Yingying Su

Collagen Sponge Functionalized with Chimeric Anti-BMP-2 Monoclonal Antibody Mediates Repair of Critical-Size Mandibular Continuity Defects in a Nonhuman Primate Model

Antibody-mediated osseous regeneration (AMOR) has been introduced by our research group as a tissue engineering approach to capture of endogenous growth factors through the application of specific monoclonal antibodies (mAbs) immobilized on a scaffold. Specifically, anti-Bone Morphogenetic Protein- (BMP-) 2 mAbs have been demonstrated to be efficacious in mediating bone repair in a number of bone defects. The present study sought to investigate the application of AMOR for repair of mandibular continuity defect in nonhuman primates. Critical-sized mandibular continuity defects were created in Macaca fascicularis locally implanted with absorbable collagen sponges (ACS) functionalized with chimeric anti-BMP-2 mAb or isotype control mAb. 2D and 3D analysis of cone beam computed tomography (CBCT) imaging demonstrated increased bone density and volume observed within mandibular continuity defects implanted with collagen scaffolds functionalized with anti-BMP-2 mAb, compared with isotype-matched control mAb. Both CBCT imaging and histologic examination demonstrated de novo bone formation that was in direct apposition to the margins of the resected bone. It is hypothesized that bone injury may be necessary for AMOR. This is evidenced by de novo bone formation adjacent to resected bone margins, which may be the source of endogenous BMPs captured by anti-BMP-2 mAb, in turn mediating bone repair.

Improved Neurological Outcome With Mild Hypothermia in Surviving Patients With Massive Cerebral Hemispheric Infarction

Background and Purpose— We conducted this randomized controlled trial to investigate the effects of therapeutic hypothermia on mortality and neurological outcome in patients with massive cerebral hemispheric infarction. Methods— Patients within 48 hours of symptom onset were randomized to either a hypothermia group or a control group. Patients in the hypothermia group were given standard medical treatment plus endovascular hypothermia with a target temperature of 33 or 34°C. Hypothermia was maintained for a minimum of 24 hours. Patients in the control group were given standard medical treatment only with a target temperature of normothermia. The primary end points were mortality and the modified Rankin Scale score at 6 months. Results— There were 16 patients in the hypothermia group and 17 patients in the control group. At 6 months, 8 patients had died in the hypothermia group versus 7 patients in the control group (P=0.732). The main cause of death was fatal herniation caused by a pronounced rise in intracranial pressure. Seven patients (43.8%) had a modified Rankin Scale of 1 to 3 in the hypothermia group versus 4 patients (23.5%) in the control group (P=0.282). Additionally, of the survivors, patients in the hypothermia group achieved better neurological outcomes compared with those in the control group (7/8, 87.5% versus 4/10, 40.0%; P=0.066; odds ratio=10.5; 95% confidence interval, 0.9–121.4). Conclusions— Mild hypothermia seems to not reduce mortality in patients with massive cerebral hemispheric infarction but may improve the neurological outcome in survivors. An adequately powered multicenter randomized controlled trial seems warranted. Clinical Trial Registration— URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-TCS-12002680.

Porphyromonas gingivalis lipopolysaccharides regulate functions of bone marrow mesenchymal stem cells

Periodontitis is one of the most widespread inflammatory diseases; it causes tooth loss and is also associated with a variety of systemic diseases. Mesenchymal stem cells (MSCs) have been used to treat periodontitis. However, it is unknown whether bacterial toxins in the periodontal environment affect MSC‐mediated periodontal regeneration. Porphyromonas gingivalis lipopolysaccharides (Pg‐LPS) are key toxins for development of periodontitis. The purpose of the present study was to investigate effects of P. gingivalis LPS on biological properties of MSCs.

Phenobarbital Versus Valproate for Generalized Convulsive Status Epilepticus in Adults: A Prospective Randomized Controlled Trial in China

ObjectiveAlthough generalized convulsive status epilepticus (GCSE) is a life-threatening emergency, evidence-based data to guide initial drug treatment choices are lacking in the Chinese population. We conducted this prospective, randomized, controlled trial to evaluate the relative efficacy and safety of intravenous phenobarbital and valproate in patients with GCSE.MethodsAfter the failure of first-line diazepam treatment, Chinese adult patients with GCSE were randomized to receive either intravenous phenobarbital (standard doses, low rate) or valproate (standard). Successful treatment was considered when clinical and electroencephalographic seizure activity ceased. Adverse events following treatment, as well as the neurological outcomes at discharge and 3 months later, were also evaluated.ResultsOverall, 73 cases were enrolled in the study. Intravenous phenobarbital was successful in 81.1% of patients, and intravenous valproate was successful in 44.4% of patients (pxa0<xa00.05). The relapse rate of status epilepticus within 24 h of receiving phenobarbital (6.7%) was significantly lower than that in patients receiving valproate (31.3%), and the total number of adverse events did not differ significantly between the two groups (pxa0>xa00.05). In the phenobarbital group, two patients (5.4%) required ventilation and two patients (5.4%) developed serious hypotension. The neurological outcomes of the phenobarbital group were generally better than those of the valproate group; however, no significant differences were observed between phenobarbital and valproate with respect to mortality (8.1 vs. 16.6%) at discharge, or mortality (16.2 vs. 30.5%) and post-symptomatic epilepsy (26.3 vs. 42.8%) at 3-month follow-up.ConclusionsIntravenous phenobarbital appears to be more effective than intravenous valproate for Chinese adult patients with GCSE. The occurrence of serious respiratory depression and hypotension caused by phenobarbital was reduced by decreasing the intravenous infusion rate; however, even at a lower infusion rate than typically used in other institutions, intravenous phenobarbital resulted in more serious adverse events than intravenous valproate. The better outcomes in the phenobarbital group compared with the valproate group suggest that phenobarbital should be considered for the early successful treatment of GCSE.

Platelet-rich fibrin/aspirin complex promotes alveolar bone regeneration in periodontal defect in rats

BACKGROUND AND OBJECTIVESnThe efficacy and outcomes of aspirin in local defects and the use of platelet-rich fibrin (PRF) in periodontal defects were investigated. Whether the PRF/aspirin complex is a suitable scaffold and delivery system to carry sustained-release aspirin/salicylic acid to promote periodontal bone regeneration was determined.nnnMATERIAL AND METHODSnPRF and PRF/aspirin complex were prepared. The concentrations of aspirin/salicylic acid released from the PRF/aspirin complex were calculated at 37°C. Periodontal ligament mesenchymal cells were cultured on six-well plates with PRF or PRF/aspirin complex gel to analyze proliferation and migration. The alveolar bone between the inferior buccal mesial root and anterior buccal distal root of the first maxillary molar was removed in 15 rats randomly divided into three groups: no treatment, PRF or PRF/aspirin complex. Twelve weeks post-transplantation, 2D/3D micro-computed tomography and histomorphometric technique were used for quantitative analyses.nnnRESULTSnThe PRF/aspirin complex provided a sustained-release aspirin/salicylic acid. Peak concentrations occurred 4xa0hours after transplantation and were sustained to 48xa0hours at 37°C; the total concentration of released aspirin/salicylic acid was 83.5xa0mg/mL, respectively. The sustained-release promoted the proliferation and migration of periodontal ligament mesenchymal cells. Micro-computed tomography and histological data showed that both the PRF and PRF/aspirin complex enhanced periodontal bone formation (P<.05). Moreover, the new bone formation was two times greater in the PRF/aspirin complex group than the PRF group.nnnCONCLUSIONnAspirin/salicylic acid could be sustained-released from PRF/aspirin complex, which could inhibit inflammation and improve the function of mesenchymal cells. The data might provide a new safe and easy clinical therapeutic strategy to promote periodontal bone reparation.

Aspirin inhibits LPS-induced macrophage activation via the NF-κB pathway

Aspirin (acetylsalicylic acid, ASA) has been shown to improve bone marrow mesenchymal stem cell-based calvarial bone regeneration by promoting osteogenesis and inhibiting osteoclastogenesis. However, it remains unknown whether aspirin influences other immune cells during bone formation. In the present study, we investigated whether ASA treatment influenced macrophage activation during the LPS inducement. We found that ASA could downregulate the expressions of iNOS and TNF-α both in mouse peritoneum macrophages and RAW264.7 cells induced by LPS via the IκK/IκB/NF-κB pathway and a COX2/PGE2/EP2/NF-κB feedback loop, without affecting the expressions of FIZZ/YM-1/ARG1 induced by IL-4. Furthermore, we created a rat mandibular bone defect model and showed that ASA treatment improved bone regeneration by inhibiting LPS-induced macrophage activation in the early stages of inflammation. Taken together, our results indicated that ASA treatment was a feasible strategy for improving bone regeneration, particularly in inflammatory conditions.

MicroRNA-21 promotes osteogenesis of bone marrow mesenchymal stem cells via the Smad7-Smad1/5/8-Runx2 pathway

Bone marrow mesenchymal stem cells (BMMSCs) are pluripotent stem cells, and the osteogenic differentiation of BMMSCs has been drawing attention for a long time. Bone formation is regulated by numerous molecular and cellular signaling pathways, and the differentiation of BMMSCs is controlled by a well-defined genetic program. In the present study, we isolated BMMSCs from the bone cavities of wild-type (WT) and microRNA-21 knock-out (miR-21-KO) mice and found that miR-21 was significantly upregulated during the osteogenic differentiation of BMMSCs. Under osteoinductive conditions, ALP staining and alizarin red staining showed that the bone formation of BMMSCs from miR-21-KO mice was less than that of BMMSCs from WT mice. Consistently, RT-PCR and western blotting revealed that ALP and Runx2 expression levels in miR-21-KO mice were downregulated compared with those in WT mice. Meanwhile, the calvarial bone defects of miR-21-KO mice showed less newly formed bone than did those of WT mice. Additionally, the Smad7-Smad1/5/8-Runx2 axis showed the same tendency; Smad7 overexpression and the expression of phosphorylated Smad1/5/8 complex decreased when miR-21 was knocked down. We identified a novel mechanism by which microRNA-21 (miR-21) promotes the bone formation of BMMSCs and found that this process is regulated, in part, by the Smad7-Smad1/5/8-Runx2 pathway.

MicroRNA-21 promotes wound healing via the Smad7-Smad2/3-Elastin pathway

&NA; Wound healing is regulated by a complex network of cells, molecules, and cytokines, as well as microRNAs (miRNAs). miRNAs were confirmed to influence the wound healing process, and miR‐21, an important member of the miRNA family, was also shown to regulate wound healing. The aim of the present study was to investigate the role of miR‐21 in the wound healing process and the possible underlying cell signaling pathways. We isolated GMSCs from WT and miR‐21‐KO mouse gingiva. Flow cytometric analysis and immunocytofluorescense staining were used to identify the GMSCs acquired from WT and miR‐21‐KO mice. RT‐PCR, western blot analysis and immunohistofluorescence staining were performed to examine the expression of extracellular matrix components and key proteins of cell signaling pathways. TargetScan and pmiR‐RB‐REPORT vectors were used to verify that Smad7 was a direct target of miR‐21. Compared to WT mice, miR‐21‐KO mice showed slower wound healing. RT‐PCR and western blot analysis indicated that Elastin expression was downregulated in miR‐21‐deficient samples. We confirmed that Smad7 was a direct target of miR‐21. miR‐21 knockout resulted in increased expression of Smad7 and impaired phosphorylation of the Smad2/3 complex. The expression of the Smad7‐Smad2/3‐Elastin axis in palate tissues sections acquired from WT and miR‐21‐KO mice showed the same trend. Based on all these results, we demonstrated that miR‐21 promoted the wound healing process via the Smad7‐Smad2/3‐Elastin pathway.

Electroencephalography reactivity for prognostication of post-anoxic coma after cardiopulmonary resuscitation: A comparison of quantitative analysis and visual analysis.

Electroencephalogram reactivity (EEG-R) is a positive predictive factor for assessing outcomes in comatose patients. Most studies assess the prognostic value of EEG-R utilizing visual analysis; however, this method is prone to subjectivity. We sought to categorize EEG-R with a quantitative approach. We retrospectively studied consecutive comatose patients who had an EEG-R recording performed 1-3 days after cardiopulmonary resuscitation (CPR) or during normothermia after therapeutic hypothermia. EEG-R was assessed via visual analysis and quantitative analysis separately. Clinical outcomes were followed-up at 3-month and dichotomized as recovery of awareness or no recovery of awareness. A total of 96 patients met the inclusion criteria, and 38 (40%) patients recovered awareness at 3-month followed-up. Of 27 patients with EEG-R measured with visual analysis, 22 patients recovered awareness; and of the 69 patients who did not demonstrated EEG-R, 16 patients recovered awareness. The sensitivity and specificity of visually measured EEG-R were 58% and 91%, respectively. The area under the receiver operating characteristic curve for the quantitative analysis was 0.92 (95% confidence interval, 0.87-0.97), with the best cut-off value of 0.10. EEG-R through quantitative analysis might be a good method in predicting the recovery of awareness in patients with post-anoxic coma after CPR.

Predicting Outcome in Comatose Patients: The Role of EEG Reactivity to Quantifiable Electrical Stimuli

Objective. To test the value of quantifiable electrical stimuli as a reliable method to assess electroencephalogram reactivity (EEG-R) for the early prognostication of outcome in comatose patients. Methods. EEG was recorded in consecutive adults in coma after cardiopulmonary resuscitation (CPR) or stroke. EEG-R to standard electrical stimuli was tested. Each patient received a 3-month follow-up by the Glasgow-Pittsburgh cerebral performance categories (CPC) or modified Rankin scale (mRS) score. Results. Twenty-two patients met the inclusion criteria. In the CPR group, 6 of 7 patients with EEG-R had good outcomes (positive predictive value (PPV), 85.7%) and 4 of 5 patients without EEG-R had poor outcomes (negative predictive value (NPV), 80%). The sensitivity and specificity were 85.7% and 80%, respectively. In the stroke group, 6 of 7 patients with EEG-R had good outcomes (PPV, 85.7%); all of the 3 patients without EEG-R had poor outcomes (NPV, 100%). The sensitivity and specificity were 100% and 75%, respectively. Of all patients, the presence of EEG-R showed 92.3% sensitivity, 77.7% specificity, 85.7% PPV, and 87.5% NPV. Conclusion. EEG-R to quantifiable electrical stimuli might be a good positive predictive factor for the prognosis of outcome in comatose patients after CPR or stroke.