Novel and reappraised wide-band EEG findings in migraineurs: Its correlation with several clinical variables.

OBJECTIVE: Cortical spreading depolarization is one possible pathogenesis of migraine, of which slow neurophysiological change is barely recorded in conventional EEG settings. Using wide-band EEG conditions, we reappraised the features of EEG in migraineurs, including subdelta-band EEG changes. METHODS: This retrospective study included 144 patients with migraine. We delineated EEG of focal delta slow (FDS) (1-4 Hz) by time constant (TC) 0.3 s and focal subdelta slow (FSDS) (< 1 Hz) by TC 2 s. Relationships between clinical variables and EEG findings were evaluated. RESULTS: Of 144 patients, 39 had aura and 105 did not. FSDS and FDS were observed in 38 and 58 patients, respectively. No EEG was recorded during the aura. In multivariate analysis with the phase of migraine, family history, age, and percentage of sleep during EEG recording, the phase of migraine was related to the occurrence of FSDS (postdrome vs interictal, prodrome, and headache respectively (OR = 49.00 [95% CI = 3.89-616.66], 46.28 [2.99-715.78], 32.79 [2.23-481.96], p = 0.0026, 0.0061, 0.011). FDS was clinically unremarkable for differential evaluation. CONCLUSIONS: Wide-band EEG abnormality in migraineurs, i.e., FSDS, can be affected by migraine phase. SIGNIFICANCE: Wide-band EEG finding could be a biomarker related to clinical variables in migraines.

[A case of Alice in Wonderland syndrome after Epstein-Barr virus (EBV) encephalitis: a mimicry of focal epileptic seizure].

A 30-year-old man who received infliximab for treatment of Crohn's disease developed Epstein-Barr virus (EBV) encephalitis, which responded well to therapy; however, he had left lower visual field loss following treatment. The patient noticed peculiar symptoms 9 months after recovery from encephalitis; objects in his view appeared smaller or larger than their actual size (micropsia/macropsia). Moreover, it appeared that objects outside moved faster or slower than their actual speed of movements and moving objects appeared as a series of many consecutive snap shots. His vision was blurred, and he had visual difficulties and a sensation that his body was floating. These symptoms mainly appeared following fatigue and persisted over approximately 10 years. Based on cerebrospinal fluid analysis, brain MRI, N-isopropyl-p-123I-iodoamphetamine with single photon emission computed tomography, fluorodeoxyglucose positron emission tomography, and electroencephalography, we excluded both recurrent encephalitis and focal epileptic seizures. By taking all symptoms and other evaluation findings into account, the patient most likely suffered from "Alice in Wonderland syndrome" which is primarily associated with cortical dysfunction in the right temporo-parieto-occipital area as the consequence of previous acute EBV encephalitis.

[Migraine with multiple visual symptoms and out-of-body experience may mimic epilepsy].

The patient was an 18-year-old man who had suffered from various visual symptoms as follows since he was 17 years old: 1) a diagonal line appeared in his visual field, shifting his upper field of view to the right and his lower field of view to the left; 2) his whole vision seemed distorted with ripples; and 3) black spots covered parts of his visual field and moved up and down. These visual symptoms were followed by out-of-body experience (OBE), which he felt as seeing his own body apart from his left back. Headache attacks followed these symptoms. On brain MRI, bilateral occipital atrophy was suspected. An electroencephalogram showed intermittent irregular delta in the bilateral occipital area. No epileptiform discharges were observed. We finally diagnosed him as having migraine with multiple visual auras and OBE. He was very well treated with a small dose of valproic acid which he tolerated well. OBE rarely occurs in migraine and should be distinguished from epilepsy.

[A Case of Cowden Syndrome Associated with Lhermitte-Duclos Disease].

A 24-year-old woman slowly developed mild unsteadiness of gait. Neurological examination revealed mild dysmetria of the left upper and lower limbs. Standing and gait were unsteady, and tandem gait was impossible. Cranial magnetic resonance imaging (MRI) showed an enlarged left cerebellar hemisphere with striated lines, a characteristic finding of Lhermitte-Duclos disease. She also had papules on the forehead, goiter, lactating adenoma, glycogenic acanthosis in the esophagus, café-au-lait spot, and hemangioma and keratosis on the dorsum of foot. The diagnosis of Cowden syndrome was established by finding the mutation in the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene. Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas in a variety of tissues. Recognition of Lhermitte-Duclos disease as a neurological condition of Cowden syndrome is important, and once the diagnosis of Lhermitte-Duclos disease is made, a close physical investigation is necessary because the hamartomas tend to develop malignancies. (Received March 15, 2017; Accepted July 24, 2017; Published December 1, 2017).

Enhancing effects of a high fat diet on 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline-induced lung tumorigenesis in female A/J mice.

Both heterocyclic amines and a high fat diet are associated with an increased risk of cancer in many organs. Female A/J mice were fed a diet supplemented with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and a high fat diet to test for the development of lung tumors. In experiment 1, the mice were divided into 6 groups. Groups 1, 2, 3 and 4 were fed a diet supplemented with MeIQx at a concentration of 600?ppm for 0-12 weeks. A high fat diet containing 20% corn oil was given to Groups 1 and 5 for 0-32 weeks, Group?2 for 12-32 weeks and Group 3 for 0-12 weeks. Group 6 was fed a basal diet without supplements. MeIQx-treated groups (Groups?1, 2, 3 and 4) showed a significant increase in macroscopic and microscopic lung nodules compared with the control (Group 6). Areas of adenomas were increased dependent on the duration of exposure to the high fat diet. In experiment 2, Group 1 mice were fed MeIQx and a high fat diet, Group?2 a MeIQx alone diet, Group 3 a high fat alone diet, and Group?4 a basal diet without supplements. CYP1A2 mRNA in the liver was significantly decreased by a high fat diet (Group?3). The MeIQx alone group (Group 2) showed a tendency towards increased CYP1A2 expression, which was partially reduced in the MeIQx + high fat-treated group (Group 1). In the lungs, CYP1A2 mRNA expression was at an extremely low level, with no intergroup differences. In conclusion, MeIQx exerts tumorigenic potential in the lungs, and a high fat diet increases the size of induced lesions. The expression level of CYP1A2 in relation to MeIQx and a high fat diet may be associated with lung carcinogenesis.

Establishment of a bioassay model for lung cancer chemoprevention initiated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice.

AIMS: In order to prevent lung cancer development in people at high risk, identification of chemopreventive agents may be important. The present study was conducted to establish a bioassay model for this purpose. In particular, the time course of 4-(methylnitrosamno)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor development was examined to determine the most appropriate shortest period to assess effects of test agents, with 8-methoxypsoralen (8-MOP) as a typical example. METHODS: A total of 124 mice were separated into two groups (Group A: 60 mice, Group B: 64 mice), pretreated with 100ppm 8-MOP (Group A) or basal diet (Group B) for 3 days before receiving single doses of NNK (2mg/0.1ml saline/mouse i.p.) on days 0 and 7. Subgroups of 15 mice of each group were then sacrificed after 8, 10, 12, and 16 weeks. RESULTS: Microscopically, the earliest time point when significant differences in data for hyperplasia, adenoma and hyperplasia and adenoma could be detected was 12 weeks. A trend was noted for 8-MOP to reduce adenomas to a greater extent than hyperplasia. DISCUSSION: In conclusion, the results of this study showed that the double i.p. treatment with NNK and 12 weeks duration are effective for detection of lung cancer chemoprevention in our A/J mouse lung tumorigenesis model.

Potential inhibitory effects of D-allose, a rare sugar, on liver preneoplastic lesion development in F344 rat medium-term bioassay.

D-allose, the C-3 epimer of d-glucose, is a monosaccharide present in minute quantities in nature and a rare sugar. The effects of D-allose on diethyl nitrosamine (DEN)-induced hepatocarcinogenesis were examined in male F344 rats by a rat medium-term bioassay based on the two-step model of hepatocarcinogenesis (experiment 1). In addition, a DNA microarray analysis was employed to clarify possible mechanisms of action of D-allose (experiment 2). The antioxidation potential of D-allose solution itself or of serum in rats treated with D-allose was also examined directly by measuring Cu(+)-reducing antioxidation power (experiment 3). Furthermore, to investigate the effects of D-allose in vivo under conditions of oxidative stress, it was administered with a choline-deficient, L-amino acid-defined diet (CDAA) in the medium-term liver carcinogenesis bioassay (experiment 4). Experiment 1 demonstrated no effects of D-allose on the development of glutathione S-transferase placental form (GST-P) positive foci in the liver. From DNA microarray analysis, several mRNA markers were found to be altered with functions related to apoptosis and cell proliferation (experiment 2), although D-allose itself and serum in vivo exhibited no antioxidation power directly (experiment 3). When D-allose was administered with the CDAA diet, decreases in the area and number of GST-P positive foci were noted with P values of 0.158 for area (%) and 0.061 for number (/cm(2)) (experiment 4). These results suggest the potential inhibitory effect of D-allose on liver carcinogenesis, particularly under oxidative stress conditions.

Lung toxicity of 16 fine particles on intratracheal instillation in a bioassay model using f344 male rats.

We have developed a bioassay model to estimate toxicity of fine particles in the lungs at an early stage after intratracheal instillation (Yokohira et al. 2005; Yokohira et al. 2007). The present experiment was conducted to improve the model by estimating appropriate doses based on dose-dependent toxicity of instilled quartz (4 mg to 0 mg) as a positive control and assessing the impact of powdered particles without suspension (Experiment 1). In addition, examination of the toxicity of a series of particles was performed with the developed bioassay (Experiments 2A, 2B, and 2C). The materials chosen were sixteen particles, including nanoparticles and diesel powder. Histopathological and immunohistochemical analysis of bromodeoxyuridine (BrdU) incorporation and inducible nitric oxide synthase (iNOS) were performed after exposure of the lungs. A dose of 2 mg quartz suspended in 0.2 mL saline was suggested to be most appropriate for sensitive detection of acute and subchronic inflammatory changes. Although some materials, including nanoparticles, demonstrated toxicity that was too strong for sensitive assessment, the ranking order could be given as follows: CuO > quartz > neutralized Na2PdCl4 > NiO > hydrotalcite > MnO2 > diesel > titanium dioxide (in Experiment 2B) > beta-cyclodextrin > diesel standard > titanium dioxide (in Experiment 2A) > CaCO3.

A 90-day toxicity study of L-asparagine, a food additive, in F344 rats.

L-asparagine is an amino acid listed as an existing food additive in Japan. The present 90-day toxicity study in F344/DuCrlCrj rats was conducted for safety assessment and to determine a no observed adverse effect level (NOAEL) of L-asparagine. Groups of 10 males and 10 females were given the material at dose levels of 0%, 1.25%, 2.5% or 5% in diet for 90 days. During the experiment, there were no remarkable changes in general conditions and no deaths occurred in any group. Final body weights of male 5% and 1.25% groups were significantly decreased. There were also significant increases in relative organ weights of the brain, kidney and testis in 5% males. On serological examination, GLU, PL, K and ALT were increased significantly in 5% females, and GLU was increased significantly and CRN was decreased significantly in the female 1.25% group. However, histopathological examination did not reveal any significant variation in development of lesions among the groups. Changes in body and organ weights, as well as other parameters, were concluded to be due to treatment with 5% L-asparagine. The NOAEL was determined to be 2.5% in the diet (males, 1.65 g/kg body weight/day; females, 1.73 g/kg body weight/day).

Induction of multiple granulomas in the liver with severe hepatocyte damage by montan wax, a natural food additive, in a 90-day toxicity study in F344 rats.

Montan wax is a mineral wax extracted from lignite type coal. It has been registered as a food additive in Japan though there have been no reports of toxicological evaluation, mainly due to the fact that it is considered a natural product. As part of a general safety assessment of montan wax, we have performed a 90-day toxicity study in Fisher 344 (F344) rats. Groups of 10 males and 10 females were given the material at dose levels of 0 (Group 1), 0.56 (Group 2), 1.67 (Group 3), or 5% (Group 4) in the diet for 90 days. During the experiment, there were no remarkable changes in general conditions and no deaths occurred in any group. On hematological examination, Hb, Ht, MCV and MCH were significantly decreased and WBC was significantly increased in all treated rats. On serum biochemical examination, AST and ALT were found to be elevated more than four fold in all treated groups as compared to the respective control group values in both sexes. Furthermore, relative organ weights for the liver, spleen, lung and kidneys were increased in all treated groups of both sexes. Histopathological examination revealed diffuse multiple granulomas in the livers with severe hepatocyte damage and lymphocytic infiltration. Granulomatous lesions were also apparent in the mesenteric lymph nodes in all treated males and females. These findings clearly demonstrate that montan wax, at doses of more than 0.56% in the diet, induces multiple granulomas with severe inflammation in the liver. Because pathological, hematological and serum biochemical changes were observed in the lowest dose group, a no-observed-adverse-effect level (NOAEL) could not be determined in the present study.

One-year chronic toxicity study of Aloe arborescens Miller var. natalensis Berger in Wistar Hannover rats. A pilot study.

This study was conducted to evaluate the chronic toxicity of Aloe arborescens Miller var. natalensis Berger (ALOE) in the diet at doses of 4.0%, 0.8% or 0.16% to groups of male and female Wistar Hannover rats. No deaths occurred at any dose level throughout the treatment period. Both sexes receiving 4.0% showed diarrhea, with a reduced body weight gain. Increase of WBCs in the male 4.0% group, decrease of Hb in the female 4.0% and 0.8% groups, decrease of IP in the male 4.0% and 0.8% groups and female 4.0% group, and decrease of Ca and ALT in the female 4.0% group were observed. Relative kidney weight showed increase in the female 4.0% group and relative heart and brain weights were decreased in the female 4.0% and 0.8% groups. Histopathologically, both sexes receiving 4.0% showed severe sinus dilatation of ileocecal lymph nodes, and yellowish pigmentation of ileocecal lymph nodes and renal tubules. In conclusion, the no observed adverse effect level (NOAEL) for ALOE was the 0.16% in diet, which is equivalent to 87.7 and 109.7 mg/kg/day in males and females, respectively.

CYP2A6 overexpression in human lung cancers correlates with a high malignant status.

CYP2A6 is a major phase I enzyme metabolizing tobacco-specific nitrosamines, implicated as risk factors for lung cancer. In this study, immunohistochemistry and in situ hybridization (ISH) for CYP2A6 with human lung cancer tissues (n=31) obtained by surgical resection showed significantly higher immunoreactivity in the cases with lymph node metastasis. The adenocarcinoma cases (n=23) with lymph node metastasis or large tumor size showed a high immunoreactivity for CYP2A6. The squamous cell carcinoma cases (n=6) with large tumor size showed a tendency for low CYP2A6 immunoreactivity. ISH for CYP2A6 revealed mRNA expression in both adenocarcinoma and squamous cell carcinoma cells. The data suggest that CYP2A6 could have an important role in the development and proliferation of lung carcinomas. With adenocarcinomas, CYP2A6 could be a target candidate for therapeutic and chemopreventive intervention.

Bioassay by intratracheal instillation for detection of lung toxicity due to fine particles in F344 male rats.

We have established and documented an in vivo bioassay for detection of hazards with intratracheally instilled fine particles, which can be used for risk assessment of toxicity of materials inhaled into deep lung tissue of humans (Yokohira et al. Establishment of a bioassay system for detection of lung toxicity due to fine particle instillation: sequential histopathological changes with acute and subacute lung damage due to intratracheal instillation of quartz in F344 male rats. J Toxicol Pathol 2005;18:13-8). For validation we here examined toxicity of fine particles from quartz, hydrotalcite, potassium octatitanate, palladium oxide and carbon black with this bioassay. A total of 108, 10-week-old F344/DuCrj male rats were randomly divided into 8 groups. Groups 1 to 5 underwent intratracheal instillation of the 5 test particles (4 mg/rat) suspended in 0.2 ml vehicle (saline or 10% propylene glycol and 1% sodium carboxymethyl cellulose in saline: PG-CMC) with a specially designed aerolizer, and subgroups of 7 rats were killed on Days 1 and 28 thereafter. Groups 6 and 7 similarly were exposed to saline and PG-CMC, respectively, as vehicle controls, while group 8 was maintained untreated. Using histopathological changes and immunohistochemically assessed bromodeoxyuridine (BrdU) labeling indices, inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-3 (MMP-3) levels as end points, the quartz treated group exhibited high toxicity, while the values for the other particle-treated groups pointed to only slight effects. Although additional efforts are needed to establish advantages and disadvantages with our bioassay, models featuring intratracheal instillation clearly can be useful for detection of acute or subacute lung toxicity due to inhaled fine particles by using histopathological scoring and markers like BrdU and iNOS for screening purposes in short-term studies.

Post-initiation chemopreventive effects of dietary bovine lactoferrin on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in female A/J mice.

We investigated the effects of bovine LF (bLF) on different phases of NNK-induced lung tumorigenesis in A/J mice. Mice were orally administered 0.02, 0.2 and 2% bLF during the initiation phase, and 2% bLF during the whole tumorigenesis phase or post-initiation phase. Administered bLF during the post-initiation phase showed significant reduction of macroscopical lung nodules, and immunohistochemically decreased expression levels of cell proliferation marker and increased expression levels of apoptosis marker in lung proliferative lesions. bLF might inhibit NNK-induced mouse lung tumorigenesis, only when given limited to the post-initiation phase, through modification of cell proliferation and/or apoptosis.

Epithelioid malignant peripheral nerve sheath tumor. Report of a case with inflammatory infiltration.

The epithelioid malignant peripheral nerve sheath tumor (EMPNST) is a rare sarcoma originating from the supportive non-neuronal components of peripheral nerves. Our patient was a 75-year-old Japanese man who presented with complaints about pain and a mass in the left thigh. Characteristic histopathological features were large epithelioid-like cells closely resembling a malignant melanoma or another type of soft tissue tumor. Notable infiltration of neutrophils in the tumor was seen. Immunohistochemically, the tumor cells proved positive for S-100, NSE, GFAP, MBP, chromogranin A and synaptophysin, and negative for CEA, keratin, HMB-45, G-CSF, and GM-CSF. Tumor-related inflammatory infiltration may be caused by an autonomous production of some cytokines. However, these tumor cells were negative for G-CSF and GM-CSF so that the mechanism triggering inflammatory infiltration is unclear. Electron microscopy revealed the presence of an extracellular basal lamina, intermediate cell junctions, and numerous dense-cored granules in the cytoplasm. These findings suggested a schwannian derivation, consistent with the diagnosis of EMPNST. There have been reports on S-100 positivity and HMB-45 negativity of this tumor type, but to the best of our knowledge, this is the first description of an EMPNST positive for MBP, chromogranin A, and synaptophisin. Where unequivocal features are lacking, these markers might be useful for differential diagnosis.

Lack of significant modifying effect of arctiin on prostate carcinogenesis in probasin/SV40 T antigen transgenic rats.

Arctiin, a plant lignan that can be extracted from the Arctium lappa (burdock) seeds, is a possible environmental endocrine disruptor compounds and have been shown to influence sex hormone metabolism as well as protein synthesis, steroid biosynthesis. Modifying effects of arctiin on prostate carcinogenesis in probasin/SV 40 T antigen (Tag) transgenic (TG) rats were examined. A total of 64 male TG rats, 6 weeks old, were randomly divided to three experimental groups (soybean free Oriental MF diet with 0.1, 0.02, or 0.004% arctiin) and a control group (soybean free Oriental MF diet). Animals were killed at the end of week 18. Histopathological evaluation of prostate revealed that all the rats in any group developed adenocarcinoma in dorsolateral lobe of prostate, except two rats in 0.1% arctiin treated and one rat in 0.002% arctiin treated groups without prostate adenocarcinoma development. However, there were no definite treatment-related changes with statistical significance in all parameters for prostate carcinomas measured in this experiment. These results indicated that arctiin might not exert significant modifying effect on prostate carcinogenesis in SV 40 Tag TG rats at least under the present experiment.