1.Establishment and Evaluation of Mouse Model of Dry Eye with Lung Yin Deficiency Syndrome
Liyuan CAO ; Pei LIU ; Yuhui QIN ; Qinghua PENG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(7):182-190
ObjectiveTo establish a model of dry eye with lung Yin deficiency syndrome in mice. MethodsA total of 40 SPF C57BL/6J mice were assigned via the random number table method into 5 groups (n=8): Normal control, model control, and high-, medium-, and low-dose (11.7, 5.85, and 2.925 g·kg-1, respectively) Yangyin Qingfeitang. Mice in the normal control group were fed normally without any intervention. Mice in Yangyin Qingfeitang group and model control group were treated with 0.2% benzalkonium chloride eye drops (5 μL) twice a day and fed in a controlled drying system in a dry environment for 28 days. At the same time, the mice were administrated with thyroxine tablet solution by gavage and placed in a glass fumigation tank (SO2 concentration: 0.5 g·m-3) for 14 days. After 4 weeks, mice in Yangyin Qingfeitang groups were treated with Yangyin Qingfeitang by gavage and those in the normal control group and model control group were administrated with deionized water at 0.01 mL·g-1. The body mass, anal temperature, four examination information (claw and nail appearance), basic tear secretion test, tear film rupture time, corneal fluorescein staining, and lacrimal gland HE staining were compared among groups. Compound Yangyin Qingfeitang granules were used to measure the syndrome to verify the success of modeling. ResultsAfter 28 days of continuous modeling, compared with the normal control group, the model group exhibited listless and emaciated status, coughing, drowsiness, dry and dull hair, dry and hard stool, reduced food intake and water intake, red lip circumference, red tongue with reduced fluid, dry nose and teeth, red claws and nails, body mass gain, decreased anal mild tear secretion (P<0.05), and shortened tear film rupture time (P<0.05). After 28 days of modeling, the mice showed large corneal fluorescein staining range, severe corneal injury, and increased content of interleukin (IL)-18, IL-β, and tumor necrosis factor (TNF)-α in lacrimal gland, compared with those in the normal control group (P<0.05). After the treatment with Yangyin Qingfeitang, the mice had good drinking and eating conditions, with lighter redness of the tongue, moist nose, moist and shiny teeth, and the claw and nail color close to that in the normal group. Compared with the model control group, Yangyin Qingfeitang groups showed increases in body mass and anal temperature (P<0.05), tear secretion (P<0.05), and tear film rupture time (P<0.05), narrowed range of corneal fluorescein staining, and declined levels of IL-18, IL-β, and TNF-α in lacrimal glands (P<0.01). The high-dose group had the best effect, with the indicators close to the levels in the normal control group. ConclusionThe animal model of dry eye with lung Yin deficiency syndrome can be established by culture in a controlled drying system, treatment with benzalkonium chloride eye drops for 28 days, and administration of thyroxine tablet solution combined with SO2 fumigation for 14 days.
2.Distribution and drug resistance of multidrug-resistant organisms in newborns in a three-A children's hospital from 2019 to 2023
Hongyan WU ; Chunai ZHANG ; Jun WANG ; Huiping LIU ; Qin WANG ; Ling ZHANG ; Nan GAO ; Xue LI ; Liyuan FU ; Yun YANG ; Yanjie WANG ; Huayu HAN
Chinese Journal of Nosocomiology 2025;35(16):2485-2489
OBJECTIVE To investigate the distribution and drug resistance of multidrug-resistant bacteria in the neonatal intensive care unit of a three-A children's hospital in Henan Province,and to provide reference for ational drug use in clinical practice.METHODS Clinical specimens from hospitalized newborns in neonatal intensive care unit from a three-A children's hospital from Jan.1,2019 to Dec.31,2023 were subjected to etiological exam-ination and drug sensitivity test,and to analyze the distribution and drug resistance of multidrug-resistant bacteri-a in hospitalized newborns.RESULTS During the 5-year period,1139 strains of multidrug-resistant bacteria were i-solated,including 229 gram-positive bacteria(20.11%)and 910 gram-negative bacteria(79.89%).There were 92 strains of methicillin-resistant Staphylococcus aureus(MRSA)(accounting for 8.08%),57 strains(accounting for 5.00%)of methicillin-resistant coagulase-negative Staphylococcus epidermidis and 28 strains(accounting for 2.46%)of methicillin-resistant coagulase-negative human Staphylococcus.370 strains(accounting for 32.48)of carbapenem-resistant Klebsiella pneumoniae(CRKP),268 strains(accounting for 23.53%)of extenspectrum β-lactamase-producing Escherichia coli and 85 strains(accounting for 7.46%)of K.pneumoniae,there were 767 sputum specimens(67.34%),160 blood specimens from peripheral intravenous puncture and central venous cath-eterization(PICC)(14.05%),63 bronchoalveolar lavage fluid specimens(5.53%),29 secretion specimens(eye and wound secretions)(2.54%),and 120 other specimens(10.54%).K.pneumoniae and E.coli producing su-per-broad spectrum β-lactamase,CRKP and MRSA were the main drug-resistant bacteria.CONCLUSION The sit-uation of drug resistance in neonatal intensive care unit is serious,therefore monitoring bacterial resistance should be strengthened according to the clinical laboratory results,and antibiotics should be applied rationally.
3.Evaluation of the preventive and therapeutic effects and safety of repetitive transcranial magnetic stimulation at different frequencies on radiation-induced brain injury
Tongzhou QIN ; Liyuan LIU ; Ling GUO ; Guiqiang ZHOU ; Yan ZHOU ; Xia MIAO ; Guirong DING
Chinese Journal of Radiological Health 2025;34(5):702-712
Objective Radiation-induced brain injury (RIBI) is a common complication of radiotherapy for the head and neck tumors, and the current treatment methods are limited. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neural regulation technique, has shown great potential in neuroprotection. However, the parameter selection and biological safety of rTMS in the prevention and treatment of RIBI have not been reported. Methods Using a mouse model of RIBI, this study employed three rTMS frequencies (5, 10, and 25 Hz) for intervention. Biochemical and pathological assays were conducted to identify the optimal stimulation parameter. Subsequently, this parameter was used to evaluate the biological safety in normal mice. Results Under the conditions of this experiment, rTMS interventions with all three frequencies could reduce the levels of serum brain injury markers (NSE and S100B) and inflammatory factors in mice (P < 0.001), and alleviate the morphological and structural damage of hippocampal tissue. The 10 Hz rTMS could significantly promote hippocampal neurogenesis in RIBI mice (P < 0.05). Furthermore, 10 Hz rTMS showed no significant effects on the cognitive function and mood of normal mice. The intervention did not significantly change the morphology and structure of the main organs, blood biochemical indicators, and the level of hippocampal neurogenesis in mice. Conclusion The 10 Hz rTMS is optimal for the prevention and treatment of RIBI with high biological safety.
4.Ameliorative effect of Xuebijing injection on acute lung injury in sepsis by interfering with cGAS/STING pathway
Xiangying QIN ; Liyuan ZHANG ; Jiahu TANG ; Meng YUE ; Junping KOU ; Yuanyuan ZHANG
Journal of China Pharmaceutical University 2025;56(3):350-357
To investigate the effect of Xuebijing injection (XBJ) on cGAS/STING pathway in alleviating sepsis-induced acute lung injury (ALI), the mouse sepsis-induced ALI model was established by cecal ligation and puncture (CLP), and the cell inflammation model was constructed by LPS stimulating RAW264.7 cells. The effects of XBJ on lung tissue injury and cGAS/STING pathway-related protein expression in septic mice were investigated by HE staining, ELISA, and Western blot. The results showed that XBJ intervention could alleviate lung tissue injury, reduce serum IL-6, TNF-α, IFN-β, IL-1-β levels, and the expression of cGAS, STING, p-TBK1, and p-IRF3 proteins in lung tissue in vivo, and reduce the mRNA level of related inflammatory factors in RAW264.7 cells and the expression of cGAS/STING pathway proteins in vitro. The results showed that XBJ could play a role in the prevention and treatment of sepsis-induced ALI by inhibiting the inflammatory response via inhibition of the activation of cGAS/STING pathway. This study provides a new molecular mechanism for the clinical prevention and treatment of sepsis-induced acute lung injury with XBJ.
5.Mutation types of CYP3A enzymes and sex differences in sufentanil metabolism
Ying JIANG ; Zhigang QIN ; Liyuan FENG ; Guanlei LIU ; Jieyu LI ; Xianzhe LIU ; Yongshuai LI ; Yan CHEN ; Peng LI ; Jianteng GU
Journal of Army Medical University 2025;47(6):581-590
Objective To explore the sex differences in drug metabolism of sufentanil in Chinese patients based on the mutation classification of cytochrome P450 3A(CYP3A)enzymes.Methods According to the possible effects of combined cytochrome P450 3A4 gene*1G locus(CYP3A4*1G)and cytochrome P450 3A5 gene*3 locus(CYP3A5*3)mutation groups on Chinese population,we added different weights to CYP3A4*1G and CYP3A5*3 polymorphisms and classified patients into 3 groups:GroupⅠ,patients carried either the CYP3A4*1G/*1G allele or both CYP3A4*1/*1G allele and CYP3A5*3/*3 allele;Group Ⅱ,patients with both CYP3A4*1/*1G allele and CYP3A5*1/*3 allele;Group Ⅲ,patients with either the CYP3A4*1/*1 allele or both CYP3A4*1/*1G allele and CYP3A5*1/*1 allele.A single-dose,double-blind,stratified random sampling was performed,and 255 patients undergoing endoscopic surgery in the First Affiliated Hospital of Army Medical University were finally subjected.According to the results of genetic testing,an independent statistician,before operation,randomly selected 30 patients from each stratified group to form a study cohort(male-female ratio of 1∶1)and named each group A,B or C.Clinical investigators and subjects kept double-blind to the results of grouping and genetic testing.After entering the operating room,the subjected 90 patients received a single dose of sufentanil followed by collection of blood samples at 10 time points including 2 min before and from 2 to 120 min after administration.After the surgery,we determined the plasma drug concentration,calculated the pharmacokinetic parameters,and compared the metabolic differences between different genders in each group and unblinded the study.Results The cohort best fitted the two-compartment pharmacokinetic model,and groups A,B and C corresponded to group Ⅰ,Ⅱand Ⅲ,respectively.In different patient groups based on mutatron types of CYP3A enzymes the females had lower plasma drug concentration-time curves at each time point,higher systemic clearance(P≤0.01)and smaller area under the plasma concentration-time curve from zero to infinity(P<0.05)when compared with the males.In addition,in group Ⅰ,the elimination rate of central compartment and movement rate of drug from central compartment to peripheral compartment were obviously greater in the females than the males(P<0.05),while the distribution half-life(P<0.05)and elimination half-life(P<0.01)were notably longer in the males than the females.In both group Ⅱ and group Ⅲ,the males obtained larger total area under the plasma concentration-time curve than the females(P<0.05).Conclusion There are sex differences in the drug metabolism of sufentanil in Chinese patients.Women show faster distribution and higher clearance of sufentanil while men present greater drug exposure.Preoperative CYP3A genotyping and intraoperative personalized medication are of great significance to ensure the safety in clinical practice.
6.Effects of normal body weight and overweight status on metabolism of sufentanil in patients with same CYP3A4/5 genotype:A prospective clinical study
Guanlei LIU ; Ying JIANG ; Bo YANG ; Zhigang QIN ; Liyuan FENG ; Zhengwei XUE ; Fang QIU ; Chunmei CHEN ; Wenzhong ZOU ; Peng LI ; Jianteng GU
Journal of Army Medical University 2025;47(22):2774-2782
Objective To explore the pharmacokinetic characteristics of sufentanil in individuals with normal body mass index(BMI),overweight BMI,and different CYP3A4/5 enzyme genotypes.Methods The patients receiving laparoscopic surgery under general anesthesia in the First Affiliated Hospital of Army Medical University from November 2020 to September 2021 were prospectively recruited in this study.Before the operation,the oral swabs were collected from all the patients for genotyping using the human CYP3A4/5 gene kit.Based on the potential impact of combination of their polymorphisms on sufentanil metabolism and the proportion of different genotype combinations of CYP3A4/5 enzymes,the patients were divided into groups I(3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation),II(3A4 heterozygous mutation+3A5 heterozygous mutation),and III(3A4 wild type or 3A4 heterozygous mutation+3A5 wild type).According to their BMI,they were also assigned into a normal body weight group(18.5~24.0 kg/m2)and an overweight group(24~<28 kg/m2),and the differences in drug metabolism parameters were statistically analyze between the 2 groups.After routine general anesthesia induction(sufentanil 0.5 μg/kg),venous blood samples were collected to detect the changes in its concentration using high performance liquid chromatography-mass spectrometry(HPLC-MS).The pharmacokinetic data of sufentanil were calculated between the normal BMI group and overweight group in all participants and between the 2 body weight groups among those with different genotype combinations.Results Among the 90 participants completing the blood drug concentration test,8 patients had their blood samples contaminated(including 1 case with an anesthesia duration of<2 h),and 3 were excluded due to low weight or overweight.Eventually,79 participants were included in the pharmacokinetic analysis on the normal body weight group and the overweight group.Compared with the normal body weight group,the central compartment volume of distribution in the overweight group was significantly reduced(P<0.05),while no obvious differences were observed between the 2 groups in terms of peripheral compartment volume of distribution,total clearance rate,peripheral compartment clearance rate,distribution half-life,clearance half-life,and area under the blood concentration-time curve.In group Ⅰ(n=26),the overweight patients(n=13)had significantly reduced central compartment volume of distribution,peripheral compartment volume of distribution,and peripheral compartment clearance rate when compared with the normal body weight patients(n=13)(P<0.05),while no differences were observed in other pharmacokinetic parameters.In groups Ⅱ(n=25)and Ⅲ(n=28),the overweight patients and normal body weight patients had no statistical differences in all pharmacokinetic parameters.Conclusion Among the patients with the same genotype combination of CYP3A4/5 mutations,there was no difference in the metabolism of sufentanil between the overweight and normal weight patients.Additionally,in the population of 3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation,the overweight patients have smaller peripheral distribution range of sufentanil,and weakened metabolic process.
7.Survey on current status of"Perioperative Infection Control"initiative monitoring indicators in 138 medical institutions in Guizhou Province
Yao YAO ; Yan XU ; Xia MU ; Tingxiu YANG ; Lan TANG ; Liyuan CHEN ; Guiqin DU ; Jing LI ; Zhaofeng JING ; Liming WANG ; Qin WU ; Qingyang ZHAO ; Yufei ZHANG ; Min HE ; Ximin FAN
Chinese Journal of Nosocomiology 2025;35(20):3068-3073
OBJECTIVE To investigate the current status of monitoring indicators related to the"Perioperative In-fection Control"in medical institutions above the secondary level in Guizhou Province,and to delve into the imple-mentation of key measures for infection prevention and control during the perioperative period for patients under-going surgical operations.METHODS Based on the"Implementation Plan for the'Perioperative Infection Control'Initiative in Guizhou Province",a"Case Investigation Form on Key Measures for Infection Prevention and Control During the Perioperative Period for Patients Undergoing Surgical Operation"was developed.A total of 138 medi-cal institutions participated in the case investigation,and a total of 2 128 cases were investigated.RESULTS The overall monitoring indicators for the"Perioperative Infection Control"initiative in the 138 medical institutions a-bove the secondary level in Guizhou Province were at a relatively low level.The skin cleansing compliance rate was 80.32%,the hair removal compliance rate was 16.43%,the prophylactic antibacterial drug administration rate within 0.5-1 hour before surgery was 55.94%and the antibacterial drug discontinuation rate within 24 hours after prophylactic medication for type Ⅰ incision surgeries was 56.48%.The hair removal compliance rate was higher in tertiary medical institutions(19.21%)than in secondary medical institutions(14.34%)(P=0.039).The distri-bution of the four monitoring indicators varied in clinical departments and surgery types,with statistically signifi-cant differences(P<0.05).The preferred method for surgical site skin cleansing in medical institutions across the province was local wiping,primarily with clean water(57.21%).The primary method for hair removal was razors(68.82%),and hair removal on the day of surgery was most common(61.75%).CONCLUSIONS Conduc-ting a survey on the current status of"Perioperative Infection Control"initiative monitoring indicators in medi-cal institutions in Guizhou Province helps to understand the implementation of key measures for perioperative in-fection prevention and control and set intervention targets,thus providing references for establishing a dynam-ic monitoring indicator change mechanism.
8.Angiotensin Ⅱ activates p53/SAT1 signaling pathway to induce ferroptosis in white adipocytes
Wei DENG ; Xiyan LIU ; Liyuan GUO ; Qian XU ; Kun ZHOU ; Yuanqin ZHAO ; Zhaoyue WANG ; Xiang LI ; Xin-mei DENG ; Xinyi QIN ; Zhong REN ; Zhisheng JIANG
Chinese Journal of Arteriosclerosis 2025;33(5):385-394
Aim To investigate the effect and mechanism of angiotensin Ⅱ(Ang Ⅱ)on ferroptosis in white adi-pocytes.Methods The 3T3-L1 preadipocytes were differentiated into white adipocytes by inducer stimulation.The experiment was divided into control group,Ang Ⅱ group,Ang Ⅱ+Fer-1(ferroptosis inhibitor)group and Ang Ⅱ+PFT-α(p53 inhibitor)group.Ang Ⅱ was used to treat cells.RT-qPCR and Western blot were used to detect the expression levels of ferroptosis factors and adipokines.JC-1 kit was used to detect mitochondrial membrane potential(MMP)level.Iron ion kit was used to detect intracellular iron content.Glutathione(GSH)kit was used to detect GSH content.Fer-1 and Ang Ⅱ were added to treat cells to detect the the changes of ferroptosis level.The expression of p53 and spermidine/spermine N1-acetyltransferase 1(SAT1)protein was detected.Subsequently,PFT-α and Ang Ⅱ were added to co-treat cells to detect the changes of p53 and SAT1 protein expression,and to observe the effect of inhibiting p53 expression on the expression levels of ferroptosis factors and adipokines.Results 3T3-L1 cells were successfully differentiated into white adipocytes by stimulator-induced differentiation.Ang Ⅱ induced ferroptosis in white adipocytes.RT-qPCR results showed that compared with control group,the mRNA expression of anti-ferroptosis factor glutathione peroxidase 4(GPX4),solute carrier family 7 member 11(SLC7A11)and iron regulatory protein 1(IRP-1)was down-regulated in Ang Ⅱ group,and the mRNA expression of pro-ferroptosis factor acyl-CoA synthetase of long-chain family member 4(ACSL4)was up-regulated.Western blot results showed that compared with control group,the protein expression of SLC7A11 and GPX4 was down-regulated in Ang Ⅱ group,and the protein expression of ACSL4 was up-regulated.Ang Ⅱ treatment increased the content of intracellular iron ions and decreased the levels of GSH and MMP.Compared with Ang Ⅱ group,the mRNA expression of IRP-1 and SLC7A11 was up-regulated in Ang Ⅱ+Fer-1 group.Ang Ⅱ induced changes in the expression profile of adipokines in white adipocytes.Western blot results showed that compared with control group,the protein ex-pression of pro-inflammatory adipokine leptin(LEP),resistin(RETN),interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)was up-regulated in Ang Ⅱ group,and the protein expression of anti-inflammatory adipokine adiponectin(AD-PN)and omentin 1(ITLN1)was down-regulated.In addition,Ang Ⅱ increased the protein expression of p53 and SAT1.Inhibition of p53 expression can improve the level of ferroptosis and adipokine expression in white adipocytes trea-ted with Ang Ⅱ.Western blot results showed that compared with Ang Ⅱ group,the protein expression of p53 and SAT1 was down-regulated in Ang Ⅱ+PFT-α group,the protein expression of SLC7A11 and GPX4 was up-regulated,and the protein expression of ACSL4 was down-regulated.The protein expression of ADPN was up-regulated in Ang Ⅱ+PFT-αgroup,and the protein expression of TNF-α,LEP and RETN was down-regulated.Conclusion Ang Ⅱ induces fer-roptosis in white adipocytes through activating the p53/SAT1 signaling pathway.
9.Practice of multidrug-resistant organism management under the mode of information reminder system combined with multidisciplinary collaboration
Liyuan QIN ; Shengbin ZHOU ; Qiufeng LAO ; Lingling XIE ; Li'e WANG ; Hong-hong FU ; Peiyun WU ; Jiaguang HU
Chinese Journal of Infection Control 2025;24(11):1641-1646
Objective To explore the application effect of constructing a data sharing-based multidrug-resistant or-ganism(MDRO)information reminder system combined with multidisciplinary standardized measures on the whole-process closed-loop management of MDRO.Methods Hospitalized patients from whom MDRO were detected from January 1 to July 31,2024 were taken as the control group,those from August 1,2024,to May 31,2025 were as the intervention group.The control group adopted the traditional manual reporting mode for MDRO,while the in-tervention group adopted the combination of MDRO reminder system and multidisciplinary management mode.Differences in isolation order issuing rate for MDRO and process-and outcome-indicators for multidisciplinary spe-cialty before and after system implementation were compared.Results After implementing information reminder system combined with multidisciplinary measures,issuing rates of ≤24 hour and<4 hour MDRO isolation orders in the intervention group were both higher than in the control group([90.20%vs 65.23%,P<0.05],[80.64%vs 55.08%,P<0.001],respectively).Antimicrobial use rate in the intervention group was lower than in the con-trol group(36.27%vs 43.41%),with a statistically significant difference(P<0.05).The implementation rates of MDRO prevention and control measures,pathogen detection rates,and fluorescence labeling clearance rates in the intervention group were all higher than those in the control group,all with statistically significant differences(all P<0.05).The detection rate of MDRO decreased compared with the control group(10.83%vs 16.49%),and the in-cidence of MDRO healthcare-associated infection in the intervention group was lower than that in the control group(0.09%vs 0.19%),both with statistically significant differences(both P<0.001).The treatment expense in the intervention group reduced by 27 422 Yuan compared with the control group.Conclusion This study constructed an MDRO reminder system,realized full-chain monitoring system for the multidisciplinary MDRO information interac-tion platform,strengthened multidisciplinary in-depth integration,and improved the prevention and control effect for MDRO.
10.Survey on current status of"Perioperative Infection Control"initiative monitoring indicators in 138 medical institutions in Guizhou Province
Yao YAO ; Yan XU ; Xia MU ; Tingxiu YANG ; Lan TANG ; Liyuan CHEN ; Guiqin DU ; Jing LI ; Zhaofeng JING ; Liming WANG ; Qin WU ; Qingyang ZHAO ; Yufei ZHANG ; Min HE ; Ximin FAN
Chinese Journal of Nosocomiology 2025;35(20):3068-3073
OBJECTIVE To investigate the current status of monitoring indicators related to the"Perioperative In-fection Control"in medical institutions above the secondary level in Guizhou Province,and to delve into the imple-mentation of key measures for infection prevention and control during the perioperative period for patients under-going surgical operations.METHODS Based on the"Implementation Plan for the'Perioperative Infection Control'Initiative in Guizhou Province",a"Case Investigation Form on Key Measures for Infection Prevention and Control During the Perioperative Period for Patients Undergoing Surgical Operation"was developed.A total of 138 medi-cal institutions participated in the case investigation,and a total of 2 128 cases were investigated.RESULTS The overall monitoring indicators for the"Perioperative Infection Control"initiative in the 138 medical institutions a-bove the secondary level in Guizhou Province were at a relatively low level.The skin cleansing compliance rate was 80.32%,the hair removal compliance rate was 16.43%,the prophylactic antibacterial drug administration rate within 0.5-1 hour before surgery was 55.94%and the antibacterial drug discontinuation rate within 24 hours after prophylactic medication for type Ⅰ incision surgeries was 56.48%.The hair removal compliance rate was higher in tertiary medical institutions(19.21%)than in secondary medical institutions(14.34%)(P=0.039).The distri-bution of the four monitoring indicators varied in clinical departments and surgery types,with statistically signifi-cant differences(P<0.05).The preferred method for surgical site skin cleansing in medical institutions across the province was local wiping,primarily with clean water(57.21%).The primary method for hair removal was razors(68.82%),and hair removal on the day of surgery was most common(61.75%).CONCLUSIONS Conduc-ting a survey on the current status of"Perioperative Infection Control"initiative monitoring indicators in medi-cal institutions in Guizhou Province helps to understand the implementation of key measures for perioperative in-fection prevention and control and set intervention targets,thus providing references for establishing a dynam-ic monitoring indicator change mechanism.

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