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The previous three decades have witnessed a prosperity of contralateral C7 nerve (CC7) transfer in the treatment of upper-extremity paralysis induced by both brachial plexus avulsion injury and central hemiplegia. From the initial subcutaneous route to the pre-spinal route and the newly-established post-spinal route, this surgical operation underwent a series of innovations and refinements, with the aim of shortening the regeneration distance and even achieving direct neurorrhaphy. Apart from surgical efforts for better peripheral nerve regeneration, brain involvement in functional improvements after CC7 transfer also stimulated scientific interest. This review summarizes recent advances of CC7 transfer in the treatment of upper-extremity paralysis of both peripheral and central causes, which covers the neuroanatomical basis, the evolution of surgical approach, and central mechanisms. In addition, motor cortex stimulation is discussed as a viable rehabilitation treatment in boosting functional recovery after CC7 transfer. This knowledge will be beneficial towards improving clinical effects of CC7 transfer.

The formation of intracranial aneurysm (IA) is associated with the destruction of various cellular and structural components, which induces pathogenic inflammatory responses that further propagate tissue damage. The regulatory immune system can suppress exacerbated inflammation and offer tissue protection; however, previous studies by others and us have demonstrated that the regulatory T (Treg) cells were functionally impaired in IA patients. Hence, strategies that can improve Treg function in IA patients should be investigated. Based on our previous finding that IL-2 strongly elevated the expression of the checkpoint molecule Tim-3 in Treg cells, we examined the effect of IL-2 in the function of Treg cells from IA patients. External IL-2 significantly improved the proliferation of Treg cells, increased the expression of CTLA-4 and LAG-3, and enhanced Treg-mediated suppression of conventional T cell (Tconv) proliferation. Importantly, compared to the Tim-3- Treg cells, the Tim-3+ Treg cells presented comparable proliferation capacity, but significantly greater expressions of CTLA-4 and LAG-3 and significantly higher capacity to suppress Tconv proliferation. In addition, blocking Tim-3 abrogated IL-2-mediated enhancement of Tim-3+ Treg cells. We then investigated the IL-2 level in IA patients, and found that although IA patients and healthy controls presented similar serum IL-2 concentration, the concentrations of IL-1β and TNF-α were significantly higher in IA patients than in healthy controls, signaling a relative reduction in IL-2 abundance. Together, we found that IL-2 could significantly enhance the function of Treg cells from IA patients in a Tim-3-dependent manner.

Pathogenic inflammation contributes to aneurysm formation by mediating the destruction of the endothelium and the extracellular matrix and promoting pathogenic proliferation of smooth muscle cells. In mouse models, tolerance-inducing T regulatory (Treg) cells could significantly reduce the incidence and severity of aneurysms. Hence, it should be investigated why in human intracranial aneurysm (IA) patients, Treg cells failed to provide protection against aneurysm formation. In this study, the frequency and function of Treg cells in IA patients were examined. The frequency of Foxp3+ Treg cells was significantly lower in IA patients than in healthy controls. This downregulation was only specific to the Treg subset of CD4+ T cells, as the frequency of total CD4+ T cell was increased in IA patients. Subsequently, we found that the expressions of Treg-associated molecules, including Foxp3, CTLA-4, TGF-β, and IL-10, were significantly lower in Foxp3+ Treg cells from IA patients than in Foxp3+ Treg cells from healthy controls. In both healthy controls and IA patients, Foxp3+ Treg cells were distinguished into a more potent Tim-3+ subset and a less potent Tim-3− subset. The Tim-3+ subset of Foxp3+ Treg cells was significantly reduced in IA patients. Signaling via IL-2, IL-7, IL-15 and IL-21 was shown to promote Tim-3 upregulation in CD4+ and CD8+ T cells. Interestingly, we found that Tim-3 could be upregulated in Treg cells via the same mechanism, but compared to the Treg cells from healthy controls, the Treg cells from IA patients presented defects in Tim-3 upregulation upon cytokine stimulation. Together, our results demonstrated that Foxp3+ Treg cells in IA patients presented reduced function, which was associated with a defect in Tim-3 upregulation.

Patients with intracranial aneurysm (IA) present a dysregulated immune system with lower frequency of regulatory T (Treg) cells. Here, we examined whether galectin 9 (Gal-9), the natural ligand of Tim-3, could promote Treg cells in IA patients. We first discovered that the intracellular and extracellular Gal-9 was primarily expressed by CD4+ CD25- T conventional (Tconv) cells, and also by monocytes at lower levels, but rarely by CD4+ CD25+ Treg cells. In IA patients, the Gal-9 expression was significantly lower than in healthy controls. CD4+ CD25- Tconv cells could be induced into Foxp3-expressing induced Treg (iTreg) cells using a TGF-β-containing milieu. We found that soluble Gal-9 significantly enhanced this process by potently upregulating the expression of Foxp3, IL-10 and TGF-β in a concentration-dependent manner. In addition, in the absence of additional Gal-9, the level of Foxp3 upregulation was directly correlated with the level of intrinsic Gal-9 expression. Notably, the strength of external Gal-9-mediated effects was significantly lower in IA patients than in healthy controls. Using a Tim-3 blocking antibody, we found that the promotion of iTreg development by soluble Gal-9 was dependent on the Tim-3 signalling pathway. Overall, our investigations demonstrated that Gal-9 presented a critical role in the development of iTreg cells. However, this mechanism was impaired in IA patients due to lower expression of both Gal-9 and Tim-3.

Intracranial aneurysms (IAs) and potential IA rupture are one of the direct causes of permanent brain damage and mortality. Interestingly, the major risk factors of IA development, including hemodynamic stress, hypertension, smoking, and genetic predispositions, are closely associated with a proinflammatory immune status. Therefore, we examined the roles of CD4(+) T cells in IA pathogenesis. IA patients exhibited peripheral CD4(+) T-cell imbalance, with overrepresented T helper 1 (Th1) and Th17 activities and underrepresented Th2 and regulatory T (Treg) activities, including increased IFN-γ, TNF-α, and IL-17 production and decreased IL-10 production from total CD4(+) T cells. Chemokine receptors CXCR3 and CCR6 were used to identify Th1, Th2, and Th17 cell subsets, and CD4(+)CD25(hi) was used to identify Treg cells. Based on these markers, the data then showed altered cytokine production by each cell type and shifted subpopulation frequency. Moreover, this shift in frequency was directly correlated with IA severity. To examine the underlying mechanism of CD4(+) T cell skewing, we cocultured CD4(+) T cells with autologous monocytes and found that coculture with monocytes could significantly increase IFN-γ and IL-17 production through contact-independent mechanisms, demonstrating that monocytes could potentially contribute to the altered CD4(+) T cell composition in IA. Analyzing mRNA transcripts revealed significantly upregulated IL-1β and TNF-α expression by monocytes from IA patients. We found a loss of CD4(+) T cell subset balance that was likely to promote a higher state of inflammation in IA, which may exacerbate the disease through a positive feedback loop.

Evidence has shown that inflammation acts as a critical contributor to the pathogenesis of intracranial aneurysm (IA), a potentially devastating clinical problem. T cell immunoglobulin and mucin protein 3 (Tim-3) is a negative regulatory molecule and plays important roles in the inflammation process. In the current study, we investigated the expression of Tim-3 and its correlation with tumor necrosis factor alpha (TNF-α) in IA patients. Data showed that both messenger RNA (mRNA) level and protein level of Tim-3 were significantly decreased in CD4+ T cells and CD8+ T cells from IA patients than from healthy controls (P

We aimed to investigate the blood brain barrier (BBB) change caused by subarachnoid hemorrhage (SAH) and to explore the molecular mechanisms of acute brain injury after SAH. The SD rat model of SAH was firstly established by endovascular filament perforation technique. The changes of regional cerebral blood flow (rCBF), BBB permeability and ultrastructure of brain tissue at different time points after SAH were respectively observed by Doppler flowmetry, evans blue extravasation and transmission electron microscopy. Meanwhile, the expression changes of Claudin-5, Occludin, Zo-1 and Caveolin-1 were detected by immunohistochemistry and Western blot. Furthermore, the expressions of Akt, P-Akt and Foxo1A were also measured by Western blot. The change of BBB permeability showed two peaks at 3 and 72 h after SAH, corresponding to the change of rCBF. The BBB tight junction opening can be observed after SAH, and the largest opening was occurred at 3 h and 72 h. There was no significant change in Caveolin-1, Claudin-5 and Akt expressions after SAH (P > 0.05), while Zo-1 and Occludin were significantly down-regulated (P < 0.05). The expression of P-Akt was obviously reduced at 30 min and then increased at 1 and 24 h, while Foxo1A was up-regulated at 1 and 24 h after SAH (P < 0.05). Down-regulated Zo-1 and Occludin, as well as Akt/FOXO signaling pathway may be involved in the regulation of tight junction opening and the BBB permeability in the early stage after SAH.

Onyx has been widely adopted for the treatment of arteriovenous malformations (AVMs). However, its control demands operators accumulate a considerable learning curve. We describe our initial experience using a novel injection method for the embolization of AVMs. We retrospectively reviewed the data of all 22 patients with brain AVMs (12 men, 10 women; age range, 12–68 years; mean age, 43.2 years) treated by the transarterial coil-augmented Onyx injection technique. The size of the AVMs ranged from 25 mm to 70 mm (average 35.6 mm). The technical feasibility of the procedure, procedure-related complications, angiographic results, and clinical outcome were evaluated. In every case, endovascular treatment (EVT) was completed. A total of 31 sessions were performed, with a mean injection volume of 6.1 mL (range, 1.5–16.0 mL). An average of 96.7% (range 85%-100%) estimated size reduction was achieved, and 18 AVMs could be completely excluded by EVT alone. The results remained stable on follow-up angiograms. A procedural complication occurred in one patient, with permanent mild neurologic deficit. Our preliminary series demonstrated that the coil-augmented Onyx injection technique is a valuable adjunct achieving excellent nidal penetration and improving the safety of the procedure.

In this report, we describe an efficient and non-enzymatic method for isolating and culturing endothelial cells (ECs) from the nidus of surgically resected arteriovenous malformation (AVM) specimens. These cultured cells possessed typical phenotypic markers (i.e. von Willebrand factor and CD34), as well as morphological and ultrastructural characteristics of ECs. However, they had activated Notch-1 signaling, which plays a critical role in the development of AVM. The present study suggests that hypoxic endothelial cells from the nidus of human cerebral arteriovenous malformation (CAVMECs) have angiogenic potentials, as our data showed that VEGF gene expression and cell proliferation were more evident with prolonged hypoxia. In our study, we successfully used the vascular tissue explants adherent method to isolate and culture CAVMECs with high purity. This may prove to be a useful tool for studying the molecular mechanisms that mediate abnormal vessel development and maintenance in AVM.

The study was performed to investigate the effect of combination therapy with melatonin and dexamethasone (DEX) on brain injury in intracerebral hemorrhage (ICH) model in rats. Compared to the control group, combination therapy group with melatonin (10 mg/kg) and DEX (0.025 mg/kg) significantly reduced the degree of (1) brain edema, (2) the permeability of blood brain barrier (measured by Evans blue), (3) Oxidative stress (evaluated by malondialdehyde assay), (4) cytokines expression (tumor necrosis factor-alpha and interleukin-1beta), and (5) apoptosis (measured by Bax and Bcl-2 expression). In addition, we have also clearly demonstrated that the combination therapy significantly ameliorated neurologic scores. Taken together, our results clearly indicated for the first time that strategies targeting multiple proinflammatory pathways may be more effective than a single effector molecule for the treatment of ICH.

Objective To evaluate the clinical value of minimally invasive stereotactic puncture therapy (MISPT) combined with external ventricular drainage (EVD) on secondary intraventricular hemorrhage (SIVH). Methods A retrospective analysis of the patients of intraventricular hemorrhage from May 2013 to January 2015 was conducted in our hospital, according to the enrollment criterion; of which 40 patients were treated by MISPT combined with EVD (ME group) and 45 patients by conventional craniotomy combined with EVD (CE group). Related indicators were compared in the two groups of patients with short- and long-term efficacy. Results The patients in the ME group showed obvious amelioration in the GCS score compared with that of the CE group. There were no statistically significant differences in Graeb score and hematoma volume. Compared with the CE group, the incidence of postoperative complications was significantly decreased in the ME group. The mortalities of the ME and CE groups were 13.3% and 22.6%, respectively. The incidences of rebleeding in the ME and CE groups were 10.0% and 15.6%, respectively. For the four parameters representing long-term efficacy of 6 months postoperation, the Glasgow Outcome Scale (GOS), Barthel Index (BI), modified Rankin Scale (mRS), and Karnofsky Scale (KPS) scores in the ME group were ameliorated more significantly than those of the CE group. Conclusions Our data showed that the main advantages of ME in the treatment for SIVH were in minimal trauma, low incidence of complications, and the possibility to improve the long-term prognosis significantly.

Chronic allograft nephropathy (CAN) is a major cause of graft loss following kidney transplantation and may result from the interactions of various immune and non-immune factors. The aim of the present study was to establish an in vitro model of glomerular mesangial cell injury in order to examine the gene expression levels of indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1) and interleukin-7 (IL-7) in mesangial cells during the healing process as well as to investigate the effects of various immunosuppressants on the expression of these genes. The HBZY-1 glomerular mesangial cell line was pre-treated in vitro with cytochalasin B for 2 h to induce reversible damage. Following the pre-treatment, the HBZY-1 cells were divided into five groups: Blank control group, cyclosporine A (CsA) group, tacrolimus (Tac) group, mycophenolate mofetil (MMF) group and rapamycin (RAPA) group. After treating the mesangial cells with each immunosuppressive drug for 6, 12 or 24 h, the mRNA and protein expression levels of IDO, HO-1 and IL-7 were examined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemical analyses. The results showed that expression levels of HO-1 were significantly upregulated in response to treatment with CsA, FK506, RAPA and MMF, whereas the expression levels of IL-7 were markedly downregulated by treatment with the above immunosuppressants. CsA, FK506 and MMF significantly enhanced the expression levels of IDO, whereas RAPA exhibited no apparent effect on IDO. The present study may contribute to the understanding of the pathogenesis of CAN and provide novel strategies for the prevention and treatment of CAN.

The key signaling networks regulating glioma cell proliferation remain poorly defined. The leucine-rich repeat containing G-protein coupled receptor 4 (Lgr4) has been implicated in intestinal, gastric, and epidermal cell functions. We investigated whether Lgr4 functions in glioma cells and found that Lgr4 expression was significantly increased in glioma tissues. In addition, Lgr4 overexpression promoted while its knockdown using small interfering RNA oligos inhibited glioma cell proliferation. In addition, Wnt/β-catenin signaling was activated in cells overexpressing Lgr4. Therefore, our results revealed that Lgr4 activates Wnt/β-catenin signaling to regulate glioma cell proliferation.

Intracranial aneurysm (IA) lingers as a potentially devastating clinical problem, in which inflammation acts as a critical contributor to the pathogenesis of this disease. Cytokines play a major role in regulating inflammation. The aim of this study was to gain insight in the inflammatory response in IA by assessing plasma cytokine profiles. Plasma levels of 10 cytokines were quantified by multiplex protein arrays in 66 patients with IA and 78 healthy controls. Results showed that plasma level of interleukin 1 beta (IL-1β) was 2.4-fold higher in patients than in controls (p < 0.05). The level of monocyte chemoattractant protein-1 (MCP-1) was 2.8-fold higher in patient than in controls (p < 0.01). The level of tumor necrosis factor-alpha (TNF-α) was 2.1-fold higher in cases than in controls (p < 0.001). When comparing the expression of cytokines in IA patients with different characteristics, cases with ruptured aneurysm revealed increased level of MCP-1 than those with unruptured aneurysm (p < 0.05), whereas cases with multiple numbers of aneurysms demonstrated higher levels of MCP-1 and TNF-α than those with single aneurysm (p < 0.05 and p < 0.05, respectively). These data indicated that IL-1β, MCP-1, and TNF-α were associated with increased risk of IA and may affect the development of this disease.

We describe a modified stent-assisted coiling technique, named the semi-deployment technique, in the endovascular treatment of wide-neck aneurysms. Thirty-one consecutive patients with 31 wide-necked or fusiform intracranial aneurysms were treated with the semi-deployment technique. The technical feasibility of the procedure, procedure-related complications, angiographic results, clinical outcome and follow-up angiography were evaluated. In every case, the semi-deployment technique was successfully deployed. Immediate angiography demonstrated complete occlusion in 24 cases (77.4%), neck remnant in four cases (12.9%), and incomplete occlusion in three cases (9.7%). Procedural-related morbidity occurred in one patient (3.2%) but no procedural-related mortality. A favorable clinical outcome (Modified Ran-kin Scale score 0–2) was observed in 90.3% of the patients (average follow-up time, 23.1 months). No rehemorrhage of treated aneurysms occurred. Angiography follow-up was obtained in 22 cases (71.0 %). Three aneurysms (13.6 % of the follow-up angiograms) demonstrated recanalization. No delayed coil or stent migration was found. One patient had in-stent stenosis as a delayed complication. We found that the semi-deployment technique was helpful in the treatment of wide-neck aneurysms.