OBJECTIVE To analyze the influencing factors for achieving target plasma drug concentration （trough） （abbreviated as “PDC”） of vancomycin in patients from high-altitude regions and establish a predictive model for PDC using single- center data， providing references for rational clinical drug use. METHODS Inpatients with vancomycin （1 g， q12 h） administered intravenously in our hospital from January 2021 to June 2024 were retrospectively included. Demographic data， liver and kidney function and hematological indexes were collected. Spearman correlation analysis was used to evaluate the correlation between vancomycin PDC and each detection index. Univariate analysis was used to evaluate the differences of each index in patients with different PDC， and the effects of different gender， body mass index， age and underlying diseases （hypertension/diabetes） on vancomycin PDC. Based on the results of correlation analysis and univariate analysis， multiple linear stepwise regression analysis was used to obtain the independent predictors of vancomycin PDC and construct the prediction model. RESULTS A total of 141 patients were included， with an overall attainment rate of 46.81% for the target PDC of vancomycin. Correlation analysis showed that the vancomycin PDC was positively correlated with age， blood urea nitrogen， uric acid （UA）， serum creatinine （CRE） and β2- microglobulin （β2-MG）， and negatively correlated with height， weight， creatinine clearance rate （CCR）， glomerular filtration rate （GFR）， alanine transaminase （ALT）， hemoglobin （HGB）， white blood cell count and neutrophils （P＜0.05）. There were significant differences in age， CRE and other 14 indexes among different PDC groups （P＜0.05 or P＜0.01）. Age and underlying diseases had significant effects on vancomycin PDC （P＜0.05 or P＜0.01）. CCR， direct bilirubin （DBil）， β2-MG， UA， HGB and height （standardized coefficients were －0.371， 0.367， 0.169， 0.232， －0.140， －0.132； P＜0.05） were independent predictors of vancomycin PDC. The F value of the regression equation was 34.858 （P＜0.05）， the R2 was 0.610， and the adjusted R2 was 0.592. CONCLUSIONS The vancomycin PDC of patients in high-altitude regions is affected by multiple factors such as renal function， liver function and hematological indexes. CCR， HGB and height could be used to predict vancomycin PDC negatively， while DBil， β2-MG and UA could be used to predict vancomycin PDC positively. The variables of the established prediction model could explain 59.2% of the variation of vancomycin PDC.

Meropenem （MEM） is one of the important drugs for the treatment of severe infections， but the standard dose is often difficult to achieve an effective therapeutic concentration target. This article reviews the related studies on the population pharmacokinetics of MEM in patients with severe infection. It is found that the apparent volume of distribution （Vd） and clearance rate are the most important factors affecting the dose adjustment， and the factors affecting Vd include serum albumin， age， overall weight， shock status， and chest/abdomen/cerebrospinal fluid drainage. The main factors affecting the clearance rate were renal function， renal replacement therapy treatment mode and combination therapy. For adult patients with severe infections in China， MEM is recommended to be administered in an individualized manner based on glomerular filtration rate， with a dosage range of 500 to 1 500 mg given every 4 to 6 hours， and prolonged infusion is preferred. When the minimum inhibitory concentration （MIC） of the pathogenic bacteria reaches 64 mg/L， therapeutic drug monitoring is required. For therapeutic efficacy， it is essential to ensure that the trough concentration remains above the MIC； to prevent drug resistance， it should be maintained above 4×MIC. Regarding safety， it is recommended that the upper limit of the trough concentration be 32 mg/L， and blood sampling for monitoring can be conducted as early as after 1 to 2 doses of administration.

Background and purpose:Colorectal cancer(CRC)is one of the major malignant tumors threatening human health worldwide,with long-term high incidence and mortality rate.Potassium channel modulatory factor 1(KCMF1)is a member of the E3 ubiquitin ligase family.It binds to target proteins through the RING domain and participates in the regulation of a variety of biological processes in vivo.However,the function of KCMF1 in CRC remains unclear.This study aimed to investigate the expression level of E3 ubiquitin ligase KCMF1 in colorectal tumor,and to explore the effects of KCMF1 on the proliferation of CRC cells and its underlying molecular mechanism.Methods:The The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression(GTEx)databases were used to analyze the expression level of KCMF1 in CRC tissues and adjacent tissues and the association between the KCMF1 expression and the prognosis of CRC patients.Furthermore,immunohistochemical staining was performed to detect the protein level of KCMF1 in 90 paired human CRC tissues and adjacent non-tumor tissues.Lentiviral shRNA delivery system was employed to specifically target the KCMF1 gene(shKCMF1)in HCT116 and HCT15 CRC cell lines.The effects of KCMF1 knockdown on cell proliferation,apoptosis and cell cycle distribution were assessed by methyl thiazoyl terazolium(MTT)assay,colony formation assay,Western blot and flow cytometry.Changes in the transcriptional profile in HCT116 cells upon KCMF1 knockdown were identified by RNA sequencing(RNA-Seq),and the affected signaling pathways were evaluated by bioinformatics analysis.Real-time fluorescence quantitative polymerase chain reaction(RTFQ-PCR),Western blot,luciferase reporter assay and cell immunofluorescence assay were utilized to validate the alteration of the affected signaling pathway.Results:The TCGA and GTEx databases and IHC results showed that the mRNA and protein expression levels of KCMF1 in CRC tissues were significantly upregulated compared with adjacent tissues(P＜0.01).KCMF1 expression level was negatively correlated with the survival time of patients with CRC(P＜0.01),and was positively associated with CRC clinical stage(P＜0.05).Compared with control cells,KCMF1 knockdown significantly inhibited the proliferation of HCT116 and HCT15 cells(P＜0.001),induced cell apoptosis(P＜0.001),and led to cell cycle arrest in G1 phase(P＜0.01).RNA-Seq analysis showed that KCMF1 was involved in the regulation of several signaling pathways,including nuclear factor-κB(NF-κB)signaling pathway.KCMF1 knockdown reduced the transcription levels of the target genes of NF-κB signaling pathway,including BCL-XL,XIAP and CIAP(P＜0.05),and suppressed the expression of phosphorylated p65 and nuclear translocation of p65(P＜0.01).Meanwhile,the activity of NF-κB reporter was reduced in tumor cells upon KCMF1 knockdown(P＜0.01).Conclusion:The expression of KCMF1 is significantly upregulated in human CRC tissues and positively associated with advanced clinical stage and poor prognosis.KCMF1 may promote the proliferation of CRC cells by activating the NF-κB signaling pathway.KCMF1 may be a potential new therapeutic target for CRC.

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.

Objective:To study the classification of persistent fifth aortic arch (PFAA) and the value of echocardiography in the diagnosis of PFAA.Methods:A total of 16 cases (male 6, female 10, at ages from 7 days to 4 years and 2 months old, the median age was 3 months) diagnosed with PFAA in Beijing Children′s Hospital Affiliated to Capital Medical University from January 2013 to June 2019 were studied retrospectively. The diagnosis standard, differential methods and misdiagnosed analysis of different subtypes of PFAA by echocardiography were summarized and analyzed.Results:The 16 cases included 1 case of type A1 double lumen aortic arch, 8 cases of type A2 single-lumen aortic arch, 3 cases of type B1 with pulmonary atresia and 4 cases of type B3 pulmonary artery branch arising from the distal end of ascending aorta. Only one patient of double lumen aortic arch missed diagnosis by echocardiography, and the rest were accurately diagnosed by echocardiography. CTA was performed in 13 cases, including 9 cases of type A, 1 case of type B1 and 3 cases of type B3, which confirmed the echocardiography diagnosis. Seven cases of Type A2 were operated.Conclusions:PFAA is a rare and complicated aortic arch malformation, which is divided into four major classification and multiple subtypes. Echocardiography can diagnose the PFAA and its classification, it is of great clinical significance for the early diagnosis, treatment and prognosis of children.

OBJECTIVE: To compare various models of diffusion-weighted imaging including monoexponential apparent diffusion coefficient (ADC), biexponential (fast diffusion coefficient [Df], slow diffusion coefficient [Ds], and fraction of fast diffusion), stretched-exponential (distributed diffusion coefficient and anomalous exponent term [α]), and kurtosis (mean diffusivity and mean kurtosis [MK]) models in the differentiation of renal solid masses. MATERIALS AND METHODS: A total of 81 patients (56 men and 25 women; mean age, 57 years; age range, 30–69 years) with 18 benign and 63 malignant lesions were imaged using 3T diffusion-weighted MRI. Diffusion model selection was investigated in each lesion using the Akaike information criteria. Mann-Whitney U test and receiver operating characteristic (ROC) analysis were used for statistical evaluations. RESULTS: Goodness-of-fit analysis showed that the stretched-exponential model had the highest voxel percentages in benign and malignant lesions (90.7% and 51.4%, respectively). ADC, Ds, and MK showed significant differences between benign and malignant lesions (p < 0.05) and between low- and high-grade clear cell renal cell carcinoma (ccRCC) (p < 0.05). α was significantly lower in the benign group than in the malignant group (p < 0.05). All diffusion measures showed significant differences between ccRCC and non-ccRCC (p < 0.05) except Df and α (p = 0.143 and 0.112, respectively). α showed the highest diagnostic accuracy in differentiating benign and malignant lesions with an area under the ROC curve of 0.923, but none of the parameters from these advanced models revealed significantly better performance over ADC in discriminating subtypes or grades of renal cell carcinoma (RCC) (p > 0.05). CONCLUSION: Compared with conventional diffusion parameters, α may provide additional information for differentiating benign and malignant renal masses, while ADC remains the most valuable parameter for differentiation of RCC subtypes and for ccRCC grading.
Carcinoma, Renal Cell ; Diffusion ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; ROC Curve

Objective To explore the appropriate nursing care of acute hyperlipidemic pancreatitis and increase nursing level.Methods The clinical data of 3 cases of hyperlipidemic pancreatitis misdiagnosed as acute appendicitis were analyzed retrospectively and the nursing experience was summarized.Results The blood sample of all 3 cases represented dramatically high level of serum triglyceride (14.1～61.0 mmol/L).Obvious inducing factors were observed in one case.Besides upper abdominal symptom and physical sign continued in spite of the right lower abdominal discomfort,ascites was discovered by early B-ultrasound.There was no significant increase of serum or urine amylase.After correct diagnosis,all of the 3 cases recovered well by close observation,mental nursing,anti-hyperlipidemic nursing,drainage nursing and health education.Conclusions The knowledge of hyperlipidemic pancreatitis should be well understood during nursing practice.Comprehensive nursing evaluation and close observation can help doctors to analyze and estimate the disease.Integrated nursing techniques can accelerate the recovery of the patients.Health education,anti-hyperlipidemic therapy,and removal of the inducing factors are the keys of prevention.

BACKGROUND: Neuroprotective role of hypothermia on cerebral ischemic-reperfusional impairment has been long acknowledged. Since general hypothermia is complicated and unfit for observing postoperative consciousness and neurological function, it is of important significance to explore novel methods of focal cerebral hypothermia.OBJECTIVE: To study the neuroprotective effect of lateral ventricle infusion of low-temperature fluid on ischemic neurons of middle cerebral artery (MAC) occlusion models established on New Zealand rabbits.DESIGN: A randomized case-control study based on experimental animal models.SETTING: Neurosurgical department and pathological department of a general military hospital of Chinese PLA.MATERIALS: This study was carried out at Neurosurgical Laboratory of Nanjing General Hospital, Nanjing Military Area Command of Chinese PLA. Altogether 18 healthy New Zealand male rabbits, weighing from 2. 8 to 3.2 kg, were selected 4 - 6 months after birth, and randomly divided into occlusion group, hypothermia group and control group.INTERVENTIONS: Cerebral focal ischemic-reperfusional model was established on the New Zealand rabbits through MCA occlusion for 2 hours followed by reperfusion for 24 hours.MAIN OUTCOME MEASURES: Scores for neurological function, water content in the left and right brain, pathological changes of nerve cells in the left MCA supplying region.pothermia group, significantly higher than that in occlusion group(7.58 ± 0.58 )( P ＜ 0.01 ), but no significant difference could be observed in contrast with brain was(81.64 ± 0.82)% and (79.26 ± 1.30)% in occlusion and hypothermia groups with significant difference between them( P ＜ 0.05), and it was significantly different between the left side [ (81.64 ± 0. 82 )% ] and opyknosis and deep staining could be observed in nerve ganglion cells in occlusion group under optical microscope, but no obvious pathological changes were observed in MCA supplying brain regions in hypothermia group.CONCLUSION: Permanent infusion of low-temperature fluid into the lateral ventricle plays an important neuroprotective role by attenuating cerebral ischemic-reperfusional impairment and improving post-ischemic neurological functions.

Objective: To explore the effects of continuous trickle of low temperature liquids through the lateral ventricle on neural cell apoptosis after rabbit local cerebral ischemia/reperfusion. Methods:The middle cerebral artery (MCA) of New Zealand rabbit was clipped by micro aneurysm clip for 2 hours and reperfused for 24 hours. Immediately after clipping the MCA, we trickled the left lateral ventricle continuously with low temperature liquids(22℃) to decrease the brain temperature to mild hypothermia (33℃-35℃)and maintained for 2 hours. After reperfusion for 24 hours , we assessed TUNEL method to determine the apoptotic cell rate in the sham-operated group, the control group and the mild hypothermia group respectively. Results:The apoptotic cell rate of the cortex tissues accommodated by MCA in the mild hypothermia group was obviously lower than that in the control group(P0.05). Conclusion:Trickling ventricle with low temperature liquids could decrease the apoptotic cell rate and alleviate cerebral ischemia/reperfusion injury.

Objectives:To explore the protective effects of continuous trickle of low temperature liquids through the lateral ventricle on neurons after rabbit local cerebral ischemia reperfusion. Methods: The middle cerebral artery (MCA) of New Zealand rabbit was clipped with micro aneurysm clip for 2 hours and reperfused for 24 hours. Immediately after clipping the MCA, we trickled the left lateral ventricle continuously with low temperature liquids to decrease the brain temperature to mild hypothermia(32-35℃) and maintained for 2 hours. After reperfusion for 24 hours, we assessed the animal's neural deficits, observe the pathology of the ischemic brain tissues dyed by HE and determined the dry wet ratio for brain edema in the sham operated group, the control group and the mild hypothermia group respectively.Results:①The grades of neural deficits in mild hypothermia group were obviously lower than that in the clipping group( P 0.05 );②The dry wet ratios were obviously different in the mild hypothermia group and clipping group;③ Pyknosis and dense dying by HE were observed in the neural nuclei of ischemic cortex tissues of the clipping group, but no obvious changes were observed in the mild hypothermia group. Conclusions:Trickling ventricle with low temperature liquids could alleviate cerebral ischemia reperfusion injury, ameliorated neural deficit after ischemia reperfusion and were protective on the brain.