Neuroprotective effect of ischemic preconditioning in focal cerebral infarction: relationship with upregulation of vascular endothelial growth factor

Neuroprotection by ischemic preconditioning has been confirmed by many studies, but the precise mechanism remains unclear. In the present study, we performed cerebral ischemic pre- conditioning in rats by simulating a transient ischemic attack twice （each a 20-minute occlusion of the middle cerebral artery） before inducing focal cerebral infarction （2 hour occlusion-reper- fusion in the same artery）. We also explored the mechanism underlying the neuroprotective effect of ischemic preconditioning. Seven days after ocdusion-reperfusion, tetrazolium chloride staining and immunohistochemistry revealed that the infarct volume was significantly smaller in the group that underwent preconditioning than in the model group. Furthermore, vascular endothelial growth factor immunoreactivity was considerably greater in the hippocampal CA3 region of preconditioned rats than model rats. Our results suggest that the protective effects of ischemic preconditioning on focal cerebral infarction are associated with upregulation of vascu- lar endothelial growth factor.

Effects of olfactory ensheathing cells on the proliferation and differentiation of neural stem cells

BACKGROUND： Olfactory ensheathing cells can promote oriented differentiation and proliferation of neural stem cells by cell-secreted neural factors. OBJECTIVE： To observe the effect of olfactory ensheathing cells on the differentiation and proliferation of neural stem cells. DESIGN, TIME AND SETTING： Cytology was performed at the Department of Neurology, Tongji Medical College, Huazhong University of Science and Technology, China, from September 2007 to October 2008. MATERIALS： Mouse anti-nestin polyclonal antibody （Chemicon, USA）, mouse anti-glial fibrillary acidic protein （GFAP） IgG1, mouse anti-2＇, 3＇-cyclic nucleotide 3＇-phosphodiesterase （CNPase） IgG1, mouse anti-Tubulin Class-Ill IgG1 （Neo Markers, USA）, Avidin-labeled Cy3 （KPL, USA）, and goat anti-mouse IgGl： fluorescein isothiocyanate （FITC） （Serotec, UK） were used in this study. METHODS：Tissues were isolated from the embryonic olfactory bulb and subependymal region of Wistar rats. Serum-free DMEM/F12 culture media was used for co-culture experiments. Neural stem cells were incubated in serum-free or 5% fetal bovine serum-containing DMEM/F12 as controls. MAIN OUTCOME MEASURES： After 7 days of co-culture, neural stem cells and olfactory ensheathing cells underwent immunofluorescent staining for nestin, tubulin, glial fibrillary acidic protein, and CNPase. RESULTS： Olfactory ensheathing cells promoted proliferation and differentiation of neural stem cells into neuron-like cells, astrocytes and oligodendrocytes. The proportion of neuron-like cells was 78.2%, but the proportion of neurons in 5% fetal bovine serum DMEM/F12 was 48.3%. In the serum-free DMEM/F12, neural stem cells contracted, unevenly adhered to the glassware wall, or underwent apoptosis at 7 days. CONCLUSION： Olfactory ensheathing cells promote differentiation of neural stem cells mainly into neuron-like cells, and accelerate proliferation of neural stem cells. The outcome is better compared with serum-free medium or medium containing 5% fetal bovine serum.

Biocompatibility of a collagen-heparin sulfate scaffold implanted into porcine brain

BACKGROUND： Collagen-heparin sulfate scaffolds have been widely used to repair nerve injury and promote nerve regeneration. Previous research has evaluated scaffold biocompatibility by measuring gliocyte proliferation but not neuronal apoptosis. OBJECTIVE： To explore the biocompatibility of collagen-heparin sulfate scaffold in porcine brain by detecting peripheral neural apoptosis and protein expression. DESIGN, TIME AND SETTING： A randomized, controlled animal experiment was performed at the Laboratory of Neurology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, between March and June, 2008. MATERIALS： Rabbit anti-human Bax, Caspase-3 polyclonal antibody, rat anti-human Bcl-2 polyclonal antibody, streptavidin biotin-peroxidase complex （SABC） immunohistochemical kit, and TUNEL kit （Roche, USA） were used in this study. METHODS： Twenty adult piglets were randomly evenly divided into implantation and control groups A collagen-heparin sulfate scaffold was implanted from the anterior fontanelle into the brain in the implantation group. The same puncture but no scaffold implantation was made in the control group. MAIN OUTCOME MEASURES： Cell apoptosis was detected using TUNEL; Bax, Bcl-2, and Caspase-3 expressions were measured using the SABC method. RESULTS： At days 1,3, 7, and 14 after scaffold implantation, a few apoptotic cells were observed in the brain tissues near the puncture site, with more apoptotic cells in the implantation group （P 〈 0.05）. However, both groups showed similar apoptosis levels by day 30 after implantation. Implantation increased Bax, Bcl-2, and Caspase-3 expressions on days 3 and 7 after implantation （P 〈 0.05） but decreased the ratio of Bcl-2 to Bax in the implantation group was significantly lower on days 3 and 7 （P 〈 0.05）, with no significant difference by day 30 after implantation （P 〉 0.05）. CONCLUSION： The collagen-heparin sulfate scaffold has good biocompatibility to porcine brain tissues.

Reconstruction of the adenosine system by bone marrow-derived mesenchymal stem cell transplantation

In the present study, we transplanted bone marrow-derived mesenchymal stem cells into the CA3 area of the hippocampus of chronic epilepsy rats kindled by lithium chloride-pilocarpine, Immunofluorescence and western blotting revealed an increase in adenosine A1 receptor expression and a decrease in adenosine A2a receptor expression in the brain tissues of epileptic rats 3 months after transplantation. Moreover, the imbalance in the A1 adenosine receptor/A2a adenosine receptor ratio was improved. Electroencephalograms showed that frequency and amplitude of spikes in the hippocampus and frontal lobe were reduced. These results suggested that mesenchymal stem cell transplantation can reconstruct the normal function of the adenosine system in the brain and greatly improve epileptiform discharges.

Efficacy and safety of rasagiline in Chinese patients with early Parkinson’s disease:a randomized, double-blind,parallel,placebo-controlled,fixed-dose study

Background:Rasagiline is a monoamine oxidase-B inhibitor used for Parkinson’s disease(PD)treatment,but its effectiveness on Chinese patients is unclear.This study aimed to evaluate the efficacy and safety of rasagiline monotherapy in Chinese patients with early PD.Methods:A 26-weeks,randomized,double-blind,placebo-controlled study has been performed at 15 sites in China and enrolled outpatients(≥35 years old)with idiopathic PD without a history of using any dopaminergic drugs.Participants were randomized 1:1 to receive rasagiline 1 mg once daily or placebo.The primary endpoint was the change of the Unified Parkinson’s Disease Rating Scale(UPDRS)total score from baseline to 26 weeks treatment.Secondary endpoints included changes in UPDRS subscale scores from part Ⅰ to Ⅲ.Health status was assessed with the PD Questionnaire(PDQ)-39 and EuroQol-Five-Dimension(EQ-5D)questionnaire.Safety profile was collected until 30 weeks after randomization.Results:A total of 130 patients(n=65/group)were recruited,and 127(rasagiline,n=64;placebo,n=63)were included in the full analysis set.Baseline characteristics were comparable between the two groups.The decrease in the mean UPDRS total score was greater in the rasagiline group than in the placebo group(−3.18±0.95 vs.−0.18±0.98,P=0.025),and the mean UPDRS part I non-motor symptoms score(−0.54±0.15 vs.-0.08±0.15,P=0.003)were significantly decreased in the rasagiline group compared with placebo treated patients.An improvement trend was observed in the active treatment group for the subscales evaluation with parts Ⅱ and Ⅲ,while the difference to placebo was not statistically significant.Life quality assessed by the EQ-5D visual analog scale improved in the rasagiline group but worsened in placebo treated patients.The overall incidence of treatment-emergent adverse events(AEs)was slightly lower in the rasagiline group(41.5%)than in the placebo group(46.2%).Conclusions:Rasagiline is effective,safe,and well tolerated as monotherapy for the treatment of Chinese PD patients.

The efficacy and safety of pramipexole ER versus IR in Chinese patients with Parkinson’s disease: a randomized, double-blind, double-dummy, parallel-group study

Objective:To evaluate the non-inferiority of pramipexole extended-release(ER)versus immediate-release(IR)in Chinese patients with Parkinson’s disease(PD)in a double-blind,randomized,parallel-group study.Methods:Subjects were Chinese patients with idiopathic PD with diagnosis≥2 years prior to trial,age≥30 years old at diagnosis,and Modified Hoehn and Yahr score 2-4 during‘on’-time.Subjects received treatment with pramipexole ER(n=234)or IR(n=239).Non-inferiority was based on the primary endpoint,the change from baseline to end of maintenance(week 18)in the UPDRS(Parts II+III)total score.Results:For the primary endpoint,the adjusted mean changes(standard error)of UPDRS Parts II+III at week 18 were−13.81(0.655)and−13.05(0.643)for ER and IR formulations,respectively,using ANCOVA adjusted for treatment and centre(fixed effect)and baseline(covariate).The adjusted mean between group difference was 0.8 for the 2-sided 95%CI(−1.047,2.566).Since the lower limit of the 2-sided 95%CI(−1.047)for treatment difference was higher than the non-inferiority margin of−4,non-inferiority between pramipexole ER and IR was demonstrated.The incidence of adverse events(AEs)was 68.8%in the ER arm and 73.6%in the IR arm with few severe AEs(ER:2.1%;IR:3.8%).Conclusion:Based on the UPDRS II+III score,pramipexole ER was non-inferior to pramipexole IR.The safety profiles of pramipexole ER and IR were similar.These results were based on comparable mean daily doses and durations of treatment for both formulations.

Adjunct rasagiline to treat Parkinson’s disease with motor fluctuations:a randomized,double-blind study in China

Background:The use of adjunct rasagiline in levodopa-treated patients with Parkinson’s disease and motor fluctuations is supported by findings from large-scale clinical studies.This study is to investigate the efficacy and safety of adjunct rasagiline in Chinese patients with Parkinson’s disease,as a product registration study.Methods:This 16-week,randomized,double-blind,parallel-group,multicenter,placebo-controlled study of rasagiline 1 mg/day included levodopa-treated patients with Parkinson’s disease and motor fluctuations.The primary efficacy endpoint was mean change from baseline in total daily OFF time over 16 weeks.Secondary endpoints were Clinical Global Impressions–Improvement(CGI-I),and change in Unified Parkinson’s Disease Rating Scale(UPDRS)Activities of daily living(ADL)and Motor scores.Patient well-being(EQ-5D),and the frequency of adverse events were also assessed.Results:In total,324 levodopa-treated patients were randomized to rasagiline 1 mg/day(n=165)or placebo(n=159).Over 16 weeks,rasagiline statistically significantly reduced the mean[95% confidence interval]total daily OFF time versus placebo(−0.5 h[−0.92,−0.07];p=0.023).There were also statistically significant improvements versus placebo in CGI-I(−0.4 points[−0.61,−0.22];p<0.001),UPDRS-ADL OFF(−1.0 points[−1.75,−0.27];p=0.008),and UPDRS-Motor ON(−1.6 points[−3.05,−0.14];p=0.032)scores,as well as the EQ-5D utility index(p<0.05).Rasagiline was safe and well tolerated.Conclusions:In levodopa-treated Chinese patients with Parkinson’s disease and motor fluctuations,adjunct rasagiline 1 mg/day statistically significantly reduced OFF time,and improved daily function and overall well-being,versus placebo.Consistent with findings in other countries,adjunct rasagiline was proven efficacious and well tolerated in Chinese patients.

Anovel BRF1mutation intwomiddle-aged siblingswith cerebellofaciodental syndrome

To the Editor:Cerebellar-facial-dental syndrome(CFDS)is a rareand autosomal recessive(AR)neurodevelopmental disease,characterized by cerebellar hypoplasia and intellectual disability,facial dysmorphisms,short stature,microcephaly,and dental anomalies.ll'in 20is,Borck et observed threepairs of siblings with apreviously undescribed pattern of abnormalities andestablished CFD's as a clinicalentity,To date,a total of six CFDS families have been reported.li'4iThe age of the reported patients ranges from infancy to early adulthood.Since the rarity of CFDS,more study is requiredforevaluatingits natural historyand clinical characteristics.This paper would liketo report a novel homozygous BRF1 gene mutation in two middleaged CFDS patients from Chinese,and to summarize its clinical and genetic characteristics,reinforcing the pathogenicity of BRF1 gene mutations and expanding the manifestation spectrum of CFDS.

Prospective research on the efficacy and safety of oxcarbazepine as monotherapy and add-on therapy for partial epilepsy

The purpose of our research was to evaluate the efficacy,tolerance,and safety of oxcarbazepine(OXC)as monotherapy and add-on therapy for partial epilepsy.We carried out a prospective clinical follow-up trial at the Epilepsy Center of Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology.Sixty-seven patients with partial epilepsy received OXC therapy.The patients were randomly divided into a monotherapy group and an add-on therapy group.We observed the efficacy and safety in thefirst three months and the following three months respectively,and compared them with each other.There was a significant difference in the decrease of seizure frequency between the two groups(P=0.002).There was a significant difference in the percentage of seizure-free between the monotherapy and the add-on therapy groups in thefirst three months(P=0.02),and there were also statistical differences in the 50%response rate(P=0.017)and the percentage of seizure-free in the following three months(P=0.019).No difference was found in the 50%response rate,the 75%response rate,and the percentage of seizure-free between thefirst three months and the following three months in the whole group and the two subgroups(P>0.05).The incidence rate of side effects due to the therapy was 19.40%(13 of 67).The side effects were mainly found in thefirst three months.It is concluded that OXC is thefirst-line anti-epileptic drug(AED)for partial seizures,and could be used as the monotherapy and add-on therapy for newly diagnosed patients and patients that failed to tolerate or benefit from other AEDs.