DX9065a, an Xa inhibitor, inhibits prothrombin-induced A549 lung adenocarcinoma cell proliferation.

In this study we demonstrate that prothrombin activates the cell proliferation of the lung adenocarcinoma A549 cells. The A549 cell expresses factor Xa-like prothrombinase activity on its surface and prothrombin was converted to thrombin on the cell surface. Furthermore, thrombin induced the activation of PKC, increased [Ca2+]i and potentiated MAP kinase activity through thrombin receptor. The mitogenic activity of prothrombin and the conversion to thrombin were completely abolished by the synthetic coagulation factor Xa inhibitor, DX9065a. These findings suggest that DX9065a is an effective agent for a therapeutic strategy against cancer itself and prothrombotic complications associated with malignancy.

Clinical features of Japanese children and adolescents with systemic lupus erythematosus: results of 1980-1994 survey.

Marked advances have been made in the past decade in the management of adults with systemic lupus erythematosus (SLE). Therefore, a nationwide retrospective survey was conducted between 1980 and 1994 to investigate the clinical manifestations of SLE in Japanese children and adolescents. Questionnaires were sent to 340 hospitals. Of 405 patients reported by 176 hospitals, 373 patients, diagnosed by the criteria established by the Pediatric Study Group of the Japanese Ministry of Health and Welfare in 1985, were enrolled in the study. Forty-nine of the 354 patients (13.8%) had relatives with a connective tissue disease within the third degree of consanguinity. The frequent manifestations in 373 patients were the presence of antinuclear antibody (98.9%), immunologic disorders (93.0%), hypocomplementemia (87.1%), malar rash (79.6%) and fever (74.0%). Lupus nephritis was present in 148 of the 309 patients (47.9%) at their first visit to a clinic, and 261 of the 373 patients (70.0%) developed renal involvement during the observation period. Of 370 patients, 92 patients (24.9%) exhibited central nervous system lupus. Of 368 patients, 192 patients (52.2%) were treated by methylprednisolone pulse therapy and 148 patients (40.2%) received immunosuppressants in combination with steroid therapy at some stage during the observation period, Survival rate at 5 years from onset was 95.9%. Management of infection, coagulopathies, and central nervous system involvement is essential to improve the prognosis of SLE in Japanese children and adolescents.

B cell epitope mapping of the bacterial superantigen staphylococcal enterotoxin B: the dominant epitope region recognized by intravenous IgG.

We showed that i.v. IgG contains Abs against a major group of bacterial superantigens, and that they can inhibit superantigen-elicited T cell activation. The B cell epitope region of the superantigen and the inhibitory mechanism have remained unknown. To analyze the dominant B cell epitopes on the bacterial superantigen SEB (staphylococcal enterotoxin B), we constructed fusion proteins of SEB deletion mutants, and the reactivities of these recombinant proteins to i.v. IgG and healthy human sera were evaluated by means of immunoblotting. Intravenous IgG and healthy human sera mostly recognized the C-terminal fragment (amino acid (aa) 133-239). The C-terminally truncated protein (aa 1-228) and the truncated mutant delta 225-234 lost reactivity, while the truncated protein (aa 1-234) did not, suggesting that the region (aa 225-234) is the dominant B cell epitope. The mutant, in which residues 226-229 of SEB were exchanged for residues 209-212 of streptococcal pyrogenic exotoxin A, reduced the reactivity with the C-terminal region-specific IgG purified by affinity chromatography. The C-terminal region-specific IgG inhibited SEB-elicited T cell activation, suggesting that this Ab that recognizes the epitope functions as the humoral defensive factor against SEB in humans. Furthermore, the assumed epitope region was homology to the residues (aa 32-41) of human thymopoietin, containing the biologic active site.

Effect of total adipose weight and systemic hypertension on left ventricular mass in children.

To investigate the effect of obesity and hypertension on left ventricular (LV) mass in children, we performed echocardiography and measured the height, weight, and blood pressure of 267 healthy children (145 boys and 122 girls) aged 12 years. The percentage of body fat was estimated using bioelectric impedance to derive the total adipose weight and lean body weight. End-diastolic measurements of LV parameters were obtained from M-mode echocardiograms. The LV mass was calculated by using the formula of Devereux et al. A strong positive correlation was demonstrated between non-normalized LV mass and height or other measures of body size. Systolic blood pressure was weakly correlated with non-normalized LV mass in boys. The impact of height on LV mass differed between boys and girls. Thus, different allometric formulas to normalize the LV mass for height were determined, using the height to the 3.1 and 1.9 powers for boys and girls, respectively. Regression analysis revealed that only total adipose weight affected the normalized LV mass, and that the effect of total adipose weight was greater in girls than in boys. The obese children had a significantly greater normalized LV mass than the nonobese children. The increase in the LV mass due to obesity appeared to be eccentric, because of the lack of an association between the indices of obesity and relative wall thickness. Our data indicate that appropriate normalization of LV mass is necessary for each study population, and that LV hypertrophy due to obesity begins in childhood.

p53 gene mutations in skin cancers with underlying disorders.

Mutations in p53, a tumor suppressor gene, are one of the most common genetic lesions of human cancers. The relationship between p53 gene mutation and ultraviolet (UV) light has been demonstrated in skin cancers of sun-exposed sites. In this study, genomic DNA from 12 skin cancers was screened for mutations in exons 5 to 9 of this gene using the polymerase chain reaction--single strange configuration polymorphism (PCR-SSCP) analysis followed by DNA sequencing. DNA samples were obtained from 8 basal cell carcinomas (BCCs): 1 from an organoid nevus, 1 from a patient with basal cell nevus syndrome, 1 from a patient with xeroderma pigmentosum, and 1 from a recurrent and 4 from primary sporadic lesions on actinic damaged skin, and from 4 squamous cell carcinomas (SCCs): 1 from a burn scar, 1 from a patient with epidermodysplasia verruciformis, and 2 from actinic keratosis. Mutation of the p53 gene was detected in only 1 case of SCC which had arisen from actinic keratosis. The mutation occurred at codon 159 in exon 5 with a GCC to CCC base-pair substitution resulting in an amino acid change of alanine to proline. This mutation does not correspond to results of UV mutagenesis studies reported in the literature. Our findings imply that, although p53 gene mutation and UV exposure play an important role in the carcinogenesis of some skin cancers, they are not crucial, especially in skin cancers that develop from underlying skin disorders.

[A case report of childhood acute lymphoblastic leukemia with leukoencephalopathy that responded to oxygenation under hyperbaric pressure therapy].

In this report, we described a case of acute lymphoblastic leukemia with leukoencephalopathy that responded to oxygenation under hyperbaric pressure (OHP) therapy. The patient was 6 year-old female who was diagnosed as acute lymphoblastic leukemia (ALL) one year and 9 months earlier. After the first relapse of the central nervous system (CNS) leukemia, intrathecal administration of methotrexate (MTX) and skull irradiation induced CNS remission. The patient was readmitted because of second CNS relapse. After the third administration of weekly intrathecal MTX injection, apathy and finger tremor were observed. Her conscious disturbance continued for two weeks and magnetic resonance imaging (MRI) revealed abnormal findings in the white matter of her brain. Subsequently OHP therapy was commenced, and the conscious disturbance was improved gradually. One month later, neuro-disturbance resolved completely and the findings of MRI were improved. We could not find any case of leukoencephalopathy which was treated with OHP in the literature. But our case suggested that OHP therapy is valuable in patient with leukoencephalopathy in the early stage.