Effects of Thioperamide on Seizure Development and Memory Impairment Induced by Pentylenetetrazole-kindling Epilepsy in Rats

背景：组胺H3受体拮抗剂是一种有潜力的治疗中枢神经系统疾病的药物。但是这类药物是否能抑制癫痫产生（epileptogenesis）尚不清楚。本项目采用选择性的H3受体拮抗剂thioperamide,研究其对大鼠戊四唑点燃癫痫的发展过程及由癫痫诱发的记忆障碍的作用。 方法：大鼠隔日腹腔注射亚惊厥剂量（35 mg/kg）的戊四唑,共注射12次,诱发化学点燃癫痫,每次注射后大鼠被观察记录30 min。对照组仅注射生理盐水。Morris水迷宫用来检测大鼠的空间记忆能力。海马的磷酸化的cAMP反应元件结合蛋白（p-CREB）采用western blotting测定。 结果：每次腹腔戊四唑注射前半小时,给予侧脑室注射thioperamide （10 g, 20 g）延缓了戊四唑点燃现象的出现。戊四唑点燃癫痫使大鼠的空间记忆功能显著受损,thioperamide则改善了这种记忆功能受损。另外,与对照组相比,戊四唑点燃癫痫使大鼠海马内p-CREB水平明显下降,而thioperamide则逆转了这种p-CREB水平的下降。 结论：我们的结果提示thioperamide在大鼠戊四唑点燃癫痫的形成过程和癫痫诱发记忆障碍中起到保护作用。其中对记忆障碍的保护作用可能与其增强CREB相关的核转录功能有关。     

Anticonvulsive and antioxidant effects of curcumin on pilocarpine-induced seizures in rats

Background  Curcumin, an active ingredient of turmeric with antioxidant and anti-inflammatory properties has recently been reported to have anticonvulsant effects in several animal models of epilepsy. This study aimed to investigate the effects of curcumin on the pilocarpine rat model of status epilepticus.

Methods  The effect of intraperitoneal administration of curcumin (30, 100, and 300 mg/kg) on pilocarpine-induced seizures in rats was tested. The correlation between seizure activity and hippocampal levels of nitric oxide synthase and free radicals was quantified. Whether curcumin treatment modulated these parameters was also investigated.

Results  Curcumin significantly increased seizure threshold at doses of 100 and 300 mg/kg. Rats with pilocarpine- induced seizures showed significantly elevated levels of malonaldehyde, nitric oxide synthase, and lactate dehydrogenase, but decreased levels of superoxide dismutase and glutathione compared with normal control rats. At doses of 100 and 300 mg/kg, curcumin reversed the effects of pilocarpine-induced seizures on nitric oxide synthase, lactate dehydrogenase, glutathione, and superoxide dismutase. However, curcumin did not restore the elevated malonaldehyde levels.

Conclusion  Curcumin has anticonvulsant activity in the pilocarpine rat model of seizures, and that modulation of free radicals and nitric oxide synthase may be involved in this effect.

     

A preliminary experimental study on the cardiac toxicity of glutamate and the role of AMPA receptor in rats

Background  Monosodium L-glutamate (MSG) is a food flavor enhancer and its potential harmfulness to the heart remains controversy. We sought to investigate if MSG could induce cardiac arrhythmias and apoptosis via the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

Methods  Myocardial infarction was created by ligating the coronary artery and ventricular arrhythmias were monitored by electrocardiogram in the rat in vivo. Neonatal rat cardiomyocytes were isolated and cultured. Cell viability was estimated by MTT assay. Calcium mobilization was monitored by confocal microscopy. Cardiomyocyte apoptosis was evaluated by acridine orange staining, flow cytometry, DNA laddering, RT-PCR and Western blotting.

Results  MSG (i.v.) decreased the heart rate at 0.5 g/kg and even serious bradycardia at 1.5 g/kg, but could not induce ventricular tachyarrhythmias in normal rats in vivo. In rats with acute myocardial infarction (MI) in vivo, however, MSG (1.5 g/kg, i.v.) induced ventricular tachyarrhythmias, and these arrhythmias could be prevented by blocking the AMPA receptor and NMDA receptor. Selectively activating the AMPA receptor or NMDA receptor both induced ventricular tachyarrhythmias in MI rats. At the cellular level, AMPA induced calcium mobilization, oxidative stress, mitochondrial dysfunction and apoptosis in cultured cardiomyocytes, especially when the AMPA receptor desensitization was blocked by cyclothiazide. The above toxic cellular effects of AMPA were abolished by AMPA receptor blockade or by H₂O₂ scavengers.

Conclusion  MSG is proarrhythmic to the infarct rat heart at least in part via activating the AMPA receptor. AMPA receptor overactivation is also proapoptotic to the cardiomyocyte.

     

Serum antibodies to 25 myelin oligodendrocyte glycoprotein epitopes in multiple sclerosis and neuromyelitis optica: clinical value for diagnosis and disease activity

Background  Whether antibody to myelin oligodendrocyte glycoprotein (MOG) can be a diagnostic marker for multiple sclerosis (MS) is still controversial. Recent studies suggested that serum specific anti-MOG epitope antibody might be an MS specific marker. However, these studies did not include neuromyelitis optica (NMO) which might be proven to also have anti-MOG antibody. Hence, the present study was undertaken to investigate the clinical value of serum antibodies to 25 MOG epitopes in conventional MS (CMS) and NMO.

Methods  Serum anti-MOG epitope IgG was detected in 61 CMS patients, 54 NMO patients, and 77 healthy controls, using enzyme-linked immunosorbent assay (ELISA).

Results  Anti-MOG_27-38 IgG levels in both CMS and NMO patients were significantly higher than that in healthy controls (optical density (OD): 0.64±0.38, 0.48±0.23 vs. 0.19±0.09; P=0.000). CMS and NMO patients in relapse stage had significantly higher anti-MOG_27-38 IgG level than patients in remission stage (OD: 0.55±0.14 vs. 0.24±0.09, P=0.027).

Conclusion  Although serum anti-MOG epitope IgG could not differentiate MS from NMO, it may be a useful marker for monitoring disease activity.

     

Specific regulator of eosinophil apoptosis: Siglec-8—new hope for bronchial asthma treatment

Objective  It is known that Siglec-8 is selectively expressed on human eosinophils at a high level and mediates eosinophil apoptosis when crosslinked with its antibody. The aim of our review is to elucidate the molecular and biological characteristic of Siglec-8 and then discuss the function and possible mechanisms of Siglec-8 in eosinophils. Thereby, we will expand our understanding to the regulation of eosinophil apoptosis, and provide important clues to the treatment of asthma and other hyper-eosinophilic diseases.

Data sources  Most articles were identified by searching of PubMed online resources using the key term Siglecs.

Study selection  Mainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected.

Results  Siglec-8 is selectively expressed on human eosinophil and can specifically induce eosinophil apoptosis.

Conclusion  The restricted expression of Siglec-8 on human eosinophil and the rapid progress in understanding its role as cell signaling and activation of death receptors have made it an attractive target for treatment of asthma and other hyper-eosinophilic diseases.

     

Antiviral therapy of decompensated hepatitis B virus-related cirrhosis

Objective  To review the development, mechanism, necessity and limitation of antiviral therapy in decompensated hepatitis B virus-related cirrhosis.

Data sources  Most information was pulled from a literature search (Pubmed 2000 to 2011) using the keywords of antiviral and decompensated hepatitis B virus-related cirrhosis. Relevant book chapters were also reviewed.

Study selection  Well-controlled, prospective landmark studies and review articles on antiviral therapy in decompesated hepatitis B virus-related cirrhosis were selected.

Results  Specific antiviral agents not only control viral replication, which permits liver transplantation, but also improve liver function so significantly that patients could be removed from the transplant waiting list. However, the emergence of drug-resistant mutants can result in treatment failure. Combination therapy is a save-strategy in drug-resistant.

Conclusions  Although the treatment of end-stage liver disease is still a challenge worldwide, antiviral therapy has altered the natural history of hepatitis B patients with decompensated cirrhosis. The approval of the new generation of antivirals is opening new perspectives for finding the optimal antiviral treatment for patients with decompensated cirrhosis and preventing antiviral resistance. A combination of antivirals may be one of the future strategies for fulfilling these goals.

     

Laparoscopic and gasless laparoscopic sigmoid colon vaginoplasty in women with vaginal agenesis

Background  In the past several decades we have seen multiple advances in the reconstruction for girls born with vaginal agenesis. This study aimed to evaluate the technical feasibility, anatomical and functional outcomes of one-stage laparoscopic and gasless laparoscopic vaginoplasty with sigmoid colon for the patients of vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome).

Methods  We did a retrospective review of a total of 150 women with Mayer-Rokitansky-Kuster-Hauser syndrome treated at Beijing Anzhen Hospital, Capital Medical University from March 2006 to August 2010. The patients were divided into the CO₂ pneumoperitoneum laparoscopic group and the abdominal wall lift of gasless laparoscopic group. Sigmoid colon vaginoplasty approaches were performed in all of the patients. The surgical techniques, perioperative results, complications, anatomical and functional outcomes of vaginoplasty were recorded.

Results  All procedures were performed successfully. Significant differences in the operative time and intraoperative blood loss existed in the laparoscopic vaginoplasty group compared with the gasless laparoscopic vaginoplasty group. The patients who underwent sigmoid colon vaginoplasty had good cosmetic results without the problem of excessive mucus production. The postoperative complications were minimal. During a mean follow-up of 15.6 months, no stenosis or shrinkage was encountered. The subjective sexual satisfaction rate with the surgical outcomes in all patients was 83.3%.

Conclusions  Laparoscopic or gasless laparoscopic vaginoplasty with sigmoid colon are effective and feasible approaches for women with congenital vaginal agenesis. The procedures have satisfactory anatomical and functional results.

     

Gene delivery in peritoneal dialysis related peritoneal fibrosis research

Objective  To summarize the development of gene delivery vectors in peritoneal fibrosis research and discuss the feasibility and superiority of lentiviral vectors.

Data sources  The data in this article were collected from PubMed database with relevant English articles published from 1995 to 2011.

Study selection  Articles regarding the gene therapy in peritoneal fibrosis research using non-viral vectors, adenoviral vectors, retroviral vectors, and lentiviral vectors were selected. Data were mainly extracted from 60 articles, which are listed in the reference section of this review.

Results  Non-viral vector-mediated gene delivery (including naked DNA for ex vivo, oligonucleotides, ultrasound- contrast agent mediated naked gene delivery, etc.) and viral vector-mediated gene delivery (including adenovirus, helper-dependant adenovirus, and retrovirus vectors) have been successfully applied both in the mechanistic investigation and the potential prevention and treatment of peritoneal fibrosis.

Conclusions  Peritoneal fibrosis is a major complication of peritoneal dialysis (PD). Recently, the wide use of the gene delivery technique made it possible to access and further research peritoneal fibrosis. The use of lentiviral vector is expected to be widely used in PD research in the future due to its advantages in gene delivery.

     

Proteomic analysis for detecting serum biomarkers related to smoking in humans

Background  Smoking is the leading cause of death in the world. This study focused on the difference of the serum proteomic profiling between healthy smokers and nonsmokers in order to find smoking-specific serum biomarkers.

Methods  Pattern-based proteomic profiling of 100 serum samples (from 50 Chinese male smokers and 50 matched nonsmokers) was performed through magnetic bead fractionation coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis (MALDI-TOF-MS) and resulting data were statistically analyzed by Ciphergen ProteinChip software 3.0.2.

Results  We found 72 serum peaks were significantly different between smokers and nonsmokers (P <0.05). Marker peaks of mass-to-charge ratio (m/z) 3159.13, 7561.03 and 9407.32 were smoking-specific.

Conclusion  The preliminary data suggested that smoking-specific serum biomarkers could be detected in humans.

     

Increased expression of serum gelsolin in patients with osteosarcoma.

Background  Identification of potential serum biomarkers of osteosarcoma to aid in its early diagnosis and in the discovery of possible therapeutic targets is an area of increasing interest.

Methods  Two-dimensional difference-in-gel electrophoresis was used to assess multiple serum samples in patients with osteosarcoma. In addition, differential expression of protein biomarkers was characterized in osteosarcoma serum by using matrix-assisted desorption/ionization time-of-flight mass spectrometry coupled with database interrogation. Serum samples from four individuals with osteosarcoma and four age- and sex-matched healthy control subjects were compared.

Results  Fifty-eight significant protein spot features in the osteosarcoma sera were found. These spot features were excised, digested with trypsin, and analyzed with mass spectrometry. Gelsolin was down-regulated only in osteosarcoma. Furthermore, Western blotting and enzyme linked immunosorbent assay (ELISA) confirmed decreased levels of gelsolin in the osteosarcoma serum samples.

Conclusions  These results indicated that gelsolin might have great potential as a biomarker of osteosarcoma and as a potential target for gene therapy.

     

Effects of estrogen on collagen gel contraction by human retinal glial cells

Background  There are definite gender differences in patients with macular holes. Menopausal women over 50 years are most affected. We aimed to observe the effect of estrogen on collagen gel contraction by cultured human retinal glial cells. It is speculated that estrogen could strengthen the tensile stress of the macula by maintaining the correct morphology and contraction.

Methods  Estrogen was used to determine its effects on collagen gel contraction, and its function was measured using morphological changes in cells. Human retinal glial cells were cultured in collagen solution. The cells were then exposed to collagen gels and the degree of contraction of the gel was determined.

Results  Estrogen at differing concentrations had no effect on the growth of human retinal glial cells. However, after exposed to collagen gel block, less contraction was noted in the estrogen-treated group than in the control group.

Conclusions  Estrogen can inhibit collagen gel contraction by glial cells. These results suggest a mechanism for macular hole formation, which is observed in menopausal females.

     

Evaluation of respiratory dysfunction in a pig model of severe acute dichlorvos poisoning

Background  Respiratory failure is the main cause of death in acute organophosphorus pesticide poisoning. In this study, a pulse-induced contour cardiac output monitor was used to evaluate the respiratory status in a pig model of acute dichlorvos poisoning.

Methods  Twenty female pigs were randomly allocated to dichlorvos (n=7), atropine (n=7), and control (n=6) groups. In the dichlorvos group, pigs were administered 80% emulsifiable dichlorvos (100 mg/kg) via a gastric tube. In the atropine group, pigs were similarly administered dichlorvos, and 0.5 hours later, atropine was injected to attain and maintain atropinization. The control group was administered saline solution. Arterial blood gas was measured at 0, 0.5, 1, 2, 4, and 6 hours post-injection. The extravascular lung water index and pulmonary vascular permeability index were recorded by the pulse-induced contour cardiac output monitor. At termination of the study, the animals were euthanized, the lung wet-to-dry weight ratio was determined, and histopathology was observed.

Results  In the dichlorvos group, the extravascular lung water index and pulmonary vascular permeability index were substantially increased from 0.5 hours and were particularly high within 1 hour. In the atropine group, these indices increased initially, but decreased from the 1-hour mark. The control group exhibited no obvious changes. In both the dichlorvos and atropine groups, the extravascular lung water index was negatively correlated with partial pressure of oxygen/fraction of inspiration oxygen (PO₂/FiO₂) and positively correlated with the pulmonary vascular permeability index. Compared with the control group, the lung wet-to-dry weight ratio markedly increased and the histopathological findings obviously changed in the dichlorvos group, but only mildly increased and changed, respectively, in the atropine group.

Conclusion  The extravascular lung water index is an appropriate and valuable parameter for assessment of respiratory function in acute dichlorvos poisoning.

     

Relationship between 6-minute walk test and pulmonary function test in stable chronic obstructive pulmonary disease with different severities

Background  The relationship between the 6-minute walk test (6MWT) and pulmonary function test in stable chronic obstructive pulmonary disease (COPD) remains unclear. We evaluate the correlation of 6MWT and spirometric parameters in stable COPD with different severities. 6MWT data assessed included three variables: the 6-minute walk distance (6MWD), 6-minute walk work (6MWORK), and pulse oxygen desaturation rate (SPO₂%).

Methods  6MWT and pulmonary function test were assessed for 150 stable COPD patients with different severities. Means and standard deviations were calculated for the variables of interest. Analysis of variance was performed to compare means. Correlation coefficients were calculated for 6MWT data with the spirometric parameters and dyspnea Borg scale. Multiple stepwise regression analysis was used to screen pulmonary function-related predictors of 6MWT data.

Results  The three variables of 6MWT all varied as the severities of the disease. The 6MWD and 6MWORK both correlated with some spirometric parameters (positive or negative correlation; the absolute value of r ranging from 0.34 to 0.67; P <0.05) in severe and very severe patients, and the SPO₂% correlated with the dyspnea Borg scale in four severities (r= -0.33, -0.34, -0.39, -0.53 respectively; P <0.05). The 6MWD was correlated with the 6MWORK in four severities (r=0.56, 0.57, 0.72, 0.81 respectively, P <0.05), and neither of them correlated with the SPO₂%. The percent of predicted forced expiratory volume in 1 second (FEV₁% predicted) and residual volume to total lung capacity ratio (RV/TLC) were predictors of the 6MWD, and the maximum voluntary ventilation (MVV) was the predictor of the 6MWORK.

Conclusions  6MWT correlated with the spirometric parameters in severe and very severe COPD patients. 6MWT may be used to monitor changes of pulmonary function in these patients.

     

Clinical features and imaging findings in pulmonary capillary hemangiomatosis: report of two cases and a pooled analysis

Background  Pulmonary capillary hemangiomatosis (PCH) is a rare disease and no Chinese case has been reported yet. The disease is often misdiagnosed and its clinical characteristics are incompletely described. The aim of this study was to describe two Chinese cases and to clarify the clinical and radiographic parameters of patients with PCH.

Methods  Two PCH cases were presented and other cases were searched from the English literature. All available clinical and radiographic data were collected from 62 literature reported PCH cases. A pooled analysis of total 64 cases was made.

Results  Dyspnea and hemoptysis were the most common clinical symptoms of PCH. Pulmonary hypertension (PH) was found in 78% of the reported cases. PCH typically showed characteristic diffuse or patchy ground-glass opacities (GGOs) and/or multiple ill-defined centrilobular nodules in the computed tomography.

Conclusions  The diagnosis of PCH requires a high clinical suspicion. However, both clinical presentations and radiographic studies often provide clues to the diagnosis, which may prompt early lung biopsy for a definite diagnosis.

     

Steady-state pharmacokinetics of zidovudine in Chinese HIV-infected patients

Background  The pharmacokinetics of zidovudine (AZT) are possibly influenced by weight, age, sex, liver and renal functions, severity of disease, and ethnicity. Currently, little information is available on the steady-state pharmacokinetics of AZT in Chinese HIV-infected patients. The current study aimed to characterize the steady-state pharmacokinetics of AZT in a Chinese set-up.

Methods  Eleven Chinese HIV-infected patients were involved in the steady-state pharmacokinetic study. In total, 300 mg of AZT, as a part of combination therapy, was given to patients, and serial blood samples were collected for 12 hours. The samples were measured by a high-performance liquid chromatography (HPLC) assay, and the results were analyzed by both the non-compartment model and the one-compartment model.

Results  The C_max of AZT in Chinese patients was higher than that in non-Asian patients. The half-life of AZT, analyzed by the non-compartment model (P=0.02), in male patients ((1.02±0.22) hours) was shorter than that of AZT in female patients ((1.55±0.29) hours). The AZT clearance, analyzed by the one-compartment model (P=0.045), in male patients ((262.60±28.13) L/h) was higher than that in female patients ((195.85±60.51) L/h).

Conclusion  The present study provides valuable information for the clinical practice of AZT-based highly active antiretroviral therapy in a Chinese set-up.

     

Evaluation and treatment of marginal grafts with surgical diseases in kidney transplantation

Background  Marginal renal grafts may alleviate the shortage of suitable organs to meet an increasing demand of kidney transplantation, especially when live donors are currently limited to relatives of patients in China. The aim of this study was to investigate how to increase the available donors pool, evaluation, and treatment of marginal donors.

Methods  We had performed 121 kidney transplantation cases with living relative donors. Five out of these cases applied marginal grafts with surgical diseases, including one renal stone, one duplex kidney, one renal leiomyoma and two cases of simple renal cysts. In each case, particular surgical interventions were exerted on the graft prior to standard engrafting procedures.

Results  All recipients recovered with functioning transplants given that their serum creatinine levels declined to a normal range within one week after operation. These recipients were subsequently followed up for 10 months on average and their kidney functions remained stable.

Conclusions  Marginal renal grafts with surgical diseases, which can be treated surgically before engrafting, may provide satisfying transplantation outcomes. Positive and cautious consideration of these grafts may increase renal donor pool.

     

Azithromycin inhibits neutrophil accumulation in airways by affecting interleukin-17 downstream signals

Background  Azithromycin can reduce neutrophil accumulation in neutrophilic pulmonary diseases. However, the precise mechanism behind this action remains unknown. Our experiment assessed whether azithromycin inhibits neutrophil accumulation in the airways by affecting interleukin-17 (IL-17) downstream signals.

Methods  Mice were pretreated with azithromycin before murine IL-17A (mIL-17) stimulation. After the mIL-17 stimulation, the levels of six neutrophil-mobilizing cytokines were determined by enzyme-linked immunosorbent assay (ELISA) tests in bronchoalveolar lavage (BAL) fluid; IL-6, CXC chemokine ligand-1 (CXCL-1), CXCL-5, macrophage inflammatory protein-2 (MIP-2), granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF). The number of neutrophils in BAL fluid were evaluated by cytospin preparations.

Results  (1) Azithromycin pretreatment significantly inhibited both the release of three neutrophil-mobilizing cytokines (MIP-2, CXCL-5 and GM-CSF) and the accumulation of neutrophils in airways caused by mIL-17 stimulation. (2) The levels of three neutrophil-mobilizing cytokines (IL-6, MIP-2 and GM-CSF) were positively correlated with the numbers of neutrophil in BAL fluid.

Conclusions  Azithromycin can inhibit neutrophil accumulation in the airways by affecting IL-17 downstream signals. This finding suggests that macrolide antibiotic application might be useful in prevention of neutrophilic pulmonary diseases characterized by high levels of IL-17.

     

Cross-sectional investigation of visual impairing diseases in Shanghai blind children school

Background  The control of blindness in children is a high priority within the VISION 2020 initiative. To determine the causes of severe visual impairment and blindness in children from Shanghai Blind Children School (SBCS) can provide useful information on childhood blindness in Shanghai.

Methods  A cross-sectional investigation of students in SBCS was conducted in May 2010. The World Health Organization/Prevention of Blindness (WHO/PBL) eye examination record system for children with low vision and blindness was used. The results were further compared with the findings of two previous investigation studies conducted in 1986 and 2004, respectively in SBCS.

Results  Of the 146 children observed, 80 children (54.8%) were blind (best corrected best visual acuity less than 0.05), 27 children (18.5%) had severe visual impairment (best corrected visual acuity less than 0.1 but better than or equal to 0.05), and 34 children (23.3%) had moderate visual impairment (best corrected visual acuity less than 0.3 but better than or equal to 0.1). The major affected anatomic sites in the 107 children with severe visual impairment and blindness (SVI/BL) were retina (47.7%), whole globe (16.8%), optic nerve (13.1%) and lens (9.3%). The leading causes of SVI/BL were retinopathy of prematurity (ROP, 25.2%), followed by retinal dystrophy (15.9%), optic nerve atrophy (9.3%) and microphthalmos (9.3%). The two leading etiologic categories of SVI/BL were perinatal/neonatal (36.4%) and congenital/hereditary groups (29.0%). The leading cause of moderate visual impairment was aphakia after cataract surgery (congenital cataract, 44.1%). Compared with the findings in two previous investigations in SBCS, the proportion of ROP in visual impairing diseases increased, while the proportion of disorders of the lens (cataract and aphakia) significantly decreased.

Conclusions  The leading cause of childhood blindness in SBCS nowadays is ROP. It is projected that without improvement in perinatal medical care that ROP will continue to be a major cause of childhood blindness.