A simple method for screening assessment of acute toxicity of chemicals

We proposed a simple method for screening assessment of acute oral and dermal toxicity using only three rats and mice of each sex at each dose level. Animals were first treated with chemicals at a dose of 2000 mg/kg and were carefully observed for compound-related morbidity and mortality. If none of the animals died, the following toxicity tests were suspended. If some of the animals died, toxicity tests at doses of 200 and 20 mg/kg were performed. The approximate LD₅₀ values calculated by this method showed little difference between two separate laboratories and were in good agreement with LD₅₀ values reported in the literature. Our toxicological data also showed that LD₅₀ values were about 2–2.5 times the MNLD (maximum non lethal dose) in acute oral and dermal toxicity. This meant that a chemical could be regarded as having an LD₅₀ of about 4000 mg/kg or higher when there was no mortality at the dose of 2000 mg/kg. A chemical with such low toxicity would not require further testing for lethal effects. Therefore, this simple method combining the fixed-dose procedure with the limit test is suitable for determination of approximate LD₅₀ values of chemicals and for screening for necessity for classical full LD₅₀ test using many animals.This work was supported by a grant from Ministry of Health and Welfare in Japan (No. 467 and 511)     

Cone dysfunction and supernormal scotopic electroretinogram with a high-intensity stimulus

An unusual form of scotopic electroretinogram with a bright white stimulus, which consisted of a rectangular a-wave of normal amplitude and a b-wave of supernormal amplitude, was recorded in three patients with cone dysfunction. In addition to poor visual acuity, abnormal color vision and reduced amplitude of the photopic electroretinogram, these patients showed a 2-log unit elevation of the dark-adaptation threshold. Funduscopic examination and fluorescein angiography revealed fine granular pigment disturbances at the mascula. The relationship between the response of the dark-adapted electroretinogram versus stimulus intensity was unique to these patients. The b-wave thresholds were elevated by 1 log unit. The b-waves were reduced in amplitude and markedly delayed in implicit time to dim stimuli, but supernormal in amplitude and normal in implicit time to bright stimuli.Abbreviations GMP guanosine monophosphate     

Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan.

BACKGROUND: The precise mechanism of high altitude pulmonary oedema (HAPE) remains unclear. The purpose of this study was to evaluate the role of cytokines and P-selectin in the development of HAPE which occurred at moderate altitude in Japan. METHODS: The following cellular and biochemical markers and chemotactic cytokines were measured in the bronchoalveolar (BAL) fluid from four patients with HAPE at 2857-3180 m in the Japanese Alps: total proteins, albumin, lactate dehydrogenase (LDH), and interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (ra), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and the soluble form of P-selectin. RESULTS: At admission there were significant increases in the levels of total cells, especially macrophages and neutrophils, total protein, albumin and LDH when compared with 13 healthy individuals. Furthermore, the levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were also considerably increased but returned quickly to the normal ranges or were not detected after recovery. The levels of IL-1 alpha, IL-10, and P-selectin did not change. CONCLUSIONS: These results suggest that an inflammatory process almost identical with acute respiratory distress syndrome (ARDS) may occur in HAPE, but that these changes are transient and are not associated with any increase in P-selectin levels in the BAL fluid.     

A case of supravalvular aortic stenosis with spontaneous remission of peripheral pulmonary stenosis

A 14-year-old junior high school boy was admitted to our institute. Previously he had been diagnosed as having peripheral pulmonary stenosis (Gay's classification, type IV) at the age of 2 years and 10 months. On this occasion, however, a diagnosis of supravalvular aortic stenosis was made, with a pressure gradient of about 120 mmHg, and all examinations showed spontaneous remission of peripheral pulmonary stenosis. He underwent a successful standard aortoplasty. This is the first reported case of spontaneous remission of peripheral pulmonary stenosis.     

Clinical study on cefixime granules in the field of pediatrics

The absorption and excretion and clinical effectiveness of cefixime (CFIX) granules, a new oral cephalosporin, were studied with pediatric patients with tonsillitis and urinary tract infection (UTI). Peak serum concentrations in 3 children given orally a single dose of 3 mg/kg on fasting were 0.545 micrograms/ml at 2 hours in 1 patient, and 1.56 and 1.26 micrograms/ml at 4 hours in the other 2. The half-lives in the 3 patients were 3.21-3.42 hours, with an average of 3.29 hours. The urinary concentration during the first 6 hours was 36.5 micrograms/ml in 1 patient showing the low serum level, and the first 6-hour urinary recovery rate was 7.3%. In the other 2 patients, urinary concentrations and recovery rates up to 6 hours were 87 and 62 micrograms/ml, and 17.0 and 15.1%, respectively. The second 6-hour urinary concentrations and recovery rates were 35.5 and 20.8 micrograms/ml, and 12.7 and 8.8%, respectively. The urinary recovery rates up to 12 hours were 29.7 and 23.9%, respectively. CFIX was given orally to 19 children with 20 diseases in daily doses of 6.4-12.9 mg/kg in 2 or 3 divided portions for 3 to 12 days. Clinical evaluations were made on 18 diseases. Clinical effects of CFIX were excellent in 4, good in 7 and poor in 1 of the 12 patients with tonsillitis, and excellent in 5 and good in 1 of the 6 patients with UTI. The overall clinical effectiveness rate was 94.4%. No side effects were observed in any of the 19 patients. Hematological tests, showed slight elevation of blood platelet counts in 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Perforin expression in lymphocytes infiltrated to human colorectal cancer

Perforin (PFP) is a cytotoxic protein released from killer cells. PFP immunoreactivity in human peripheral blood lymphocytes (PBL) and tumour infiltrating lymphocytes (TIL) was investigated immunocytochemically with the aid of an anti-PFP monoclonal antibody. PFP was detected in the cytoplasm of 10% of PBL. We performed a double staining of PFP+ cells with Leu11b/CD16, Leu2a/CD8, or Leu3a/CD4 and showed that PFP was produced by 9% of CD8+ cells and 18% of CD16+ cells but not by CD4+ cells. In 28 colorectal cancer tissues, PFP immunoreactivity was observed in the lymphocytes infiltrating to the tumour stroma. The PFP+ cells were most numerous in Dukes A and decreased in number according to the progression of tumours. The PFP+ cells in TIL exhibited the same phenotypes as those in PBL but the PFP+ cells were more numerous in CD8+ cells than in CD16+ cells at all stages. This study represents the first evidence that PFP is mainly secreted from CD8+ cells in tumour tissues. It is hypothesised that the decrease in the number of PFP+ cells in accordance with tumour progression may reflect the suppression of the hosts local immunity.     

Experimental and clinical studies on the effect of reticuloendothelial system (RES) potentiator in the depressed RES function in cirrhotics

Among the patients with liver cirrhosis (LC) who undergo the operation, the postoperative complications are not infrequent and sometimes prove fatal. The impaired hepatic function, especially the impaired reticuloendothelial system (RES) function, has been claimed to be a possible pathogenic factor for these complications. The present experimental and clinical studies were undertaken to investigate the RES function and the effect of preoperative OK-432 administration as an RES potentiator in LC. The results are as follows: 1) CCl4-induced LC rats were evaluated for RES global phagocytic function, Kupffer cell phagocytic function, plasma opsonic activity and plasma opsonic substances such as fibronectin, C3 and IgG. All parameters except IgG showed significant depression compared to those values in normal rats. However, the administration of OK-432 (0.1 KE/rat, ip) improved all these depressed parameters. The OK-432 administration also significantly improved the survival following panperitonitis in LC rats. 2) Among 18 LC patients with hepatocellular carcinoma undergoing partial hepatectomy, the RES global phagocytic function, plasma opsonic activity and plasma opsonic substances were evaluated. Same as the experimental study, all parameters except IgG were significantly depressed among the LC patients compared to those values in the patients with normal liver. However, the preoperative OK-432 administration (5 KE/day sc for 4 days) significantly improved these parameters and consequently decreased the postoperative complications. These results indicate that the preoperative RES activation by the OK-432 was effective and useful for the prevention of the postoperative complications in the LC patients.