism is introduced in the hidden state to focus attention on more important details and improve the capture of detailed features, thus greatly reducing the computational load of the network. Secondly, a motion gradient highway unit (MGHU) is proposed by combining motion perception modules and adding them between adjacent layers, which can adaptively learn the important information of input features and fuse motion change features to significantly improve the predictive performance of the model. Finally, a high-speed channel is provided between layers to quickly transmit important features and alleviate the gradient vanishing problem caused by back-propagation. The experimental results show that compared with mainstream video prediction networks, the proposed method can achieve better prediction results in long-term video prediction, especially in motion scenes.

Bedaquiline resistance pattern in clofazimine-resistant clinical isolates of tuberculosis patients.

OBJECTIVES: Bedaquiline (BDQ) is a potent drug for treating drug-resistant tuberculosis (TB). Here, we analysed the resistance profiles of BDQ in CFZ-resistant clinical isolates and investigated the clinical risk factors of BDQ and CFZ cross/co-resistance. METHODS: The AlarmarBlue microplate assay was performed to determine the minimum inhibitory concentration (MIC) of the CFZ-resistant Mycobacterium tuberculosis (MTB) clinical isolates to CFZ and BDQ. The clinical characteristics of the respective patients were analysed to explore the possible risk factors of BDQ resistance. The drug-resistance-associated genes including Rv0678, Rv1979c, atpE, pepQ and Rv1453 were sequenced and analysed. RESULTS: A total of 72 clinical CFZ-resistant MTB isolates were collected; among these, half were identified as BDQ-resistant. The MIC value of BDQ closely correlated with CFZ (Spearman's q = 0.766, P < 0.005). Among the isolates with a MIC of CFZ ≥4 mg/L, 92.31% (12/13) were resistant to BDQ. Pre-XDR and exposure to BDQ or CFZ are the major risk factors for concurrent BDQ resistance. Among the 36 cross/co-resistant isolates, 50% (18/36) had mutations in Rv0678, 8.3% (3/36) had mutations in Rv0678+Rv1453, 5.6% (2/36) had mutations in Rv0678+Rv1979c, 2.8% (1/36) had mutations in Rv0678+Rv1979c+Rv1453, 2.8% (1/36) had mutations in atpE+Rv0678+Rv1453, 2.8% (1/36) had mutations in Rv1979c, and 27.7% (10/36) had no variations in the target genes. CONCLUSION: Nearly half of the CFZ-resistant isolates were still sensitive to BDQ, whereas this rate dramatically decreased among patients with pre-XDR TB or those who had been exposed to BDQ or CFZ.

Prevalence and related factors of depressive symptoms among HIV/AIDS in Ningbo, China: A cross-sectional study.

Background: Depressive symptoms were common among HIV/AIDS patients. Previous studies had shown that HIV-infected patients were twice as likely to be diagnosed with depression as the general population. However, only few studies have explored the prevalence and related factors of depressive symptoms among HIV/AIDS in China. Materials and methods: A cross-sectional study was conducted to study the prevalence of depressive symptoms among HIV/AIDS from January to December 2021 through the database of HIV/AIDS antiretroviral therapy and psychological evaluation system in Ningbo, China. The Patient Health Questionnaire-2 (PHQ-2) was used to screen for depressive symptoms (PHQ-2 > 0), the Patient Health Questionnaire-9 (PHQ-9) was used to diagnose depressive symptoms, and multivariate Logistic regression model was carried on to evaluate the related factors. Results: A total of 3,939 HIV/AIDS patients were enrolled, and the age of initiation of antiretroviral therapy was 37.15 (IQR = 28.41-48.73) years. Among them, 3,230 (82.00%) were male, 3,844 (97.59%) were Han nationality, 1,391 (35.49%) were unmarried, 1,665 (42.27%) were homosexual transmission, and 2,194 (55.70%) were HIV-infected patients. There were 265 patients (6.73%) with depressive symptoms, and the proportion of mild, moderate, moderate and severe depressive symptoms was 4.01% (158/3939), 1.65% (65/3939), 0.76% (30/3939), and 0.30% (12/3939), respectively. Multivariate analysis showed that married [odds ratio (OR) = 0.675, 95% CI = 0.501-0.908], divorced or widowed (OR = 0.571, 95% CI = 0.380-0.860), homosexual transmission (OR = 1.793, 95% CI = 1.349-2.396) were associated with depressive symptoms among HIV/AIDS. Conclusion: The prevalence of depressive symptoms among HIV/AIDS patients was 6.73% in Ningbo, China. More attention should be paid to the psychological status of unmarried and homosexual HIV/AIDS patients in Ningbo and timely psychological intervention or treatment should be given to those patients with depressive symptoms.

In Vitro Activity of the Sudapyridine (WX-081) against Non-Tuberculous Mycobacteria Isolated in Beijing, China.

Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows an anti-tuberculosis activity but, unlike BDQ, did not prolong QT interval (QT) in animal model studies. This study evaluated the antimicrobial activity of this novel drug against non-tuberculous mycobacteria (NTM). Fifty reference strains of different mycobacterial species, and 132 NTM clinical isolates from four commonly isolated NTM species were recruited. The microplate alamarBlue assay was performed to determine the MIC of WX-081 and BDQ. Cytotoxicity assay was performed for both drugs using the THP-1 cells, and the minimum bactericidal concentrations (MBCs) of both drugs against the reference strains of five selected NTM species were also determined. All the tested reference strains had MICs lower than 0.5 µg/mL, with the majority having MICs far below 0.1 µg/mL for WX-081. The epidemiological cut-offs of WX-081 ranged from 0.0156 µg/mL to 0.25 µg/mL against commonly isolated NTM, and this value was comparable with that of BDQ. The MBC/MIC ratios suggest a bacteriostatic activity for both drugs against the five selected NTM species. Cytotoxicity assays indicated that THP-1 cells had nearly 100% viability when exposed to WX-081 for 24 h below 4 µg/mL, 200- to 300-fold the MICs of Mycobacterium intracellulare, Mycobacterium avium, and Mycobacterium kansasii. WX-081 has a strong antimicrobial activity against different NTM species with low cytotoxicity and therefore has the potential to be used for treating NTM infections. IMPORTANCE Due to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. Over 200 species or subspecies of NTM have been reported, whereas pulmonary diseases in humans are caused mainly by M. avium complex (MAC), M. kansasii, and M. abscessus. Treatment of NTM infection is often challenging as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant-tuberculosis (MDR-TB) may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the antituberculosis efficacy but eliminate the severe side effect of BDQ. This study initially evaluated the antimicrobial activity of this novel drug against non-tuberculous mycobacteria (NTM).

Doubled Nontuberculous Mycobacteria Isolation as a Consequence of Changes in the Diagnosis Algorithm.

Background: Nontuberculous mycobacteria (NTM) and their associated diseases remain neglected. Through minor modifications in our diagnostic algorithm, we observed an unexpected higher number of cultivable NTM isolates. Therefore, a retrospective study was performed thoroughly to investigate the effect of changed laboratory procedures on NTM isolation in a specialized tuberculosis hospital. Methods: NTM isolation rates and composition of NTM species were compared for the two diagnostic algorithms: (1) by using traditional p-nitrobenzoic acid (PNB) selective medium as a preliminary test to identify NTM isolates among the positive cultures (procedure I) and (2) by using the MPT64 antigen detection method to distinguish between Mycobacterium tuberculosis complex (MTBC) isolates and possible NTM isolates after a positive MGIT960 liquid culture (procedure II). Results: The NTM isolation rate in procedure II was significantly higher than the procedure I (18.08% vs 9.71%; P<0.001). A noticeable increase in the ratio of NTM isolates among the identified mycobacteria was observed over the studied years (ie, from 58.18% in 2019 to 72.93% in 2021), which indicated a more precise prescription of species identification test after prompt information was provided in procedure II. In addition, the consistency of the identified species using multiple specimens from the same patient did not present a significant difference between the procedures. Conclusion: According to our study, NTM infection might be far more underestimated than it is. A diagnostic procedure combining MGIT960 culture and MPT64 antigen detection could timely and easily identify clues of NTM isolates and improve the diagnosis of NTM infections.

Differential Acceptance of Advance Directives Between Millennials and Baby Boomer Generations: A Cross-Sectional Survey Study Among College Students and Their Relatives.

Objectives: This study aims to explore the differentials of knowledge and attitude of advance directives (ADs) between millennials and baby boomer generations, and the effects of the intention to sign the advance directives. Methods: This is a cross-sectional study using a self-administered questionnaire to collect data from 325 students in a health-related college of a University of Science and Technology in Taiwan, and their parents, as total of 226, who are baby boomers. The statistical methods include descriptive statistics and inferential statistics. Results: Only 10 people from the 2 generations signed an AD. The multivariate logistic regression showed that baby boomer generation, AD knowledge, and AD attitude were significant positive associate of willingness to sign AD in the future. Conclusions: The government may enhance promotion of ADs among millennials and improve the connection between millennials' knowledge of and attitude toward ADs, and their AD signing behavior.

High-Resolution Remote Sensing Image Classification with RmRMR-Enhanced Bag of Visual Words.

A ReliefF improved mRMR (RmRMR) criterion-based bag of visual words (BoVW) algorithm is proposed to filter the visual words that are generated with high information redundancy for remote sensing image classification. First, the contribution degree of each word to the classification is represented by its weighting parameter, which is assigned using the ReliefF algorithm. Next, the relevance and redundancy of each word are calculated according to the mRMR criterion with the addition of a dictionary balance coefficient. Finally, a novel dictionary discriminant function is established, and the globally discriminative small-scale dictionary subsets are filtered and obtained. Experimental results show that the proposed algorithm effectively reduces the amount of redundant information in the dictionary and better balances the relevance and redundancy of words to improve the feature descriptive power of dictionary subsets and markedly increase the classification precision on a high-resolution remote sensing image.

Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP) Exhibits Direct Antibacterial Activity Against Mycobacterium abscessus.

OBJECTIVE: Treatment choices for Mycobacterium abscessus (M. abscessus) infections are very limited, and the prognosis is generally poor. Effective new antibiotics or repurposing existing antibiotics against M. abscessus infection are urgently needed. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a member of the lipophilic weak acid class, is known as an efflux pump inhibitor for Mycobacterium tuberculosis. The aim of this study was to determine the inhibitory activity of CCCP as a potential novel antibiotic against M. abscessus. METHODS: A total of 47 reference strains of different mycobacterial species and 60 clinical isolates of M. abscessus were enrolled. In vitro inhibitory activity of CCCP was accessed using microplates alamar blue method with the reference and clinical isolates. The activity of CCCP against intracellular M. abscessus residing within macrophage was also evaluated by intracellular colony numerating assay. RESULTS: CCCP exhibited good activity against M. abscessus clinical isolates in vitro, the minimum inhibitory concentration (MIC) ranged from 0.47 µg/mL to 3.75 µg/mL, with a MIC50 of 1.875 µg/mL and MIC90 of 3.75 µg/mL. At concentrations safe for the cells, CCCP exhibited highly intracellular bactericidal activities against M. abscessus and M. massiliense reference strains, with inhibitory rates of 84.8%±8.8% and 72.5%±13.7%, respectively. CCCP demonstrated bactericidal activity against intracellular M. abscessus that was comparable to clarithromycin, and concentration-dependent antimicrobial activity against M. abscessus in macrophages was observed. In addition, CCCP also exhibited good activities against most reference strains of rapidly growing mycobacterial species. CONCLUSION: CCCP could be a potential candidate of novel antimicrobiological agent to treat M. abscessus infection.

Prevalence and molecular characterizations of seven additional drug resistance among multidrug-resistant tuberculosis in China: A subsequent study of a national survey.

The drug resistance prevalence data facilitates selection of the initial drug for treating multidrug-resistant tuberculosis (MDR-TB). The aim of this study was to investigate the prevalence and molecular characterization of seven additional types of drug resistances among MDR-TB isolates collected from the first/only nationwide drug resistance surveillance in China. A total of 391 out of the 401 MDR-TB strains were successfully recovered by Löwenstein-Jensen medium. Drug susceptibility testing was performed against moxifloxacin (Mfx), bedaquiline (Bdq), linezolid (Lzd), clofazimine (Cfz), cycloserine (Cs), delamanid (Dlm) and pyrazinamide (PZA). The strains were subjected to whole-genome sequencing for the analysis corresponding drug resistant genes and their profiles. 269 (68.80%) were simple MDR-TB, 28 (7.16%) were extensively drug-resistant tuberculosis (XDR-TB) and 94 (24.04%) were pre-XDR-TB. Dlm, Lzd, Cfz and Bdq presented the lowest drug resistant rates i.e. 3.32% (13/391), 3.84% (15/391),6.65% (26/391) and 7.16% (28/391), respectively. Mfx (17.39%, 68/391) and CS (13.55%, 53/391) also demonstrated strong potencies against the MDR strains, whereas PZA (38.36%, 150/391) presented much higher resistant rate. 54.41% (37/68) Mfx-resistant strains carried mutations located within gyrA or gyrB. 70.15% (94/134) PZA-resistant strains had pncA mutations. Two of the 26 Cfz-resistant isolates had mutation in Rv0678 were also resistant to Bdq. Dlm, Lzd, Cfz and Bdq exhibited excellent activity against MDR-TB, including XDR-TB. These data highlighted the necessity of a timely, feasible and reliable DST, while genotypic DST for Mfx and PZA is promising at this moment.

The aceE involves in mycolic acid synthesis and biofilm formation in Mycobacterium smegmatis.

BACKGROUND: The integrity of cell wall structure is highly significant for the in vivo survival of mycobacteria. We hypothesized that changes in morphology may indicate changes in cell wall metabolism and identified an aceE gene mutant (aceE-mut) which presented a deficient colony morphology on 7H10 agar by screening transposon mutagenesis in Mycolicibacterium smegmatis, basonym Mycobacterium smegmatis (M. smegmatis). This study aimed to identify the functional role of aceE gene in cell wall biosynthesis in M. smegmatis. RESULTS: We observed that the colony morphology of aceE-mut was quite different, smaller and smoother on the solid culture medium than the wild-type (WT) strain during the transposon library screening of M. smegmatis. Notably, in contrast with the WT, which aggregates and forms biofilm, the aceE-mut lost its ability of growing aggregately and biofilm formation, which are two very important features of mycobacteria. The morphological changes in the aceE-mut strain were further confirmed by electron microscopy which indicated smoother and thinner cell envelope images in contrast with the rough morphology of WT strains. Additionally, the aceE-mut was more fragile to acidic stress and exhibited a pronounced defects in entering the macrophages as compared to the WT. The analysis of mycolic acid (MA) using LC-MS indicated deficiency of alpha-MA and epoxy-MA in aceE-mut strain whereas complementation of the aceE-mut with a wild-type aceE gene restored the composition of MA. CONCLUSIONS: Over all, this study indicates that aceE gene plays a significant role in the mycolic acid synthesis and affects the colony morphology, biofilm formation of M. smegmatis and bacteria invasion of macrophage.

Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21.

A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid ß-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

Fibroblast growth factor 21 ameliorates neurodegeneration in rat and cellular models of Alzheimer's disease.

Our understanding of the mechanisms underlying process in Alzheimer's disease (AD) is far from completion and new therapeutic targets are urgently needed. Recently, the link between dementia and diabetes mellitus (DM) prompted us to search for new therapeutic strategies from glucose metabolism regulators for neurodegeneration. Previous studies have indicated that fibroblast growth factor 21 (FGF21), an attractive and potential therapeutic treatment for DM, may exert diverse effects in the central nervous system. However, the specific biological function and mechanisms of FGF21 on AD is still largely unknown. We report here a study in vivo and in vitro of the neuroprotective effects of FGF21 on cell apoptosis, tau hyperphosphorylation and oxidative stress induced by amyloid ß-peptide 25-35. In the present study, the results also further provided evidence for molecular mechanisms by which FGF21 exerted its beneficial effects in neuron and suggested that the regulation of protein phosphatase 2A / mitogen-activated protein kinases / hypoxia-inducible factor-1α pathway may play a key role in mediating the neuroprotective effects of FGF21 against AD-like pathologies.

Determination of the Critical Concentration of Rifabutin for Susceptibility Testing Using the Proportion Method with Löwenstein-Jensen Medium against Mycobacterium Tuberculosis Isolates.

OBJECTIVE: To determine the critical concentration of rifabutin (RFB) for susceptibility testing against Mycobacterium tuberculosis (Mtb) on Löwenstein-Jensen (L-J) medium using the proportion method. METHODS: We used 47 strains were used to determine the critical concentration of RFB. The microplate antimicrobial assay (MABA) was used as a reference method. We used 160 strains to evaluate its correlation with the classification results derived from the MABA method. We performed antimicrobial susceptibility testing (AST) against RFB and rifampin (RIF) for 2748 other strains using the proportion method on L-J medium. RESULTS: The determined critical concentration for RFB was 20 µg per mL. Identical classification as susceptible or resistant was observed in 93.8% and 92.5% strains for RFB and RIF, respectively, using the 2 different methods. The cross-resistance ratio between RFB and RIF was 72.7% in the 2748 Mtb strains. CONCLUSIONS: We determined that a critical concentration of 20 µg per mL RFB was reliable for AST of Mtb.

Evidence of metabolic memory-induced neurodegeneration and the therapeutic effects of glucagon-like peptide-1 receptor agonists via Forkhead box class O.

Metabolic memory, which refers to diabetic stresses that persist after glucose normalization, is considered a major factor in addition to hyperglycaemia for diabetes complications, including dementia. We previously reported that glucagon-like peptide-1 receptor agonist (GLP-1RA) alleviated neuronal injury in diabetes-related dementia models. However, our understanding of the effects and mechanisms of GLP-1RA on metabolic memory-induced neurodegeneration are limited. The present study mainly focuses on the mechanisms of action of GLP-1RA on metabolic memory-induced neurotoxicity in vivo and in vitro. Thus, in this study, aiming at mimicking metabolic memory phenomena, in vivo and in vitro models were exposed to high glucose first and then normal glucose. We also used advanced glycation end products, which are key metabolic memory-related factors, to induce neuronal injury in vitro. Based on the models, here, we report that GLP-1RA alleviated neurodegeneration in db/db mice with normalized blood glucose levels controlled with metformin and neuronal damage induced by high glucose treatment followed by withdrawal. GLP-1RA ameliorated metabolic memory-induced amyloid-ß and tau pathologies in vivo and in vitro. Furthermore, the data suggested that GLP-1RA can protect neurons against metabolic memory via Forkhead box class O (FoxO) pathways, and silent information regulator 2 homolog 1-dependent deacetylation and protein kinase B-dependent phosphorylation of FoxO1 were involved in the mechanisms underlying protective effects. This study provides evidence of the beneficial effects of GLP-1RA on neuronal cell metabolic memory, as well as GLP-1 analogues and metformin combination therapy efficiency on cognitive impairment.