Diagnostic utility of skin autofluorescence when patch test results are doubtful.

BACKGROUND: The standard diagnostic test for allergic contact dermatitis is the patch test, which can also be used to identify irritant contact dermatitis. Doubtful reactions (?+) can be often clinically relevant to individuals and can require additional tests. OBJECTIVES: The purpose of this study was to examine whether autofluorescence (AF) measurements in patients with doubtful reactions are helpful in diagnosing contact dermatitis. METHODS: Patients with a history of contact dermatitis were patch tested on the upper back for 48-hours of occlusion using aqueous solutions of 5% sodium lauryl sulfate. Reaction intensity was scored, and AF was measured on reactive lesions and non-lesions. Three dermatologists classified the results as positive or negative using the fluorescence photographs of patients with a doubtful reaction. RESULTS: Among doubtful reactions, the R/G% values were significantly higher in the AF- based positive group than in the negative group (P = .0086). On the other hand, the heterogeneity values of R, G, and B (HR, HG, HB) were significantly lower in the AF-based positive group (P = .0026, .0046, .0004 respectively). CONCLUSIONS: Measuring AF along with the clinical readings can help confirm doubtful patch test reactions.

Comparative analysis of the effects of CO2 fractional laser and sonophoresis on human skin penetration with 5-aminolevulinic acid.

Successful delivery of a photosensitizer into the skin is an important factor for effective photodynamic therapy (PDT). The effective method to increase drug penetration within short incubation time overcoming skin barrier have been investigated. This study was performed to analyze and compare the effectiveness of ablative fractional laser (FXL) pretreatment and/or sonophoresis for enhancing the penetration of 5-aminolevulinic acid (ALA) into human skin in vivo. Twenty-four identical 1 × 1 cm2 treatment areas were mapped on the backs of ten healthy male subjects. Each area received FXL pretreatment and/or sonophoresis with different energy settings and ALA incubation times. After treatments, porphyrin fluorescence reflecting the ALA penetration were measured. Application of ablative CO2 FXL pretreatment resulted to higher fluorescence intensities than the non-treatment group. Incubation times were positively correlated with the increments of ALA penetration. However, increasing pulse energy or combining with sonophoresis did not show additional positive effects on ALA penetration. Ablative CO2 FXL pretreatment effectively facilitated ALA penetration in human skin in vivo. Ablative CO2 FXL alone without sonophoresis setting pulse energy of 10 and 20 mJ with more than 60 min of ALA incubation time could be an ideal setting for ALA penetration.

Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn's disease: a phase II clinical trial for safety and efficacy.

PURPOSE: Injection of adipose tissue-derived stem cells (ASCs) is a novel method for the treatment of complex perianal fistulas. We aimed to evaluate the safety and efficacy of ASCs in the treatment of complex anal fistulas not associated with Crohn's disease. METHODS: A phase II clinical trial was performed comparing two different doses of ASCs (group 1: 1 × 107 cells/mL and group 2: 2 × 107 cells/mL). Eligible patients were administered an amount of ASCs proportional to the length of the fistula by injection into the submucosal layer surrounding the internal opening and inside of the fistula tract. ASCs at twice the initial concentration were administered if complete closure was not achieved within 8 weeks. The efficacy endpoint was the complete closure of fistulas 8 weeks after injection. Patients demonstrating complete closure at week 8 were subjected to follow-up for 6 months. RESULTS: Fifteen patients were injected with ASCs; thirteen completed the study. Complete closure was observed in 69.2% (9/13) of patients at 8 weeks. Three of five patients in group 1, and six of eight in group 2 displayed complete closure; no significant differences were observed between the groups. Six of nine patients who showed complete closure participated in additional follow-up; five (83.3%) showed persistent response at 6 months. No grade 3 or 4 adverse events (AEs) were observed; observed AEs were not related to ASC treatment. CONCLUSION: ASCs might be a good option for the treatment of complex perianal fistulas are not healed by conventional operative procedures.

Antifungal effect of gamma irradiation and sodium dichloroisocyanurate against Penicillium expansum on pears.

UNLABELLED: Gamma irradiation (GI) was evaluated for its in vitro and in vivo antifungal activity against Penicillium expansum on pear fruits. GI showed a complete inhibition of spore germination, germ tube elongation and mycelial of P. expansum, especially 1·8 kGy. GI affected the membrane integrity and cellular leakage of conidia in a dose-dependent manner. Furthermore, the leakage of protein and sugar from mycelia increased along with the dose. GI was evaluated at lower doses in combination with a chlorine donor, sodium dichloro-s-triazinetrione (NaDCC), to examine the inhibition of P. expansum. Interestingly, only a combined treatment with 0·2 kGy of GI and 70 ppm of NaDCC exhibited significant synergistic antifungal activity. The mechanisms by which the combined treatment decreased the blue mould decay of pear fruits could directly associated with the disruption of the cell membrane of the fungal pathogen, resulting in a loss of cytoplasmic materials from the hyphae. SIGNIFICANCE AND IMPACT OF THE STUDY: Gamma irradiation (GI) is used as an effective nonchemical approach to inactive pathogens. This study investigated the antifungal effect of gamma irradiation and its combined treatment with a chlorine donor on this fungal pathogen, both in vitro and in vivo. This study emphasized that the integration of low-dose GI and a chlorine donor, NaDCC, exhibited a significant antifungal effect, and that its mechanisms are directly associated with membrane integrity of fungal spores, promising that GI has the potential to be an antifungal approach.

Clinical features and outcomes of advanced HER2+ esophageal/GEJ cancer with brain metastasis.

BACKGROUND: Brain metastasis (BRM) is uncommon in gastroesophageal cancer. As such, clinicopathologic and molecular determinants of BRM and impact on clinical outcome remain incompletely understood. METHODS: We retrospectively analyzed clinicopathologic data from advanced esophageal/gastroesophageal junction (E/GEJ) patients at Johns Hopkins from 2003 to 2021. We investigated the association between several clinical and molecular features and the occurrence of BRM, with particular focus on human epidermal growth factor receptor 2 (HER2) overexpression. Survival outcomes and time to BRM onset were also evaluated. RESULTS: We included 515 patients with advanced E/GEJ cancer. Tumors were 78.3% esophageal primary, 82.9% adenocarcinoma, 31.0% HER2 positive. Cumulative incidence of BRM in the overall cohort and within HER2+ subgroup was 13.8% and 24.3%, respectively. HER2 overexpression was associated with increased risk of BRM [odds ratio 2.45; 95% confidence interval (CI) 1.10-5.46]. On initial presentation with BRM, 50.7% had a solitary brain lesion and 11.3% were asymptomatic. HER2+ status was associated with longer median time to onset of BRM (14.0 versus 6.3 months, P < 0.01), improved median progression free survival on first-line systemic therapy (hazard ratio 0.35, 95% CI 0.16-0.80), and improved median overall survival (hazard ratio 0.20, 95% CI 0.08-0.54) in patients with BRM. CONCLUSION: HER2 overexpression identifies a gastroesophageal cancer molecular subtype that is significantly associated with increased risk of BRM, though with later onset of BRM and improved survival likely reflecting the impact of central nervous system-penetrant HER2-directed therapy. The prevalence of asymptomatic and solitary brain lesions suggests that brain surveillance for HER2+ patients warrants prospective investigation.

Effect of Mn and P on the macroscopic texture of Ti-Nb stabilized interstitial free steels.

The effect of Mn and P on the macroscopic texture of Ti-Nb stabilized IF steels was investigated. In order to examine the evolution of microstructure and macroscopic texture during the hot-rolling, cold-rolling and annealing processes, microstructure characterization was conducted for hot-rolled, cold-rolled and annealed specimens. The initial grain size of hot-rolled specimens was a main parameter in determining the development of the macroscopic texture of the annealed specimens.

Long-term randomized controlled trial of a novel nanopowder hemostatic agent (TC-325) for control of severe arterial upper gastrointestinal bleeding in a porcine model.

BACKGROUND AND STUDY AIM: Endoscopic therapy of brisk upper gastrointestinal bleeding remains challenging. A proprietary nanopowder (TC-325) has been proven to be effective in high pressure bleeding from external wounds. The efficacy and safety of TC-325 were assessed in a survival gastrointestinal bleeding animal model. METHOD: 10 animals were randomized to treatment or sham. All animals received intravenous antibiotics, H2-blockers and heparin (activated clotting time 2 × normal). In a sterile laparotomy the gastroepiploic vessels were dissected, inserted through a 1-cm gastrotomy, and freely exposed in the gastric lumen, and the exposed vessel lacerated by needle knife. The treatment group received TC-325 by a modified delivery catheter while the sham group received no endoscopic treatment. Time to hemostasis, and mortality at 60 minutes, 24 hours, 48 hours, and 7 days were noted. Necropsy was performed in all animals. RESULTS: Spurting arterial bleeding was achieved in all animals. No control animal showed hemostasis within the first hour compared with 100 % (5 / 5) in the treatment arm (mean 13.8 minutes, P < 0.0079). Durable hemostasis was achieved with no evidence of rebleeding after 1 and 24 hours in 80 % (4 / 5) of the treated animals compared with none in the control group ( P < 0.0098). None of the control animals survived more than 6 hours. Necropsy at 1 week in treated animals revealed healed gastrotomy without foreign body granuloma or embolization to the lung or brain. CONCLUSION: TC-325 is safe and highly effective in achieving hemostasis in an anticoagulated severe arterial gastrointestinal bleeding animal model.

Non-destructive evaluation of nano-sized structure of thin film devices by using small angle neutron scattering.

Nano-sized multi-layers copper-doped SrZrO3, platinum (Pt) and silicon oxide (SiO2) on silicon substrates were prepared by dense plasma focus (DPF) device with the high purity copper anode tip and analyzed by using small angle neutron scattering (SANS) to establish a reliable method for the non-destructive evaluation of the under-layer structure. Thin film was well formed at the time-to-dip of 5 microsec with stable plasma of DPF. Several smooth intensity peaks were periodically observed when neutron beam penetrates the thin film with multi-layers perpendicularly. The platinum layer is dominant to intensity peaks, where the copper-doped SrZnO3 layer next to the platinum layer causes peak broadening. The silicon oxide layer has less effect on the SANS spectra due to its relative thick thickness. The SANS spectra shows thicknesses of platinum and copper-doped SrZnO3 layers as 53 and 25 nm, respectively, which are well agreement with microstructure observation.

Endoscopic retrograde cholangiopancreatography, but not esophagogastroduodenoscopy or colonoscopy, significantly increases portal venous pressure: direct portal pressure measurements through endoscopic ultrasound-guided cannulation.

BACKGROUND AND STUDY AIMS: Changes in portal pressure during endoscopy have not been previously evaluated. The aims of this study were to assess the effect of esophagogastroduodenoscopy (EGD), colonoscopy, and endoscopic retrograde cholangiopancreatography (ERCP) on portal vein, inferior vena cava (IVC), and systemic pressures. PATIENTS AND METHODS: Five acute experiments were performed on 50-kg pigs utilizing endoscopic ultrasound (EUS)-guided catheterization of the portal vein and IVC. Systemic, intra-abdominal, IVC, and portal vein pressures were monitored during colonoscopy, EGD, and ERCP with endoscopic sphincterotomy. After endoscopy the animals were sacrificed for necropsy. The main outcome measure was pressure change during each type of endoscopic procedure. RESULTS: There were no significant changes in heart rate or systemic pressure during all endoscopic procedures. Intra-abdominal pressure increased during colonoscopy ( P = 0.02) and ERCP ( P = 0.007). However, mean portal venous pressure was significantly elevated only after the injection of contrast into the common bile duct, reaching its peak value at the time of biliary sphincterotomy (39.0 +/- 15.2 mm Hg vs. 13.4 +/- 3.6 mm Hg at baseline, P = 0.006). Mean peak IVC pressure was also elevated during ERCP, but it did not reach statistical significance (24.0 +/- 10.7 mm Hg vs. 12.6 +/- 4.1 mm Hg at baseline, P = 0.06). CONCLUSION: EGD and colonoscopy did not cause significant changes in portal vein, IVC, or systemic pressures. ERCP with biliary sphincterotomy increased portal pressure with only limited effect on IVC and systemic pressures. These new data indicate a possible connection between ERCP with sphincterotomy and portal pressure, and may be clinically important for patients with liver disease and other causes of portal hypertension who undergo this procedure.

Severity of post-ERCP pancreatitis directly proportional to the invasiveness of endoscopic intervention: a pilot study in a canine model.

BACKGROUND AND STUDY AIMS: Pancreatitis complicates 1% - 22% of endoscopic retrograde cholangiopancreatography procedures. The study aims were to develop a reproducible animal model of post-ERCP pancreatitis (PEP), and investigate the impact of endoscopic technique on severity of PEP. PATIENTS AND METHODS: ERCP was carried out in six male hound dogs. Pancreatitis was induced by one of three escalating methods: 1) pancreatic acinarization with 20 - 30 mL of contrast; 2) acinarization + ductal balloon occlusion + sphincterotomy; 3) acinarization + intraductal synthetic bile injection + ductal balloon occlusion + sphincterotomy. Dogs 5 and 6 received a pancreatic stent. Necropsy was performed on postoperative day 5. All pancreatic specimens were graded by two blinded pathologists according to a validated scoring system. All dogs were compared with three control dogs. RESULTS: Dogs 1 - 4 developed clinical pancreatitis and hyperamylasemia (11 736 vs. 722 U/L, P = 0.02). Total injury scores were significantly elevated compared with controls (6.85 vs. 1.06, P = 0.004). There was significant increase in acinar cell necrosis (0.86 vs. 0.06, P = < 0.001), and all other categories (except fibrosis) demonstrated elevated injury scores . Dogs 5 and 6 developed clinical pancreatitis without significant hyperamylasemia; total injury scores were elevated compared with controls (4.83 vs. 1.06, P = 0.01), but lower than in Dogs 1 - 4 (4.83 vs. 6.85, P = 0.25). There was escalating severity of pancreatic injury from Dogs 1 to 4 correlating with the method of endoscopic injury used. CONCLUSION: Severity of PEP is directly proportional to invasiveness of endoscopic intervention. Pancreatic acinarization, even without balloon occlusion and sphincterotomy, can be used as a reliable animal model for future studies investigating therapy and prevention of disease.

The utility of contrast-enhanced endoscopic ultrasound in monitoring ethanol-induced pancreatic tissue ablation: a pilot study in a porcine model.

BACKGROUND AND STUDY AIMS: Pancreatic ablation is gaining popularity for the treatment of focal pancreatic lesions. The aim of our study was to evaluate local effects of intrapancreatic alcohol injection and the utility of contrast-enhanced endoscopic ultrasound (EUS) for its monitoring in a porcine model. METHODS: We performed four survival experiments on 50-kg pigs. Under linear EUS guidance, 0.5 mL of 50% ethanol plus purified carbon particle solution (GI Spot) was injected into the pancreatic body to create a focal area of pancreatic necrosis. The animals survived for 24-48 hours (pigs # 1, # 2, and # 3) and 7 days (pig # 4). EUS was then repeated with and without perflutren lipid microspheres (Definity) administration through the peripheral vein. Standard and microsphere-enhanced images of the pancreas were compared. Afterwards the animals were euthanized for necropsy. RESULTS: Alcohol injection caused focal pancreatic necrosis, which was barely seen by standard EUS as a subtle hypoechoic lesion 1 cm in diameter. Color and power Doppler EUS of this region did not reveal any blood flow. After intravenous injection of microspheres, color Doppler EUS revealed marked contrast enhancement of normal pancreatic parenchyma with a clearly delineated avascular alcohol-treated area, which on postmortem examination corresponded to the discrete necrotic area marked with carbon particles. CONCLUSIONS: EUS-guided alcohol injection consistently causes focal areas of pancreatic necrosis. Contrast-enhanced EUS with microspheres improves visualization of altered pancreatic vascular perfusion and can be used to facilitate detection of small pancreatic lesions and its follow-up post-ablation.

Preliminary pneumoperitoneum facilitates transgastric access into the peritoneal cavity for natural orifice transluminal endoscopic surgery: a pilot study in a live porcine model.

BACKGROUND AND STUDY AIMS: Safe entrance into the peritoneal cavity through the gastric wall is paramount for the successful clinical introduction of natural orifice transluminal endoscopic surgery (NOTES). The aim of the study was to develop alternative safe transgastric access to the peritoneal cavity. PATIENTS AND METHODS: We performed 11 survival experiments on 50-kg pigs. In sterile conditions, the abdominal wall was punctured with a Veress needle. The peritoneal cavity was insufflated with 2 L carbon dioxide (CO (2)). A sterile endoscope was introduced into the stomach through a sterile overtube; the gastric wall was punctured with a needle-knife; after balloon dilation of the puncture site, the endoscope was advanced into the peritoneal cavity. Peritoneoscopy with biopsies from abdominal wall, liver and omentum, was performed. The endoscope was withdrawn into the stomach. The animals were kept alive for 2 weeks and repeat endoscopy was followed by necropsy. RESULTS: The pneumoperitoneum, easily created with the Veress needle, lifted the abdominal wall and made a CO (2)-filled space between the stomach and adjacent organs, facilitating gastric wall puncture and advancement of the endoscope into the peritoneal cavity. There were no hemodynamic changes or immediate or delayed complications related to pneumoperitoneum, transgastric access, or intraperitoneal manipulations. Follow-up endoscopy and necropsy revealed no problems or complications inside the stomach or peritoneal cavity. CONCLUSIONS: Creation of a preliminary pneumoperitoneum with a Veress needle facilitates gastric wall puncture and entrance into the peritoneal cavity without injury to adjacent organs, and can improve the safety of NOTES.

Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis.

The specific role of endogenous glutathione in response to neuronal degeneration induced by trimethyltin (TMT) in the hippocampus was examined in rats. A single injection of TMT (8 mg/kg, i.p.) produced a rapid increase in the formation of hydroxyl radical and in the levels of malondialdehyde (MDA) and protein carbonyl. TMT-induced seizure activity significantly increased after this initial oxidative stress, and remained elevated for up to 2 weeks post-TMT. Although a significant loss of hippocampal Cornus Ammonis CA1, CA3 and CA4 neurons was observed at 3 weeks post-TMT, the elevation in the level of hydroxyl radicals, MDA, and protein carbonyl had returned to near-control levels at that time. In contrast, the ratio of reduced to oxidized glutathione remained significantly decreased at 3 weeks post-TMT, and the glutathione-like immunoreactivity of the pyramidal neurons was decreased. However glutathione-positive glia-like cells proliferated mainly in the CA1, CA3, and CA4 sectors and were intensely immunoreactive. Double labeling demonstrated the co-localization of glutathione-immunoreactive glia-like cells and reactive astrocytes, as indicated by immunostaining for glial fibrillary acidic protein. This suggests that astroglial cells were mobilized to synthesize glutathione in response to the TMT insult. The TMT-induced changes in glutathione-like immunoreactivity appear to be concurrent with changes in the expression levels of glutathione peroxidase and glutathione reductase. Ascorbate treatment significantly attenuated TMT-induced seizures, as well as the initial oxidative stress, impaired glutathione homeostasis, and neuronal degeneration in a dose-dependent manner. These results suggest that ascorbate is an effective neuroprotectant against TMT. The initial oxidative burden induced by TMT may be a causal factor in the generation of seizures, prolonged disturbance of endogenous glutathione homeostasis, and consequent neuronal degeneration.

Irradiation time and ablation rate of enamel in contact and non-contact irradiation with Er:YAG laser.

OBJECTIVE: The relationship between changes in ablation rate of enamel with irradiation time was investigated to find the most effective irradiation time for tooth ablation by Er:YAG laser. BACKGROUND DATA: Previous studies have shown that the Er:YAG laser has the ability to ablate tooth material effectively, but that the efficiency and effectiveness of ablation are determined by various parameters such as energy, pulse frequency, the amount of water, and irradiation time. METHODS: Contact and non-contact irradiation of the Er:YAG laser were carried out respectively for 1, 3, 5, and 7 s on the enamel surface of each specimen using a combination of a 400 mJ/pulse at 20 Hz and water flow rate of 6.75 mL/min, and quantitative measurements using a mass balance were performed to compare the resulting ablation rates. RESULTS: The ablation weight, by taking the mean of both contact and non-contact irradiation, generally increased with irradiation exposure time, but no significant increases in ablation were seen in specimens that had been exposed for > 3 s in either the contact or non-contact irradiation group. Results in the non-contact irradiation group indicated superior ablation of enamel compared to that in the contact irradiation group. CONCLUSION: Irradiation exposure of < or = 3 s per application of laser beam is recommended to ablate enamel effectively in both non-contact and contact irradiation.

Characterization of a MEN1 ortholog from Drosophila melanogaster.

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by tumors of the parathyroid, entero-pancreatic neuroendocrine and pituitary tissues and caused by inactivating mutations in the MEN1 gene. Menin, the 610-amino acid nuclear protein encoded by MEN1, binds to the transcription factor JunD and can repress JunD-induced transcription. We report here the identification of a MEN1 ortholog in Drosophila melanogaster, Menin1, that encodes a 763 amino acid protein sharing 46% identity with human menin. Additionally, 69% of the missense mutations and in-frame deletions reported in MEN1 patients appear in amino acid residues that are identical in the Drosophila and human protein, suggesting the importance of the conserved regions. Drosophila Menin1 gene transcripts use alternative polyadenylation sites resulting in 4.3 and 5-kb messages. The 4.3-kb transcript appears to be largely maternal, while the 5-kb transcript appears mainly zygotic. The binding of Drosophila menin to human JunD or Drosophila Jun could not be demonstrated by the yeast two-hybrid analysis. The identification of the MEN1 ortholog from Drosophila melanogaster will provide an opportunity to utilize Drosophila genetics to enhance our understanding of the function of human menin.

Immunocytochemical evidence that amyloid beta (1-42) impairs endogenous antioxidant systems in vivo.

Amyloid beta, the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. We have previously demonstrated that potent antioxidants idebenone and alpha-tocopherol prevent learning and memory impairment in rats which received a continuous intracerebroventricular infusion of amyloid beta, suggesting a role for oxidative stress in amyloid beta-induced learning and memory impairment. To test the hypothesis, in the present study, we investigated alterations in the immunoreactivity of endogenous antioxidant systems such as mitochondrial Mn-superoxide dismutase, glutathione, glutathione peroxidase and glutathione-S-transferase following the continuous intracerebroventricular infusion of amyloid beta for 2 weeks. The infusion of amyloid beta (1-42) resulted in a significant reduction of the immunoreactivity of these antioxidant substances in such brain areas as the hippocampus, parietal cortex, piriform cortex, substantia nigra and thalamus although the same treatment with amyloid beta (40-1) had little effect. The alterations induced by amyloid beta (1-42) were not uniform, but rather specific for each immunoreactive substance in a brain region-dependent manner. These results demonstrate a cytological effect of oxidative stress induced by amyloid beta (1-42) infusion. Furthermore, our findings may indicate a heterogeneous susceptibility to the oxidative stress produced by amyloid beta.

Selegiline potentiates the effects of EGb 761 in response to ischemic brain injury.

We evaluated whether combined treatment with selegiline, a selective MAO-B inhibitor, and EGb 761, a standard extract of Ginkgo biloba, has synergistic effects against ischemic reperfusion injury (IRI) in gerbils. Interestingly, we observed that pretreatment with EGb 761 significantly attenuated selegiline-induced hyperactivity. This finding paralleled striatal fos-related antigen immunoreactivity (FRA-IR) in mice. Four minutes of bilateral carotid artery occlusion caused substantial cell loss in the CA1 of the hippocampus 5 days post-ischemic insult. Pretreatment with EGb 761, with or without selegiline, significantly attenuated this neuronal loss. Combined treatment with EGb 761 plus selegiline was more efficacious in preventing this loss. Synaptosomal formations of protein carbonyl, lipid peroxidation (malondialdehyde (MDA) + 4-hydroxyalkenal (4-HDA)), and reactive oxygen species (ROS) in the hippocampus remained elevated 5 days post-ischemic insult. The antioxidant effects appeared to be most significant in the group treated with EGb 761 plus selegiline. This combined treatment produced more significant attenuation of IRI-induced alterations in intramitochondrial calcium accumulation, the mitochondrial transmembrane potential, and mitochondrial Mn-superoxide dismutase-like immunoreactivity (Mn-SOD-IR) than either treatment alone. Our results suggest that co-administration of EGb 761 and selegiline produces significant neuroprotective effects via suppression of oxidative stress and mitochondrial dysfunction without affecting neurological function.

Effects of dextromethorphan on the seizures induced by kainate and the calcium channel agonist BAY k-8644: comparison with the effects of dextrorphan.

BAY k-8644 (an L-type Ca(2+) channel agonist of the dihydropyridine class) is recognized as a potent convulsant agent. In this study, we used BAY k-8644 to explore the effects of dextromethorphan (DM) and its major metabolite, dextrorphan (DX), on the (pro)convulsant activity regulated by calcium channels. BAY k-8644 (2 mg/kg, s.c) potentiated seizures induced in rats by kainic acid (KA) (10 mg/kg, i.p.). DM appears more efficacious than DX in attenuation of KA-induced seizures. The anticonvulsant effect of a low dose (12.5 mg/kg, s.c.) of DM was reversed by BAY k-8644 (2 mg/kg) challenge. In contrast, BAY k-8644 (1 or 2 mg/kg) did not significantly affect an anticonvulsant effect from a higher dose (25 mg/kg) of either DM or DX. Intracerebroventricular injection of BAY k-8644 (37.5 microg) significantly induced seizures in mice. DM (12.5 or 25 mg/kg) pretreatment more significantly attenuated seizures evoked by BAY k-8644 than did DX (12.5 or 25 mg/kg). Furthermore, seizure activity induced by KA or BAY k-8644 was consistent with respective activator protein-1 DNA binding activity of the hippocampus. Therefore, our results suggest that the anticonvulsant effects of the morphinans involve, at least in part, the L-type calcium channel. They also suggest that DM is a more potent anticonvulsant than DX in the KA and BAY k-8644 seizure models.