Impact of end-expiratory pressure fluctuation on tidal volume in the trilevel positive airway pressure mode.

INTRODUCTION: In noninvasive positive-pressure ventilation (NPPV), the changes in the expiratory positive airway pressure (EPAP) directly affect the magnitude of the tidal volume. OBJECTIVES: This experimental study aims to verify the precise effects of end-expiratory fluctuation on the body tidal volume to better assist NPPV in clinical practice. METHODS: We selected the TestChest-simulated lung simulation of different populations, including healthy subjects (normal group), patients with chronic obstructive pulmonary disease (COPD) with emphysema as their primary phenotype (COPD1 group), and patients with COPD with bronchitis as their primary phenotype (COPD2 group). RESULTS: Regarding the tidal volume curves of the three groups under various conditions, sixfold charts revealed that the tidal volume changed with the end-expiratory pressure fluctuations. In addition, regression coefficients for end-expiratory pressure fluctuations, (IPAP-EPAP) and (IPAP-EEPAP) exhibited a significant contribution to the tidal volume. The two coefficients in the normal, COPD1 and COPD2 groups were 52.294 and 10.414, 46.192 and -8.816, and 11.922 and 17.947, respectively. The circuit simulation results showed that the simulation curve fitted the experimental curve better by changing the coefficient of the descending edge of the expiratory phase. CONCLUSIONS: The study results suggest that the end-expiratory pressure fluctuation affects the body tidal volume. Compared with the bilevel positive airway pressure (PAP), the trilevel PAP provides additional respiratory support to the body during a respiratory difference in initial respiration and descent.

C-type lectin domain family 5, member A (CLEC5A, MDL-1) promotes brain glioblastoma tumorigenesis by regulating PI3K/Akt signalling.

OBJECTIVES: Glioblastoma is the most common malignant glioma of all brain tumours. It is difficult to treat because of its poor response to chemotherapy and radiotherapy and high recurrence rate after treatment. The aetiology of glioblastoma is a result of disorders of multiple factors. Depending on cell signal transduction, these glioblastoma-associated factors lead to cell proliferation, differentiation and apoptosis. Therefore, investigation of the potential factors which involved in the development of glioblastoma could provide a new target for the treatment of glioblastoma. MATERIALS AND METHODS: We analysed the transcript expression of CLEC5A in glioblastoma by accessing The Cancer Genome Atlas (TCGA). qRT-PCR was performed to detect the RNA expression of genes in cells and tissues, and Western blot was used to measure the protein levels (Cyclin D1, Bcl-2, BAX, PCNA, MMP2, MMP9, Akt and Akt phosphorylation) in tissues and cells. Cell proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8, transwell and flow cytometry assays, respectively. Ki67 level and lung metastasis were determined by immunochemistry and H&E staining. RESULTS: In this study, we found that CLEC5A was highly upregulated in glioblastoma compared to normal brain tissues, which had an opposite relation with the overall patient survival. Downregulation of CLEC5A could inhibit cell proliferation, migration and invasion via promoting apoptosis and G1 arrest. In contrast, overexpression of CLEC5A stimulated cell proliferation, migration and invasion. In addition, we found that CLEC5A level was positively correlated with Akt phosphorylation level. Akt inhibitor or agonist could reverse the modulation effects of CLEC5A in glioblastoma. Moreover, In vivo results suggested that inhibition of CLEC5A significantly reduced tumour size, weight, cell proliferation ability and lung metastasis via inhibition of phosphorylation Akt. CONCLUSION: Both in vitro and in vivo evidences supported that CLEC5A was involved in glioblastoma pathogenesis via regulation of PI3K/Akt pathway. Thus, CLEC5A might serve as a potential therapeutic target in the treatment of glioblastoma in the future.

Pharmacokinetics and Bioequivalence Study of Hydroxychloroquine Sulfate Tablets in Chinese Healthy Volunteers by LC-MS/MS.

INTRODUCTION: Hydroxychloroquine (HCQ), 4-aminoquinoline, is an antimalarial drug and has become a basic therapy for rheumatic disease treatment. It can stabilize the condition of SLE patients and reduce the chances of patient relapse through its immunosuppressive function and antiinflammatory effects. This drug was absorbed completely and rapidly by oral administration, but has a prolonged half-life for elimination. The objective of this study was to evaluate the pharmacokinetic parameters and relative bioequivalence of a new generic (test) formulation with the branded (reference) formulation of HCQ in healthy Chinese male volunteers. This study was designed to acquire regulatory approval for the test formulation. METHODS: This study was conducted with a randomized, single-dose, two-period, and crossover design. The male subjects were randomly assigned to two groups at a 1:1 ratio to receive 0.2 g hydroxychloroquine sulfate tablets (0.1 g/piece) of the two formulations after a 3-month washout period then administered the alternate formulation. Study drugs were administered after overnight fasting (over 10 h). Plasma concentrations of hydroxychloroquine were measured by a validated LC-MS/MS method. The following pharmacokinetic properties were determined by a noncompartmental pharmacokinetic method: C max, T max, AUC0-t , AUC0-∝, and t 1/2. The bioequivalence between the test and reference products was assessed based on the following parameters: C max, AUC0-60d, and AUC0-∝ using the ANOVA method. If the 90% CI for AUC0-t was within 80-125% and for C max was within 70-143% of the statistical interval proposed by the SFDA, the two formulations were assumed bioequivalent. Concerning the main pharmacokinetic charateristics of hydroxychloroquine, a long half-life drug, the pharmacokinetic parameters of 0-72 h were determined according to the FDA. Furthermore, a comparison was made between the parameters at 0-60 days and 0-72 h to evaluate whether a truncated AUC method can be applied to estimate the relative bioavailability of HCQ. Tolerability was assessed by monitoring vital signs and laboratory tests and by questioning subjects about adverse events. RESULTS: The 90% CI of C max for HCQ is 103.8-142.3%; the AUC0-60 is 100-114.2% and AUC0-∝ 100-115.5%. Both met the criteria according to the SFDA's guidelines for bioequivalence. The relative bioavailability was 109.5% (according to AUC0-60d) and 110.7% (according to AUC0-∝). No serious or unexpected adverse events were observed. CONCLUSIONS: In this study, the pharmacokinetic studies and results were conducted so that the test and reference formulations of HCQ met the Chinese criteria for assuming bioequivalence. Both formulations were well tolerated in the population studies.