Physiological pharmacokinetic model of children and its application of modeling software / 药学学报

Developmental changes in children can affect drug disposition and clinical effects. A physiologically-based pharmacokinetic (PBPK) model is a mathematical model that can be used to predict blood drug concentrations in children and gain insight into age-dependent physiological differences in drug disposition impact. Pediatric PBPK (P-PBPK) models have attracted attention over the past decade. With the concerted efforts of academia, pharmaceutical companies, and regulatory agencies, there are more and more examples of pediatric clinical studies using PBPK models. Nevertheless, the number of P-PBPK models and their predictive performance still lag behind adult models. By referring to the literature, we study the process of children adapting to adult absorption, distribution, metabolism, and excretion (ADME) parameters and analyze the general principles of P-PBPK model establishment. In addition, we summarize the functions and application examples of commonly used P-PBPK modeling software to provide a basis for the rational application of modeling software.

Mechanism of Dihuang Yinzi in Improving Astrocyte Injury and Regulating Synaptic Structure and Function in AD Mice / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Dihuang Yinzi in improving astrocyte injury and protecting synaptic structure and function in the brain of Alzheimer's disease （AD） mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. The learning and memory ability of mice was tested by the light-dark box test and Y-maze spontaneous alternation test. The content of glutamate （Glu） and glutamine （Gln） was measured by liquid chromatography-tandem mass spectrometry （LC-MS）. Long-term potentiation （LTP） assay was used to detect synaptic plasticity in brain tissues. The protein expression levels of excitatory amino acid transporter 2 （EAAT2）， postsynaptic density protein95 （PSD95）， and synaptophysin （SYN） in brain tissues were measured by Western blot. Immunofluorescence was used to assess the localization and expression of EAAT2. Colorimetry was performed to detect Na+-K+ ATPase activity in mouse brain tissues. ResultAs compared with the control group， the model group showed shortened residence latency （P<0.01）， increased number of errors （P<0.01） in the light-dark box test， reduced spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， down-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， blunted activity of Na+-K+ ATPase （P<0.01）， up-regulated Glu level （P<0.01）， down-regulated Gln level （P<0.01）， and reduced relative population spike （PS） amplitude and the slope of excitatory postsynaptic potential （EPSP） （P<0.05， P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group displayed prolonged residence latency （P<0.05）， decreased number of errors （P<0.01） in the light-dark box test， increased spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， up-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， potentiated activity of Na+-K+ ATPase （P<0.01）， reduced Glu level （P<0.01）， up-regulated Gln level （P<0.01）， and increased PS amplitude and EPSP slope （P<0.01）. ConclusionDihuang Yinzi can improve cognitive dysfunction in AD mice by protecting astrocytes， increasing Glu uptake to reduce its abnormal accumulation， and protecting synaptic structure and function.

Mechanism of Dihuang Yinzi in Improving Energy Metabolism Disorder and Autophagy Injury of Astrocytes in Brain of AD Mice / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Dihuang Yinzi （DHYZ）in improving astrocyte injury in the brain and regulating energy metabolism and autophagy disorder in Alzheimer's disease （AD） model mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + DHYZ group （2.5 g·kg-1）， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + DHYZ group （2.5 g·kg-1）， with 20 mice in each group. The mice in the control group and the model group were administered with an equal volume of sterilized normal saline by gavage， once a day for 150 days. Novel object recognition test and step-down test were performed to evaluate the learning and memory ability of mice. The expression of glial fibrillary acidic protein （GFAP） in astrocytes was detected by immunofluorescence and Western blot. High-performance liquid chromatography （HPLC） was used to detect adenosine triphosphate （ATP）， adenosine diphosphate （ADP）， and adenosine monophosphate （AMP） in brain tissues of mice， and the data obtained were used to calculate energy charge （EC） levels. The phosphorylation levels of liver kinase B1 （LKB1）， adenosine 5′-monophosphate （AMP）-activated protein kinase （AMPK）， UNC-51-like kinase 1 （ULK1）， and mammalian target of rapamycin （mTOR） and the expression levels of autophagy-related proteins Beclin-1， microtuble-associated protein 1 light chain 3 （LC3）-Ⅱ/LC3-Ⅰ， and p62 in mouse brain were measured by Western blot. ResultCompared with the control group， the model group showed decreased novel object recognition index， shortened retention latency， increased error times in the step-down test， up-regulated protein expression of GFAP， decreased content of ATP， ADP， and EC in brain tissues， elevated AMP ， increased levels of p-AMPK， p-LKB1， and p-mTOR， and protein expression of p62 ， and down-regulated p-ULK1 level and protein expression of Beclin-1 and LC3-Ⅱ/LC3-Ⅰ（P<0.01）， while the above experimental indexes were not significantly different in the control + DHYZ group. Compared with the model group， the model + DHYZ group showed increased novel object recognition index（P<0.05）， prolonged retention latency（P<0.01）， decreased error times（P<0.01） in the step-down test， reduced protein expression of GFAP（P<0.05）， increased content of ATP， ADP， and EC in brain tissues （P<0.05， P<0.01）， decreased AMP content（P<0.05）， reduced p-AMPK， p-LKB1， and p-mTOR levels and protein expression of p62， and up-regulated p-ULK1 level and protein expression of Beclin-1 and LC3-Ⅱ/LC3-Ⅰ（P<0.01）. ConclusionBy protecting astrocytes， DHYZ can improve energy metabolism and autophagy disorder in AD mice to improve the learning and memory ability of model mice.

Mechanism of Dihuang Yinzi in Improving Astrocyte Injury and Glycolysis in AD Mice via PI3K/Akt Pathway / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Dihuang Yinzi in improving astrocyte injury and glycolysis in Alzheimer's disease （AD） mice via regulating the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， thereby improving the cognitive function of AD mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. Morris water maze test was performed to test the ability of navigation and space exploration of mice. The protein expression of p-PI3K， PI3K， p-Akt， Akt， phosphofructokinase-1 （PFK-1）， and aldehyde dehydrogenase 3 family member B2 （ALDH3B2） in mouse brain tissues was measured by Western blot. An immunofluorescence assay was performed to detect astrocyte morphology and the expression level of ALDH3B2. ResultAs compared with the control group， the model group showed prolonged escape latency during the 2nd to 5th days of the location-based navigation （P<0.05， P<0.01）， reduced number of times crossing the target area of the platform， shortened residence time in the target quadrant （P<0.05， P<0.01）， prolonged residence time in the opposite quadrant （P<0.05）， increased surface area of the cell body and total length of cell protrusions of astrocytes （P<0.05， P<0.01）， and down-regulated protein expression of p-PI3K， p-Akt， ALDH3B2， and PFK-1 （P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group showed shortened escape latency of APP/PS1 mice during the 2nd to 5th days of the location-based navigation （P<0.05， P<0.01）， increased number of times crossing the platform， prolonged target quadrant residence time （P<0.05， P<0.01）， shortened residence time in the opposite quadrant （P<0.05）， reduced surface area of the cell body and total length of cell protrusions of astrocytes （P<0.05）， and up-regulated protein expression of p-PI3K， p-Akt， ALDH3B2， and PFK-1 （P<0.01）. ConclusionDihuang Yinzi can improve the learning and memory ability of AD mice by activating the PI3K/Akt signaling pathway and up-regulating the protein expression of PFK-1 and ALDH3B2 to protect against astrocyte injury in brain tissues and improve glycolysis.

Effect of Astrocyte-neuron Coupling Imbalance in Development of Alzheimer's Disease and Intervention Mechanism of Kidney-tonifying and Marrow-filling TCM Prescriptions / 中国实验方剂学杂志

Astrocytes are important nerve cells in the central nervous system （CNS）， which mainly play a key role in nutrition and support. Astrocytes and neurons undergo close energy coupling and substance coupling， which are closely related and interact with each other. In recent years， many studies have shown that the astrocyte-neuron coupling imbalance plays a central role in the occurrence and progression of Alzheimer's disease （AD） and serves as an important therapeutic target receiving increasing attention. According to traditional Chinese medicine （TCM） theory， the main pathogenesis of AD is kidney deficiency and marrow inadequacy， and in clinical medication， kidney-tonifying and marrow-filling TCM prescriptions are often employed with satisfactory results achieved. As reported， many kidney-tonifying and marrow-filling prescriptions exhibit regulatory and protective effects on the imbalance of astrocyte-neuron coupling， suggesting that the effect of kidney-tonifying and marrow-filling prescriptions in treating AD may have some internal relationship with its regulation of the imbalance of astrocyte-neuron coupling. This article reviewed the underlying internal relationship between the imbalance of astrocyte-neuron coupling and the pathogenesis of kidney deficiency and marrow inadequacy in AD and the research progress in the intervention mechanism of TCM for tonifying the kidney and filling the marrow.

Proteinuria associated with hookworm infection: a case report / 中国血吸虫病防治杂志

As a common soil-borne nematode, hookworm is mainly parasitized in the intestine, and the clinical manifestations of hookworm infections mainly include gastrointestinal symptoms and iron-deficiency anemia. In addition, hookworm may be also parasitized in other organs in addition to gastrointestinal system, resulting in development of disorders in other systems. Proteinuria caused by hookworm infections is rare and easy to be misdiagnosed in clinical practices. Hereby, the diagnosis and treatment of a case of proteinuria associated with hookworm infections was reported, in order to increase the understanding of hookworm infection-associated proteinuria among clinicians.

Epidemiological characteristics and spatial clustering of scrub typhus in Nanjing from 2011 to 2020 / 中华地方病学杂志

Objective:To understand the reported incidence level, change of the trend, epidemic characteristics and spatial clustering of scrub typhus in Nanjing, to explore key seasons, populations and areas for prevention and control, and to guide formulation of scientific and precise prevention and control strategies and measures.Methods:The reported data of scrub typhus in Nanjing from January 1, 2011 to December 31, 2020 were collected in the "Infectious Disease Surveillance System" from Chinese Center for Disease Control and Prevention. The reported incidence level and change of the trend were analyzed, and the seasonal, population and spatial distribution characteristics were described. Global spatial autocorrelation analysis was carried out by ArcGIS 10.3 software, and the spatial clustering scanning was carried out by using FleXScan 3.1.2 software.Results:A total of 192 cases of scrub typhus were reported in Nanjing from 2011 to 2020. Median annual reported incidence was 0.21/100 000 (0.12/100 000 - 0.49/100 000). Totally 87.5% (168/192) of cases were reported from October to November, and the peak occurred in November (57.8%, 111/192). Among these cases, males accounted for 64.1% (123/192); and the median age was 59 years old (6 - 84 years old). The groups ≥60 years old and 45 - 59 years old accounted for 47.9% (92/192) and 31.2% (60/192), respectively, which accounted for 79.2% (152/192) in all groups. Farmers accounted for 43.8% (84/192), household chores and unemployed people accounted for 16.7% (32/192), retired persons accounted for 15.6% (30/192) and workers accounted for 6.8% (13/192), which accounted for 82.8% (159/192) in all occupations. The top four areas in the total number of reported cases were Jiangning District (23.4%, 45/192), Luhe District (22.9%, 44/192), Gulou District (10.4%, 20/192) and Jiangbei New Area (8.9%, 17/192), which accounted for 65.6% (126/192) in all districts. According to global spatial autocorrelation analysis, Moran's I = 0.34 ( Z = 5.90, P < 0.001). FlexScan 3.1.2 software scanned and detected two spatial clusters areas, the first-class of cluster area covered three streets in Jiangning District, one street in Yuhuatai District and two streets in Pukou District [restricted log likelihood ratio ( RLLR) = 26.91, P < 0.001]. The second-class of cluster area included six townships/streets in Luhe District and four streets in Jiangbei New Area ( RLLR = 26.48, P < 0.001). All the cluster areas were agriculture-related. Conclusions:The reported incidence level of scrub typhus in Nanjing is low and stable which belongs to a typical autumn epidemic area. The middle-aged and elderly population is the key population and the agriculture-related area is key area. It is suggested that scrub typhus should be included in the management of statutory or regional key infectious diseases in Nanjing. Additionally, training on diagnosis and treatment technology and information report management of scrub typhus need to be carried out, and comprehensive prevention and control interventions such as health education, personal protection, rodent prevention and control and vector control should be strengthened and implemented in the high incidence season.

Dosimetric comparison of intensity-modulated photon radiotherapy planning and intensity-modulated proton radiotherapy planning for glioma / 肿瘤研究与临床

Objective:To compare the dosimetric difference between intensity-modulated photon radiaotherapy (IMRT) planning and intensity-modulated proton radiotherapy (IMPT) planning for glioma.Methods:The clinical data of 15 glioma patients who underwent IMRT in ion medical center of the First Affiliated Hospital of USTC from November 2020 to April 2022 were retrospectively analyzed. IMRT planning and IMPT planning were designed for the image of each patient in the therapy planning system. Main dosimetric parameters were compared including plan target volume (PTV), coverage index (CI), dose homogeneity index (HI), and maximal dose (D max) and mean dose (D mean) of organs at risk between both plans. Results:There were no significant differences between IMRT planning and IMPT planning in terms of D max and D mean of PTV1 and PTV2, CI and HI (all P > 0.05). Compared with IMRT planning, brainstem D mean [6.92 GyE (0.09 GyE, 12.58 GyE) vs. 24.41 GyE (2.59 GyE, 34.18 GyE)], left optic nerve D max [0.78 GyE (0.04 GyE, 25.18 GyE) vs. 20.42 GyE (6.38 GyE, 37.17 GyE)], left optic nerve D mean [0.10 GyE (0.01 GyE, 11.63 GyE) vs. 9.74 GyE (2.99 GyE, 20.87 GyE)], right optic nerve D mean [1.57 GyE (0.13 GyE, 14.90 GyE) vs. 14.08 GyE (2.66 GyE, 23.67 GyE)], left len D max [0 GyE (0 GyE, 2.91 GyE) vs. 4.84 GyE (1.42 GyE, 5.48 GyE)], left len D mean [0 GyE (0 GyE, 1.73 GyE) vs. 3.84 GyE (1.25 GyE, 4.30 GyE)], right len D max [0.25 GyE (0.04 GyE, 4.55 GyE) vs. 4.28 GyE (1.58 GyE, 5.84 GyE)], right len D mean [0.16 GyE (0.01 GyE, 1.95 GyE) vs. 3.73 GyE (1.04 GyE, 4.86 GyE)], pituitary D max [6.97 GyE (0.18 GyE, 39.70 GyE) vs. 36.60 GyE (2.74 GyE, 45.19 GyE)], pituitary D mean [1.36 GyE (0.06 GyE, 13.85 GyE) vs. 24.74 GyE (2.42 GyE, 32.80 GyE)], hippocampus D max [5.10 GyE (0.24 GyE, 26.52 GyE) vs. 35.83 GyE (5.03 GyE, 46.11 GyE)], hippocampus D mean [0.36 GyE (0.04 GyE, 25.65 GyE) vs. 18.79 GyE (2.37 GyE, 28.10 GyE)] in IMPT planning were lower, and the differences were statistically significant (all P < 0.05). There were no statistical differences in brainstem D max [51.98 GyE (0.66 GyE, 53.43 GyE) vs. 53.29 GyE (3.87 GyE, 53.48 GyE)], right optic nerve D max [9.60 GyE (0.01 GyE, 43.32 GyE) vs. 25.37 GyE (3.45 GyE, 41.25 GyE)] of both plans (all P > 0.05). Conclusion:In the radiotherapy for glioma, IMRT and IMPT can meet the dose demand in clinic. Furthermore, IMPT planning can protect organs at risk and reduce radiation dose in hippocampus, brainstem, optic nerve, lens and pituitary.

Expression of the transmembrane emp24 domain-containing protein 4 in liver tissues of patients with hepatocellular carcinoma and its effects on biological behavior of hepatocellular carcinoma cells / 中华消化杂志

Objective:To examine the expression of transmembrane emp24 domain-containing protein 4(TMED4) in liver tissue of patients with hepatocellular carcinoma, and to investigate the effects of TMED4 gene on the proliferation and migration of hepatocellular carcinoma cells and related molecular mechanisms. Methods:The expression of TMED4 at protein level in liver cancer tissue and paracancerous tissue of patients with hepatocellular carcinoma were detected by Western blotting and immunohistochemical stainning, and the correlation between its expression and clinicopathological features was analyzed. The effects of TMED4 overexpression or knockdown on proliferation, migration and healing ability of hepatocellular carcinoma cells in vitro and in vivo were determined by cell proliferation test, Transwell test, wound healing test and subcutaneous tumor formation in nude mice. The molecular mechanism of TMED4 in regulating the biological behavior of hepatocellular carcinoma cells was preliminarily explored by pathway analysis. Independent sample t test, Mann-Whitney U test and chi-square test were used for statistical analysis. Results:The results of Western blotting showed that the expression of TMED4 at protein level in hepatocellular carcinoma tissue was lower than that in paracancerous tissue(0.52±0.29 vs. 0.83±0.22), and the difference was statistically significant( t=2.54, P=0.022). The results of immunohistochemical examination indicated that the expression of TMED4 at protein level in liver cancer tissue was lower than that in paracancerous tissue(5.46±3.37 vs. 7.58±3.08), and the difference was statistically significant( t=3.49, P<0.001). The expression of TMED4 at protein level was significantly correlated with vascular invasion and Barcelona clinic liver cancer stage( χ2=6.83 and 4.20, P=0.009 and 0.040). The results of cell proliferation assay showed that the absorbance value of SMMC-7721 cells in TMED4 overexpression group was lower than that in control group(1.38±0.05 vs. 2.37±0.08), while the optical density value of HepG2 in TMED4 knockdown group was higher than that in control group(0.76±0.04 vs. 0.54±0.01), and the differences were statistically significant( t=18.23 and 8.85, both P<0.001). The results of Transwell test showed that the number of migrated SMMC-7721 cells in TMED4 overexpression group was less than that in control group(286.30±13.01 vs. 439.70±12.34), while the number of migrated HepG2 cells in TMED4 knockdown group was higher than that in control group(249.00±6.00 vs. 160.00±6.56), and the differences were statistically significant( t=14.81 and 17.34, both P<0.001). The wound healing test showed that the healing rate of SMMC-7721 cells in TMED4 overexpression group was lower than that in control group((0.21±0.01)% vs.(0.45±0.01)%), the healing rate of HepG2 cells in TMED4 knockdown group was higher than that in control group((0.46±0.01)% vs.(0.20±0.01)%), and the differences were statistically significant( t=200.10 and 30.46, both P<0.001). The results of subcutaneous tumor formation assay in nude mice showed that the growth rate of cells in TMED4 overexpression group was slower than that in control group. After cell inoculation for 6 weeks, the subcutaneous tumor volume of mice in TMED4 overexpression group was smaller than that in control group(27.36 mm 3(138.70 mm 3) vs. 1 741.62 mm 3(1 783.39 mm 3)), the tumor weight was lower than that in control group(0.06 g(0.14 g) vs. 1.46 g(1.09 g)), and the differences were statistically significant(both Z=-2.31, both P<0.001). The results of Western blotting showed that the expression of Snail at protein level in SMMC-7721 cells of the TMED4 overexpression group was lower than that of the control group(0.32±0.01 vs. 0.90±0.03), the protein level of Snail in HepG2 cells of TMED4 knockdown group was higher than that of control group(1.03±0.01 vs. 0.97±0.01), and the differences were statistically significant( t=28.49 and 12.31, both P<0.001). The results of real time fluorescent quantitative polymerase chain reaction showed that the expression of Snail at mRNA level in SMMC-7721 cells of TMED4 overexpression group was lower than that of control group(0.13±0.05 vs. 1.00±0.15), the expression of Snail at mRNA level in HepG2 cells of TMED4 knockdown group was higher than that of control group(1.25±0.32 vs. 0.21±0.14), and the differences were statistically significant( t=9.62 and 5.10, P<0.001 and P=0.007). Conclusion:TMED4 may affect the proliferation and migration of hepatocarcinoma cells by regulating the expression of Snail, and which is expected to become a potentially therapeutic target for hepatocellular carcinoma.

Distal embolic filter protection during debulking treatment of peripheral artery disease / 中华普通外科杂志

Objective:To discuss the strategies of distal embolic filter protection(DEFP) during excimer laser ablation (ELA) or percutaneous mechanical thrombectomy (PMT) in treatment of peripheral artery disease.Methods:Clinical data of 29 patients undergoing ELA or PMT under the DEFP from Oct 2019 to Aug 2021 were retrospectively collected to analyze the strategies of DEFP and high-risk factors of capturing clinically significant macrodebris.Results:There were 21 males and 8 females, aged (70.3±11.0) years with 32 lesions (29 limbs) including 5 in-stent restenosis (ISR), 10 thrombosis and 17 chronic total occlusion (CTO). The technical success rate of DEFP device release and recovery was 100%. The overall debris capture rate was 77.3% and the macrodebris capture rate was 36.4%. Even with DEFP the distal embolization (DE) incidence was 3.4%. When ELA for CTO with severe calcification or long-segment ISR lesions, the capture rate of macrodebris was as high as 60.0%, and the former was significantly higher than ELA for CTO without high calcification lesions ( P<0.05). Conclusion:ELA or PMT under the DEFP in treatment of peripheral artery disease appears to be of great significance in preventing DE.

Application of methoxyamine combined with target guided fluid in elderly patients undergoing pancreaticoduodenectomy / 中国医师杂志

Objective:To investigate the effect of methoxyamine combined with target guided fluid in elderly patients undergoing pancreaticoduodenectomy.Methods:90 elderly patients undergoing pancreaticoduodenectomy were randomly divided into methoxyamine group and control group, with 45 cases in each group. The patients in both groups were treated with intravenous inhalation combined anesthesia. The stroke volume variation (SVV) was maintained at 7%-10% and the central venous pressure (CVP) was 4-8 cmH 2O. In methoxyamine group, 3 μg/(kg·min) methoxyamine was continuously pumped, while the control group was pumped with the same amount of normal saline at the same speed. The intraoperative infusion volume, urine volume, bleeding volume, blood transfusion cases, intraoperative mean arterial pressure, heart rate, blood gas analysis results, B-type natriuretic peptide (BNP), creatinine, urea nitrogen level and postoperative exhaust time were compared between the two groups. Results:Compared with the control group, the patients in methoxyamine group had less infusion volume, urine volume, lower postoperative BNP level and heart rate, shorter postoperative exhaust time (all P<0.05), and higher mean arterial pressure ( P<0.05). There was no significant difference in blood loss, blood transfusion cases, PaO 2, PaCO 2, pH, creatinine and urea nitrogen between the two groups (all P>0.05). In addition, the number of patients in the methoxyamine group who used pressor drugs was less than that in the control group ( P<0.05), and the frequency of bradycardia was more than that in the control group ( P<0.05). The proportion of tachycardia and urapidil was similar in the two groups (all P>0.05). Conclusions:Methoxyamine combined with target guided fluid therapy can reduce the intraoperative infusion volume of pancreaticoduodenectomy in elderly patients, stabilize circulation, shorten postoperative exhaust time, and contribute to the recovery of gastrointestinal function.

Research progress of ferroptosis related pathways in sepsis / 中华危重病急救医学

Sepsis is a disease caused by pathogenic microorganisms such as bacteria, which is characterized by host response disorder, organ dysfunction and high mortality. In early stage, it is mainly inflammatory reaction, howeverin late stage, it is mainly immunosuppression. It is a little pale to explain the poorprognosis caused by sepsis only by severe infection and immunosuppression. From the perspective of the absolute mortality of sepsis over the world, the battle against sepsis has not won a comprehensive victory. It has been 10 years since "ferroptosis" was formally proposed by Dixionet al. in 2012. The research areahas never decreased from the initial tumor related diseases to nervous system diseases and cardiovascular system diseases, and has made some progress. At present, in the context of sepsis, it is found that ferroptosis plays an increasingly important role in organ dysfunction, and also has an important impact on the treatment and prognosis of the disease. This article summarizes the related pathways and interventions of several major ferroptosis at present, in order to have a more comprehensive understanding of the pathogenesis of sepsis, seek new treatment targets, optimize diagnosis and treatment strategies, and improve survival rate, quality of life and clinical prognosis.

Pharmacokinetics and bioequivalence study of efavirenz tablets in healthy Chinese subjects under fasting administration / 药学学报

A randomized, open, fasting, single dose, two sequence, two cycle and double cross administration trial design was adopted. Took the test or reference efavirenz tablets of 200 mg orally in a single time. The plasma concentration of efavirenz in healthy subjects was determined by LC-MS/MS. WinNonLin8.1 software was used to calculate the main pharmacokinetic parameters of efavirenz and to evaluate the bioequivalence. The main pharmacokinetic parameters within 72 h: tmax were 2.574 ± 0.871 and 2.808 ± 0.912 h; Cmax were 1 586.732 ± 424.538 and 1 549.518 ± 366.086 ng·mL-1; AUC0-72 h were 28 464.672 ± 5 682.518 and 27 828.826 ± 5 082.487 h·ng·mL-1; t1/2 were 63.524 ± 26.037 and 58.748 ± 20.950 h; λz were 0.013 ± 0.006 and 0.013 ± 0.005 h-1. The main bioequivalence indicators were as follows: The 90% confidence interval of Cmax was 95.62%-107.15%, and the geometric mean ratio was 101.22%; The 90% confidence interval of AUC0-72 h was 100.43%-104.38%, and the geometric mean ratio was 102.38%. The results showed that the main pharmacokinetic parameters of the test drug and the reference drug were similar, and the two preparations had bioequivalence. This human bioequivalence clinical study was approved by the drug clinical trials ethics committee of the Second Hospital of Anhui Medical University (ethics approval No.: YW2021-110).

Effect of Notch on femoral periprosthetic fractures after primary total knee arthroplasty / 中华骨科杂志

Objective:To investigate the effect of Notch on periprosthetic fracture (PPF) of the femoral prosthesis after primary total knee arthroplasty.Methods:A total of 34 patients diagnosed with femoral PPF at Xi'an Honghui Hospital were retrospectively collected from January 2013 to December 2020. There were 4 males and 30 females with a mean age of 69.2±7.2 years (range, 55-84 years). A total of 102 patients without PPF were matched by gender and age as the control group in a ratio of 1∶3. There were 12 males and 90 females with a mean age of 69.2±7.2 years (range, 55-84 years). The main observation indexes included patients' general information and factors such as coronal alignment, prosthesis design and Notch conditions. Then, subgroup analysis was performed with the depth and Tayside classification of Notch to analyze their effects on PPF.Results:The PPF and control groups were comparable in terms of baseline information such as gender, age, body mass index (BMI), and surgical side. There was no significant difference between the two groups in coronal alignment (χ 2=1.019, P=0.601) and prosthesis design (χ 2=1.545, P=0.214). There was no statistical difference in Notch between the PPF and control groups (χ 2=3.548, P=0.060). The mean length of Notch in the PPF group was 4.5±2.7 mm, compared with 4.9±2.8 mm in the control group, with no significant difference between the two groups ( t=0.732, P=0.465). Further subgroup analysis using a Notch depth of 3 mm as a cut-off and Tayside classification revealed a statistical difference between the two groups (χ 2=11.262, P=0.004; χ 2=14.601, P=0.003). Compared with patients without Notch, the risk of PPF was higher when the depth of Notch exceeded 3 mm, with an odds ratio ( OR) of 4.88 (95% CI: 1.76, 13.51). The incidence of PPF was higher when Notch depth reached Tayside grade 3 or 4. Compared with patients without Notch, the risk of PPF would be 6.99-fold (95% CI: 1.85, 26.32) higher when Notch depth reached grade 3. In female patients, there was a significant difference in Notch status between the PPF and control groups (χ 2=3.956, P=0.047), with a higher risk of PPF in female patients with Notch, OR 2.33 (95% CI: 1.01, 5.43). In patients who underwent right-sided TKA, the risk of PPF was higher in patients with Notch compared to those without Notch (χ 2=5.502, P=0.019), with an OR of 3.58 (95% CI: 1.19, 10.75). Conclusion:The Notch has no significant effect on the femoral PPF after primary total knee arthroplasty. However, the risk of PPF will increase significantly when the Notch depth exceeds 3 mm or is above Tayside grade 3.

Optimized arterial perfusion strategy in total arch replacement for acute type A aortic dissection with malperfusion syndrome / 中国胸心血管外科临床杂志

@#Objective    To investigate the effect of optimized arterial perfusion strategy on total arch replacement for acute type A aortic dissection (AAAD) with malperfusion syndrome (MPS). Methods    From 2017 to 2019, 51 patients with AAAD and MPS who had received total arch replacement with optimized arterial perfusion strategy in our hospital were included in the optimized perfusion group, including 40 males and 11 females, with an average age of 47.43±13.39 years. A total of 40 patients with AAAD and MPS who had been treated with traditional Sun's surgery were taken as the traditional control group, including 31 males and 9 females, with an average age of 50.66±12.05 years. The perioperative clinical data of the two groups were compared. Results    The preoperative baseline data of the two groups were basically consistent (P>0.05). The comparison of operative data between the optimized perfusion group and the traditional control group showed that in the optimized perfusion group, the extracorporeal circulation time, aortic occlusion time, and circulation-out cerebral perfusion time were significantly less than those in the traditional control group (223.64±65.13 min  vs. 266.77±87.04 min, 114.48±27.28 min vs. 138.20±39.89 min, 8.28±3.81 min vs. 50.53±23.60 min, all P≤0.05). The lowest intraoperative nasopharyngeal temperature in the optimized perfusion group was significantly higher than that in the traditional control group (27.10±1.18℃ vs. 23.6±3.30℃, P=0.000). Postoperative wakefulness time of the optimized perfusion group was earlier than that of the traditional control group (4.50±1.35 h vs. 5.27±1.15 h, P=0.019). The volume of blood transfusions in the optimized perfusion group was significantly less than that in the traditional control group (13.25±9.06 U vs. 16.95±7.53 U, P=0.046). There was no significant difference in ICU time and invasive ventilation time between the two groups (P>0.05). Postoperative complications of the two groups showed that the incidence of postoperative continuous renal replacement therapy in the optimized perfusion group was significantly lower than that in the traditional control group, with a statistically significant difference (21.6% vs. 42.5% P=0.003). The incidence of postoperative delirium, coma, low cardiac row syndrome and limb ischemia in the optimized perfusion group was lower than that in the traditional control group, but the difference was not statistically significant (P>0.05). The incidence of postoperative hemiplegia, sepsis, and secondary thoracotomy in the optimized perfusion group was higher than that in the traditional control group, and the difference was not statistically significant (P>0.05). Postoperative mortality in the optimized perfusion group was significantly lower than that in the traditional control group (13.7% vs. 27.5%), but the difference was not statistically significant (P=0.102). Conclusion    Optimized arterial perfusion strategy and its related comprehensive surgical technique reduce surgical trauma, shorten the operation time, reduce perioperative consumption of blood products. Postoperative wakefulness is rapid and the incidence of complications of nervous system, kidney and limb ischemia is low. Optimized arterial perfusion strategy is suitable for operation of AAAD with MPS by inhibiting the related potential death risk factors to reduce operation mortality.

Isobavachalcone induces cell death through multiple pathways in human breast cancer MCF-7 cells / 南方医科大学学报

OBJECTIVE@#To explore the effects of isobavachalcone (IBC) on cell death of human breast cancer MCF-7 cells and explore the possible mechanism.@*METHODS@#MCF-7 cells were treated with different concentrations of IBC, and the changes in cell proliferation were assessed using MTT assay. Apoptosis of MCF-7 cells following treatment with 10, 20, and 40 μmol/L IBC was analyzed using flow cytometry with annexin V-FITC/PI double staining and fluorescence microscopy, and the expressions of apoptosis- and autophagy-related proteins (Bax, Bcl-2, Akt, p-Akt, p62, and LC3) were detected with Western blotting. Electron microscopy was used to observe the changes in submicrostructure of the cells following treatment with 40 μmol/L IBC. JC-1 assay kit, ATP assay kit, and reactive oxygen species (ROS) kit were used to determine the effect of IBC on mitochondrial function of the cells.@*RESULTS@#MTT assay showed that IBC significantly inhibited the proliferation of MCF-7 cells in a concentration- and time-dependent manner, with IC50 values of 38.46, 31.31, and 28.26 μmol/L at 24, 48, and 72 h, respectively. IBC also concentration-dependently induced apoptosis of MCF-7 cells. IBC-induced cell death was inhibited by z-VAD-fmk, a caspase inhibitor (P < 0.05), but not by the necroptosis inhibitor necrostatin-1 (Nec-1). Western blotting showed that IBC-induced MCF-7 cell apoptosis by increasing Bax expression and down-regulating the expressions of Bcl-2, Akt and p-Akt-473 (all P < 0.05). With the increase of IBC concentration, the expression of autophagy-related protein p62 and the LC3-II/I ratio increased progressively. Electron microscopy revealed the presence of autophagic bodies in IBC-treated MCF-7 cells. IBC treatment also resulted in decreased mitochondrial membrane potential and intracellular ATP level and increased ROS accumulation in MCF-7 cells (P < 0.05).@*CONCLUSION@#IBC is capable of inducing both apoptosis and autophagy in MCF-7 cells, suggesting the potential value of IBC as a lead compound in the development of anti-breast cancer agents.

Efficacy and Mechanism of Yishen Shengjing Prescription in Treatment of Oligoasthenospermia / 中国实验方剂学杂志

ObjectiveWe aimed to investigate the efficacy and mechanism of Yishen Shengjing Prescription （YSP） in the treatment of oligoasthenospermia in rats. MethodThe oligoasthenospermia rat model was established by injection with cyclophosphamide （35 mg·kg-1·d-1） for 5 consecutive days. Rats were randomly assigned into control group （without treating with cyclophosphamide）， model group， low- （YSP-L）， medium- （YSP-M）， and high- （YSP-H） dose （2.91， 5.83， and 11.66 g·kg-1， respectively） groups， Wuzi Yanzongwan （WYW， 1.03 g·kg-1） group， and L-carnitine （0.17 g·kg-1） group， with 8 rats in each group. After 28 days of drug intervention， the body weight， testicular weight， and testicular index of rats were recorded. The sperm quality in epididymis was detected by computer-assisted sperm analysis （CASA） system. Hematoxylin-eosin （HE） staining was employed for observation of testicular tissue morphology. The levels of malondialdehyde （MDA） and superoxide dismutase （SOD） in testicular tissue were detected by colorimetry. The levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， and testosterone （T） in serum were determined by enzyme-linked immunosorbent assay（ELISA）. TdT-mediated dUTP nick-end labeling （TUNEL） was employed to detect the apoptosis of testicular cells. The protein levels of B cell lymphoma-2（Bcl-2）， Bax， and cleaved Caspase-3 in testicular tissue were detected by Western blot. ResultCompared with the control group， the model group showed decreased body weight， testicular weight and index， sperm concentration and motility （P<0.01） and increased testicular pathological score （P<0.01）. Compared with the model group， the YSP-M， YSP-H， WYW， and L-carnitine groups showed increased body weight， testicular weight， testicular index， sperm concentration and motility and decreased testicular pathological score. After modeling， the SOD level decreased （P<0.01） while the MDA content increased （P<0.01） in the testicular tissue. YSP-H， WYW， and L-carnitine reversed the SOD and MDA level changes caused by modeling. Compared with the control group， the model group exhibited declined T level （P<0.01） and increased FSH and LH levels （P<0.01）. Compared with the model group， YSP， WYW， and L-carnitine increased the T level （P<0.01） and decreased the LH level （P<0.05， P<0.01）. The apoptosis rate of spermatogenic cells in the model group was higher than that in the control group （P<0.01）， whereas YSP-M， WYW， and L-carnitine reversed such changes （P<0.01）. The model group rats showed decreased expression of Bcl-2（P<0.05） and increased expression of Bax and cleaved Caspase-3 （P<0.05， P<0.01）. Compared the model group， YSP-M， YSP-H， WYW， and L-carnitine up-regulated the Bcl-2 expression and down-regulated the cleaved Caspase-3 expression （P<0.05， P<0.01）. ConclusionYSP improved the sperm quality of oligoasthenospermia model rats by regulating the antioxidant system and sex hormone levels and inhibiting the apoptosis of spermatogenic cells.

Progress in the research of medial column reconstruction of proximal humerus fractures in the elderly / 中国骨伤

The proximal medial column of the humerus is a continuous cortical region in the inner and lower part of the humerus head, which has attracted more and more attention in clinical and scientific research since it was proposed. It has been shown to increase the stability of internal fixation, maintain the height of the humeral head to prevent varus, and reduce the risk of screw penetration. Biomechanical studies have also shown that the medial column has an outstanding performance in increasing the stiffness, torsion resistance, and shear resistance of the locking plate. Although it has many benefits, there is no unified definition of its concept and specific region, and the existing classification does not include the medial column, therefore more researches are required to provide supporting information. The methods of medial column reconstruction mainly include locking plate combined with talus screw, locking plate combined with bone grafting, internal and external double plate combined support, locking plate combined with bone cement, and humeral cage. These methods have their own characteristics, however they will increase the cost of surgery and bring new complications. How to determine the best way of reconstruction is one of the focuses of future research. In this review, the concept of the proximal medial humerus column, the role of maintaining internal fixation, the role of biomechanics and the reconstruction methods are reviewed.

Treatment strategy of peripheral arterial diseases with Rotarex / 中华普通外科杂志

Objective:To evaluate the effect of Rotarex in peripheral arterial disease (PAD).Methods:The clinical data of 90 PAD patients treated with Rotarex from Aug 2018 to Feb 2020 were retrospectively analyzed.Results:Among the 90 patients, 45 patients had atherosclerotic obliterans complicated with acute thrombosis (ASOCAT), 27 patients had graft restenosis or reocclusion, 16 patients had primary or embolism-induced thrombosis, 2 patients had traumatic or iatrogenic arterial occlusion. Except for 2 patients undergoing hybrid surgery, 88 patients underwent endovascular treatment. Two patients died perioperatively. Within 12 months follow-up, 2 patients died, 4 patients underwent major amputation, target arteries of 10 patients were re-stenosed or re-occluded and 5 patients were lost to follow-up. Compared with the preoperative ankle-branchial index (ABI), significant increase was observed in the 12-month ABI (0.80±0.22 vs. 0.43±0.16, P<0.01). The 12-month restenosis/re-occlusion-free rate was 82.7%, and the 12-month major amputation-free survival (MAFS) was 91.6%. Conclusion:For PAD patients, acceptable outcomes can be achieved with reasonable use of Rotarex for debulking, combined with balloon, stent and other techniques to correct the residual lesions.

Practice of high-level innovative talent training in medicine-engineering interdisciplinary based on CDIO / 中华医学教育探索杂志

Xi'an Jiaotong University Health Science Center introduces the concept of CDIO (conceive, design, implement and operate) into the training practice of medicine-engineering interdisciplinary talents. By optimizing the curriculum and graduate training mechanism, building academic exchanges and innovative experimental platforms, and guiding students to carry out scientific research oriented to clinical problems, Xi'an Jiaotong University Health Science Center uses medical and industrial methods to solve clinical problems and produce medical achievements. The application of the CDIO model is conducive to deepening students' understanding of interdisciplinary knowledge, forming a fused innovative thinking, and improving the ability to solve problems and cooperate with others. The CDIO model is also conducive to the growth of high-level composite innovative talents, clinical technology innovation, team construction and discipline development, which provides new ideas for exploring the training of medical and engineering interdisciplinary talents.