The relationship between SDF-1α/CXCR4 and neural stem cells appearing in damaged area after traumatic brain injury in rats

Abstract

Objective: The actual relationship between neural stem cells and SDF-1α/CXCR4 after brain injury has not yet been elucidated, although recent studies have speculated that stromal cell-derived factor-1α (SDF-1α) and its receptor, CXCR4, could contribute to neural stem cells migration after brain injury. In the present study, the temporal relationship between neural stem cells (NSCs) and SDF-1α/CXCR4 around a damaged area was investigated using a rat traumatic brain injury (TBI) model.

Methods: We used molecular biology techniques and immunohistochemistry to investigate the relationship between SDF-1α/CXCR4 expression and NSCs existence around a damaged area after TBI in the rat brain.

Results: SDF-1α mRNA expression and SDF-1α protein synthesis did not increase after TBI. However, SDF-1α leaked from the injured area and diffused into the cortex 1–3 days after TBI. Subsequently, the levels of CXCR4 mRNA expression and CXCR4 protein synthesis increased significantly. Many small cells with a nestin-positive cytoplasm and fibers also showed immunopositivity for both CXCR4 and SOX-2, but not for GFAP, 3–7 days after TBI. Moreover, a proportion of the CXCR4-positive cells and fibers also showed immunostaining for neurofilaments.

Discussion: These results suggest that the leaked SDF-1α attracted CXCR4-positive NSCs as well as elongated nerve fibers. It is considered that the SDF-1α/CXCR4 system in the brain contributes to neural stem cells appearance and maturation after TBI. Therefore, exploitation of the SDF-1α/CXCR4 system around a damaged area may improve the brain dysfunction after TBI.     

Control of neuromuscular stimulation for ambulation by complete paraplegics via artificial neural networks

Abstract

The paper describes the application of a neural network (ANN) for controlling a functional neuromuscular stimulation (FNS) system to facilitate patient-responsive ambulation by paralyzed patients with traumatic, thoracic-level spinal cord injuries. The particular ANN that is employed is a modified Adaptive-ResonanceTheory (ART-1) network. It serves as a controller in an FNS system (the Parastep system) that is presently in use by approximately 500 patients worldwide (but still without ANN control) and which was the first and only FNS system approved by FDA. The proposed neural network discriminates above-lesion upper-trunk electromyographic (EMG) time series to activate standing and walking functions under FNS and controls FNS stimuli levels using response-EMG signals. For this particular application, several modifications are introduced into the standard ART-1 ANN. First, a modified on-line learning rule is proposed. The new rule assures bi-directional modification of the stored patterns and prevents noise interference. Second, a new reset rule is proposed, which prevents 'exact matching' when the input is a subset of the chosen pattern. A single ART-1-based structure is being applied to solving two problems, namely (1) signal pattern recognition and limb function determination, and (2) control of stimulation levels. This also facilitates ambulation of paraplegics under FNS, with adequate patient interaction in initial system training, retraining the network when needed, and in allowing patient's manual over-ride in the case of error, where any manual over-ride serves as a re-training input to the neural network. The ANN control facilitates continuous update of control settings during normal use, without formal retraining. [Neurol Res 2001; 23: 472-481]     

Developmental expression of fibroblast growth factor (FGF) receptors in neural stem cell progeny. Modulation of neuronal and glial lineages by basic FGF treatment

Abstract

Neural stem cells (NSCs) are self-renewable, multipotential cells capable of differentiating into the three major neural cell types, but the mechanisms which regulate their development are not fully understood. Both basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) promote the proliferation of NSCs. However, studies on the role of FGFs in the differentiation of EGF-expanded NSCs are still incomplete. We have studied the expression of distinct FGF receptors (FGFRs) in the progeny of EGFexpanded NSCs isolated from E15 rat striatum. In situ hybridization analysis and immunocytochemistry showed a developmentally related expression pattern and a cell lineage-specific distribution of these receptors. FGFR1 and FGFR2 were identified in many early precursors and in the oligodendrocyte lineage. The latter receptor was also present in a subpopulation of astrocytes. FGFR3 was detected in a restricted population of early precursors, in oligodendroglial progenitors, and in neurons and protoplasmic astrocytes of late-term cultures. Basic FGF treatment of the progeny of NSCs increased the proliferative rate of precursors and the number of oligodendrocytes generated, whereas the number of differentiating neurons was significantly reduced. Together these data provide evidence that FGFs modulate the development of EGF-expanded NSCs, and that this is at least partly determined by a cell lineage-specific expression of multiple FGFRs. [Neurol Res 2001; 23: 612-621]     

Alterations in cortical excitability in chronic stroke after constraint-induced movement therapy

Abstract

Objective: Cerebral stroke is a major cause for long-term disability in the elderly and it is often manifested in hemiparesis of the upper extremity. Constraint-induced movement therapy (CIMT), an intensive 2 week rehabilitation program, improves affected upper limb motor abilities in subjects with stroke. Intensive training has also been suggested to modify neural function. We wanted to find out if there are changes in cortical excitability in subjects with chronic stroke after CIMT.

Methods: Participants were 13 subjects with stroke who fulfilled the entry criteria for the CIMT program. The motor function of the affected arm and hand was assessed using a structured motor behavior test (WMFT). The cortical excitability changes were assessed in regard to involuntary and voluntary motor control, former with transcranial magnetic stimulation (TMS) and latter with movement-related cortical potentials (MRCP).

Results: The motor abilities of the affected arm improved after 2 week rehabilitation (total time in WMFT shortened 36%). The motor-evoked potential (MEP) amplitudes were unchanged following the stimulation of the non-affected hemisphere; however, the MEP amplitudes of lateral stimulation locations increased significantly in the affected side after the intervention. The power spectra of MRCPs revealed reduced peak frequency over the supplementary motor area when the affected hand was moved. However, no changes occurred when the healthy hand was moved.

Discussion: We show changes in cortical electrical excitability while performing both involuntary and voluntary movements after 2 weeks of CIMT in subjects with chronic stroke. These changes may be seen as a sign of neural reorganization instigated by the intervention.     

Sclerostin antibody treatment improves bone mass,bone strength,and bone defect regeneration in rats with type 2 diabetes mellitus

Type 2 diabetes mellitus results in increased risk of fracture and delayed fracture healing. ZDF fa/fa rats are an established model of type 2 diabetes mellitus with low bone mass and delayed bone healing. We tested whether a sclerostin‐neutralizing antibody (Scl‐AbVI) would reverse the skeletal deficits of diabetic ZDF rats. Femoral defects of 3 mm were created in 11‐week‐old diabetic ZDF fa/fa and nondiabetic ZDF +/+ rats and stabilized by an internal plate. Saline or 25 mg/kg Scl‐AbVI was administered subcutaneously (s.c.) twice weekly for 12 weeks (n = 9–10/group). Bone mass and strength were assessed using pQCT, micro–computed tomography (µCT), and biomechanical testing. Bone histomorphometry was used to assess bone formation, and the filling of the bone defect was analyzed by µCT. Diabetic rats displayed lower spinal and femoral bone mass compared to nondiabetic rats, and Scl‐AbVI treatment significantly enhanced bone mass of the femur and the spine of diabetic rats (p < 0.0001). Scl‐AbVI also reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load at the femoral shaft and neck, respectively (p < 0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl‐AbVI increased by sixfold, consistent with a pronounced anabolic effect. Nondiabetic rats filled 57% of the femoral defect, whereas diabetic rats filled only 21% (p < 0.05). Scl‐AbVI treatment increased defect regeneration by 47% and 74%, respectively (p < 0.05). Sclerostin antibody treatment reverses the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improves bone defect regeneration in rats. © 2013 American Society for Bone and Mineral Research.     

Deletion of FGFR3 in Osteoclast Lineage Cells Results in Increased Bone Mass in Mice by Inhibiting Osteoclastic Bone Resorption

Fibroblast growth factor receptor 3 (FGFR3) participates in bone remodeling. Both Fgfr3 global knockout and activated mice showed decreased bone mass with increased osteoclast formation or bone resorption activity. To clarify the direct effect of FGFR3 on osteoclasts, we specifically deleted Fgfr3 in osteoclast lineage cells. Adult mice with Fgfr3 deficiency in osteoclast lineage cells (mutant [MUT]) showed increased bone mass. In a drilled‐hole defect model, the bone remodeling of the holed area in cortical bone was also impaired with delayed resorption of residual woven bone in MUT mice. In vitro assay demonstrated that there was no significant difference between the number of tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclasts derived from wild‐type and Fgfr3‐deficient bone marrow monocytes, suggesting that FGFR3 had no remarkable effect on osteoclast formation. The bone resorption activity of Fgfr3‐deficient osteoclasts was markedly decreased accompanying with downregulated expressions of Trap, Ctsk, and Mmp 9. The upregulated activity of osteoclastic bone resorption by FGF2 in vitro was also impaired in Fgfr3‐deficient osteoclasts, indicating that FGFR3 may participate in the regulation of bone resorption activity of osteoclasts by FGF2. Reduced adhesion but not migration in osteoclasts with Fgfr3 deficiency may be responsible for the impaired bone resorption activity. Our study for the first time genetically shows the direct positive regulation of FGFR3 on osteoclastic bone resorption. © 2016 American Society for Bone and Mineral Research.     

P物质和组胺在经络信息传递中的作用

应用电生理学方法，观察到微量Ｐ物质或组胺注于大鼠背部足太阳膀胱经的＂肝俞＂至＂胆俞＂一段的皮下部位，可以引起外周感觉神经末梢的传入放电明显增多。表明Ｐ物质和组胺可能是经脉线上传递信息的化学物质。     

静脉桥接修复喉返神经缺损的实验研究

目的 探讨自体静脉桥接修复喉返神经缺损的可行性。方法 将２０只杂种健康成犬,随机分成实验１组（ｎ＝６）,２组（ｎ＝６）,３组（ｎ＝５）及对照组（ｎ＝３）。实验１,２,３组分别造成受试犬左侧喉返神经缺损１ｃｍ,２ｃｍ,３ｃｍ,用各自大隐静脉进行桥接修复,对照组未用自体静脉修复。术后６个月分别观察实验犬声音变化及声带活动情况,并行喉肌诱发动作电位和形态学检查。结果 实验１组受试犬６个月后发音均恢复正常     

Polylysine-Modified PEG-Based Hydrogels to Enhance the Neuro–Electrode Interface

Neural prostheses are a promising technology in the treatment of lost neural function. However, poor biocompatibility of these devices inhibits the formation of a robust neuro–electrode interface. Several factors including mechanical mismatch between the device and tissue, inflammation at the implantation site, and possible electrical damage contribute to this response. Many researchers are investigating polymeric brain mimetic coatings as a means to improve integration with nervous tissue. Specifically, hydrogels, constructs also employed in tissue engineering, have been explored because of their structural and mechanical similarity to native tissue. However, many hydrogel materials (e.g., poly(ethylene glycol) (PEG)) do not support cell adhesion. In this work, we report a technique to enhance the interface between polymeric brain mimetic coatings and neural tissue using adhesion molecules. In particular, polylysine-modified PEG-based hydrogels were synthesized, characterized and shown to promote neural adhesion using a PC12 cell line. In addition, we examined adhesion behavior of a PEG-co-polymer and found that these materials adhere to electrodes for at least 4 weeks. These results suggest that polylysine–PEG hydrogel biomaterials are biocompatible and can enhance stability of chronic neural interfaces.