Aniracetam,a Pyrrolidinone-type Cognition Enhancer,Attenuates the Hydroxyl Free Radical Formation in the Brain of Mice with Brain Ischaemia

We demonstrate here that aniracetam has the ability to block the formation of cytotoxic hydroxyl radicals (· OH) during ischaemia-reperfusion of mouse brain. The fact that brain ischaemia for 40 min followed by reperfusion increased ·OH was evidenced by detection of a peaked increase at 20 min after an ischaemic insult in the formation of 2,3-dihydroxy-benzoate (DHBA) from salicylate in cerebroventricular perfusate, a means of monitoring ·OH formation. A clearcut increase in dopamine was also observed during and after brain ischaemia. The ischaemia-reperfusion mice given aniracetam at an intraperitoneal dose of 30 or 100 mg kg^?1 showed a smaller increase in the formation of DHBA than those given the vehicle only. Aniracetam at 100 mg kg^?1 significantly suppressed the formation of DHBA by approximately 80%, becoming evident at 20 min after reperfusion and thereafter. Protection against death in mice insulted with a 40-min brain ischaemia (3/13 vs 13/25) was observed following 100 mg kg^?1 aniracetam. The increase in the dopamine levels was substantially reduced following aniracetam treatment and the reduction became significant at 20 min after reperfusion and thereafter in parallel with attenuation by aniracetam of DHBA formation. This finding suggests that the inhibitory activity of aniracetam in attenuating the hydroxyl free-radical formation in ischaemic mice is probably due, at least in part, to its palliative action on the dopaminergic neurons.     

The Acute and Chronic Toxicities of Nivalenol in Mice

The Acute and Chronic Toxicities of Nivalenol in Mice. Ryu,J.-C, Ohtsubo, K., Izumiy-ama, N., Nakamura, JL, Tanaka, T.,Yamamura, H., and Ueno, Y. (1988). Fundam. Appl Toxicol. 11,38–47. In an attempt to ascertain precisely the toxiceffects of nivalenol (N1V), we conducted the determination ofLD50 values, and interim kills during the carcinogenic studyin mice. LD50 values (mg/kg) of NIV in 6-week-old male ddY micewere determined as 38.9 (po), 7.4 (ip), 7.2 (sc), and 7.3 (iv).Seven-week-old female C57BL/6CrSlc SPF mice were fed diets containing0, 6, 12, and 30 ppm (mg/kg) NIV over 1 year, and were assessedfor effects on body weight gain, feed efficiency, terminai organweights, hematology, and histopathology. The rates of body weightgain and feed efficiency showed a good dose-dependent correlationin all experimental periods. Gross and histopathological evaluationof the liver, thymus, spleen, kidneys, stomach, adrenal glands,pituitary gland, ovaries, sternum, bone marrow, lymph node,brain, and small intestines with or without Peyer's patch portionfrom control and all NIV-exposed mice revealed that these tissueswere normal in appearance and in histopathological structure.Also, no changes were observed in the ultrastructural studieson the bone marrow. Dietary NIV did, however, cause dose-dependentdecreases of absolute organ weights (mg) and increases of relativeorgan weights (mg/g body weight) in the terminal organ weightsrecorded. A significant leukopenia was observed in the 30 ppmgroup at 6 months and in all NIV-treated groups at 1 year. Nomarked changes were observed in the other hematological parameters.These results indicated that 6 ppm or more of dietary NIV for1 year showed a characteristic toxic effect of trichothecenemycotoxins in mice.     

A Case of Pneumocytoma (So-Called Sclerosing Hemangioma) With Lymph Node Metastasis

A case of "sclerosing hemangionia" (pneumocytoma) of the lungwith lymph node metastasis is reported. A 22-year-old Japaneseman was found to have a well-defined round lesion in the rightlung (S⁷), which increased in size slightly during a 2-yearfollow-up period. He underwent right lower lobectomy with a preoperative diagnosisof a benign lung tumor. The pulmonary tumor revealed histologicalfeatures characteristic of "sclerosing hemangioma" of the lung,in addition to which there were many large polygonal foamy cells,forming tubular or papillary structures. These cells were foundby electron microscopy to contain numerous cytoplasmic lamellarbodies and showed a positive reaction with anti-surfactant apoproteinantibody immunohistochemically. Therefore, they were consideredto be cells differentiating toward type II pneumocytes. Reviewof 21 typical "sclerosing hemangionia" disclosed a few or somesuch foamy cells in 10 cases. A single hilar lymph node wasthe site of microscopic metastases, which consisted of "largeclear foamy cells" and smaller polygonal or round cells withslightly eosinophilic cytoplasm, both of which were componentsof the pulmonary "sclerosing hemangioma" This case supportsthe theory that "sclerosing hemangioma" is a neoplasm of typeII pneumocyte lineage. Although it is said to be benign, rarecases apparently show metastatic potential.     

The Role of the Biopsy in Diagnosis of Early Gastric Cancer

In order to determine the reliability of endoscopic biopsy indiagnosis of early gastric cancer, and to clarify the problemswith biopsies, preoperative endoscopic biopsies from 771 earlygastric cancer cases were reviewed and analyzed clinicopathologicallyin comparison with surgically resected specimens. The 771 cancerswere surgically resected at the National Cancer Center Hospitalduring the period from 1972 to 1982. Definite histological diagnosiswas obtained in 87.4% of the carcinomas at the initial biopsies.Repeated biopsy raised the percentage of correct definite diagnosesto 96.1%. False-negative (including suspicion of cancer) diagnosiswas most frequent in the case of depressed lesions (50 lesions).Half of the false negatives were found to be due to samplingerrors by the endoscopists. The other half of these 50 lesionswere diagnosed as "suspicious of malignancy" because of thehistological difficulty in differentiating early gastric cancerfrom regenerative atypia with intestinal metaplasia, or becausethere was not enough information, or for the other reasons.Most of the 31 false-negative diagnoses at the initial biopsyfrom elevated lesions were reported as adenoma (group III) orsuspicious of carcinoma (group IV), indicating that differentialdiagnosis between well-differentiated adenocarcinoma and adenomais very difficult. The result of the present study suggeststhat repeated biopsy from correct sites and discussion of thelesions between clinicians and pathologists are very important. ^**Present affiliation: Toranomon Hospital, Toranomon 2-2-2,Minato-ku, Tokyo 105, Japan.     

Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test (OECD): Familiarization Using Cyclophosphamide

Combined Repeat Dose and Reproductive/Developmental ToxicityScreening Test (OECD): Familiarization Using Cyclophosphamide.TANAKA, S., KAWASHIMA, K., NAITO, K., USAMI, M., NAKADATE, M.,IMAIDA, K., TAKAHASHI, M., HAYASHI, Y., KUROKAWA, Y., AND TOBE,M. (1992A, Y., AND TOBE, M. (1992). Fundam. Appl. Toxicol. 18,89–95. A familiarization study was conducted on the "Combined RepeatDose and Reproductive/Developmental Toxicity Screening Test(ReproTox)" proposed by the OECD. Cyclophosphamide (CP) at dosesof 6.7, 4.5, 3, 2, and 0 mg/kg body wt was given daily by gavageto groups of 12 male and 12 female Sprague-Dawley rats. As aresult, anemia and leukopenia were evident in treated males.The absolute and relative thymus and spleen weights were decreasedin treated rats. Histopathologically, atrophy of the thymus,spleen, and bone marrow was observed. With respect to the reproductive/developmentaltoxicity, dose-dependent increases in postimplantation lossof fetuses and postnatal death were found in dams given CP.The body weight of pups treated with CP was significantly loweredin a dose-related manner. Thus the results demonstrated mostof the known toxicological properties of CP, except the adverseeffects on spermatogenesis and fertility. Therefore ReproToxcan be considered as a useful screening test for assessing repeatdose and reproductive/developmental toxicity of existing chemicalsof high production volume.     

Aqueous fraction of Sauropus androgynus might be responsible for bronchiolitis obliterans

Background and objective: Bronchiolitis obliterans (BO) has been reported to develop following ingestion of Sauropus androgynus (SA), a leafy shrub distributed in Southeast Asia. Little is known about direct effects of SA on airway resident cells or haematopoietic cells in vitro. Identification of the SA component responsible for the development of BO would be an important key to elucidate its mechanism. We sought to elucidate the direct effects of SA on airway resident cells or haematopoietic cells and identify the SA element responsible for the pathogenesis of BO. Methods: SA dry powder was partitioned into fractions by solvent extraction. Human and murine monocytic cells, epithelial cells and endothelial cells were cultured with SA solution or fractions eluted from SA. We also investigated the effect of SA in vivo using a murine BO syndrome (BOS) model. Results: The aqueous fraction of SA induced significant increases of inflammatory cytokine and chemokine production from monocytic lineage cells. This fraction also induced significant apoptosis of endothelial cells and enhanced intraluminal obstructive fibrosis in allogeneic trachea allograft in the murine BOS model. We found individual differences in tumour necrosis factor α (TNF‐α) production from monocytes of healthy controls stimulated by this aqueous fraction of SA, whereas it induced high‐level TNF‐α production from monocytes of patients with SA‐induced BO. Conclusions: These results suggest that an aqueous fraction of SA may be responsible for the pathogenesis of BO.     

Comparison of Injection Materials for the Elevation of Gastric Mucosa Prior to Endoscopic Mucosal Resection

Endoscopic mucosal resection (EMR), namely strip biopsy, to eradicate gastric mucosal lesions requires certain special techniques, including submucosal injection of appropriate agents. This experimental study using dogs was conducted to compare, with regard to the degree of duration of mucosal elevation and subsequent histologic changes of the gastric wall, three injection materials; physiological saline, hypertonic saline with epinephrine (HSE) and 10% soybean oil. The duration of mucosal elevation which should be sufficient for the EMR procedure did not differ between the three agents. The post-injection histologic changes included vessel dilatation in the peri-muscularis mucosae, dilatation of the lymphatic channels and vessel congestion. These changes appeared in all injection material groups, and the vessel congestion was found to be more conspicuous in the HSE group. All EMRs in this series were performed by single snare cutting, which was also evaluated. The margin of the stripped material was well limited to the submucosal layer in all cases, but the depth of the ulcers formed varied. The healing process of the ulcer for the first 4 weeks was delayed in the soybean oil group. Although there were few cases of perforation in this experiment and some subjects had adhesion between the gastric serosa and adjacent organs, the single snare method could be applicable for clinical use by skilled hands.     

Effects of Nonanal,trans-2-Nonenal and 4-Hydroxy-2,3-trans-nonenal on Cyclooxygenase and 12-Lipoxygenase Metabolism of Arachidonic Acid in Rabbit Platelets

The effects of nonanal, trans-2-nonenal and 4-hydroxy-2,3-trans-nonenal on the formation of thromboxane B₂ (TXB₂), 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) from exogenous arachidonic acid in washed rabbit platelets were examined. Nonanal and trans-2-nonenal at concentrations ranging from 0.25 to 2 μm inhibited TXB₂, HHT and 12-HETE formation, reducing the amounts of these three arachidonic acid metabolites by 50% at nonanal and trans-2-nonenal concentrations of approximately 0.25 μm. The inhibition of TXB₂, HHT and 12-HETE formation induced by 4-hydroxy-2,3-trans-nonenal (50% inhibition by 4-hydroxy-2,3-trans-nonenal at a concentration of approximately 100 μm) was 400 times weaker than that induced by nonanal and trans-2-nonenal. These results suggest that nonanal and trans-2-nonenal can be modulators of platelet arachidonic acid metabolism by affecting the activity of cyclooxygenase and 12-lipoxygenase.     

The influence of physical restraint or fasting on plaque-forming cell response in mice

Abstract This study was designed to investigate the effects of 1- and 3-day (16 h/day) physically restrained or fasting on immunological and endocrine responses in CBF1 mice. The influence of stressors on these responses was evaluated using anti-sheep red blood cell plaque-forming assay, and by examining T cell subsets, thymus weight and endocrine hormone levels. The results revealed that a significant elevation of the plaque-forming cells (PFC) was found in spleen cells in 1-day restrained mice, that the PFC were conversely suppressed following 3-day physically restrained stress, and that the PFC were not affected by 1- or 3-day fasting stress. Serum levels of norepinephrine were found to be significantly increased only in 1-day physically restrained mice. No change of T cell subsets and thymus weight was found in 1-day physically restrained mice. A significant increase in serum corticosterone levels was elicited in both 1- and 3-day physically restrained mice, and 3-day fasting mice, while increased Lyt2-positive T cells and thymic atrophy were found only in 3-day physically restrained mice. These findings suggest that immune function was differentially affected by the duration and types of stressors.     

Resetting of Tachycardia Cycle by Single and Double Ventricular Extrastimuli in Recurrent Sustained Ventricular Tachycardia

In two cases with recurrent sustained ventricular tachycardia (VT) due to re-entry, the response pattern to extrastimuli during the tachycardia was studied. In each case, right ventricular extrastimuli with longer coupling intervals during VT were followed by fully compensatory pauses and with shorter coupling intervals reset the tachycardia cycle. In one case, a plateau was produced by a single extrastimulus, resembling that seen in the response curve of sinus node automaticity as well as ectopic atrial tachycardia. Two successive stimuli produced three definite zones, i.e., fully compensatory, reset producing a plateau, and progressive prolongation zones with shortening of the coupling intervals between the two stimuli, and terminated the tachycardia with further shortening of the coupling intervals. In conclusion, resetting phenomenon was confirmed on two cases with re-entrant VT. This phenomenon cannot be used as a criterion to determine the mechanism responsible for VT.