Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.The subthalamic nucleus (STN) has long been a structure of interest for researchers and clinicians alike. There is ample evidence that high-frequency stimulation of the STN improves symptoms such as tremor, rigidity, and slowness of movement, so called bradykinesia, in patients with Parkinson disease (see ref. 1 for review), but the mechanism through which this is achieved is still unknown. Some studies suggest that electrical stimulation causes a hyperexcitation of this structure (2), whereas others find evidence that the opposite is true (3–5). Other possible interpretations include the activation of the zona incerta, a neighboring white-matter structure (6) or of fibers coming from the motor cortex (7). Bilateral lesions of the STN improve locomotion (8), a result that is consistent with the inactivation hypothesis. However, previous studies have also found cognitive side effects when using high-frequency stimulation of the STN (9), findings supported by lesion studies in experimental animals, which led to abnormalities in operant tasks involving attention and impulsivity (10, 11). The projections of the STN to other regions help explain the multiple roles of this structure: It sends projections to other targets in the basal ganglia, such as the internal segment of the globus pallidus [also termed the entopeduncular nucleus (EP) in rodents] and the substantia nigra pars reticulata (SNr) (12, 13). The STN is also part of a circuit that includes the prefrontal cortex and the nucleus accumbens (14). It is currently unknown, however, whether these different roles reflect a heterogeneous population of cells, characterized by distinct gene expression. If that is the case, it would allow direct control over each cell population, facilitating the investigation of their respective roles. In rodents, the STN is believed to be composed solely of glutamatergic neurons, characterized by expression of the subtype 2 Vesicular glutamate transporter (Vglut2), whereas the other two subtypes (Vglut1 and Vglut3) have not been detected (15, 16). Selective targeted deletion of Vglut2 expression in this nucleus would therefore provide a specific loss-of-function model that would bypass a common problem presented by traditional lesions with pharmacological agents, which have patterns of diffusion that likely affect surrounding structures (17). It is known, however, that Vglut2 is expressed in many other parts of the brain (18), and a complete knockout in the mouse is not viable (19, 20). There is also evidence that the promoter driving expression of the Paired-like homeodomain 2 (Pitx2) gene is strong in the mouse STN (21) but is also not specific to this structure and a full knockout of Pitx2 expression results in premature death (22). To achieve the desired level of specificity, using a conditional knockout technique previously used to eliminate glutamatergic transmission in other cell types (23), we crossed Pitx2-Cre and Vglut2-lox mice, producing Vglut2^{f/f;Pitx2-Cre} conditional knockout (cKO) mice in which Vglut2 expression in the STN was strongly reduced in comparison with expression levels in littermate control mice. To understand the physiological contribution of the selected subpopulation of STN cells, we characterized these cKO mice with regard to anatomical, electrophysiological, and molecular properties, as well as their performance in a range of behavioral tasks.     

Design of the standardizing care to improve outcomes in pediatric end stage renal disease collaborative

The Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (SCOPE) Collaborative is a North American multi-center quality transformation effort whose primary aim is to minimize exit-site infection and peritonitis rates among pediatric chronic peritoneal dialysis patients. The project, developed by the quality improvement faculty and staff at the Children’s Hospital Association’s Quality Transformation Network (QTN) and content experts in pediatric nephrology and pediatric infectious diseases, is modeled after the QTN’s highly successful Pediatric Intensive Care Unit and Hematology-Oncology central line-associated blood-stream infection (CLABSI) Collaboratives. Like the Association’s other QTN efforts, the SCOPE Collaborative is part of a broader effort to assist pediatric nephrology teams in learning about and using quality improvement methods to develop and implement evidence-based practices. In addition, the design of this project allows for targeted research that builds on high-quality, ongoing data collection. Finally, the project, while focused on reducing peritoneal dialysis catheter-associated infections, will also serve as a model for future pediatric nephrology projects that could further improve the quality of care provided to children with end stage renal disease.     

The Reliability of a Scoring System for Corrosion and Fretting,and Its Relationship to Material Loss of Tapered,Modular Junctions of Retrieved Hip Implants

It has been suggested that corrosion and fretting at the tapered, modular junctions of hip arthroplasties may contribute to implant failure. In this study the reliability of a commonly used peer-reviewed scoring system for visual assessment of corrosion and fretting at these junctions was evaluated. Volumetric material loss at the tapered head surface was measured and associations with the visual scores were investigated. We found that the inter-observer reproducibility and single-observer repeatability of the corrosion scores were substantial using Cohen’s weighted Kappa statistic (k = 0.64–0.71). The reproducibility and repeatability of the fretting scores however were slight to fair (k = 0.18–0.31). Taper corrosion scores were significantly and moderately correlated with the volume of material loss measured (Spearman’s r = 0.59; P < 0.001). We recommend the continued use of this scoring system but it should not be a substitute for measurement of material loss.     

治疗骨质疏松新靶点：辅助T细胞-17

骨质疏松是一种常见疾病,骨质疏松的病因学和发病机制至今还没有被阐明清楚,目前还没有彻底治疗骨质疏松的方法,但是研究疾病的发病机制可以为骨质疏松患者提供全新的治疗方法。最近的研究表明了辅助T细胞（ Th）在骨量丢失（一种系统性的炎症反应）发病机制中可能存在作用。然而,在一些已经发表的文章中,Th1／Th2细胞在调节破骨细胞的功能上存在着争议,这一争议被新近发现的Th17细胞所解决。 Th17是一种新亚型的T细胞,可以选择性的分泌不同的促炎因子,刺激破骨细胞分裂,已经被证实在炎症动物模型中可以加速骨量的丢失。因此Th17细胞会是未来治疗骨质疏松的目标靶点。