Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice.

BACKGROUND: Cognitive deficit is mainly clinical characteristic of Alzheimer's disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-ß protein (Aß) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. OBJECTIVE: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. METHODS: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. RESULTS: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1ß, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. CONCLUSION: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.

Suvorexant ameliorates cognitive impairments and pathology in APP/PS1 transgenic mice.

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.

A GLP-1/GIP/Gcg receptor triagonist improves memory behavior, as well as synaptic transmission, neuronal excitability and Ca2+ homeostasis in 3xTg-AD mice.

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health and cannot be stopped by current treatments. Type 2 diabetes mellitus (T2DM) is a risk factor for AD. Our recent studies reported the neuroprotective effects of a GLP-1/GIP/Glucagon receptor triagonist (Triagonist), a novel unimolecular anti-diabetic drug, in cognitive and pathological improvements of 3xTg-AD mice. However, the detailed electrophysiological and molecular mechanisms underlying neuroprotection remain unexplored. The present study investigated the underlying electrophysiological and molecular mechanisms further by using whole-cell patch clamp techniques. Our results revealed that chronic Triagonist treatment effectively reduced working memory and reference memory errors of 3xTg-AD mice in a radial maze test. In addition, the Triagonist increased spontaneous excitatory synaptic activities, differentially modulated voltage- and chemically-gated Ca2+ flux, and reduced the over-excitation of pyramidal neurons in hippocampal slices of 3xTg-AD mice. In addition, chronic Triagonist treatment also up-regulated the expression levels of synaptophysin and PSD-95 in the hippocampus of 3xTg-AD mice. These results indicate that the Triagonist could improve memory formation, as well as synaptic transmission, Ca2+ balance, and neuronal excitability in 3xTg-AD mice. These neuroprotective effects of Triagonist may be involved in the up-regulation of synaptophysin and PSD-95. Therefore, the study suggests that multi-receptor agonists might be a novel therapeutic strategy for the treatment of AD.

[Application of wireless neuronal recording system in fear conditioning of Alzheimer's disease mice - hippocampal Theta oscillation observation].

APP/PS1/tau triple transgenic (3xTg) mouse is a classical animal model of Alzheimer's disease (AD), which has abnormalities in recognition and electrophysiological properties at early 6-month-old age. However, few studies were performed by using simultaneously recording cognitive behavior and brain electrical activity in the conscious 3xTg mice. By using a new wireless recording system, we recorded hippocampal Theta oscillations in 3xTg mice during the process of fear conditioning test. The results showed that: (1) in training session, no significant difference in the fear behavior and hippocampal Theta activity was found between 3xTg mice and WT mice; (2) in test session, 3xTg mice showed a significant decrease in freezing ratio compared with WT mice when they were exposed to conditioning stimulus (CS); (3) the 3xTg mice showed lower peak power in Theta oscillation in both Pre-CS and CS duration compared with WT mice; (4) CS effectively induced an increase in the peak frequency of Theta oscillation in WT mice, but not in 3xTg mice. These results indicated that the impairment of cognition behavior in 3xTg mice was accompanied with the decreased peak power and peak frequency of Theta oscillation in the hippocampus, suggesting that a decline in Theta oscillation might be involved in the impairments of the fear conditioning, and the enhanced hippocampal Theta oscillation may be beneficial for improving AD cognitive function.

Comparative study on effect and safty of treating on calcaneus fractures with manipulative reduction with percutaneous K-wire fixation / 中国骨伤

<p><b>OBJECTIVE</b>To explore the clinical effects and safty of manipulative reduction with percutaneous poking K-wire fixation for the treatment of the calcaneus fractures and analyze the indication of the minimal invasion.</p><p><b>METHODS</b>From December 2008 to December 2011,135 closed calcaneal fractures cases were divided randomly into poking group and plate group, treated respectively by percutaneous poking reduction and operative reduction. In poking group, there were 69 cases (82 feet) including 60 males and 9 females, with an average age of (43.29+/-10.46) years ranging from 18 to 64 years; 30 cases of left, 26 cases of right and 13 cases of double; 54 feet of Essex-Lopresti classification tongue form, 28 feet of joint compression; 33 feet of Sanders type II ,49 of type III. In plate group, there were 66 cases (75 feet) including 58 males and 8 females,with an average age of (46.00+/-2.42) years ranging from 21 to 63 years; 31 cases of left, 26 cases of right and 9 cases of double; 48 feet of Essex-Lopresti classification tongue form, 27 feet of joint compression; 28 feet of Sanders type II, 47 of type III. According to Kerr scoring standard,clinical effects and complications were evaluated combining with Sanders and Essex-Lopresti classification.</p><p><b>RESULTS</b>All 135 cases were followed up after 24 weeks. Fractures were recoveried in 8 to 12 weeks (means 10.2 weeks). In poking group, there were 2 cases of infection, 5 cases of wire movement; in plate group,18 cases of wound local skin necrosis, 5 cases of calf intestines nerve injured; there were statistical significant (P<0.05). Postoperative evaluation of Sanders type II after 24 weeks, the proportion of excellent results was above 70%,and there were no significant differences on effects of tongue form and compressing form of calcaneus fractures with percutaneous poking and operative redution (P>0.05). In the caes of Sanders type III, there were no significant differences on effects of tongue form fractures with percutaneous poking and operative reduction (P>0.05). There were significant differences on effects and complications of compressing form fractures (P<0.01), operative reduction better than percutaneous poking. Pain, walking,Kerr scoring of tongue form fractures of Sanders II , III with poking reduction were better than compression fractures. In compression fractures of Sanders Ill, plate internal fixation was better than poking redution in working and walking function, there were significant difference (P<0.05).</p><p><b>CONCLUSION</b>For tongue form or compressing form of Sanders type II and tongue form of Sanders type III, manipulative reduction with percutaneous poking K-wire fixation has advantages of minimal invasion, minimized complications. Compressing form of Sanders type III fracture should be treated with operative redution.</p>

[Clinical significance of radical cystectomy with extended lymphadenectomy].

OBJECTIVE: To evaluate the prognosis of patients treated with radical cystectomy and extended lymphadenectomy for invasive bladder cancer and to describe the association of the primary bladder tumor grade, stage, lymph node status and lymph node density with clinical outcomes. METHODS: A retrospective analysis was done of 32 consecutive cases with bladder cancer who received radical cystectomy and extended lymph node dissection from January 2006 to December 2010 in the Department of Urology, Peking University First Hospital. All the patients were scheduled for the follow-up. The survival data were analyzed with the tumor grade, stage, lymph node status and other factors that might relate to the prognosis by statistics. RESULTS: All the cases were diagnosed as invasive urothelial bladder cancer by preoperative biopsy or TUR-Bt. During the follow-up, 6 patients (18.8%) got disease progression, and 4 patients died (12.5%). Overall survival rate was 87.5%. In 32 patients, 17 months and 3 year survival rates were (88.7 ± 12.1)% and (81.8 ± 17.0)%, respectively. From the tumor grade point of view, 6 patients belonged to G2, and 26 cases G3. All deaths were graded G3. G3-class 3-year survival rate was (74.6 ± 23.9)% (P> 0.05, compared with G2). From the analysis of stage, T1 and T2 stages had no death during the follow-up. The 17-month survival rate of T3 group was (60.0 ± 42.9)%, the 8-month survival rate of T4 group was (87.5 ± 22.9)%. There were 9 patients with positive lymph nodes (28.1%) and 23 with negative in (71.9%). The number of dissection lymph nodes was from 7-50 ( average 22.8 ). The 17-month survival rate of patients with positive lymph node was (50.0 ± 44.6)%. The 3-year survival rate of patients with negative lymph node was (92.3 ± 14.5)% (P<0.05). The 3-year survival rate of patients with lymph node density less than 20% was (88.8 ± 15.4)%. The 8-month survival rate of patients with lymph node density greater than 20% was (66.7 ± 53.3)% (P<0.05). CONCLUSION: Radical cystectomy with extended lymph node dissection can improve the prognosis of patients with invasive bladder cancer. Tumor stage, lymph node status and lymph node density are closely related to the patient's survival.