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Objective:To observe the synaptic plasticity and characteristics of transmembrane calcium flux in the hippocampus of 3xTg-AD mice.Methods:According to different genotypes, 6-month-old mice were divided into two groups: APP/PS1/tau triple transgenic AD (3xTg-AD) model mice and wild type (WT) mice, with 13 mice in each group.Six mice were randomly selected from each group to do in vivo electrophysiological recording.Field excitatory postsynaptic potential (fEPSP) was evoked by test stimulation, paired-pulse facilitation (PPF) was induced by two stimuli, and long-term potentiation (LTP) was induced by high frequency stimulation (HFS) in the hippocampal CA1 region of mice.The remaining seven mice in each group were used to detect the transmembrane calcium influx and efflux in the slices of hippocampal CA1 region by using non-invasive micro-test technology (NMT). In the electrophysiological and NMT experiments, one mouse fell off respectively.Finally, five mice were enrolled in the electrophysiological experiment and six in the NMT experiment.SPSS 18.0 was used for statistical analysis of all data, and two independent sample t-test was used for comparison between the two groups. Results:(1) In the in vivo electrophysiological experiments, the fEPSP slopes of 3xTg-AD mice and WT mice evoked by test stimulation were stable within 30 min, and the average fEPSP slopes were ((97.8±2.3)%) and ((92.6±12.6)%), respectively.There was no statistical difference of the average fEPSP slopes between the two groups ( t=0.91, P>0.05). After paired-pulse stimulation, the PPF values of 3xTg-AD mice and WT mice were (1.58±0.69) and (1.74±0.17) respectively, and there was no statistical difference between the two groups ( t=0.50, P>0.05). At 30 min and 60 min post-HFS, the LTP values in 3xTg-AD mice were ((104.9±10.9)%) and ((98.0±10.8)%) respectively, which were significantly lower than those in WT mice((156.5±21.3)%, t=4.43, P<0.01; (162.5 ±19.7)%, t=5.92, P<0.01). (2) In NMT experiments, the standardized mean and peak velocities of glutamate-induced Ca 2+ influx in hippocampal CA1 region of 3xTg-AD mice were ((-2 166.0±425.0)%) and ((-3 539.6±1 270.9)%) respectively, which were significantly higher than those in WT mice((-735.3±262.9)%, t=6.81, P<0.01; (-917.3±271.7)%, t=4.89, P<0.01). The standardized average and peak velocities of low Ca 2+ solution-induced Ca 2+ efflux in 3xTg-AD mice were ((1 451.6±297.1)%) and ((1 968.7±227.3)%) respectively, which were significantly lower than those in WT mice((2 579.3±810.9)%, t=2.92, P<0.05; (3 420.4±954.8)%, t=3.31, P<0.01). Conclusion:The hippocampal synaptic plasticity impairment observed in 6-month-old 3xTg-AD may be closely related with the intracellular Ca 2+ overload caused by increased calcium influx and decreased calcium efflux.
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Objective To observe the effects of adiponectin (APN) on anxiety-and depression-like behaviors occurred in APP/PS1/tau triple transgenic Alzheimer's disease (3xTg-AD) model mice and investigate the possible mechanism.Methods The 9-month-old 3xTg-AD mice and wild type (WT) mice were randomly divided into four groups (n=8 for each group):WT+Saline,WT+APN,3xTg-AD+Saline and 3xTg-AD+APN groups.The mouse was chronically intracerebroventricular injection of APN or saline under free moving condition.Elevated plus maze task was used to evaluate the anxiety-like behaviors.Sucrose preference test and tail suspension test were used to evaluate the depression-like behaviors.Western blot was used to detect the protein expression levels of p-AMPK,AMPK,p-GSK-3β (Ser9),GSK-3β and SIRT1 in the hippocampus of each mouse.Results In the elevated plus maze test,the time percentage spent in open arms of 3xTg-AD+Saline mice was ((4.2±2.7) ％),which significantly lower than that in WT+Saline group ((10.1±4.1)％) (q=4.349,P＜0.01) and in 3xTg-AD+APN group ((9.7±3.3)％) (q=4.065,P＜0.01).In the sucrose preference test,the sucrose preference percentage in 3xTg-AD+Saline group((48.8±5.3) ％) was lower than that in WT+Saline group ((60.9±6.7) ％) (q=4.522,P＜0.01) and in 3xTg-AD+APN group ((59.3±6.2)％) (q=3.911,P＜0.05).As for tail suspension test,the immobility time percentage in 3xTg-AD+Saline group((40.7±9.9)％) was higher than that in WT+Saline group ((27.1±4.8)％) (q=5.257,P＜0.001) and in 3xTg-AD+APN group ((31.4±6.0)％) (q=3.624,P＜0.05).The result of Western blot showed that there was no significant difference in expression level of AMPK and GSK-3β among four groups.However,compared with that in WT+Saline group,the expression levels of p-AMPK (q=3.586,P＜0.05),p-GSK-3β (Ser9) (q=3.125,P＜0.05),and SIRT1 (q=3.044,P＜0.05) in 3xTg-AD+Saline group were significantly decreased.In addition,compared with that in 3xTg-AD+Saline group,the expression levels of p-AMPK (q=3.374,P＜0.05) and p-GSK-3β (Ser9) (q=3.063,P＜0.05) in 3xTg-AD+APN group were obviously up-regulated without affecting the SIRT1.Conclusion Adiponectin can effectively alleviate the anxiety-and depression-like behaviors of 9-month-old 3xTg-AD mice by up-regulating the protein expression of p-AMPK and p-GSK-3β (Ser9) in the hippocampus.
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Objective To investigate the behavioral characteristics of circadian rhythm disturbance in 3xTg-AD mice.Methods The free-running period,average activity per hour,total amount of exercise and circadian amplitude were examined with voluntary wheel-running test in 3-to 9-month-old C57BL/6 and 3xTg-AD mice under 12 h light/12 h dark cycle and constant darkness environment.Results In constant darkness environment,the free-running period in 3-month-old 3xTg-AD mice was (23.2±0.4) h,and shorter than the period((23.5±0.2) h) in C57BL/6 mice.In 6-and 9-month-old 3xTg-AD mice,activity pattern was disorganized,without clear boundary between activity and rest phase.The free-running period was unavailable.The circadian amplitude and total exercise amount were(40.6± 11.5) counts/5 min and(2.6±0.1) × 104 counts/d,(37.0±20.8) counts/5 min and(2.3±0.4) × 104 counts/d,(29.3± 11.0) counts/5 min and(1.6± 0.9) × 104 counts/d in 3-,6-and 9-month-old 3xTg-AD mice,respectively,which was significantly lower than that in age-matched C57BL/6 mice.In 12 h light/12 h dark cycle,the circadian amplitude and total exercise amount of 3-,6-and 9-month-old 3xTg-AD mice were (87.0 ± 37.8) counts/5 min and (2.2 ± 0.8) × 104 counts/d,(25.9± 6.3) counts/5 min and (1.1 ± 0.2) × 104 counts/d,(14.3 ± 5.7) counts/5 min and (0.6 ± 0.3)× 104 counts/d respectively,and with a significant decrease from the age of 6 months.Meanwhile,the locomotor activity decreased at night and increased during the day.Conclusion The endogenous circadian rhythm disturbance emerges in 3xTg-AD mice at 3-month-old,while the exogenous circadian rhythm disorder appears at 6-month-old;the degree of disorder in circadian rhythm is gradually aggravated with the increase of age in of the AD mice.
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ObjectiveTo investigate the correlation of hippocampal synaptic plasticity with spatial learning and memory under normal and pathological condition,and provide experimental evidence for the coincidence of hippocampal late-phase long-term potentiation (L-LTP) and behavioral experiments.Methods 38 SD rats were randomly divided into two groups,control and AD model.First,Morris water maze was used to test the ability of spatial learning and memory of rats.The escape latencies for rats to search for an underwater platform in 5 days of navigation tests and the swimming time percentage in target qtuadrant on the 6th day after withdrawing the platform in probe trails were recorded.Then,in vivo hippocampus L-LTP of field excitatory postsynaptic potential (fEPSP)in CA1 region was recorded after delivering high frequency stimulation (HFS).ResultsBilateral intrahippocampal injection of 4 nmol amyloid β peptide ( Aβ 25-35 ) significantly impaired spatial learning and memory of rats in water maze tests,as well as in vivo hippocampal L-LTP.In control group,there was a significant negative correlation between the amplitude of fEPSP and the escape latency ( r =-0.8306,P ＜ 0.01 ) and a significant positive correlation between the amplitude of fEPSP and the swimming time percentage in target quadrant ( r=0.7709,P＜0.01 ).In AD model group,similar correlations were found,with a correlation coefficient of r =-0.7675 (P ＜0.01 ) and r =0.8049 (P ＜ 0.01 ),respectively.When putting all data from the two groups together,the hippocampal L-LTP was more correlated with escape latency ( r =-0.9124,P ＜ 0.01 ) and swimming time percentage ( r=0.9745,P＜0.01).ConclusionThere is very close correlation between the hippocampal L-LTP and the spatial learning and memory behavior in rats,suggesting that the hippocampal L-LTP may be involved in the electrophysiological mechanism of spatial learning and memory in rats,and the impairment of L-LTP could partly represent the deficits in cognitive function of animals.
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Objective To study the clinical application of trigemino-cervical reflex(TCR)in migraine without aura(MWOA)and chronic tension-type headache(CTTH).Methods The TCR was recorded using surface electromyographic recordings bilaterally from the sternocleidomastoid muscle after stimulation of infraorbital branch of the trigeminal nerve.The reflex was investigated in 25 patients with unilateral MWOA,25 patients with CTTH and 36 healthy subjects.The patients were outpatients who visited Fujian provincial institution hospitals from January 2009 to February 2010.Results Compared with the healthy subjects,the bilateral peak latency of P19/N31(PLP19 and PLN31)was significantly shortened in the subjects with MWOA(left and fight side were(19.49 ± 1.95)ms and(19.81 ± 1.79)ms respectively)or CTTH(left:(19.56 ±2.02)ms,and right:(19.16 ± 1.67)ms),t values were between 2.027 and 3.654,all P ＜ 0.05.The values of PLP19 and PLN31 between the patients with MWOA and with CTTH were not significantly different.Conclusions The peak latency of P19/N31 was shortened in the subjects with MWOA or CTTH,suggesting that the trigeminal and brainstem may participate in the pathophysiology of MWOA and CTTH.There was no significant difference in PLP19 and PLN31 between the patients with MWOA and CTTH,indicating similar abnormalities in the endogenous pain control mechanisms in both migraine and
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<p><b>BACKGROUND</b>It is well known that more than 40% patients were initially diagnosed with advanced non-small cell lung cancer (NSCLC) with intrapulmonary or/and distant metastasis. However, up to now, the reports about effects of different metastatic sites on survival were limited. The aim of this study is to investigate the clinicopathologic and survival difference by retrospective analysis among sole intrapulmonary metastasis, sole extrathoracic distant metastasis and simultaneous metastasis of lung and other extrathoracic organs for the patients with advanced NSCLC, and to analyze the prognosis-related factors of NSCLC with intrapulmonary metastasis.</p><p><b>METHODS</b>Of the 425 patients with stage IV NSCLC diagnosed by pathology and through staging evaluation and treated at Beijing Cancer Hospital with long follow-up during Oct. 1995 to Dec. 2003, 81 cases had sole intrapulmonary metastasis, 98 cases had sole extrathoracic distant metastasis and 68 cases presented simultaneous lung metastasis and extrathoracic spread. Kaplan-Meier survival curve was performed to estimate the survival of patients with different metastasis, Log-Rank test was used to compare their survival difference, and univariate analysis was used to find prognostic related factors.</p><p><b>RESULTS</b>Median survival time (MST) and 1-, 2-, 3-year survival rate (SR) for patients with sole intrapulmonary metastasis were 13 months (95% CI: 11-15), 57%, 21%, 7%, respectively; MST was 22 months (95% CI: 18-26) for patients with N1 and/or N2 and 10 months (95%CI: 7-13) for patients with N3 (P=0.001). Among the patients with ipsilateral, contralateral and bilateral intrapulmonary metastasis, difference of MST and 1-, 2-, 3-year SR had no statistical significance (P > 0.05); Survival of patients with sole intrapulmonary metastasis was not significantly different from that of patients with sole brain or bone metastasis (P > 0.05), but was longer than that of patients with simultaneous lung and extrathoracic spread (P=0.021). One way analysis of variance showed that no significant association were found among age, pathologic subtype, differentiation degree or response of first-line chemotherapy and survival of the patients with sole intrapulmonary metastasis (P > 0.05), but sex and invasive status of lymph node (N1/N2 vs N3) were found to influence the survival of the patients (P= 0.018, P=0.001). Further stratified analysis by age showed that invasion of lymph node was independent prognostic factor (P=0.002); whereas for the patients with simultaneous metastasis of lung and distant organs, metastatic numbers (2 vs ≥3) of organ were independent prognostic factor (P=0.013).</p><p><b>CONCLUSIONS</b>No statistical difference is found among survival of NSCLC patients with sole intrapulmonary metastasis and with sole brain, bone metastasis. Invasive status of lymph node and metastatic number of organ are important prognostic factors for patients with sole intrapulmonary metastasis and simultaneous metastasis of lung and extrathoracic organs, respectively.</p>
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<p><b>BACKGROUND</b>Now the treatment of non-small cell lung cancer (NSCLC) patients with brain metastasis is not a standard program. The aim of this study is to summarize the factors related to survival of patients with brain metastases from NSCLC.</p><p><b>METHODS</b>A total of 111 NSCLC patients with brain metastases (from September 1995-May 2004) were defined as symptomatic group (37 patients) and asymptomatic group (74 patients) according to central nervous system (CNS) symptoms. The patients in the symptomatic group were given whole brain radiation therapy (WBRT, DT 30-40Gy/20f) first, and then received cisplatin-based chemotherapy. The patients in the asymptomatic group were given cisplatin-based chemotherapy first, and then received WBRT. During the treatment, 49 patients received chemotherapy of BCNU or VM-26 irregularly.</p><p><b>RESULTS</b>The median survival time was 11 months. The 1-and 2-year survival rate was 40.79% and 13.26% respectively. The survival time was not significantly different between the symptomatic group and asymptomatic group. Median chemotherapy of asymptomatic group was 3 cycles (1-6 cycles) before WBRT. Those patients who received 3 or 4 cycles of chemotherapy before WBRT had better survival (P= 0.0188 , P=0.0035). The treatment of BCNU or VM-26 was a benefit factor for survival (P=0.0219) in asymptomatic group. The hematologic toxicity of grade III or IV was not significantly different between the two groups (P > 0.05). The number of brain metastasis (P=0.000), extracranial metastasis (P=0.022) and WHO performance status (P=0.001) were independent prognostic factors.</p><p><b>CONCLUSIONS</b>The patients with asymptomatic brain metastases receive 3-4 cycles of chemotherapy before WBRT may be reasonable. During the therapy, the patients with administration of BCNU or VM-26 may have survival benefit.</p>
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<p><b>BACKGROUND</b>To investigate the prognostic factors of 355 patients with advanced non-small cell lung cancer for researching an individual treatment module.</p><p><b>METHODS</b>From March 1988 to October 2000, after diagnosed by histology or cytology and staged by staging examinations, 355 novel advanced NSCLC patients (stage III, 134; stage IV, 221) were enrolled, who were given at least 2-cycle chemotherapy. Response rate and survival were observed and prognostic factors were analysed.</p><p><b>RESULTS</b>Out of 355 patients, 101 got partial response and 147 had stable disease. Response rate was 28.45%, and tumor control rate was 69.86%. Median survival duration was 16 months. The 1-, 2-, 3- and 5-year survival rates were 58.41%, 29.35%, 14.60% and 8.60%, respectively. In the patients with stage IV, median survival duration was 14 months, and 1-, 2-, 3- and 5-year survival rates were 54.62%, 25.59%, 12.70% and 6.73%, respectively. COX multiple variable analysis showed that improved/stable ECOG score (P=0.044 0) and chemotherapy (after second line failure) combined with γ-IFN (P=0.039 0) had prognostic significance.</p><p><b>CONCLUSIONS</b>Improvement of quality of life is quite important in the treatment of advanced NSCLC. Combination with γ-IFN or TAM and radiotherapy of primary tumor may be helpful to improve the survival of patients with stage IV.</p>
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Purpose: To evaluate the efficacy and toxicity of vinorelbine combined with cisplatin (NP regimen) in the treatment of advanced non-small-cell lung cancer ( NSCLC). Methods: ninety-one patients with advanced NSCLC were confirmed by pathology or cytology. There were 56 patients with lung adenocarcinoma, 27 with squamous carcinoma and 4 with alveoli cell cancer, 3 with large-cell lung cancer, one case diagnosed by cytological smear section. The eighty patients had no prior chemotherapy and 11 were those without received previously chemotherapy. Thirty-two patients had stage Ⅲ disease and 59 had stage Ⅳ. Results: Partial response was observed in 37 patients with an overall response rate of 40. 7% (95%CI:30. 5%-50. 7%). Median time to progression (TTP) were 5 months(95% CI: 4-6 months). Median survival duration was 13 months (95% CI: 11-15months), one-year survival rate was 52. 7% ( CI: 42. 4%-62. 9%). The dose limiting toxicity was neutropenia that was observed in 87. 9% of the patients (40.7% in grades Ⅲ and Ⅳ). The remission response rate is 40. 6% , TTP is 5 months, MS is 13 months and 1-year survival rate was 52.7% . Conclusions: The results indicate NP regimen for advanced NSCLC is promise, and the toxicities are tolerable.