Distinctive immunoglobulin VH gene usage in Japanese patients with chronic lymphocytic leukemia

The incidence of chronic lymphocytic leukemia (CLL) is low in Asian countries including Japan, while CLL is the most common type of leukemia in the west. To elucidate which factors contribute to the low frequency of CLL in Japan, we investigated immunoglobulin (Ig) heavy chain gene usage and somatic hypermutation status in 44 Japanese patients with CLL. Only one of these patients used V(H)1-69. The finding is in striking contrast to data from western countries, where the frequency of CLL expressing V(H)1-69 ranges from 12 to 21%.     

Flavor components of monoterpenes in citrus essential oils enhance the release of monoamines from rat brain slices

Citrus essential oils have been utilized widely in traditional medicine, and there are various reports of actions such as effects on behavior and effects on pain stimulation response due to exposure. However, there are no reports concerning effects on neurotransmitters after ingestion, and uptake within the brain. We used brain tissue slices to investigate the effect of compounds in lemon essential oil on monoamine release. We investigated R-limonene, gamma-terpinene and citral, major components of lemon essential oil; S-limonene, an isomer of R-limonene and metabolites of these compounds. The effect of each compound on monoamine release from brain tissue slices was found to be dose-dependent. R-Limonene and its S-isomer demonstrated differences with regard to monoamine release from brain tissue. S-Limonene and its metabolites were found to have a stronger effect than the R-isomer. Limonene metabolites taken up in vivo were also found to have a stronger effect on monoamine release than both the R-form and the S-form. In an investigation of dopamine release using stratum slices, terpinene and pinene demonstrated no clear differences in activity attributable to isomers. However, rho-cymene, a gamma-terpinene metabolite, was found to have a stronger effect than gamma-terpinene. These results suggest that the metabolites of these monoterpene compounds contained in citrus essential oils have a stronger effect on monoamine release from brain tissue than the monoterpene compounds themselves.     

Nongenetic factors associated with human handedness and footedness in Japanese twin children

Objective The aim of this study is to clarify the factors related to the handedness and footedness of twins using two of the largest databases on Japanese twins available. Methods The first group consisted of 1,131 twin pairs, all school children either 11 or 12 years old (S group), and the second group consisted of 951 twin pairs of different ages (1–15 years) in several maternal associations (M group). All data were gathered using a questionnaire. Factors associated with the handedness or footedness of twin individuals were analyzed by univariate and multivariate logistic analyses. Results Multivariate logistic analysis showed that for handedness, birth year (OR=1.02) and neonatal asphyxia (OR=1.62) were selected in the S group, and sex (OR=1.34), the age of twins (OR=1.56), parity (OR=1.31), gestational age (OR=1.58), and family history (OR=1.82) were selected in the M group. for footedness, birth complications (OR=1.37) were selected in the S group, and sex (OR=1.33), the age of twins (OR=1.69), gestational age (OR=1.83), and family history (OR=2.49) were selected in the M group. Factors associated with handedness and footedness specific to twins, such as zygosity, placentation, birth order within twin pairs and the sex of the cotwin, were not found, although being a twin might have some effects. Conclusion It was concluded that factors that affect handedness or footedness in general, such as sex, birth year, age, parity, neonatal asphyxia, gestational age, birth complications, and family history, seem to have stronger effects on handedness and footedness than being a twin.     

Physical growth charts from birth to six years of age in Japanese twins

BACKGROUND: The purpose of this study was to analyze the characteristics of the physical growth of twins in childhood and to present growth charts of Japanese twins. METHODS: The subjects consisted of 2029 pairs of normally developed Japanese twins. Growth data were obtained by mailed or hand-distributed questionnaires. Factors that affect body weight and height/length at selected ages were analyzed by stepwise regression analysis. Selected percentiles of body weight, height/length, and body mass index were calculated according to sex, and growth curves were drawn using a spline function. The size deficit of the twins compared to the standards for the general population of Japan was calculated. RESULTS: Gestational age, parity, zygosity, and birth order affected physical growth in varying degrees, although the overall effects themselves were small and mostly disappeared by one year of age. Growth charts of the twins present growth at selected percentiles from birth to 6 years of age according to sex. The size deficit of the twins was largest at birth: more than 20% for weight and approximately 6% for length compared to the 50th percentile of the standard for the general population of Japan. These deficits decreased rapidly in the first 6 to 12 months, and were found to be as low as 0-2% at 4 to 6 years of age. CONCLUSION: Growth charts specifically for twins are needed, at least for the first 1 to 3 years of age but not beyond the age of 6 years.     

Combined treatment with selective cyclooxygenase-2 inhibitor and fluorinated pyrimidines for liver metastasis of colon cancer

Liver metastasis is a major contributor to mortality in patients with colorectal cancer. Hence, it is essential to establish preventive therapy to control liver metastasis. Recently, it has become widely accepted that cyclooxygenase (COX)-2 inhibitors possess anti-cancer activity for various types of tumor, especially colorectal. The clinical application of COX-2 inhibitors may therefore be beneficial. In this study, we have developed a combined treatment with a selective COX-2 inhibitor and fluorinated pyrimidines for liver metastasis of colorectal cancer, and examined the effect of these agents on proliferation and invasion of a highly metastatic human colon cancer cell line, LM-H3. The COX-2 inhibitor etodolac was found to inhibit cell invasion of LM-H3. 5-Fluorouracil (5-FU) inhibited proliferation of this line in vitro. Etodolac did not increase the inhibitory effect of 5-FU on cell proliferation. We also examined the inhibitory effect of etodolac and UFT, belonging to the fluorinated pyrimidines, on liver metastasis by using a liver metastatic model in the nude mouse. Combined treatment with etodolac and UFT markedly reduced liver metastasis. Serious side effects were not observed. In conclusion, combined treatment with etodolac and UFT might be a promising preventive therapy for liver metastasis of colon cancer.     

Renal accumulation and excretion of radioiodinated 3-iodo-α-methyl-<Emphasis Type="SmallCaps">L</Emphasis>-ty rosine

OBJECTIVE: We investigated mechanisms of renal accumulation of radioiodinated 3-iodo-alpha-methyl-L-tyrosine (IMT), which has been used clinically for tumor imaging and as an amino acid transport marker in studies of brain and pancreas function. METHODS: In this study, we used 125I- or 123I-labeled IMT ([125I]IMT or [123I]IMT) as the transport marker. Partition coefficients of [125I]IMT were determined for hypothetic urine at pH ranging from 5 to 8. The examination of uptake and inhibition of [125I]IMT was performed using normal human renal proximal tubule epithelial cells (RPTEC), which are characteristic of the proximal convoluted tubule. The plasma protein binding ratio of [125I]IMT was determined using rats. In the in vivo experiments using mice, we examined biodistribution and excretion inhibition, and performed whole body autoradiography. Also, renal SPECT using [123I]IMT was performed using a normal canine. RESULTS: Very low lipophilicity of [125I]IMT in hypothetic urine suggests that a carrier-mediated pathway contributes to its marked kidney accumulation. [125I]IMT uptake into RPTEC was significantly inhibited by 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) in a sodium-dependent manner, suggesting reabsorption mainly via system B0 in apical membrane of proximal tubule. Plasma protein binding ratio of IMT was 45.4 +/- 5.6%. At 6 hr after administration of IMT to mice, excretion via urinary tract was 77.51% of injected dose, and excretion into feces was 0.25%. Furosemide, ethacrynic acid and probenecid inhibited tubular secretion of [125I]IMT in mice. We obtained very clear autoradiographs of mouse renal cortex and a canine renal SPECT image (S2-like region). CONCLUSIONS: We believe that [123I]IM-T is useful for kidney imaging. In future studies, we plan to examine the use of [123I]IMT in diagnosis of disease.     

Heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

Activation of the PI3K-Akt pathway is known to induce tumor radioresistance. In the current study, we examined the ability of 17AAG, which decreases the levels of Hsp90 client proteins including components of the PI3K-Akt pathway, to sensitize radioresistant human squamous cell carcinoma cells to X-irradiation. Human squamous cell carcinoma cell lines (SQ20B, SCC61 and SCC13) were incubated for 16 h at 37 degrees C in medium containing 17AAG. Radiation sensitivity was determined by clonogenic assays, and protein levels were examined by western blotting. Apoptosis was determined in monolayer cells by AO/EB double staining and in spheroids using the TdT-mediated dUTP nick end labeling assay. 17AAG (0.2 microM) enhanced the radiosensitivity more effectively in radioresistant SQ20B and SCC13 cells than in radiosensitive SCC61 cells. However, in all three cell lines, 17AAG increased radiation-induced apoptosis by reducing the expression of EGFR and ErbB-2 and inhibiting the phosphorylation of Akt. Furthermore, 17AAG (1 microM) sensitized SQ20B spheroids to radiation, and inhibition of Akt activation by 17AAG increased radiation-induced apoptosis in spheroids. The findings suggest that 17AAG effectively sensitizes radioresistant cells to radiation by inhibiting the PI3K-Akt pathway. Targeting the PI3K-Akt pathway with 17AAG could be a useful strategy for radiosensitization of carcinomas.     

Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma

A number of genetic events have been reported in prostate carcinogenesis, including frequent loss of heterozygosity (LOH) on chromosomes 8q, 10q, 16q and 18q, In samples of heterogeneous, multifocal prostate carcinomas, we focused on chromosome 6q using PCR-based techniques with 15 microsatellite markers to identify the specific 6q deletion within tumors. LOH of one or more polymorphic markers was detected in 10 of 21 tumors (48%). Two of these 10 tumors demonstrated LOH in all cancerous foci at specific loci and 4 tumors showed deletion in one focus. Different deletion patterns were found in 3 tumors when different polymorphic markers were used. In 90% of tumors showing LOH in one or more foci, however, two common regions of LOH were identified; one at 1.81 cM on 6q15–16.3 between markers D6S1631 and D6S1056, and the other at 5.11 cM on 6q16–21 between markers D6S424 and D6S283. By RT-PCR analysis, the TAK1 gene located at these loci did not correlate with LOH status, indicating that TAK1 is not a target gene in prostate carcinoma. The 6q deletion occurs heterogeneously and LOH was more frequent in tumors of higher pathological stages, implying that this alteration is a late event in prostate carcinogenesis. Because prostate carcinomas are genetically multicentric and of multifocal origin, it remains unclear whether the foci containing 6q deletions specifically expand within tumors or to what extent they contribute to the histological heterogeneity characteristic of the disease.     

Effects of the volume and shape of voxels on the measurement of phantom volume using three-dimensional magnetic resonance imaging

Recently, an increasing number of volumetric studies of the human brain have been reported, using three-dimensional magnetic resonance imaging (3D-MRI). To our knowledge, however, there are few investigations on the relation of the volume and shape of voxels which constitute an MR image to the accuracy in volume measurement of an imaged object. The purpose of this study was to evaluate the effect of a different shape of voxel, that is, isotropic or anisotropic, as well as the volume of a voxel on the volume measurement based on the original image data and multiplanar reconstruction (MPR) data, respectively. In the experiment, we repeatedly acquired contiguous sagittal images of a single globe phantom with a known volume under the condition in which the volume and shape of voxels varied, on a 1.5T MR scanner. We used a gradient echo sequence (3D FLASH). The volume of the globe phantom from both original images and MPR ones was measured on workstations employing a semi-automated local thresholding technique. As a result, the smaller volume of voxels tended to give us the more correct measurement, and an isotropic voxel reduced measurement errors as compared to an anisotropic one. Therefore, it is concluded that the setting of voxel with both an isotropic shape and small volume, e.g., a voxel of 1 mm x 1 mm x 1 mm at present, is recommended in order to get a precise volume measurement using 3D-MRI.