Chronic kidney disease(CKD)comprises a group of clinical syndromes affecting kidney structure and function,with various causes,high treatment costs,and a poor prognosis.Epigenetic modification of gene expression and cell function has been shown to play a key regulatory role in the occurrence and development of CKD.Homocysteine(Hey)is a common amino acid-containing thiol group in the body.Hyperhomocysteinemia(HHcy)is a damaging condition involving many organs,and is an independent predictor of end-stage renal disease morbidity and mortality.This review considers the relationship between HHcy and chronic renal injury,and examines research progress in the role of epigenetic modification in the mechanism of Hcy-mediated chronic renal injury,with the aim of furthering our understanding of the occurrence and development of CKD.This process and its mechanism provide new ideas and a theoretical basis for further research into CKD.

OBJECTIVE To analyze the clinical characteristics of the patients with severe infections who were treated with polymyxin B and compare the plasma concentration of polymyxin B among the patients with severe infections with different creatinine clearance rates(Ccr).METHODS The clinical data were collected from 152 patients with severe infections who were treated with intravenous polymyxin B in intensive care unit(ICU)of Zhongda Hospital Affiliated to Southeast University from Jan.2021 to Mar.2023.The trough concentration(Cmin),median concen-tration(C1/2t)and peak concentration(Cmax)of polymyxin B were determined after 5 doses were completed.Based of the area under the curve(AUC)of drug concentration of polymyxin B(AUC0～24h)combined with the Ccr level[the ≤30 to＜60 ml/min group(n=40),the 60 to＜130ml/min group(n=79),and the ≥ 130ml/min group(n=33)],the AUC0～24h of polymyxin B were calculated,and the influence of Ccr on the plasma concentration was observed.RESULTS Among the 152 patients with severe infections,118 were male,and 34 were female,with the age ranging between 20 and 90 years old;the patients with high blood pressure accounted for 14.47％(22/152),the patients with diabetes mellitus 7.24％(11/152).Polymyxin B is primarily used in clinical settings for the treatment of pulmonary infections and bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae.The median initial dose and the median maintenance dose were 1.35(1.00,1.67)mg/kg q12 h and 1.07(0.83,1.25)mg/kg q12 h,respectively.The median AUC0～24h of polymyxin B was 76.57(54.65,106.47)μg·h/ml among the 152 patients,and the patients with AUC0～24 h ranging between 50 and 100 μg·h/ml accounted for 53.95％(82/152).Although the median AUC0～24h of polymyxin B of all the three groups ranged between 50 and 100)μg·h/ml,there were significant differences in Cmin,C1/2t,Cmax and AUC0～24h among the three groups(P＜0.05).In addition,there were significant differences in the AUC0～24h of polymyxin B less than 50 μg·h/ml,ranging between 50 and 100 μg·h/ml and more than 100 μg·h/ml among the three groups of patients(x2=21.632,P＜0.001).CONCLUSION Therapeutic drug monitoring(TDM)is nec-essary for the patients with severe infection who receive the polymyxin B for treatment,especially for the patients with Ccr ≤30 to＜60 ml/min and Ccr ≥130 ml/min.

Chronic kidney disease(CKD)comprises a group of clinical syndromes affecting kidney structure and function,with various causes,high treatment costs,and a poor prognosis.Epigenetic modification of gene expression and cell function has been shown to play a key regulatory role in the occurrence and development of CKD.Homocysteine(Hey)is a common amino acid-containing thiol group in the body.Hyperhomocysteinemia(HHcy)is a damaging condition involving many organs,and is an independent predictor of end-stage renal disease morbidity and mortality.This review considers the relationship between HHcy and chronic renal injury,and examines research progress in the role of epigenetic modification in the mechanism of Hcy-mediated chronic renal injury,with the aim of furthering our understanding of the occurrence and development of CKD.This process and its mechanism provide new ideas and a theoretical basis for further research into CKD.

OBJECTIVE To analyze the clinical characteristics of the patients with severe infections who were treated with polymyxin B and compare the plasma concentration of polymyxin B among the patients with severe infections with different creatinine clearance rates(Ccr).METHODS The clinical data were collected from 152 patients with severe infections who were treated with intravenous polymyxin B in intensive care unit(ICU)of Zhongda Hospital Affiliated to Southeast University from Jan.2021 to Mar.2023.The trough concentration(Cmin),median concen-tration(C1/2t)and peak concentration(Cmax)of polymyxin B were determined after 5 doses were completed.Based of the area under the curve(AUC)of drug concentration of polymyxin B(AUC0～24h)combined with the Ccr level[the ≤30 to＜60 ml/min group(n=40),the 60 to＜130ml/min group(n=79),and the ≥ 130ml/min group(n=33)],the AUC0～24h of polymyxin B were calculated,and the influence of Ccr on the plasma concentration was observed.RESULTS Among the 152 patients with severe infections,118 were male,and 34 were female,with the age ranging between 20 and 90 years old;the patients with high blood pressure accounted for 14.47％(22/152),the patients with diabetes mellitus 7.24％(11/152).Polymyxin B is primarily used in clinical settings for the treatment of pulmonary infections and bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae.The median initial dose and the median maintenance dose were 1.35(1.00,1.67)mg/kg q12 h and 1.07(0.83,1.25)mg/kg q12 h,respectively.The median AUC0～24h of polymyxin B was 76.57(54.65,106.47)μg·h/ml among the 152 patients,and the patients with AUC0～24 h ranging between 50 and 100 μg·h/ml accounted for 53.95％(82/152).Although the median AUC0～24h of polymyxin B of all the three groups ranged between 50 and 100)μg·h/ml,there were significant differences in Cmin,C1/2t,Cmax and AUC0～24h among the three groups(P＜0.05).In addition,there were significant differences in the AUC0～24h of polymyxin B less than 50 μg·h/ml,ranging between 50 and 100 μg·h/ml and more than 100 μg·h/ml among the three groups of patients(x2=21.632,P＜0.001).CONCLUSION Therapeutic drug monitoring(TDM)is nec-essary for the patients with severe infection who receive the polymyxin B for treatment,especially for the patients with Ccr ≤30 to＜60 ml/min and Ccr ≥130 ml/min.

Objective To investigate the mechanism of iron death induced by TRPC6/NF-κB in glomerular podiocytes mediated by high homocysteine(Hcy).Methods Mouse glomerulopocytes were cultured in vitro and divided into Control group(0 μmol/L Hcy)and Hcy group(80 μmol/L Hcy).After 48h of intervention,Western blot was used to detect the expression levels of iron death related proteins GPX4 and SLC7A11 and TRPC6 and NF-κ B.Real-time quantitative fluorescence PCR(qRT-PCR)and immunofluorescence were used to detect the expression of TRPC6.The level of podocyte apoptosis was detected by flow cytometry.Malondialdehyde(MDA)assay kit was used to determine intracellular MDA levels.After transfection of TRPC6 interference fragment and TRPC6 negative control(NC),qRT-PCR was divided into Control,si-NC and si-TRPC6(Si-TRPC6-1,Si-TRPC6-2,Si-TRPC6-3).Western Blot was divided into Control,Hcy,si-NC+Hcy,si-TRPC6+Hcy.The expression of TRPC6 mRNA was detected by qRT-PCR.The expression levels of GPX4,SLC7A11,NF-κB and TRPC6 were detected by Western Blot.The level of podocyte apoptosis after interference was detected by flow cytometry.Results(1)Compared with Control group,the expression levels of iron death related proteins GPX4 and SLC7A11 in Hcy group were decreased,and the apoptosis rate was increased(P<0.05).(2)Compared with Control group,TRPC6 protein,mRNA levels and immunofluorescence expression were increased in Hcy group.The level of MDA and the expression of NF-κB signaling pathway protein increased in Hcy group,and the comparison between the two groups had statistical significance(P<0.05).(3)Compared with the si-NC group,the mRNA expression level of TRPC6 in si-TRPC6(Si-TRPC6-1,Si-TRPC6-2,Si-TRPC6-3)group was decreased,and the interference effect of Si-TRPC6-3 was the best(P<0.05).After transfecting TRPC6 NC and TRPC6 interference fragment and administering Hcy,there was no difference in GPX4,SLC7A11,NF-κB and TRPC6 expression in si-NC+Hcy group compared with Hcy group.Compared with the si-NC+Hcy group,the si-TRPC6+Hcy group had higher expression of iron death related proteins,GPX4 and SLC7A11,lower expression of NF-κB and TRPC6,and decreased apoptosis rate(P<0.05).Conclusion This study confirmed that TRPC6/NF-κB can regulate iron death of renal podocytes under the induc-tion of Hcy,which is one of the mechanisms leading to kidney injury.

Objective To investigate the role of lncRNA SNHG1 in homocysteine-induced pyroptosis of podocyte.Methods Cbs+/-mice were randomly divided into two groups:a normal diet group(ND)and a high me-thionine diet group(HMD).Western blotting was used to detect the protein expression levels of Caspase-1,Cleaved Caspase-1,and NLRP3.Mouse renal glomerular podocytes were cultured in vitro,and then assigned into a control group(Control,0 μmol/L Hcy)and a homocysteine intervention group(Hcy,80 μmol/L Hcy).Western blotting was used to detect the protein expression levels of Caspase-1,Cleaved Caspase-1,and NLRP3.Mouse renal glomerular podocyion group(OE-NC + Hcy)and the lncSNHG1 overexpression + homocysteine intervention group(OE-SNHG1 + Hcy)were also established.After 48 hours of intervention,Real-time fluorescence quantita-tive PCR was used to detect the expression of lncSNHG1 in podocytes after Hcy intervention.Western blot was used to detect the expressions of Caspase-1,Cleaved Caspase-3 and NLRP3.Immunofluorescence was used to de-tect the expression levels of GSDMD and GSDMD-N.ELISA was used to detect the contents of IL-1β and IL-18.Results(1)In the animal experiments,the expression levels of pyroptosis-related proteins Caspase-1,Cleaved Caspase-1,NLRP3,GSDMD,and GSDMD-N were all increased in the HMD group compared with the ND group.(2)In the cellular experiments,the expression levels of Caspase-1,Cleaved Caspase-1,NLRP3,GSDMD,and GSDMD-N were all increased in the Hcy group compared with the Control group,and the contents of pyroptosis-mediated inflammatory factors IL-1β and IL-18 were increased as well.(3)In the cellular experiments,the expres-sion of lncSNHG1 was increased in the Hcy group compared with the control group.After transduction with lnc-SNHG1 lentivirus,the expression of lncSNHG1 was increased in the OE-SNHG1 group,compared with the control group and the OE-NC group.(4)In the cellular experiments,the expressions of pyroptosis-related proteins Cas-pase-1,Cleaved Caspase-1,NLRP3,GSDMD,and GSDMD-N were increased compared with the OE-NC+Hcy group,and the contents of pyroptosis-mediated inflammatory factors IL-1β and IL-18 were increased in the OE-SNHG1+Hcy group.Conclusion These results indicate that lncSNHG1 may play a role in promoting Hcy induced podocytepyroptosis.

Objective:To explore the clinical characteristics of tigecycline-associated hypofibrinogenemia in critically ill patients, and analyze risk factors for its occurrence.Methods:Clinical data of patients treated with tigecycline in the Intensive Care Unit (ICU) at Zhongda Hospital Affiliated to Southeast University from January 2021 to December 2022 were collected and retrospectively analyzed. Patients were divided into hypofibrinogenemia group and non-hypofibrinogenemia group according to their fibrinogen levels. General information, laboratory tests results, tigecycline application, combined drugs, and blood concentration of tigecycline were compared between the 2 groups. Variables with P<0.10 in intergroup comparisons were included in a multivariate logistic regression model to analyze the risk factors for tigecycline-associated hypofibrinogenemia, and odds ratios ( OR) and its 95% confidence intervals ( CI) were calculated. Results:A total of 79 patients using tigecycline were collected, including 43 cases with hypofibrinogenemia and 36 cases without hypofibrinogenemia. Univariate analysis showed that the differences in patients with diabetes [41.9%(18/43) vs. 16.7%(6/36)], acute kidney injury [41.9%(18/43) vs. 19.4%(15/36)], and baseline fibrinogen (before tigecycline treatment) ≤4 g/L [37.2%(16/43) vs. 16.7%(6/36)] between the 2 groups were statistically significant (all P<0.05). The related factors ( P<0.10) of the 2 groups, including diabetes, acute renal injury, continuous renal replacement therapy, baseline FIB ≤4 g/L (before using tigecycline), larger total dose of tegacycline and longer treatment duration, were included in the multivariate logistic regression analysis. The results showed that diabetes ( OR=4.851, 95% CI: 1.180-19.494, P=0.029), continuous renal replacement therapy ( OR=8.610, 95% CI: 1.987-37.311, P=0.004), and longer treatment duration ( OR=1.452, 95% CI: 1.018-2.071, P=0.040) were independent risk factors for tigecycline-related hypofibrinogenemia. Conclusion:In critically ill patients, with diabetes, continuous renal replacement therapy, and longer treatment duration of tigecycline may increase the risk of hypofibrinogenemia.

Objective:To explore the clinical characteristics of tigecycline-associated hypofibrinogenemia in critically ill patients, and analyze risk factors for its occurrence.Methods:Clinical data of patients treated with tigecycline in the Intensive Care Unit (ICU) at Zhongda Hospital Affiliated to Southeast University from January 2021 to December 2022 were collected and retrospectively analyzed. Patients were divided into hypofibrinogenemia group and non-hypofibrinogenemia group according to their fibrinogen levels. General information, laboratory tests results, tigecycline application, combined drugs, and blood concentration of tigecycline were compared between the 2 groups. Variables with P<0.10 in intergroup comparisons were included in a multivariate logistic regression model to analyze the risk factors for tigecycline-associated hypofibrinogenemia, and odds ratios ( OR) and its 95% confidence intervals ( CI) were calculated. Results:A total of 79 patients using tigecycline were collected, including 43 cases with hypofibrinogenemia and 36 cases without hypofibrinogenemia. Univariate analysis showed that the differences in patients with diabetes [41.9%(18/43) vs. 16.7%(6/36)], acute kidney injury [41.9%(18/43) vs. 19.4%(15/36)], and baseline fibrinogen (before tigecycline treatment) ≤4 g/L [37.2%(16/43) vs. 16.7%(6/36)] between the 2 groups were statistically significant (all P<0.05). The related factors ( P<0.10) of the 2 groups, including diabetes, acute renal injury, continuous renal replacement therapy, baseline FIB ≤4 g/L (before using tigecycline), larger total dose of tegacycline and longer treatment duration, were included in the multivariate logistic regression analysis. The results showed that diabetes ( OR=4.851, 95% CI: 1.180-19.494, P=0.029), continuous renal replacement therapy ( OR=8.610, 95% CI: 1.987-37.311, P=0.004), and longer treatment duration ( OR=1.452, 95% CI: 1.018-2.071, P=0.040) were independent risk factors for tigecycline-related hypofibrinogenemia. Conclusion:In critically ill patients, with diabetes, continuous renal replacement therapy, and longer treatment duration of tigecycline may increase the risk of hypofibrinogenemia.

OBJECTIVE: To explore the genetic basis for a child with mental retardation. METHODS: Whole exome sequencing was carried out for the child. Candidate variant was screened based on his clinical features and verified by Sanger sequencing. RESULTS: The child was found to harbor a c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant in the SYNGAP1 gene. Bioinformatic analysis suggested it to be pathogenic. The same variant was not detected in either parent. CONCLUSION The c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant of the SYNGAP1 gene probably underlay the mental retardation in this child. Above finding has expanded the spectrum of SYNGAP1 gene variants and provided a basis for the diagnosis and treatment for this child.
Child ; Humans ; Intellectual Disability/genetics* ; Frameshift Mutation ; High-Throughput Nucleotide Sequencing ; Computational Biology ; Heterozygote ; Mutation ; ras GTPase-Activating Proteins/genetics*

Anaplastic lymphoma kinase (ALK) fusions represent the second most common oncogenic driver mutation in non-small cell lung cancer (NSCLC). As the new class of 3rd generation of ALK tyrosine kinase inhibitor (TKI), lorlatinib has shown robust potency and brain-penetrant clinical activity against a wide spectrum of multiple resistance mutations within the ALK domain detected during crizotinib and 2nd generation ALK TKI treatment. Lorlatinib is generally well-tolerated with unique adverse drug reaction/adverse event, including hyperlipidemia and central nervous system effects, which are mostly mild to moderate severity and manageable through dosage modifications and/or standard medical intervention. For advanced NSCLC with ALK positivity, patients should be evaluated for baseline characteristics and pre-existing medication, informed of the potential toxicities, and periodically monitored to balance benefits and risks. Moreover, a multidisciplinary group of experts is essential to establish a comprehensive diagnostic and therapeutic strategy.
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Aminopyridines ; Carcinoma, Non-Small-Cell Lung/pathology* ; China ; Consensus ; Drug Resistance, Neoplasm/genetics* ; Drug-Related Side Effects and Adverse Reactions/drug therapy* ; Humans ; Lactams ; Lactams, Macrocyclic/adverse effects* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/adverse effects* ; Protein-Tyrosine Kinases/genetics* ; Pyrazoles