Region‐specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6‐AP ubiquitin protein ligase Ube3a (Ube3a^m?/p+), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum‐dependent task. We used whole‐cell patch‐clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a^m?/p+ mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild‐type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a^m?/p+ mice were more habitual, impervious to changes in outcome value and action–outcome contingency. In the DMS, but not the DLS, Ube3a^m?/p+ mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.     

Decoding the individual finger movements from single‐trial functional magnetic resonance imaging recordings of human brain activity

Multivariate pattern classification analysis (MVPA) has been applied to functional magnetic resonance imaging (fMRI) data to decode brain states from spatially distributed activation patterns. Decoding upper limb movements from non‐invasively recorded human brain activation is crucial for implementing a brain–machine interface that directly harnesses an individual's thoughts to control external devices or computers. The aim of this study was to decode the individual finger movements from fMRI single‐trial data. Thirteen healthy human subjects participated in a visually cued delayed finger movement task, and only one slight button press was performed in each trial. Using MVPA, the decoding accuracy (DA) was computed separately for the different motor‐related regions of interest. For the construction of feature vectors, the feature vectors from two successive volumes in the image series for a trial were concatenated. With these spatial–temporal feature vectors, we obtained a 63.1% average DA (84.7% for the best subject) for the contralateral primary somatosensory cortex and a 46.0% average DA (71.0% for the best subject) for the contralateral primary motor cortex; both of these values were significantly above the chance level (20%). In addition, we implemented searchlight MVPA to search for informative regions in an unbiased manner across the whole brain. Furthermore, by applying searchlight MVPA to each volume of a trial, we visually demonstrated the information for decoding, both spatially and temporally. The results suggest that the non‐invasive fMRI technique may provide informative features for decoding individual finger movements and the potential of developing an fMRI‐based brain–machine interface for finger movement.     

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Objective

Orexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone.

Design and methods

We generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts.

Results

Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection.

Conclusions

Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.     

Differences in Perioperative Care at Low- and High-Mortality Hospitals with Cancer Surgery

Objective

To evaluate adherence to perioperative processes of care associated with major cancer resections.

Background

Mortality rates associated with major cancer resections vary across hospitals. Because mechanisms underlying such variations are not well-established, we studied adherence to perioperative care processes.

Methods

There were 1,279 hospitals participating in the National Cancer DataBase (2005–2006) ranked on a composite measure of mortality for bladder, colon, esophagus, stomach, lung, and pancreas cancer operations. We sampled hospitals from among those with the lowest and highest mortality rates, with 19 low-mortality hospitals [(LMHs), risk-adjusted mortality rate of 2.84 %] and 30 high-mortality hospitals [(HMHs), risk-adjusted mortality rate of 7.37 %]. We then conducted onsite chart reviews. Using logistic regression, we examined differences in perioperative care, adjusting for patient and tumor characteristics.

Results

Compared to LMHs, HMHs were less likely to use prophylaxis against venous thromboembolism, either preoperative or postoperatively [adjusted relative risk (aRR) 0.74, 95 % CI 0.50–0.92 and aRR 0.80, 95 % CI 0.56–0.93, respectively]. The two hospital groups were indistinguishable with respect to processes aimed at preventing surgical site infections, such as the use of antibiotics prior to incision (aRR, 0.99, 95 % CI 0.90–1.04), and processes intended to prevent cardiac events, including the use of β-blockers (1.00, 95 % CI 0.81–1.14). HMHs were significantly less likely to use epidurals (aRR, 0.57, 95 % CI 0.32–0.93).

Conclusions

HMHs and LMHs differ in several aspects of perioperative care. These areas may represent opportunities for improving cancer surgery quality at hospitals with high mortality.     

骨关节炎中影响软骨细胞凋亡的因素

目的:近年来国外对骨关节炎的发生及发展机制有许多研究成果,骨关节炎中软骨细胞凋亡影响因素的研究颇具新意。资料来源:应用计算机检索Medline1985-01/2004-12与骨关节炎中软骨细胞凋亡相关的文献,检索词“osteoarthritis,chondrocyte,apoptosis”并限定文献语种为English。资料选择:对资料的摘要进行阅读初审,选取包括试验组和对照组的文献,开始查找全文。纳入标准:①随机对照试验。②试验包括对照组。排除标准:①没有设立对照组的文献。②综述类文献、Meta分析、重复研究。资料提炼:共收集到111篇关于骨关节炎中软骨细胞凋亡影响因素的试验,纳入符合标准的文献35篇。排除的文献为综述类文献28篇和重复研究48篇。35篇文献多为软骨细胞体外培养有关的试验,分别对各种凋亡影响因素进行评价。资料综合:在骨关节炎患者和老年人的软骨中,由于细胞外基质成分降解或通过高级糖基化、酪氨酸亚硝基化等修饰作用破坏了正常的细胞外基质从而使软骨细胞发生炎症反应并促进其死亡。各种机械性刺激是软骨细胞功能的重要调节因素,施加机械压力的加速率也决定软骨损伤和软骨细胞死亡的类型与程度。经某些细胞因子作用的正常软骨和分离培养的软骨细胞产生高水平的NO,而NO产物又能诱导软骨细胞死亡。肿瘤坏死因子受体超家族成员与相应的死亡配体结合能激活凋亡信号通路,当存在其他前凋亡因子或缺乏某些促存活因子时肿瘤坏死因子α能诱导软骨细胞凋亡。正是由于能量代谢受损使软骨细胞对其他的致死因子变得更加敏感。在发育和骨关节疾病相关过程中,软骨细胞的死亡虽然有p53的参与,但其精确的机制有待阐明,同时没有足够的直接证据表明c-myc能够影响软骨细胞的存活或死亡。结论:骨关节炎中影响软骨细胞凋亡的因素很多,机制复杂,许多因素导致软骨细胞凋亡的通路有待进一步阐明。     

Prognostic Factors of Patients with Spinal Chondrosarcoma: A Retrospective Analysis of 98 Consecutive Patients in a Single Center

Purpose

Chondrosarcoma (CHS) in the spine is relatively rare and minimal information has been published in the literature regarding this subject. The objective of our study was to discuss the factors that may affect outcomes of patients with spinal CHS.

Methods

Univariate and multivariate analyses were performed to identify prognostic factors for recurrence, distant metastasis, and survival of spinal CHS. T test, χ ² test and rank sum test were used to analyze a single factor for recurrence and metastasis, while survival rate was estimated using the Kaplan–Meier method. Factors with p values of ≤0.1 were subjected to multivariate analyses by binary logistic regression analyses or Cox regression analyses. p Values of ≤0.05 were considered statistically significant.

Results

A total of 98 patients with spinal CHS were included in the study. The mean follow-up period was 49.7 months (range 6–178). Recurrence was detected in 42 patients after initial surgery in our center, while distant metastasis and death occurred in 24 and 32 cases, respectively. The statistical analyses suggested that pathology grade III was closely related with distant metastasis which was an independent prognostic factor for overall survival. Total en bloc spondylectomy could significantly decrease the risk of recurrence, distant metastasis, and death of patients with spinal CHS.

Conclusions

Total en bloc spondylectomy could significantly decrease the risk of recurrence and distant metastasis, and meanwhile improve overall survival of spinal CHS. Distant metastasis which was closely associated with pathology grade III was an adverse prognostic factor for overall survival of spinal CHS.     

A novel reference coordinate system to locate the inferomedial point of the transverse-sigmoid sinus junction

Background

A coordinate system was previously developed to identify landmarks on the skull surface to help locate the transverse-sigmoid sinus junction in order to reduce surgical morbidity in retrosigmoid craniotomy; however, in practice we found that this system has important flaws.

Objective

To develop and evaluate a novel reference coordinate system to precisely locate the inferomedial point of the transverse-sigmoid sinus junction (IMTS) and evaluate the effect of gender and skull side (left or right).

Methods

Forty-two adult skulls (84 sides) were obtained for analyses. The X-axis was defined by point A (where the upper edge of the zygomatic arch joins with the frontal process of the zygomatic bone) and point B (where the upper edge of the zygomatic arch blends posterosuperiorly into the supramastoid crest). The Y-axis was defined by the line perpendicular to the X-axis and extending across the tip of the mastoid. The x and y coordinates of IMTS (IMTS-x and IMTS-y) were measured in this coordinate system.

Results

There were 20 male skulls and 22 female skulls. The mean IMTS-x measurements were significantly higher on the right side compared with the left side in both males and females. For the left skull side, the mean IMTS-y measurements were significantly lower in females compared with males.

Conclusion

This novel reference coordinate system may be a reliable and practical method for identifying the IMTS during retrosigmoid craniotomy. There are significant differences in location of the axes with regard to gender and skull side.