Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2 mg every 2-4 weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

The effect of infections on the mortality of cirrhotic patients with hepatic encephalopathy.

Cirrhotic patients are prone to having infections, which may aggravate hepatic encephalopathy (HE). However, the effect of infections on mortality in HE cirrhotic patients is not well described. The National Health Insurance Database, derived from the Taiwan National Health Insurance Programme, was used to identify 4150 adult HE cirrhotic patients hospitalized between 1 January 2004 and 31 December 2004. Nine hundred and eighty-five patients (23.7%) had one or more co-existing infections during their hospitalization. After Cox proportional hazard regression modelling adjusted by the patients' gender, age, and medical comorbidity disorders, the hazard ratios (HRs) in HE patients with infections for 30-day, 30- to 90-day, and 90-day to 1-year mortalities were 1.66 [95% confidence interval (CI) 1.42-1.94], 1.51 (95% CI 1.23-1.85) and 1.34 (95% CI 1.13-1.58), respectively. Compared to the non-infection group, the HRs of pneumonia, spontaneous bacterial peritonitis, urinary tract infection, sepsis without specific focus (SWSF), cellulitis, and biliary tract infection were 2.11, 1.48, 1.06, 2.21, 1.06, and 0.78, respectively, for 30-day mortality; 1.82, 1.22, 0.93, 2.24, 0.31, and 2.82, respectively, for 30- to 90-day mortality; and 2.03, 0.82, 1.24, 1.64, 1.14, and 0.60, respectively, for 90-day to 1-year mortality for HE cirrhotic patients. We conclude that infections increase the mortality of HE cirrhotic patients, especially pneumonia and SWSF.

Heparin protects BALB/c mice from mite-induced airway allergic inflammation.

More and more studies have demonstrated the anti-inflammatory effects of heparin. However, in the aspect of allergic airway inflammation, data about its daily use in animal model is scarce. To evaluate the efficacy of 22-day intranasal heparin administration in mite-induced airway allergic inflammation in BALB/c mice, the murine model of house dust-mite allergen-induced asthma was used to assess the effect of heparin (h) and low molecular weight heparin (l mwh) administered intra-nasally (IN) throughout the full study period (22 days). Effects were monitored by histopathology, cell counts in broncho-alveolar lavage fluid (BALF), local cytokine production, serum, specific antibody levels, and airway resistance measurements. Compared to the positive control group, both hIN and lmwhIN groups had lower peri-bronchiolar/alveolar inflammatory pathology score and lower goblet cell scores (p less than 0.01); lower eosinophil and neutrophil counts in BALF (p less than 0.0001); and lower cytokine levels including IL-17A/F, IL-5, IL-13, IL-8 and eotaxin in lung tissue (p less than 0.001). Serum Der p-specific IgE level was also lower in heparin-treated groups (p less than 0.004). The two heparin-treated groups also revealed lower value of Penh after Mch stimulation. In conclusion, heparin and lmw heparin decrease serum Der p-specific IgE level and possess anti-inflammatory effects on mite-induced airway allergic inflammation model in BALB/c mice.

Immune responses to tyrophagus putrescentiae-induced airway inflammation in mice.

BACKGROUND: Storage mites are a source of aeroallergens that affect patients with allergic rhinitis and asthma. Tyrophagus putrescentiae is a causative factor of airway hypersensitivity, but the mechanisms and pathogenesis of Tputrescentiae-induced allergy are not well understood. OBJECTIVE: This study aimed to develop a murine model of T putrescentiae-induced allergic asthma. METHODS: Immune responses and physiologic variations in immunoglobulins (Ig), leukocyte subpopulations, cytokines, gene expression, pulmonary function, and lung pathology were evaluated after intraperitoneal sensitization and intratracheal challenge with crude extract of T putrescentiae. RESULTS: After sensitization with aluminum hydroxide and challenge with T putrescentiae in mice, levels of T putrescentiae-specific IgE and IgG1 in sera increased significantly compared to the normal saline group (P < .01): Values for inflammatory leukocytes (neutrophils and eosinophils) and cytokines (interleukin [IL] 4, IL-5, and IL-13) increased significantly after sensitization. In terms of pulmonary function, pause values were significantly enhanced in T putrescentiae-sensitized mice after intratracheal challenge with T putrescentiae (P < .05). Expression of type 2 helper T cell (T(H)2)-related genes (IL4, IL5, IL13, and RANTES), T(H)2-specific transcription factor (GATA-3), and proinflammatory genes (IL6), and T(H)(H)17-related genes (IL17F) increased significantly after airway challenge. Sensitization with T putrescentiae crude extract led to inflammation of lung tissue, thickening of the tracheal wall, and tracheal rupture. CONCLUSIONS: Intraperitoneal sensitization followed by intratracheal challenge with crude extract of T putrescentiae can induce airway inflammation in BALB/c mice. The symptoms observed in a mouse model of allergic asthma, in terms of immune and clinical parameters, are reminiscent of the symptoms of allergic asthma in humans. A mouse model can be used to evaluate the therapeutic effectiveness of drugs on T putrescentiae-induced airway inflammation in humans.

Nonadverse effects on allergenicity of isopentenyltransferase-transformed broccoli.

BACKGROUND: Genetically modified organisms (GMOs) provide modern agriculture with improvements in efficiency and the benefits of enhanced food production; however, the potential impact of GMOs on human health has not yet been clarified. OBJECTIVE: To investigate the allergenicity of isopentenyltransferase (ipt)-transformed broccoli compared with non-GM broccoli. METHODS: Sera from allergic individuals were used to identify the allergenicity of GM and non-GM broccoli. Immunoglobulin (Ig) binding of different lines of GM and non-GM broccoli was identified using immunoblotting, enzyme-linked immunosorbent assay, and the histamin release assay. RESULTS: Positive reactions to broccoli (Brassica Oleracea) were observed in 7.02% of individuals. Specific IgE to broccoli and total IgE fro allergic individuals were well correlated. The different tests performed showed no significant differences in the allergenicity of conventionally raised and GM broccoli, indicating the absence of unexpected effects on allergenicity in ipt-transformed plants. Using Western blot analysis we detected heterogeneous IgE-reactive allergenic components in broccoli-allergic sera, but no significant differences between GM an non-GM broccoli were observed in serum from the same patients. CONCLUSIONS: Our study demonstrates that there are no differences between GM (ipt-transformed) broccoli and non-GM broccoli, as determined by specific IgE in sera from broccoli-allergic patients. This indicates that there were no unexpected effects on allergenicity in this GM broccoli.

Factors associated with isolated anti-hepatitis B core antibody in HIV-positive patients: impact of compromised immunity.

In regions that are hyperendemic for chronic hepatitis B virus (HBV) infection, prevalence of and risk factors associated with isolated anti-hepatitis B core antibody (anti-HBc) in HIV-positive patients are less well described. HIV-positive patients who were tested for hepatitis B surface antigen (HBsAg), anti-hepatitis B surface antibody (anti-HBs) and anti-HBc at designated hospitals for HIV care in Taiwan were included for analysis. HBV DNA was detected by real-time polymerase chain reaction in patients with and without isolated anti-HBc. Of 2351 HIV-positive patients, 450 (19.1%) were HBsAg positive, 411 (17.5%) were anti-HBc positive alone and 963 (41.0%) for both anti-HBs and anti-HBc. Compared with patients who were positive for both anti-HBs and anti-HBc, patients with isolated anti-HBc were older, less likely to have anti-hepatitis C virus antibody (anti-HCV), had lower CD4 lymphocyte counts and higher plasma HIV RNA loads. Older age (adjusted odds ratio, 1.029; 95% confidence interval, 1.015-1.043) and CD4 <100 cells/microL (adjusted odds ratio, 1.524; 95% confidence interval, 1.025-2.265) were independently associated with isolated anti-HBc by logistic regression, while presence of anti-HCV and injecting drug use were not. HBV DNA was detectable in 8.3% of 277 patients with isolated anti-HBc and 14.3% of 56 patients with both anti-HBs and anti-HBc (P = 0.160). In a country hyperendemic for HBV infection, HIV-positive patients at older age and with CD4 <100 cells/microL were more likely to have isolated anti-HBc, suggesting that compromised immunity plays a role in the presence of this marker.

Imiquimod simultaneously induces autophagy and apoptosis in human basal cell carcinoma cells.

BACKGROUND: Imiquimod shows antitumour activity through the stimulation of cell-mediated immunity in vivo. Recent studies have shown that imiquimod promotes apoptosis in melanoma cells and induces autophagy in macrophage cell lines. OBJECTIVES: To evaluate the imiquimod-induced apoptosis, autophagy and their relationship in a basal cell carcinoma (BCC) cell line. METHODS: Cell viability was determined by XTT test. Apoptosis was evaluated by DNA content assay, annexin V/propidium iodide staining assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling assay. Autophagy was determined by LC3 immunoblotting, EGFP-LC3 puncta formation and quantification of acidic vesicular organelles with acridine orange staining. The temporal and spatial differences of imiquimod-induced apoptosis and autophagy were examined by immunoblotting and simultaneously monitored by staining the EGFP-LC3 transfected cells with caspase 3 fluorogenic substrate. We inhibited the apoptosis and autophagy by pancaspase inhibitor and siRNA for Beclin 1 or Atg5, respectively, to evaluate the interplay between imiquimod-induced apoptosis and autophagy. RESULTS: We found that imiquimod induces autophagy and apoptosis in BCC cells in a time- and dose-dependent manner. Imiquimod not only induced EGFP-LC3 puncta formation for autophagy, but also simultaneously activated an apoptotic caspase cascade in the same cells. Both apoptosis and autophagy induced by imiquimod cooperate to cause BCC cell death. However, inhibition of imiquimod-induced apoptosis increased the strength of autophagy, and inhibition of imiquimod-induced autophagy further promoted cell apoptosis. CONCLUSIONS: This study not only demonstrates that imiquimod can directly induce autophagy and apoptosis in BCC cells, but also shows the cooperation and coordination between these two processes to induce cell death.

Estimating allergenicity of latex gloves using Hev b 1 and hevamine.

BACKGROUND: Latex allergy continues to be an increasingly serious occupational health problem in Taiwan, where it affects approximately 6.8% to 12% of health care workers. Contrasting with reports from western countries, Hev b 1 and hevamine, and not Hev b 3, 5 or 6.02, are the major latex allergens among health care workers in Taiwan. This study aimed at evaluating the allergenicity of 30 brands of commercially available medical latex gloves in Taiwan in 2007. METHODS: Residual Hev b 1 and hevamine from the gloves were measured by inhibition enzyme-linked immunosorbent assay using polyclonal antibodies against purified recombinant Hev b 1 and hevamine. The results were compared to those achieved with quantification of residual total extractable proteins and skin prick testing. RESULTS: The residual extractable protein levels in 30 medical gloves all conformed to United States Food and Drug Administration regulations. All the gloves except one yielded strong skin prick reactions in latex-allergic individuals. The only brand of gloves that consistently produced no skin prick reactions in latex-allergic individuals contained the lowest residual levels of Hev b 1 (0.60 microg/g) and hevamine (0.07 microg/g). CONCLUSIONS: Our results suggest that the measurement of residual extractable total proteins is not sufficient to assess the allergenicity of latex gloves and that Hev b 1 and hevamine may be used as indicator allergens in areas where they are major latex allergens, such as Taiwan.

Topiramate in prevention of cluster headache in the Taiwanese.

Topiramate could potentially effective as prophylaxis for cluster headache, but the experience remains limited in Asians. We performed an open-label clinical study to evaluate the efficacy of topiramate in the tolerable dosage to prevent cluster headache. We studied patients who fulfilled the criteria of episodic or chronic cluster headaches (International Classification of Headache Disorders second edition) prospectively. Headache severity was assessed using a verbal rating scale (excruciating, severe, moderate, mild, and no headache). Treatment was started with a topiramate dose of 50 mg twice daily and was increased by 50-100 mg a day every 3 to 7 days as tolerated to a maximal daily dosage of 400 mg. Of the 12 patients with episodic cluster headache, nine patients had remission of headache at a mean daily dosage of 273 mg (range 100-400 mg), and the patient with chronic cluster headache had remission at a daily dosage of 400 mg. The adverse effects included: paresthesia (84%), slow speech (54%), and dizziness (46%), but were tolerated by most patients. Two patients discontinued topiramate due to adverse events and one due to lack of efficacy. This open-label study suggests that topiramate is effective in the treatment of cluster headache in Taiwanese patients.

Single crystalline film on glass for thin film solar cells.

A simple Ge-on-glass metal-oxide-semiconductor solar cell has been demonstrated by wafer bonding and smart-cut. Since single crystalline Ge is directly bonded on glass, the crystalline substrate is not necessary. The metal-oxide-semiconductor structure can be easily fabricated without n and p dopant diffusion or implantation. The reason for low efficiency is discussed, and then the optimized structures are designed by simulation. An outstanding enhancement on efficiency can be achieved with the Si/Ge/Si structure. The best performance can be achieved by optimization of the position of the Ge layer, the thickness of the Ge layer, and the number of the Ge layers. The efficiency of the thin film Si/Ge/Si solar cell with single layer of 30-nm-thick Ge outside the depletion region reaches 15.9%, as compared to the control Si sample of 11.8%. Based on the simulation and technologies, high efficiency thin film solar cells can be demonstrated in the future.

Identification of immunoglobulin E (IgE)-binding epitopes and recombinant IgE reactivities of a latex cross-reacting Indian jujube Ziz m 1 allergen.

Ziz m 1 is a major Indian jujube (Zizyphus mauritiana) allergen involved in latex-fruit syndrome, and cDNA of the allergen has been cloned, sequenced and expressed in yeast by our laboratory previously. In this study, we performed an immunoglobulin E (IgE)-binding epitope analysis of Ziz m 1 using overlapping recombinant fragments. Eight overlapping recombinant fragments were generated from the recombinant Ziz m 1 allergen. The fragments were expressed in Escherichia coli and IgE-binding activities were evaluated by sera of latex-Indian jujube-allergic subjects and normal subjects using immunoblotting. Human allergic sera are not able to recognize fragments consisting of amino acid sequences 26-71, 119-280 and 119-291. However, residues at positions 26-199, 26-105, 26-86, 119-320 and 238-330 were found relevant in the IgE-binding. Our results indicate that (72)NISGHCSDCTFLGEE(86) and (292)VWNRYYDLKTNYSSSIILEYVNSGTKYLP(320) of Ziz m 1 are the sequences required for human IgE binding. Four corresponding peptides, (72)NISGHCSDCTE(86), (292)VWNRYYDLKT(301), (300)KTNYSSSIILEY(311) and (309)LEYVNSGTKYLP(320), were synthesized, and these peptides reacted with 70%, 100%, 70% and 70% of 10 allergic sera tested, as revealed by enzyme-linked immunosorbent assay. Sensitization to (292)VWNRYYDLKT(301) correlated significantly with the presence of allergic symptoms (P < 0.001). These findings will be useful in designing diagnostic and therapeutic approaches, thereby contributing to the development of specific immunotherapy for subjects with latex-fruit syndrome.

Rheumatological manifestations in patients with melioidosis.

Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, has a wide range of clinical manifestations. Here, we describe rheumatological melioidosis (involving one or more of joint, bone or muscle), and compare features and outcome with patients without rheumatological involvement. A retrospective study of patients with culture-confirmed melioidosis admitted to Sappasithiprasong Hospital, Ubon Ratchathani during 2002 and 2005 identified 679 patients with melioidosis, of whom 98 (14.4%) had rheumatological melioidosis involving joint (n=52), bone (n = 5), or muscle (n = 12), or a combination of these (n=29). Females were over-represented in the rheumatological group, and diabetes and thalassemia were independent risk factors for rheumatological involvement (OR; 2.49 and 9.56, respectively). Patients with rheumatological involvement had a more chronic course, as reflected by a longer fever clearance time (13 vs 7 days, p = 0.06) and hospitalization (22 vs 14 days, p < 0.001), but lower mortality (28% vs 44%, p = 0.005). Patients with signs and symptoms of septic arthritis for longer than 2 weeks were more likely to have extensive infection of adjacent bone and muscle, particularly in diabetic patients. Surgical intervention was associated with a survival benefit, bur not a shortening of the course of infection.

Thermophilic composting of food waste.

A laboratory reactor was designed to study the effects of operating parameters (air suction rate, seeding and agitation) on the composting process of a synthetic food waste made of dog food. Experimental results showed that the synthetic food waste could be composted within 4 days and the final compost passed the maturity tests. In most cases except those with 32% of seeding, the process involved two major stages of composting. The two peak temperatures between 50 and 60 degrees C occurred at 8-12th hour and 50-65th hour, respectively. Operating parameters that converted the most volatile solids and carbons in the feedstock were as follows: 1.6 l air/kg dry solid-min of air suction rate, 32% of seeding and 50% of agitation time.

Characterization of factor-independent variants derived from TF-1 hematopoietic progenitor cells: the role of the Raf/MAP kinase pathway in the anti-apoptotic effect of GM-CSF.

Human hematopoietic progenitor cells (TF-1) undergo apoptosis upon deprivation of their dependent cytokine. In this report, we have isolated and characterized some spontaneously derived cytokine-independent variants from TF-1 cells. Analysis of several signaling molecules known to be activated by the GM-CSF pathway revealed that two non-autocrine variants were still responsive to GM-CSF stimulation. However, both variants, without ligand stimulation, already had some activated forms of Raf and MAP kinases. Given current knowledge, the activated Raf/MAP kinase pathway was likely to be responsible for the survival of both variants in the cytokine-free medium. However, the growth of hybrids between wild type and either variant was unexpectedly dependent on GM-CSF. Both variants like the wild type cells were still susceptible to apoptosis induced by other stimuli. These results suggest that either the activated Raf/MAP kinase pathway in both variants is not sufficient to repress the 'two-fold' death signals generated from the hybrids or that there is another mechanism that is responsible for the factor-independent growth of both variants.

Mathematical model for carbon dioxide evolution from the thermophilic composting of synthetic food wastes made of dog food.

The impacts of the aeration and the agitation on the composting process of synthetic food wastes made of dog food were studied in a laboratory-scale reactor. Two major peaks of CO(2) evolution rate were observed. Each peak represented an independent stage of composting associated with the activities of thermophilic bacteria. CO(2) evolutions known to correlate well with microbial activities and reactor temperatures were fitted successfully to a modified Gompertz equation, which incorporated three biokinetic parameters, namely, CO(2) evolution potential, specific CO(2) evolution rate, and lag phase time. No parameters that describe the impact of operating variables are involved. The model is only valid for the specified experimental conditions and may look different with others. The effects of operating parameters such as aeration and agitation were studied statistically with multivariate regression technique. Contour plots were constructed using regression equations for the examination of the dependence of CO(2) evolution potentials on aeration and agitation. In the first stage, a maximum CO(2) evolution potential was found when the aeration rate and the agitation parameter were set at 1.75 l/kg solids-min and 0.35, respectively. In the second stage, a maximum existed when the aeration rate and the agitation parameter were set at 1.8 l/kg solids-min and 0.5, respectively. The methods presented here can also be applied for the optimization of large-scale composting facilities that are operated differently and take longer time.

Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese.

Cytochrome P450 (CYP) 2C9 catalyses the metabolism of a wide range of drugs. Previous studies have shown the differences in the amino acid composition among CYP2C9 variants at Cys144/Arg, Tyr358/Cys, Leu359/Ile, and Gly417/Asp. PCR-endonuclease digestion methods have been developed to detect these four possible polymorphisms. The T416-->C mutation in exon 3 of CYP2C9 (Cys144-->Arg) creates an Ava II site. In the 135 subjects we tested, all leukocyte DNA samples showed a complete Ava II digestion indicating homozygous C416 (Arg144). A Tyr358-->Cys mutation will create a Nsi I site at codon 1057-1063 in exon 7. In 40 subjects tested, all samples showed negative results. DNA sequencing on a few samples showed Tyr358Ile359. A mismatched PCR primer pair was then designed to detect codon C1061-->A (Leu359-->Ile) mutation. In 115 subjects tested, 111 samples showed a complete Nsi I digestion (Ile359) and four samples showed heterozygous results. Another mismatched PCR primer pair was used to confirm the C1061 codon in heterozygous subjects. The four heterozygous subjects showed partial digestion with endonuclease Kpn I, which confirmed the heterozygous Ile/Leu at amino acid 359. The G1236-->A mutation in exon 8 of CYP2C9 (Gly417-->Asp) creates a Hph I site. In all 46 subjects, homozygous G1236 (Gly417) was found. Most Chinese subjects actually have Arg144 Tyr358 Ile359 Gly417 in CYP2C9 as previously reported human-2. Furthermore, we found an A-->T (+12 position in intron 2) mutation in our CYP2C9 sequencing process. The mutation creates a NIa III site.(ABSTRACT TRUNCATED AT 250 WORDS)

Working memory of school-aged children with a history of febrile convulsions: a population study.

OBJECTIVE: A prospective, population-based, case-control study was performed to ascertain whether febrile convulsion (FC) in early childhood is associated with specific working memory characteristics in school age. METHODS: From a population survey of 4,340 live-birth newborns in Tainan City, Taiwan, 103 children with confirmed FC by age 3 years were followed-up until they were at least 6 years old. Three analogous searching tasks dissociating the mnemonic and executive aspects of performances were administered to 87 of these school-aged children and to 87 randomly selected age-matched control subjects to assess the learning, spatial, and sequential working memory. RESULTS: The FC group performed significantly and consistently better than control subjects on all but one working memory measure, jumping errors. Multivariate analysis using linear regression revealed that the onset of FC before age 1 year was the only significant risk factor for deficits in mnemonic function. Prior neurodevelopmental delay was the only significant risk factor for deficits in executive function. Factors such as socioeconomic status, family predisposition for seizures, complex FC, recurrent FC, and subsequent unprovoked seizures were not risk factors for working memory deficits. CONCLUSION: The authors found that school-aged children with a history of FC demonstrated significantly better mnemonic capacity, more flexible mental processing, and higher impulsivity than their age-matched control subjects. The underlying mechanism for the facilitated working memory function in children with a history of FC needs further delineation.

Lamotrigine inhibits tetraethylammonium-induced synaptic plasticity in the rat amygdala.

Although long-term potentiation was generally initiated by a brief tetanus, in the hippocampus, it could also be evoked by application of the K+ channel blocker tetraethylammonium. The present study was aimed at investigating the effect of lamotrigine, a new anticonvulsant, on the tetraethylammonium-induced potentiation in brain slices of the rat amygdala using intracellular recording techniques. Bath application of tetraethylammonium (20 mM) for 10 min resulted in a long-lasting enhancement of the amplitude of excitatory postsynaptic potentials to 235 +/- 12% of control (n = 6, P < 0.001). Pretreatment of the slices with nifedipine (10 microM) abolished the potentiation, suggesting that tetraethylammonium long-term potentiation in the amygdala is due to Ca2+ influx through voltage-dependent Ca2+ channels. By contrast, N-methyl-D-aspartate receptor activation was not required because D-2-amino-5-phosphonovalerate (50 microM) did not prevent the tetraehylammonium long-term potentiation. Superfusion of lamotrigine (50 microM) depressed the excitatory postsynaptic potential to 53.8 +/- 3.9% of control. Tetraethylammonium was subsequently added in the presence of lamotrigine but failed to enhance the excitatory postsynaptic potential. Bursts of Ca2+ spikes evoked by a depolarizing pulse or by synaptic stimulation under tetraethylammonium were depressed by lamotrigine. It is concluded that lamotrigine is capable of inhibiting tetraethylammonium-induced synaptic plasticity. The underlying mechanism is likely due to lamotrigine's inhibition of postsynaptic voltage-dependent Ca2+ channels. Considering that tetraethylammonium is a convulsant agent and brief seizure episodes induced long-term potentiation, fibre sprouting and the development of aberrant synaptic contacts, lamotrigine could be a potential neuroprotective agent, especially in pathological situations where excessive glutamate release occurs.

The TNF2 allele does not contribute towards susceptibility to systemic lupus erythematosus.

The uncommon allele (TNF2) of a polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene has been reported to be increased in Caucasian systemic lupus erythematosus (SLE) patients (associated with HLA-DR3). To investigate whether TNF2 contributes towards susceptibility to Chinese SLE patients (not associated with HLA-DR3), 100 patients with SLE and 107 controls were studied. The frequency of TNF2 allele in controls was 0.140. There was a strong association between TNF2 allele and HLA-DR3 (P < 10(-8)) in controls. The frequency of TNF2 allele in SLE patients was 0.15. There was no difference in frequencies of TNF2 allele between patients and controls. This finding strongly suggests that TNF2 does not play a direct role in the susceptibility of SLE.

Frequency-dependent inhibition of neuronal activity by topiramate in rat hippocampal slices.

1. Topiramate is a structurally novel anticonvulsant which was recently approved for adjunctive therapy in partial and secondarily generalized seizures. The present study was aimed at elucidating the mechanisms underlying the anticonvulsant efficacy of topiramate using intra- and extracellular recording techniques in the in vitro hippocampal slices. 2. When stimuli were delivered every 20 s, topiramate had no measurable effect on both field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs). However, increasing the stimulation frequency from 0.05-0.2 Hz, topiramate significantly decreased the slope of fEPSP and the amplitude of PS in a concentration-dependent manner. The amplitude of presynaptic fiber volley was also reduced. 3. Topiramate did not affect the magnitude of paired-pulse inhibition and monosynaptically evoked inhibitory postsynaptic potentials (IPSPs). 4. Sustained repetitive firing was elicited by injection of long duration (500 ms) depolarizing current pulses (500-800 pA). Superfusion with topiramate significantly reduced the number of action potentials evoked by a given current pulse. 5. After blockade of GABA receptors by bicuculline, burst firing which consisted of a train of several spikes riding on a large depolarizing wave termed paroxysmal depolarizing shift (PDS) was recorded. Application of topiramate reduced the duration of PDS and later spikes with less effect on the initial action potential. 6. These results suggest that frequency-dependent inhibition of neuronal activity due to blockade of Na+ channels may account largely for the anticonvulsant efficacy of topiramate.