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1.
Cognitive processes that require spatial information rely on synaptic plasticity in the dorsal CA1 area (dCA1) of the hippocampus. Since the function of the hippocampus is impaired in aged individuals, it remains unknown how aged animals make spatial choices. Here, we used IntelliCage to study behavioral processes that support spatial choices of aged female mice living in a group. As a proxy of training-induced synaptic plasticity, we analyzed the morphology of dendritic spines and the expression of a synaptic scaffold protein, PSD-95. We observed that spatial choice training in young adult mice induced correlated shrinkage of dendritic spines and downregulation of PSD-95 in dCA1. Moreover, long-term depletion of PSD-95 by shRNA in dCA1 limited correct choices to a reward corner, while reward preference was intact. In contrast, old mice used behavioral strategies characterized by an increased tendency for perseverative visits and social interactions. This strategy resulted in a robust preference for the reward corner during the spatial choice task. Moreover, training decreased the correlation between PSD-95 expression and the size of dendritic spines. Furthermore, PSD-95 depletion did not impair place choice or reward preference in old mice. Thus, our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices, old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment.SIGNIFICANCE STATEMENT It remains poorly understood how aging affects behavioral and molecular processes that support cognitive functions. It is, however, essential to understand these processes to develop therapeutic interventions that support successful cognitive aging. Our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices (i.e., choices that require spatial information), old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment. Second, the contribution of PSD-95-dependent synaptic functions in spatial choice changes with age.  相似文献   
2.
BackgroundCompared with invasive fractional flow reserve (FFR), coronary CT angiography (cCTA) is limited in detecting hemodynamically relevant lesions. cCTA-based FFR (CT-FFR) is an approach to overcome this insufficiency by use of computational fluid dynamics. Applying recent innovations in computer science, a machine learning (ML) method for CT-FFR derivation was introduced and showed improved diagnostic performance compared to cCTA alone. We sought to investigate the influence of stenosis location in the coronary artery system on the performance of ML-CT-FFR in a large, multicenter cohort.MethodsThree hundred and thirty patients (75.2% male, median age 63 years) with 502 coronary artery stenoses were included in this substudy of the MACHINE (Machine Learning Based CT Angiography Derived FFR: A Multi-Center Registry) registry. Correlation of ML-CT-FFR with the invasive reference standard FFR was assessed and pooled diagnostic performance of ML-CT-FFR and cCTA was determined separately for the following stenosis locations: RCA, LAD, LCX, proximal, middle, and distal vessel segments.ResultsML-CT-FFR correlated well with invasive FFR across the different stenosis locations. Per-lesion analysis revealed improved diagnostic accuracy of ML-CT-FFR compared with conventional cCTA for stenoses in the RCA (71.8% [95% confidence interval, 63.0%–79.5%] vs. 54.8% [45.7%–63.8%]), LAD (79.3 [73.9–84.0] vs. 59.6 [53.5–65.6]), LCX (84.1 [76.0–90.3] vs. 63.7 [54.1–72.6]), proximal (81.5 [74.6–87.1] vs. 63.8 [55.9–71.2]), middle (81.2 [75.7–85.9] vs. 59.4 [53.0–65.6]) and distal stenosis location (67.4 [57.0–76.6] vs. 51.6 [41.1–62.0]).ConclusionIn a multicenter cohort with high disease prevalence, ML-CT-FFR offered improved diagnostic performance over cCTA for detecting hemodynamically relevant stenoses regardless of their location.  相似文献   
3.
目的 观察电针“百会”“神庭”对血管性痴呆(vascular dementia,VD)大鼠学习和记忆功能的影响,并从突触结构及突触相关蛋白表达水平的角度揭示其作用机制。方法 将35只雄性SD大鼠随机分为假手术组、模型组、电针穴位组、电针非穴位组和奥拉西坦组,每组7只。采用改良双侧颈动脉结扎模型,电针穴位组大鼠选择“百会”“神庭”两穴治疗,电针非穴位组大鼠选择固定非穴位刺激,每次电针30 min,每日1次,连续干预14 d;奥拉西坦组大鼠选择腹腔注射奥拉西坦,50 mg/kg,每日1次,连续14 d。采用Morris水迷宫检测各组大鼠学习和空间记忆能力;透射电子显微镜观察各组大鼠海马CA1区突触结构;Western blot检测各组大鼠海马突触后致密蛋白95(postsynaptic density protein 95, PSD95)、GluA1、GluN2B和磷酸化GluN2B蛋白表达水平。结果 与假手术组比较,模型组大鼠学习期逃避潜伏时间延长,测试期跨越平台次数减少,目标象限停留时间显著缩短,大脑质量显著增加,海马CA1区突触结构数明显减少,海马PSD95、GluA1、GluN2B和磷酸化GluN2B蛋白表达水平均显著降低,差异均有统计学意义(P<0.05);与模型组比较,电针穴位组大鼠的学习期逃避潜伏时间缩短,测试期跨越平台次数增加,目标象限停留时间延长,大脑质量降低,CA1区突触结构数增多,海马PSD95、GluA1、GluN2B和磷酸化GluN2B蛋白表达水平增加,差异均有统计学意义(P<0.05)。结论 电针“百会”“神庭”能改善VD大鼠的学习记忆功能,改变海马突触结构,分子机制可能和增加突触蛋白PSD95、GluA1和GluN2B的蛋白表达水平相关。  相似文献   
4.
目的测定不同剂量丙泊酚复合布托啡诺无痛胃镜检查时,布托啡诺抑制吞咽反射的ED50和ED95值。方法将76例无痛胃镜检查患者随机分为P1组和P2组,P1组给予丙泊酚2.0 mg/kg复合布托啡诺静脉麻醉,P2组给予2.5 mg/kg丙泊酚复合布托啡诺静脉麻醉。布托啡诺初始剂量为5.0μg/kg,根据吞咽反射抑制情况,运用Dixon序贯法确定下一例患者使用剂量,应用Probit分析得出两组患者布托啡诺抑制吞咽反射ED50和ED95值。结果P2组低血压发生率明显高于P1组(P<0.05);P1组和P2组布托啡诺抑制吞咽反射的ED50分别为3.5μg/kg(95%CI:2.9~4.1)和3.1μg/kg(95%CI:2.4~3.5);P1组和P2组抑制吞咽反射的ED95分别为5.8μg/kg(95%CI:4.7~15.9)和5.0μg/kg(95%CI:4.1~12.3)。结论布托啡诺复合丙泊酚2.0和2.5 mg/kg无痛胃镜检查时,抑制吞咽反射的ED50分别为3.5和3.1μg/kg,ED95分别为5.8和5.0μg/kg,对临床无痛胃镜麻醉用药具有指导意义。  相似文献   
5.

Objective

To determine the efficacy of a participation-focused therapy (ParticiPAte CP) on leisure-time physical activity goal performance and satisfaction and habitual physical activity (HPA) in children with CP.

Design

Randomized waitlist-controlled trial.

Setting

Home and community.

Participants

Children classified at Gross Motor Function Classification System (GMFCS) levels I-III were recruited (n=37; 18 males; mean age ± SD, 10.0±1.4y) from a population-based register.

Interventions

Participants were randomized to ParticiPAte CP (an 8-wk goal-directed, individualized, participation-focused therapy delivered by a physical therapist) or waitlist usual care.

Main Outcome Measures

The primary outcome was Canadian Occupational Performance Measure. Accelerometers were worn for objective measurement of HPA (min/d moderate-to-vigorous physical activity [MVPA], sedentary time). Barriers to participation, community participation, and quality-of-life outcomes were also collected. Data were analyzed by intention-to-treat using generalized estimating equations.

Results

ParticiPAte CP led to significant improvements in goal performance (mean difference [MD]=3.58; 95% confidence interval [95% CI], 2.19-4.97; P<.001), satisfaction (MD=1.87; 95% CI, 0.37-3.36, P=.014), and barriers to participation (MD=26.39; 95% CI, 6.13-46.67; P=.011) compared with usual care at 8 weeks. There were no between-group differences on minutes per day of MVPA at 8 weeks (MD=1.17; 95% CI, ?13.27 to 15.61; P=.874). There was a significant difference in response to intervention between participants who were versus were not meeting HPA guidelines at baseline (MD=15.85; 95% CI, 3.80-27.89; P<.0061). After ParticiPAte CP, low active participants had increased average MVPA by 5.98±12.16 minutes per day.

Conclusion

ParticiPAte CP was effective at increasing perceived performance of leisure-time physical activity goals in children with CP GMFCS I-III by reducing modifiable barriers to participation. This did not translate into change in HPA on average; however, low active children may have a clinically meaningful response.  相似文献   
6.

Objectives

We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults.

Methods

We fitted multivariable Cox models to assess whether circulating levels of inflammation markers were associated with incident lung cancers in the Health Aging, Body and Composition (HealthABC) prospective cohort of 3075 older adults aged 70–79?years at baseline. IL-6 and CRP were measured biennially, whereas TNF-α was measured at baseline.

Results

Baseline levels of IL-6 were significantly associated with incident lung cancer risk in a model that adjusted for age, gender, race, and site (Model 1) (Hazard RatioT3 vs. T1: 3.34, 95% Confidence Interval: 1.91, 5.85) and in a model adjusted for health factors linked to chronic inflammation (Model 2) (HR T3 vs. T1: 2.57, 95% CI: 1.41, 4.65). The associations observed in time-updated IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.28), cumulatively averaged IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.35), and baseline CRP levels (HR T3 vs. T1: 1.85, 95% CI: 1.11, 3.08) with incident lung cancer in Model 1 were not statistically significant in Model 2.

Conclusions

Baseline CRP and IL-6 levels were associated with increased risk of lung cancer in Model 1 and both models, respectively. Chronic IL-6 inflammation, as quantified by repeated measures was associated with incident lung cancer in Model 1, but not Model 2. Further research is needed to understand the role of CRP and IL-6 in lung carcinogenesis.  相似文献   
7.
【目的】探讨肉桂醛对子宫内膜癌RL95-2细胞凋亡的影响及其作用机制。【方法】选取肉桂醛作用子宫内膜癌RL95-2细胞,噻唑蓝(MTT)比色法检测子宫内膜癌RL95-2细胞的增殖活性和肉桂醛的IC50,Hoechst33258染色荧光显微镜观察细胞凋亡形态学改变,流式细胞术检测RL95-2细胞的凋亡百分率,Western blot检测肉桂醛对RL95-2细胞Cleavedcaspase-3、Caspase-3、NF-κB、IL-6和IGF-R蛋白表达的影响。【结果】肉桂醛可降低子宫内膜癌RL95-2细胞的增殖率,与药物浓度和作用时间有关;与溶剂对照组比较,肉桂醛组(0.29、0.59和1.20mg/mL)作用48h后RL95-2细胞的凋亡百分率明显增高(P<0.01),出现典型的凋亡小体,Cleavedcaspase-3蛋白的表达明显增加(P<0.01),Caspase-3蛋白的表达无明显变化(P>0.05),而NF-κBp65、IL-6和IGF-R蛋白的表达均明显降低(P<0.05)。【结论】肉桂醛可降低RL95-2细胞NF-κB·p65、IL-6和IGF-R蛋白的表达,促进RL95-2细胞的凋亡,从而起到抗子宫内膜癌作用。  相似文献   
8.
Paired associative stimulation has been used in stroke patients as an innovative recovery treatment. However, the mechanisms underlying the therapeutic effectiveness of paired associative stimulation on neurological function remain unclear. In this study, rats were randomly divided into middle cerebral occlusion model(MCAO) and paired associated magnetic stimulation(PAMS) groups. The MCAO rat model was produced by middle cerebral artery embolization. The PAMS group received PAMS on days 3 to 20 post MCAO. The MCAO group received sham stimulation, three times every week. Within 18 days after ischemia, rats were subjected to behavioral experiments—the foot-fault test, the balance beam walking test, and the ladder walking test. Balance ability was improved on days 15 and 17, and the footfault rate was less in their affected limb on day 15 in the PAMS group compared with the MCAO group. Western blot assay showed that the expression levels of brain derived neurotrophic factor, glutamate receptor 2/3, postsynaptic density protein 95 and synapsin-1 were significantly increased in the PAMS group compared with the MCAO group in the ipsilateral sensorimotor cortex on day 21. Resting-state functional magnetic resonance imaging revealed that regional brain activities in the sensorimotor cortex were increased in the ipsilateral hemisphere, but decreased in the contralateral hemisphere on day 20. By finite element simulation, the electric field distribution showed a higher intensity, of approximately 0.4 A/m~2, in the ischemic cortex compared with the contralateral cortex in the template. Together, our findings show that PAMS upregulates neuroplasticity-related proteins, increases regional brain activity, and promotes functional recovery in the affected sensorimotor cortex in the rat MCAO model. The experiments were approved by the Institutional Animal Care and Use Committee of Fudan University, China(approval No. 201802173 S) on March 3, 2018.  相似文献   
9.
10.
《Vaccine》2015,33(24):2813-2822
BackgroundIn the first five I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe) influenza seasons vaccine effectiveness (VE) results were relatively homogenous among participating study sites. In 2013–2014, we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in six European Union (EU) countries to measure 2013–2014 influenza VE against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. Influenza A(H3N2) and A(H1N1)pdm09 viruses co-circulated during the season.MethodsPractitioners systematically selected ILI patients to swab within eight days of symptom onset.We compared cases (ILI positive to influenza A(H3N2) or A(H1N1)pdm09) to influenza negative patients. We calculated VE for the two influenza A subtypes and adjusted for potential confounders. We calculated heterogeneity between sites using the I2 index and Cochrane's Q test. If the I2 was <50%, we estimated pooled VE as (1 minus the OR) × 100 using a one-stage model with study site as a fixed effect. If the I2 was >49% we used a two-stage random effects model.ResultsWe included in the A(H1N1)pdm09 analysis 531 cases and 1712 controls and in the A(H3N2) analysis 623 cases and 1920 controls. For A(H1N1)pdm09, the Q test (p = 0.695) and the I2 index (0%) suggested no heterogeneity of adjusted VE between study sites. Using a one-stage model, the overall pooled adjusted VE against influenza A(H1N1)pdm2009 was 47.5% (95% CI: 16.4–67.0).For A(H3N2), the I2 was 51.5% (p = 0.067). Using a two-stage model for the pooled analysis, the adjusted VE against A(H3N2) was 29.7 (95% CI: −34.4–63.2).ConclusionsThe results suggest a moderate 2013–2014 influenza VE against A(H1N1)pdm09 and a low VE against A(H3N2). The A(H3N2) estimates were heterogeneous among study sites. Larger sample sizes by study site are needed to prevent statistical heterogeneity, decrease variability and allow for two-stage pooled VE for all subgroup analyses.  相似文献   
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