Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model.

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-ß1, oxidative loads, Masson's trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

Epidemiology and outcomes of multidrug-resistant bacterial infection in non-cystic fibrosis bronchiectasis.

PURPOSE: Multidrug-resistant (MDR) bacteria impose a considerable health-care burden and are associated with bronchiectasis exacerbation. This study investigated the clinical outcomes of adult patients with bronchiectasis following MDR bacterial infection. METHODS: From the Chang Gung Research Database, we identified patients with bronchiectasis and MDR bacterial infection from 2008 to 2017. The control group comprised patients with bronchiectasis who did not have MDR bacterial infection and were propensity-score matched at a 1:2 ratio. The main outcomes were in-hospital and 3-year mortality. RESULTS: In total, 554 patients with both bronchiectasis and MDR bacterial infection were identified. The types of MDR bacteria that most commonly affected the patients were MDR- Acinetobacter baumannii (38.6%) and methicillin-resistant Staphylococcus aureus (18.4%), Extended-spectrum-beta-lactamases (ESBL)- Klebsiella pneumoniae (17.8%), MDR-Pseudomonas (14.8%), and ESBL-E. coli (7.5%). Compared with the control group, the MDR group exhibited lower body mass index scores, higher rate of chronic bacterial colonization, a higher rate of previous exacerbations, and an increased use of antibiotics. Furthermore, the MDR group exhibited a higher rate of respiratory failure during hospitalization (MDR vs. control, 41.3% vs. 12.4%; p < 0.001). The MDR and control groups exhibited in-hospital mortality rates of 26.7% and 7.6%, respectively (p < 0.001); 3-year respiratory failure rates of 33.5% and 13.5%, respectively (p < 0.001); and 3-year mortality rates of 73.3% and 41.5%, respectively (p < 0.001). After adjustments were made for confounding factors, the infection with MDR and MDR bacteria species were determined to be independent risk factors affecting in-hospital and 3-year mortality. CONCLUSIONS: MDR bacteria were discovered in patients with more severe bronchiectasis and were independently associated with an increased risk of in-hospital and 3-year mortality. Given our findings, we recommend that clinicians identify patients at risk of MDR bacterial infection and follow the principle of antimicrobial stewardship to prevent the emergence of resistant bacteria among patients with bronchiectasis.

Cell death of alveolar lymphocytes and monocytes is negatively correlated with driving pressure and mechanical power in patients with acute respiratory distress syndrome.

BACKGROUND: Pathogenesis of acute respiratory distress syndrome (ARDS) involves immune cell death and removal from the injured lungs. ARDS severity is related to lung compliance. However, the correlation between the respiratory mechanics and alveolar immune cell death in patients with ARDS remains unclear. METHODS: Twenty-four patients with respiratory failure and ARDS were enrolled in the intensive care unit between November 2019 and November 2021. Neutrophil extracellular traps (NETs) and cell death of lymphocytes and monocytes in bronchoalveolar lavage fluid were detected on days 1 and 8. RESULTS: Lung compliance was positively correlated with the cell death percentage of alveolar CD4/CD8 lymphocytes and monocytes on day 8 (Pearson's correlation coefficient (r) = 0.554, p = 0.005; r = 0.422, p = 0.040; r = 0.569, p = 0.004, respectively). There was no association between lung compliance and the percentage of alveolar NETs on days 1 and 8. The cell death percentages of alveolar CD4/CD8 lymphocytes and monocytes were negatively correlated with driving pressure (DP) on days 1 (r = - 0.440, p = 0.032; r = - 0.613, p = 0.001; r = -0.557, p = 0.005, respectively) and 8 (r = - 0.459, p = 0.024; r = - 0.407, p = 0.048; r = - 0.607, p = 0.002, respectively). The cell death percentages of alveolar CD4/CD8 lymphocytes and monocytes were also negatively correlated with mechanical power (MP) on days 1 (r = - 0.558, p = 0.005; r = - 0.593, p = 0.002; r = - 0.571, p = 0.004, respectively) and 8 (r = - 0.539, p = 0.007; r = - 0.338, p = 0.107; r = - 0.649, p < 0.001, respectively). The percentage of alveolar NETs on days 1 and 8 was not associated with DP or MP. CONCLUSION: Patients with higher cell death rates of alveolar CD4/CD8 lymphocytes and monocytes exhibited lower DP and MP. Patients with less cell death of alveolar CD4/CD8 lymphocytes and monocytes required more DP or MP to maintain adequate ventilation.

Application of 3.0 T Multimodal Intestinal MRI in Quantitative Evaluation of Ulcerative Colitis / 中山大学学报(医学科学版)

@#【Objective】To investigate the diagnostic value of multimodal intestinal MRI with routine MRI ，diffusion- weighted imaging（DWI）and multi-phase dynamic enhanced MR scanning by 3D-VIBE sequence in patients with ulcerative colitis（UC）.【Methods】Twenty-five patients with UC confirmed by endoscopic biopsy were enrolled. According to the modified Truelove-Witt′s criteria，patients were divided into remission group and active group，and the active group was divided into three subgroups as mild，moderate，and severe. The intestinal wall edema，comb sign，enlarged mesenteric lymph nodes，enhanced degree of intestinal wall，the maximum thickness of intestinal wall and the ADC value of the intestinal wall were observed and measured. The patient′ s C-reactive protein（CRP）and erythrocyte sedimentation rate （ESR）results were collected to evaluate the diagnostic value.【Results】The sensitivity and specificity in diagnosing the UC activity were not high by using CRP and ESR. There were significant differences in the stratification of intestinal wall edema ，comb sign ，intestinal wall thickness ，and ADC value between the four groups in the UC remission period and active period（P<0.05）. There were no significant differences between the four groups in mesenteric lymph nodes enlargement. ADC value had higher diagnostic efficiency for identification the activity group and remission group. Cutoff ADC values for differentiating the activity group and the remission group was calculated as（1.52 ± 0.16）× 10- 3 mm2/s，with 70.8% sensitivity and 79.8% specificity，respectively.【Conclusions】The diagnostic value of multimodal MRI for UC is higher than that of routine MRI，and multimodal MRI has high clinical value.

Association analysis of genetic polymorphisms of TCF7L2, CDKAL1, SLC30A8, HHEX genes and microvascular complications of type 2 diabetes mellitus / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study the associations of single nucleotide polymorphisms (SNPs) of TCF7L2, CDKAL1, SLC30A8, HHEX with diabetic retinopathy (DR) and nephropathy (DN) in type 2 diabetes mellitus.</p><p><b>METHODS</b>A total of 479 subjects with DR,248 with DN and 650 without DR or DN were recruited to assess the associations between SNPs of TCF7L2 (rs7903146, rs6585205, rs11196218), CDKAL1 (rs10946398,rs4712527), SLC30A8 (rs13266634, rs3802177, rs11558471) and HHEX (rs1111875, rs7923837) and the development of DR and DN.</p><p><b>RESULTS</b>There were significant differences in genotypic and allele frequencies of rs11558471 (SLC30A8) between DR and control groups (P< 0.05), the odds ratio (OR) values of A and AA were 1.27 and 1.68. The distributions of genotype and allele frequency for rs11196218 (TCF7L2) were significantly different between DN and control group (P=0.0051,OR=1.37). However, the P value after Bonferroni correction showed no significant difference. No significant differences were found in the distributions of rs13266634 and rs3802177 (SLC30A8), rs10946398 (CDKAL1), rs6585205, rs7903146 and rs11196218 (TCF7L2) and rs7923837 (HHEX) between DR and control groups, and nor significant differences were found in distributions of rs6585205 (TCF7L2), rs4712527 (CDKAL1), rs13266634, rs3802177 and rs11558471 (SLC30A8), and 7923837 (HHEX) between DN and control groups, though for all comparison the OR values were greater than 1.</p><p><b>CONCLUSION</b>Polymorphisms of SLC30A8 and TCF7L2 genes may be associated with the development of DR and DN, respectively. Association between the polymorphisms of CKDAL1, TCF7L2 and HHEX genes and DR, and between the polymorphisms of SLC30A8, HHEX and CDKAL1 genes and DN, cannot be excluded.</p>

Experimental study of celecoxib inducing the apoptosis of cyst liner epithelial cells of polycystic kidney / 中华肾脏病杂志

Objective To initially investigate the mechanism of COX-2 inhibitor inducing cell apoptosis through the observation of celecoxib (CXB),a specific COX-2 inhibitor,inducing apoptosis of cyst lining epithelial cells of human polycystic kidney.Methods (1)Primarily cultured cell was divided into control group and CXB group to evaluate the proliferative state by Brdu assay.(2)The cell apoptosis was observed by transmitted electronic microscope after being cultured in CXB 2?10~(-5) mol/L for 24,48 hours.(3)The cell apoptosis and apoptotic rate were detected by TUNEL assay.(4) The cell apoptotic rate were measured by AnnexinV,PI-labeled flow cytometry after being cultured in CXB 2?10~(-5) mol/L for 0,24,48 hours.(5)Protein expression of Bax,Bcl-2,caspase 3 was examined by Western blotting.Results (1)The Brdu assay revealed that CXB inhibited cell growth in a concentration-dependent manner,with the maximum growth inhibition ratio of 63.9% when treated by CXB 2?10~(-5) mol/L for 24 h.(2)Typical morphological changes of apoptotic cell were apoptotic body, nuclear concentration,chromatin aggregation,endochylema vacuolization and ravinement under eletrou microscope.(3)TUNEL assay showed that the apoptotic rate was (2.8?0.2)% in control group,and (28.5?1.6)%,(48.5?1.2)% in CXB group for 24,48 hours respectively,with significant differences to control group(P＜0.05).(4) AnnexinV,PI-labeled flow cytometry showed that,in 0,0.5,1,2?10~(-5) mol/L CXB group,the apoptotic rates were (3.15?0.05)%,(7.15?0.11)%,(7.76?0.08)%, (12.15?0.07)% for 24 hours respectively,and (13.53?0.21)%,(18.36?0.17)%,(24.87?0.25)%, (53.66?0.32)% for 48 hours respectively.Significant differences were found among corresponding groups(all P＜0.01 ).(5) Extracted total cell protein in every group and more protein of Bax,Bcl-2 expressed in CXB-treated group was detected by Western blotting than that in control group. Conclusions CXB can inhibit the proliferation of cyst liner epithelial cells in a time- and concentration- dependent manner,and induce cell apoptosis through increasing the ratio of Bax/Bcl-2.CXB is hopeful to become an effective drug to treat ADPKD.