Repetitive Transcranial Magnetic Stimulation Alleviates MPTP-Induced Parkinson's Disease Symptoms by Regulating CaMKII-CREB-BMAL1 Pathway in Mice Model.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that shows promise for the treatment of Parkinson's disease (PD). However, there is still limited understanding of the optimal stimulation frequencies and whether rTMS can alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. Methods: A PD mouse model was induced intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 1 Hz, 5 Hz, and 10 Hz rTMS. The neurological function, survival of dopaminergic neurons, and protein levels of Tyrosine hydroxylase (TH), α-synuclein(α-syn), and brain-derived neurotrophic factor (BDNF) in the striatum were measured to determine the optimal stimulation frequencies of rTMS treatment in PD mice. The levels of melatonin, cortisol, and the circadian rhythm of Brain and muscle ARNT-like 1 (BMAL1) in PD model mice were detected after optimal frequency rTMS treatment. Additionally, KN-93 and Bmal1siRNA interventions were used to verify that rTMS could alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. Results: Administration of 10 Hz rTMS significantly improved neurological function, increased the protein levels of TH and BDNF, and inhibited abnormal aggregation of a-syn. Furthermore, administration of 10 Hz rTMS regulated the secretion profile of cortisol and melatonin and reversed the circadian arrhythmia of BMAL1 expression. After the KN-93 intervention, the MPTP+rTMS+KN-93 group exhibited decreased levels of P- Ca2+/calmodulin-dependent protein kinase II (CaMKII)/CaMKII, P-cAMP-response-element-binding protein (CREB)/CREB, BMALI, and TH. After Bmal1siRNA intervention, the protein levels of BMAL1 and TH were significantly reduced in the MPTP+10 Hz+ Bmal1siRNA group. At the same time, there were no significant changes in the proportions of P-CaMKIIα/CaMKIIα and P-CREB/CREB expression levels. Finally, immunohistochemical analysis showed that the number of TH-positive neurons was high in the MPTP+10 Hz group, but decreased significantly after KN-93 and Bmal1siRNA interventions. Conclusion: Treatment with 10 Hz rTMS alleviated MPTP-induced PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. This study provides a comprehensive perspective of the therapeutic mechanisms of rTMS in PD.

Tofacitinib therapy in systemic lupus erythematosus with arthritis: a retrospective study.

OBJECTIVE: To estimate the effectiveness and safety of tofacitinib in treating systemic lupus erythematosus (SLE) patients with arthritis. METHODS: This research was a retrospective cohort study that focused on SLE patients who had arthritis and were treated with tofacitinib at the Department of Rheumatology and Immunology from January 2020 to January 2022. Clinical outcomes, disease activity, immunological parameters, and adverse events were systematically evaluated pre- and post-treatment at 4, 12, and 24 weeks. RESULTS: Twenty-two patients were analyzed. At the 4-week mark, 5 (22.7%) patients were partially relieved, and 17 (77.3%) unalleviated. By the 12-week assessment, CR off corticosteroids was observed in four patients (18.2%), and CR on corticosteroids was seen in six patients (27.3%), with an additional six (27.3%) maintaining partial remission. At 24 weeks after treatment, three patients (13.6%) achieved CR off corticosteroids, ten patients (45.5%) achieved CR on corticosteroids, and all patients received remission. Compared to before treatment, The SLEDAI and PGA scores significantly improved. The level of C3 was increased significantly, and the absolute CD3+ T cell count, the 28-tender and the 28-swollen joint count, and the levels of serum IL-6 were significantly decreased at 24 weeks after treatment. CONCLUSION: Tofacitinib demonstrates significant therapeutic potential in SLE patients with arthritis, with a safety profile, and the therapeutic mechanism of tofacitinib may be related to reducing IL-6 expression and inhibiting T cell activation. Key Points • Tofacitinib demonstrates significant therapeutic potential in SLE patients with arthritis • The therapeutic mechanism of tofacitinib may be related to reducing IL-6 expression and inhibiting T cell activation.

Trends and future projections of incidence rate and mortality of rheumatoid arthritis in China: a systematic analysis based on GBD 2021 data.

This study aims to evaluate the trends in rheumatoid arthritis (RA) in China from 1990 to 2021 by analyzing data from the Global Burden of Disease (GBD) 2021 study and to predict the trends for the next 25 years. Age-standardized incidence rates (ASIR) and age-standardized mortality rates (ASMR) were calculated, and the estimated annual percentage change was used to illustrate differences in age distribution among various populations. Age-period-cohort (APC) analysis and Bayesian APC (BAPC) models were employed to forecast the burden of RA in China from 2022 to 2046. From 1990 to 2021, the ASIR of RA in China increased from 11.6 to 13.7, with a significantly higher ASIR in females than in males. Despite the increase in incidence, the ASMR related to RA decreased from 0.7 to 0.5. Predictions using the BAPC model indicate that the incidence of RA will continue to rise, with an expected ASIR of approximately 16.4 by 2046, and the total number of RA cases is projected to reach around 342,000. In terms of mortality, the ASMR is expected to decline to 0.3 by 2046, although the total number of deaths might reach about 40,000. The incidence of RA in China has significantly increased over the past 30 years. Although the incidence rate and the total number of RA cases may continue to rise in the future, the mortality rate of RA has been consistently declining. Key Points • Over the past 30 years, the incidence of RA in China has significantly increased; although the incidence rate and total number of cases may continue to rise, the mortality rate has been consistently declining.

Clinical features and risk factors of primary Sjögren's syndrome complicated with severe pneumonia: a case-control study.

OBJECTIVES: To analyze clinical characteristics, risk factors, pathogen distribution, and prognostic markers in primary Sjögren's syndrome (pSS) patients with severe pneumonia (SP) compared to those without severe pneumonia (NSP). METHODS: This case-control study included 24 hospitalized pSS patients with SP and 96 NSP at the first affiliated hospital of Soochow university from June 2014 to May 2023. Data encompassing demographics, comorbidities, treatments, and laboratory results were retrospectively collected. Univariate and multivariate regression analyses, ROC curves, and statistical analyses using SPSS 23.0 assessed risk factors. The study retrospectively analyzed clinical features and risk factors, highlighting distinct parameters between pSS patients with and without SP. RESULTS: Marked differences were observed in several parameters: pSS activity(P < 0.001), white blood cell (P = 0.043), lymphocyte (P < 0.001), neutrophils (P = 0.042), C-reactive protein (P = 0.042), and CD8+ T cell (P = 0.017). Notably, lymphocyte count and SS activity demonstrated robust discrimination ability (AUC > 0.85). C-reactive protein (CRP), procalcitonin, CD4+ T cell, and IgA showed significant associations with SP; higher CRP levels correlated with increased risk, while lower CD4+ T cell and IgA levels associated with increased risk. SS activity significantly impacted outcomes. Various biomarkers exhibited diverse discriminatory abilities but lacked strong predictive associations with outcomes. CONCLUSION: pSS patients with SP exhibited higher disease activity and altered immune profiles compared to those NSP. Lymphocyte count and SS activity emerged as robust discriminators. Higher CRP levels correlated with increased risk of SP, while lower CD4+T cell and IgA levels associated with increased risk. SS activity significantly impacted patient outcomes. Key Points • pSS patients with SP exhibited higher disease activity and altered immune profiles compared to those NSP. • Lymphocyte count and SS activity emerged as robust discriminators. • Higher CRP levels correlated with increased risk of SP, while lower CD4+ T cell and IgA levels associated with decreased risk. • SS activity significantly impacted patient outcomes.

Increased ILT2+ natural killer T cells correlate with disease activity in systemic lupus erythematosus.

OBJECTIVE: Numerous immune cell types, such as B and T lymphocytes, natural killer cells (NK), and NKT cells, are related to the pathogenesis of diseases in systemic lupus erythematosus (SLE). Our goal in this investigation is to examine the phenotype of NK cells and NKT cells alterations in individuals with SLE. METHODS: Typically, 50 SLE patients and 24 age-matched healthy people had their PBMCs obtained. Employing flow cytometry, the phenotype of NK and NKT cells and immunoglobulin-like transcript 2 (ILT2) expressions were identified. ELISA was utilized to evaluate the amounts of interleukin-15 (IL-15) and sHLA-G in the serum. RESULTS: The frequencies of the circulating NK and NKT cells in individuals with SLE were decreased compared to healthy controls. Furthermore, ILT2 expression was significantly increased in NKT cells, but showed no obvious change in NK cells. Clinical severity and active nephritis were substantially associated with ILT2+ NKT cell frequencies. The correlation study showed that the upregulation of ILT2 expression was related to sHLA-G in plasma but not to IL-15. CONCLUSIONS: ILT2+ NKT cells have a vital function in the immune abnormalities of SLE, which can also supply a viable goal for therapeutic intervention. Key Points •ILT2 expression was significantly increased in NKT cells in SLE patients. •ILT2+ NKT cell frequencies were associated with clinical severity which may be used as an indicator for evaluating disease activity in patients with SLE.

CD56brightCD16- to CD57+CD56dimCD16+ NK cell ratio discriminates disease activity and renal involvement in patients with systemic lupus erythematosus.

OBJECTIVES: We aimed to discriminate subpopulations of peripheral natural killer (NK) cells of patients with systemic lupus erythematosus (SLE) and evaluate their usability in monitoring disease activity. METHODS: The total number of NK cells and their subpopulations were determined by flow cytometry in 68 patients with SLE and 35 healthy controls. Clinical data were extracted from medical records, including serum anti-double-stranded-DNA (anti-dsDNA), complement C3 and C4, and urine protein. Disease activity in patients with SLE was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K). RESULTS: The percentages and absolute numbers of NK cells decreased, and the proportions of three major NK cell subsets defined by cell maturation status altered in SLE patients. The frequency of CD56brightCD16- NK (immature, Im NK) cells increased, while that of the CD57+CD56dimCD16- subset (mature, more differentiated, MD NK) decreased in patients with high-activity SLE, resulting in a significant increase in the Im NK-to-MD NK ratio as compared with that in patients with low-activity SLE. The area under the receiver operating characteristic curve indicated that the ratio was 0.722 in severe SLE and 0.773 in lupus nephritis, with optimal cut-off levels of 0.075 and 0.108, respectively. The ratio correlated positively with the SLEDAI-2K score, proteinuria, and serum anti-dsDNA antibody levels but negatively with C3 and C4 levels. CONCLUSIONS: Our data indicate that the imbalance in Im NK and MD NK cells may play a role in lupus development and serve as a predictive biomarker to assess disease activity and renal involvement in patients with SLE.

Post-traumatic growth in adult patients with systemic lupus erythematosus: a cross-sectional study in China.

This cross-sectional study aims to evaluate the post-traumatic growth (PTG) level and explores its predictors among adult patients with SLE in China. From April 2020 to April 2021, 135 hospitalized adult SLE patients completed the questionnaire including sociodemographic and disease-related data, Post-traumatic Growth Inventory (PTGI), Medical Coping Modes Questionnaire (MCMQ), Social Support Rating Scale (SSRS), Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), and Self-Perceived Burden Scale (SPBS). Descriptive analysis, pearson's correlation analysis, and forward multiple line regression analysis were used for analysis by SPSS 22.0. Results showed that, the mean PTGI score was 57.52 ± 20.82. Pearson correlation analysis showed that, complicated autoimmune hemolytic anemia (r = - 0.185), CD4 +/CD8 + (r = - 0.383), acceptance-resignation (r = - 0.185), poor PSQI (r = - 0.215), and depression (r = - 0.322) were negatively associated with total PTGI score; while the relationship with lupus nephritis (r = 0.247), confrontation (r = 0.313), avoidance (r = 0.379), and SSRS (r = 0.242) were positive (all P < 0.05). The total score of PTGI and its five sub-dimensions were not correlated with anxiety and self-perceived burden. Further, CD4 +/CD8 +, confrontation of MCMQ, and SSRS could explain 30.3% of the variance in total PTGI (F = 6.646, P < 0.01). In summary, Chinese adults with SLE experience moderate levels of PTG. Clinical nurses need pay attention to the current disease status and individual characteristics of patients, as well as their mental health, to promote their growth experience, so that they can cope with the future life in a better state and coexist well with SLE.

Tacrolimus therapy in primary Sjögren's syndrome with refractory immune thrombocytopenia: a retrospective study.

OBJECTIVES: To evaluate the efficacy and safety of tacrolimus (TAC) for the treatment of primary Sjögren's syndrome (pSS) with refractory immune thrombocytopenia (RITP). METHODS: Twenty-three pSS patients with RITP treated with TAC from June 2018 to June 2021 at the First Affiliated Hospital of Soochow University were enrolled in this retrospective cohort study. Platelet response, clinical and immunological parameters, toxicity and safety were compared and analysed at baseline and different points after TAC treatment. RESULTS: At 4 weeks after treatment, 2 patients (8.7%) attained a complete response (CR, platelet count ≥100×109/L and no bleeding), 15 patients (65.2%) achieved a partial response (PR, platelet count ≥ 30×109/L but <100×109/L and no bleeding or a platelet count at least twice that before treatment), and the other 6 patients (26.1%) did not respond to TAC treatment. At 8 weeks after treatment, a CR was seen in 4 patients (17.4%), and the percentage of patients with a PR increased to 78.3% (18 patients). The percentage of patients with a CR increased to 47.8% (11 patients), and 9 patients (39.1%) achieved a PR without relapse at 12 weeks after treatment. At 24 weeks after treatment, 14 patients (60.9%) achieved a CR, and 8 patients (34.8%) achieved a PR. Compared to before treatment, the level of IgG was decreased significantly at 24 weeks after treatment, whereas there was no significant difference in the levels of IgM or IgA between baseline and 24 weeks after treatment. Additionally, the absolute CD3+ T cell count, European SS Disease Activity Index (ESSDAI) score, and levels of IL-2 and INF-γ were significantly decreased at 24 weeks after treatment. CONCLUSIONS: TAC is effective and well tolerated by pSS patients with RITP, and the mechanism underlying the effect of TAC in these patients may be related to reduced Th1 cytokine expression.

Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor.

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-ß type I receptor (TGFßRI) is pivotal in determining T cell activation. Here, we showed that TGFßRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFßRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFßRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFßRI expression and inhibited T cell activation in vivo. TGFßRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFßRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

Umbilical cord mesenchymal stem cells enhance the therapeutic effect of imipenem by regulating myeloid-derived suppressor cells in septic mice.

BACKGROUND: Umbilical cord mesenchymal stem cells (UC-MSCs), which possess potent immunomodulatory effects and low immunogenicity, are considered to be a promising stem cell-based therapy for sepsis. In the current study, we aimed to investigate whether the combined use of UC-MSCs and imipenem has a better effect than imipenem alone in treating Escherichia coli (E. coli)-induced sepsis and to explore the mechanism by which UC-MSCs exert their therapeutic effect in septic mice. METHODS: We randomly divided mice into five groups with 10 mice in each group: the normal control group (control group), the sepsis group (vehicle group), the MSCs treatment group (MSCs group), the imipenem treatment group (imipenem group), and the imipenem plus MSCs treatment group (imipenem + MSCs group). We monitored the survival rate in each group every 12 h for 3 days. After observing the survival rate, another 50 mice were also randomly divided into five groups, and the mice were sacrificed after 24 h. Bacterial colonies from the blood and peritoneal lavage fluid were counted in a blinded manner. Organ injury was analyzed by hematoxylin and eosin (HE) staining. Frequencies of myeloid-derived suppressor cells (MDSCs) in the blood, spleen, and bone marrow (BM) were determined by flow cytometry. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with imipenem treatment, the co-administration of UC-MSCs and imipenem dramatically improved the survival rate, decreased the bacterial load, and ameliorated organ injury. Furthermore, UC-MSCs treatment, either alone or in combination with imipenem, significantly increased plasma levels of IL-10 and the percentage of MDSCs by inducing arginase-1 in septic mice. CONCLUSIONS: Our results indicated that UC-MSCs protect mice against sepsis by acting on MDSCs. Combination therapy of UC-MSCs and imipenem may be a new approach for the future clinical treatment of sepsis.

Effects of repetitive transcranial magnetic stimulation combined with transcranial direct current stimulation on motor function and cortex excitability in subacute stroke patients: A randomized controlled trial.

OBJECTIVE: To explore effects of repetitive transcranial magnetic stimulation (rTMS) combined with transcranial direct current stimulation (tDCS) on motor function and cortex excitability in subacute stroke patients. DESIGN: Randomized controlled trial. SETTING: Inpatient hospitals. SUBJECTS: Sixty-five participants were randomly assigned to four groups: sham, 1Hz rTMS, cathodic tDCS combined with 1Hz rTMS (tDCS-/rTMS-) and anodic tDCS combined with 1Hz rTMS (tDCS+/rTMS-). INTERVENTIONS: Four interventions were used, including sham, 1Hz rTMS, and cathodal or anodal tDCS, followed by 1Hz rTMS over contralesional motor cortex, which continued for four weeks. MAIN MEASURES: Outcome measures were motor function and cortical excitability, evaluated by Fugl-Meyer Assessment, National Institutes of Health Stroke Scale and Barthel Index, resting Motion Threshold, Motor Evoked Potentials and Central Motor Conduction Time, assessed at baseline, four weeks and eight weeks. RESULTS: At four weeks after interventions, Fugl-Meyer Assessment lower limb change score in tDCS+/rTMS- group was significantly larger than other three groups (P < 0.001). There were significant differences in bilateral Motor Evoked Potentials changes between tDCS+/rTMS- group and sham group (P < 0.05). At eight weeks, compared to other groups, National Institutes of Health Stroke Scale (P = 0.003), Barthel Index (P = 0.002), FMA lower limb score (P < 0.001), and bilateral resting Motion Threshold, Motor Evoked Potentials (P < 0.05) showed significant changes in tDCS+/rTMS- group. Furthermore, Fugl-Meyer Assessment lower limb change score was associated with increased ipsilesional Motor Evoked Potentials (r = 0.703 P < 0.001) in tDCS+/rTMS- group. CONCLUSION: 1Hz rTMS combined with anode tDCS stimulation protocol could be a preferable rehabilitative strategy for motor recovery in subacute stroke patients.

The changes and prognostic value of liver function in young adults with severe burn: A retrospective observational study.

To analyze the changes in liver functions and the relationship between alterations in liver function and mortality risk in young adults with third-degree burn wounds on over 90% of the total body surface area (TBSA).A total of 23 fatally burned factory workers in an inflammable dust explosion and fire were enrolled from 2 intensive care units. Clinical data, particularly the laboratory tests for liver function, were retrospectively analyzed and compared between the survivor and non-survivor groups.Compared to survivors, non-survivors had significantly higher total bilirubin (TBIL), glutamate-pyruvate transaminase (GPT), glutamic-oxaloacetic transaminase, alkaline phosphatase, prothrombin time, and activated partial thromboplastin time (APTT) at the terminal point of this study (P <.05). In addition, the peak values of TBIL, GPT, and longer APTT were higher in non-survivors than in survivors during hospital course, and the peak values of TBIL was one of major prognostic factors for mortality risk. Furthermore, at the first 2 weeks, the cumulative survival rates were significantly lower in patients with liver dysfunction than those without liver dysfunction (P <.01).Our findings show that the great changes in liver function occurred in first 2 weeks after severe burns. Liver dysfunction may have an effect on clinical outcomes of post-burn. Measures to protect liver function and prevent from deterioration could be beneficial in improvement survival rate, especially during the first 2 weeks.

[Elevation of red cell distribution width during hospitalization predicts mortality in patients with sepsis].

OBJECTIVE: To investigate the association of red cell distribution width (RDW) with prognosis in patients with sepsis. METHODS: Patients with sepsis admitted to intensive care unit (ICU) of the First Hospital of Soochow University from January 2011 to December 2016 were enrolled. All clinical data were collected for participants, which mainly included basic data, main underlying disease, site of infection, acute physiology and chronic health evaluation II(APACHE II) score, blood routine test, biochemical test, blood gas analysis, coagulation index, procalcitonin (PCT), hospitalization days, and 28-day and 90-day mortality. Patients were divided into two groups according to whether the RDW levels were higher than the time of admission or not. Kaplan-Meier survival curve was performed to analyze 28-day and 90-day cumulative survival rates in two groups. Multivariate Cox regression analysis was done to find the independent risk factors of death in patients with sepsis. RESULTS: 196 septic patients were eligible to participate into this study. 150 patients (53.57%) had higher RDW levels than those at the time of admission. Compared to negative or static change of RDW group, positive change of RDW group had higher APACHE II score (20.42±6.29 vs. 16.17±6.37), more percentage of chronic kidney insufficiency (35.24% vs. 19.78%), bloodstream infection (32.38% vs. 15.38%), continuous renal replacement therapy (CRRT: 32.38% vs. 16.48%), higher level of C-reactive protein [CRP (mg/L): 14.71±3.52 vs. 11.15±7.94], and higher serum creatinine [SCr (µmol/L): 128.0 (74.0, 263.5) vs. 90.0 (57.0, 145.5)], PCT [µg/L: 3.45 (2.39, 6.64) vs. 2.35 (0.56, 3.54)], and lactic acid [Lac (mmol/L): 3.40±1.72 vs. 2.70±1.61]; and had lower levels of hematocrit (Hct: 0.357±0.128 vs. 0.437±0.143), hemoglobin [Hb (g/L): 103.60±22.63 vs. 115.67±28.49], platelets [PLT (×109/L): 133.37±87.29 vs. 191.43±87.65], albumin [Alb (g/L): 28.15±5.72 vs. 35.51±5.91], total cholesterol [TC (mmol/L): 2.43±1.12 vs. 3.05±1.55], estimated glomerular filtration rate [eGFR (mL×min-1×1.73 m-2): 82.02±63.90 vs. 125.46±83.47], and oxygenation index [PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 229.69±60.61 vs. 264.21±74.78]; and longer time of hospitalization [days: 17.0 (12.0, 21.7) vs. 11.0 (7.0, 18.0)], higher 28-day and 90-day mortality (57.14% vs. 36.26%, 62.86% vs. 47.25%) with statistically significant differences (all P < 0.05). It was shown by Kaplan-Meier survival curve that the 28-day and 90-day cumulative survival rate in positive change of RDW group was significantly lower than that of negative or static change of RDW group (χ 12 = 8.462, χ 22 = 6.411, both P < 0.05). It was shown by multivariate Cox regression that high APACHE II score [odds ratio (OR) = 1.049, 95% confidence interval (95%CI) = 1.010-1.090, P = 0.013] and positive change of RDW (OR = 0.517, 95%CI = 0.280-0.953, P = 0.034) were the risk factors of death in patients with sepsis. CONCLUSIONS: The change of RDW values during hospitalization was related to the poor outcomes in patients with sepsis. The increase of RDW predicts the progress of sepsis and bad prognosis. Serial surveillance of RDW values could provide useful information for long-term prognosis in sepsis.

[Relationship of distortion product in cochlea with cochlear activity revealed by laser interferometry].

OBJECTIVE: To study the relationship of distortion product in cochlea with cochlear activity and hearing. METHOD: Time variances of distortion product of basilar membrane vibration in vitro guineapig cochlea were observed by laser interferometry. RESULT: Within half hour after a cochlea was isolated from a guineapig, distortion product accompanied with two-tone inhibition in cochlea, can be observed. As time passed, distortion product and two-tone inhibition effect disappeared at the same time. After that, the membrane contiune vibrating in response to the sound stimulus, but the vibration amplitude decreased obviously and continued decreasing until it disappeared completely. CONCLUSION: Distortion product in cochlea is a symbol of cochlear activity which makes the membrane respond in large amplitude vibration to sound stimulus and exhibit two-tone inhibition. The former makes the hearing highly sensitive to sound stimulus, the later makes the hearing perform information abstract well.