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Objective To investigate the application value of tenofovir alafenamide fumarate (TAF) in elderly patients with chronic hepatitis B (CHB) and its influence on bones and kidneys. Methods A total of 36 CHB patients, aged ≥60 years, who received TAF antiviral therapy in Qingdao Municipal Hospital, The Affiliated Hospital of Qingdao University, Qingdao Sixth People's Hospital, Chengyang People's Hospital, and Jimo People's Hospital from June 2021 to October 2022 were enrolled in this study, and all patients received TAF (25 mg/d) antiviral therapy. Related data were collected at baseline and weeks 24 and 48 of treatment, including virological indicators, biochemical parameters, urinary protein electrophoresis indices, transient elastography (FibroScan), and bone mineral density. Virological indicators included high-sensitivity HBV DNA quantification; biochemical parameters included total bilirubin, direct bilirubin (DBil), indirect bilirubin (IBil), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bile acid (TBA), glucose, blood urea nitrogen, creatinine, estimated glomerular filtration rate, and cystatin C (Cys C); urinary protein electrophoresis indices included urinary β2 microglobulin (β2-MG), urinary retinol (URBP), and urinary α1 microspherin (α1-MG). The paired t -test was used for comparison of normally distributed continuous data before and after treatment, and the Wilcoxon signed-rank test was used for comparison of non-normally distributed continuous data before and after treatment; the chi-square test or the Fisher's exact test was used for comparison of categorical data. Results A total of 36 CHB patients completed 24 weeks of follow-up. The complete virological response rate after 24 weeks of treatment was higher than that at baseline [83.3% (30/36) vs 77.8% (28/36), χ 2 =0.36, P =0.55], and there were significant reductions in DBil ( t =-2.42, P =0.02) and Cys C ( t =-4.34, P 0.05). Conclusion TAF has a good antiviral effect in CHB patients aged ≥60 years and can help more CHB patients achieve complete virological response, without causing damage to the kidney, and it can also improve bone mineral density and liver fibrosis degree.
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A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.
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Objective:To evaluate the relationship between changes in Golgi apparatus morphological structure and endotoxin-induced acute lung injury (ALI) in mice.Methods:Twenty healthy male C57BL/6J mice, weighing 18-20 g, aged 6-8 weeks, were divided into 2 groups ( n=10 each) using a random number table method: sham operation group (group Sham) and endotoxin-induced ALI group (group ALI). Lipopolysaccharide (LPS) 10 mg/kg was injected intravenously in group ALI, while the equal volume of normal saline 0.5 ml was given instead in group Sham.The animals were sacrificed at 12 h after LPS injection and the lung tissues were taken for detection of the content of reactive oxygen species (ROS) and wet to dry weight ratio (W/D ratio), for observation of the pathological changes (using HE staining) and Golgi apparatus morphological structure (with a transmission electron microscope) and for determination of expression of Golgi matrix protein 130 (GM130), Golgin97 and mannosidase alpha class II member 1 (MAN2A1) and its mRNA (by Western blot and quantitative polymerase chain reaction). Results:Compared with group Sham, ROS content and the W/D ratio in lung tissues were significantly increased, GM130, MAN2A1, Golgin97 protein and its mRNA expression were down-regulate ( P<0.01), the pathological changes of lung tissues were accentuated, the Golgi cisternae was swollen, and Golgi fragments were dispersed in the cytoplasm in group ALI. Conclusion:The mechanism of endotoxin-induced ALI may be related to the changes in Golgi apparatus morphological structure.
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Three hundred and twenty endophytic actinobacterial strains were isolated from psammophytes collected from Taklamakan Desert and identified.Among them,three strains already had been identified as new species of two genera and sixteen isolates showed relatively low 16S rRNA similarities＜98.6％to validly described species.Seventy-five of the isolates were selected as representative strains to screen antibacterial activity and mechanism.Forty-seven strains showed antagonistic activity against at least one of the indicator bacteria.Two Streptomyces strains produced bioactive compounds inducing DNA damage,and two Streptomyces strains produced bioactive compounds with inhibitory activity on protein biosynthesis.Notably,the strain Streptomyces sp.8P21H-1 that demonstrated both strong antibacterial activity and inhibitory activity on protein biosynthesis was prioritized for exploring new antibiotics.Under the strategy of integrating genetics-based discovery program and MS/MS-based molecular networking,two new streptogramin-type antibiotics,i.e.,acetyl-griseoviridin and desulphurizing gri-seoviridin,along with known griseoviridin,were isolated from the culture broth of strain 8P21H-1.Their chemical structures were determined by HR-MS,and 1D and 2D NMR.Desulphurizing griseoviridin and griseoviridin exhibited antibacterial activities by inhibiting translation.
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The clinical data of patients with severe acute pancreatitis admitted to the Department of Intensive Care Unit in our hospital from January 1, 2016 to December 31, 2020 were retrospectively collected.The patients were divided into electroacupuncture combined with Qingyi decoction treatment group (acupuncture group) and conventional group according to whether the patients received electroacupuncture combined with Qingyi decoction treatment.A prediction model of treatment propensity score was established for paired screening, with 122 cases in each group.The acupoints such as Zusanli, Sanyinjiao, Hegu, Shangjuxu, Xiajuxu, and Taichong were selected, and then electroacupuncture treatment was performed after qi arrival using the manipulation technique, 1 or 2 times per day.Qingyi decoction was injected through the stomach and/or Qingyi decoction was given by coloclysis, 2-4 doses per day.The main outcome was the incidence of acute respiratory distress syndrome (ARDS), and the secondary outcome was the occurrence of complications and outcome of discharge.Compared with conventional group, the incidence of ARDS was significantly decreased, the time of mechanical ventilation was shortened, the incidence of renal dysfunction, score for acute physiology and chronic health score system, sequential organ failure score, and score for the severity of bedside acute pancreatitis were decreased, the rate of surgical intervention was increased, the total length of hospital stay was prolonged, and the fatality rate during hospitalization was reduced in acupuncture group ( P<0.05). The results of subgroup analysis showed that the onset time of disease (<1 week), a history of cardiovascular disease, diabetes mellitus, biliary pancreatitis and alcoholic pancreatitis, high fever, puncture and drainage were influencing factors for ARDS developed in the patients who received electroacupuncture combined with Qingyi decoction for treating severe acute pancreatitis.In conclusion, electroacupuncture combined with Qingyi decoction as an adjuvant treatment for severe acute pancreatitis can reduce acute lung injury, promote recovery, and decrease fatality rate.
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Objective:To explore the application value of single source dual energy CT (DECT) scanning technique in improving the image quality of the pancreas.Methods:Imaging data of 21 patients with normal pancreas and 36 patients with pancreas related diseases in the First Affiliated Hospital of Naval Medical University from July 2021 to August 2021 were collected. All the patients first underwent multi-slice CT (MDCT) scan with no-contrast, and then dynamic enhanced MDCT scan. And the DECT scan was used in the delay period. Virtual single energy images (VMI, 40~100keV) of normal pancreas and mixed energy images of pancreatic lesions (PI, 80 and 140kVp) were obtained. The regions of interest (ROI) of fat on abdominal wall, normal pancreas and abdominal aorta were delineated, the CT values and standard deviation (SD) of each ROI were measured and recorded, and the pancreatic signal-to-noise ratio (SNR) and contrast-to-noise ratio (SNR) of each energy image were calculated. The objective index and subjective score of VMI(40-100keV) and PI (80kVp and 140kVp) with iodine (water) base map and VMI best CNR were compared between groups. The correlation between VMI(40-100keV) and PI(80, 140kVp) with iodine (water) base map and VMIbest CNR was analyzed by univariate regression.Results:In VMI(40-100keV) of normal pancreas, the highest SNR value was VMI best CNR and iodine (water) base map, and the highest CNR values were VMI 60keV and iodine (water) base map. There were significant differences on SNR and CNR values between different energy VMI and iodine (water) base map ( P<0.05). Among the four images of PI 80kVp, PI 140kVp, VMI best CNR and iodine (water) base map for pancreatic lesions, the SNR and CNR values of iodine (water) base map were the highest. The SNR and CNR values of VMI best CNR were higher than those of PI 80kVp, and the differences were statistically significant ( P<0.05). The lesion significance and edge sharpness score of iodine (water) base map was the highest, which was better than other groups; the lesion significance and edge sharpness score of VMI best CNR was better than PI 140kVp, and the differences were statistically significant ( P<0.05). The results of univariate regression analysis showed that the SNR values of PI 80kVp, PI 140kVp and VMI best CNR for pancreatic lesions were positively correlated with those of the iodine (water) base map ( P<0.05), the CNR values of PI 140kVp and VMI best CNR images were positively correlated with the iodine (water) base map ( P<0.05), and the SNR and CNR values of PI 140kVp were positively correlated with VMI best CNR ( P<0.05). Conclusions:VMI with different energy and iodine (water) base maps can be obtained by single source DECT enhanced scanning of pancreas related diseases. The VMI best CNR was the best among all VMIs, while the SNR and CNR values of iodine (water) base maps were the highest in all images. The VMI best CNR and iodine (water) base maps can improve the image quality of pancreas related diseases.
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Objective:To evaluate the role of heme oxygenase-1 (HO-1)-induced endogenous protection in lipopolysaccharide (LPS)-caused apoptosis in rat alveolar macrophages and the relationship with endoplasmic reticulum stress.Methods:Alveolar macrophages of rats were randomized into 4 groups ( n=32 each) using a random number table method: control group (group C), LPS group (group L), Con siRNA group and HO-1 siRNA group. Cells were cultured normally in group C, and 10 μg/ml LPS was added to the culture medium in the other three groups. Con siRNA and HO-1 siRNA transfection was performed at 48 h before adding LPS in Con siRNA and HO-1 siRNA groups. At 24 h of treatment with LPS, MTT method was used to measure the cell viability, flow cytometry was used to determine the cell apoptosis rate, and Western blot was used to detect the expression of glucose regulatory protein 78 (GRP78), phosphorylated kinase receptor-like endoplasmic reticulum kinase (p-PERK), CCAAT/enhancer-binding protein homologous protein (CHOP), phosphorylated type I endoplasmic reticulum transmembrane protein kinase (p-IRE-1), phosphorylated stress-activated protein kinase (p-JNK) and caspase-12. Results:Compared with group C, the cell viability was significantly decreased, cell apoptosis rate was increased, and the expression of HO-1, GRP78, CHOP, p-PERK, p-IRE-1, p-JNK and caspase-12 was up-regulated in the other three groups ( P<0.05). Compared with group L, the cell viability was significantly decreased, cell apoptosis rate was increased, and the expression of HO-1 was down-regulated, and the expression of GRP78, CHOP, p-PERK, p-IRE-1, p-JNK and caspase-12 was up-regulated in group HO-1 siRNA ( P<0.05), and no significant change was found in each parameter in group Con siRNA ( P>0.05). Compared with group Con siRNA, the cell viability was significantly decreased, cell apoptosis rate was increased, and the expression of HO-1 was down-regulated, and the expression of GRP78, CHOP, p-PERK, p-IRE-1, p-JNK and caspase-12 was up-regulated in group HO-1 siRNA ( P<0.05). Conclusion:The mechanism of HO-1-induced endogenous protection is related to inhibiting endoplasmic reticulum stress and then reducing LPS-induced apoptosis in alveolar macrophages of rats.
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As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate and activity of d-serine alone and in combination with -lactams against methicillin-resistant (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, -lactams alone and in combinations was evaluated both by standard MICs, time-kill curves and checkerboard assays, and by murine systemic infection model as well as neutropenic thigh infection model. An synergistic effect was demonstrated with the combination of d-serine and -lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to -lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with -lactams against MRSA strains both and . Considering the relatively good safety of d-serine alone or in combination with -lactams, d-serine is worth following up as new anti-MRSA infection strategies.
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Objective@#To summarize the clinical manifestation and treatment of temporomandibular joint (TMJ) disc ossification, providing reference for clinical diagnosis and treatment of TMJ disc ossification.@*Methods@#From January 2006 to January 2018, 4 patients with TMJ disc ossification (2 males and 2 females, aged 20-55 years with an average age of 35.5 years) which were admitted to the Department of Oral and Maxillofacial Surgery, Shenzhen Second People′s Hospital were analyzed retrospectively. Ossification of TMJ disc was found in 4 cases during TMJ surgery. Two cases underwent partial ossification resection plus disc reduction and anchorage, and two cases underwent discectomy plus temporalis myofascial flap replacement. The causes, clinical manifestations and surgical effects of TMJ disc ossification were analyzed by comparing the maximal interincisal opening, visual analogue scale (VAS) score and MRI imaging indexes before and after operation.@*Results@#The history of anterior disc displacement of TMJ in 4 patients was long (average 11.5 years). In clinic, TMJ disc ossification was characterized by TMJ pain and limitation of mouth opening. The maximal interincisal opening was (32.1±6.1) mm and the VAS score was (7.3±0.4) before operation. MRI showed that the displaced discs of the affected sides were displaced and the condyle bones were worn. During the operation, ossification of TMJ discs was found yellow and hard, and the original elasticity was lost. Pathologic findings showed that the TMJ disc cartilage were ossified to osteoid tissue. Under the microscope, bone cells scattered around the bone cells and red trabecular bone were seen, and there were bone trabecula formed. In a follow-up of one year, TMJ pain was significantly decreased [VAS: (1.7±0.2)], and the maximal interincisal opening was (38.5±2.2) mm. MRI showed that the TMJ disc returned to normal position, and the sign of repairing and reconstruction of condyle bone could be found.@*Conclusions@#Long term displacement of TMJ disc may cause ossification with pain and limitation of interincisal opening. According to the degree and extent of ossification, partial ossification plus disc reduction and anchorage or discectomy plus temporalis myofascial flap replacement is feasible, and the clinical effects are satisfactory.
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Objective To investigate the ultrastructural changes of mitochondria and dynamic changes of mitochondrial dynamics related genes in chronic ocular hypertension rat models.Methods Forty Sprague-Dawley (SD) rats were randomized into normal control group,modeling 3 day-group,modeling 7 day-group and modeling 14 day-group.Glaucoma models were induced by translimbal laser photocoagulation of trabecular meshwork in rats.The number of survival retinal ganglion cells was evaluated by retrogradely labeling of FluoroGold.The morphological change of mitochondria in optical nerve was observed under the transmission microscope.The dynamic changes of mitochondrial dynamic-related gene expression in the retina in gene and protein levels were detected by real-time fluorescence quantitative PCR and Western blot assay,respectively.The experiment complied ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Animal Experimentation Ethics Committee of the Eye and ENT Hospital of Fudan University.Results The intraocular pressure was significantly higher in the modeling 3-day group,modeling 7-day group and modeling 14-day group than that in the normal control group (all at P＜0.01).Compared with the normal control group,the immunoreactivity of glial fibrillary acidic protein (GFAP) was increased in the Müller cells in all modeling retinas,and the relative expressing levels of GFAP protein were significantly mcreased in all modeling groups (F =91.47,17.58,both at P＜0.01).Compared to the normal control group,the number of mitochondria was increased,and the mitochondrial health degree in the optic nerve and the nearest neighbor distance between adjacent mitochondria were decreased in the modeling 3-day group and 14-day group (all at P＜0.05).The expression levels of dynamics-related protein 1 (Drp1),parkin protein,PINK1,KIF5B and Miro1 mRNA in the retina were significantly elevated in the modeling 3-day group (all at P＜0.05).In addition,the expression levels of optineurin,parkin and OPA1 proteins were higher in the modeling 3-,7-and 14-day groups than those in the normal control group (all at P＜0.05).Conclusions Dysfunction of mitochondria and changes of mitochondrial dynamics exist in RGCs of glaucomatous rats,including increased mitochondrial fission and fusion as well as the activation of mitophagy pathway,which probably are the mechanism of RGC damage in glaucoma.
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Mitochondrial dynamics refers to the constant fission,fusion,docking,transportation,and mitophagy of mitochondria within cells.These dynamic processes are not only critical to regulating mitochondrial morphology and function,but also playing key roles in cell survival,metabolism and function.Retinal ganglion cells (RGCs) are special and important neurons in retina and are exquisitely sensitive to disturbances in mitochondrial dynamics.Recent studies on autosomal dominant optic atrophy have demonstrated that genes which encode a mitochondrial protein involved in mitochondrial fusion are closely associated with the function of RGCs.In experimental glaucoma models,increased intraocular pressure induced mitochondrial fission,changes of optic atrophy 1 (OPAl) mRNA and protein expression,and resulted in RGCs death.The normal transportation and distribution of mitochondria in RGCs are critical for the function of axons.The studies on inherited and experimental optic neuropathies suggest that mitochondrial dynamics plays a central role in regulating the survival of RGCs.Manipulating mitochondrial dynamics has emerged as a promising strategy in RGCs protection.This paper reviewed the main content of mitochondrial dynamics and the role of mitochondrial dynamics in RGCs.
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Chuangxinmycin (CM) from Actinoplanes tsinanensis was an antibiotic discovered by Chinese scientists about 40 years ago. It contains a new heterocyclic system of indole fused with dihydrothiopyran, whose biosynthetic mechanism remains unclear. CM is used as an oral medicine in the treatment of bacterial infections in China. The simple structure makes CM as an attractive candidate of structure modification for improvement of antibacterial activity. Recently, we analyzed the secondary metabolites of Actinoplanes tsinanensis CPCC 200056, a CM producing strain, as a natural CM analogue. We discovered the first natural CM analogue 3-demethylchuangxinmycin (DCM) as a new natural product. Compared to CM, DCM exhibited a much weaker activity in the inhibition of the bacterial strains tested. The finding provides valuable information for the structure-activity relationship in the biosynthesis of CM.
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Objective We set up an uncertainty assessment method for determination of iodides in water by As3+-Ce4+ catalytic spectrophotometry, in order to assess the accuracy of the method and the major influencing factors, and to build up an equation to assess the uncertainty in the mobility of working curve and an uncertainty assessment method for pipettors.Methods According to Methods for Water Iodine Detection Suitable for Iodine Deficiency and Iodine Excess Areas, the uncertainty items of the two standard materials (GBW09114c and GBW09113c) in different concentrations, such as repeatability of measurement, the mobility of working curve, the uncertainty of standard solution and sample solution, etc, were analyzed.Results The contents of iodide in GBW09114c and GBW09113c were (61.3 ± 1.4) and (8.1 ± 0.3)μg/L;relative expanded uncertainty RU1 and RU2 were 2.25％ and 3.46％, both of them were in the range of acceptable deviation in the standard material certification (10.0％ and 14.8％).Major influencing factors were repeatability of measurement, the uncertainty of standard solution (including the uncertainty of potassium iodide reference reagent and glass equipment), and the uncertainty of sample solution (including the uncertainty of pipettors).A more adaptable equation for the mobility of working curve had been proposed;the factors involved in environment temperature and operation repeatability were used as the items of the pipettors' uncertainty.Conclusion This method can be used to assess the uncertainty in determination of water iodides by As3+-Ce4+ catalytic spectrophotometry.
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Objective To investigate the phenotypic and genetic characteristics of the lysostaphin‐resistant Staphylococcus aureus variants induced by recombinant lysostaphin in vitro .Methods Three clinical isolates of S . aureus ,including two resistant to methicillin (MRSA ) and one susceptible to methicillin (MSSA ) were induced by treatment with sub‐MIC of recombinant lysostaphin via one‐step selection in vitro .Susceptibility of the variants to antibiotics were determined and compared with their parental strains .The full length of femABX genes was amplified by polymerase chain reaction and sequenced to identify the potential mutation sites in these genes .The growth‐curve in liquid medium and virulence in a mouse systemic infection model of both parental and variant strains were observed . Results The frequency of lysostaphin resistance in S . aureus was between 10-4 to 10-8 following induction by lysostaphin . Resistance to lysostaphin was associated with a significant decrease in growth rate in vitro and virulence in vivo ,as well as increased susceptibility toβ‐lactams evidenced by the M IC of β‐lactams against the variants as low as 1/4 000 to 1/2 of the M IC against their parental strains . Sequencing of f emA BX genes showed mutation in femA gene in both variants ,which resulted in a premature termination codon .Conclusions Resistance of S . aureus to lysostaphin may develop following induction by recombinant lysostaphin in vitro . The lysostaphin‐resistant S . aureus variants are characteristic of lower growth rate , decreased virulence ,and higher susceptibility to β‐lactams .
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The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing, China. 173 A. baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance (HLAR, MIC to gentamicin and amikacin>512 µg/mL) phenotype selection by broth microdilution method. The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes (aac(3)-I, aac(3)-IIc, aac(6')-Ib, aac(6')-II, aph(4)-Ia, aph(3')-I, aph(3')-IIb, aph(3')-IIIa, aph(3')-VIa, aph(2″)-Ib, aph(2″)-Ic, aph(2″)-Id, ant(2″)-Ia, ant(3″)-I and ant(4')-Ia) and the 16S rRNA methylase genes (armA, rmtB and rmtC). Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS. Totally 102 (58.96%) HLAR isolates were selected. The HLAR rates for year 2006, 2007, 2008 and 2009 were 52.63%, 65.22%, 51.11% and 70.83%, respectively. Five modifying enzyme genes (aac(3)-I, detection rate of 65.69%; aac(6')-Ib, detection rate of 45.10%; aph(3')-I, detection rate of 47.06%; aph(3')-IIb, detection rate of 0.98%; ant(3″)-I, detection rate of 95.10%) and one methylase gene (armA, detection rate of 98.04%) were detected in the 102 A. baumannii with aac(3)-I+aac(6')-Ib+ant(3″)-I+armA (detection rate of 25.49%), aac(3)-I+aph(3')-I+ant(3″)-I+armA (detection rate of 21.57%) and ant(3″)-I+armA (detection rate of 12.75%) being the most prevalent gene profiles. The values of chi-square tests showed correlation of armA, ant(3″)-I, aac(3)-I, aph(3')-I and aac(6')-Ib with HLAR. armA had significant correlation (contingency coefficient 0.685) and good contingency with HLAR (kappa 0.940). The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A. baumannii infections. As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides (gentamicin, amikacin, tobramycin, etc), the function of aminoglycoside modifying enzyme gene(s) in A. baumannii carrying armA deserves further investigation.