Comparative studies in induction of micronuclei by three genetically recombinant and urinary human erythropoietins

Comparative studies on the induction of micronucleated erythrocytesby three recombinant human erythropoietins (rhEPOs) such asepoetin     

Twenty-six-Week carcinogenicity study of chloroform in CB6F1 rasH2-transgenic mice

The carcinogenic potential of chloroform was evaluated in a short-term carcinogenicity testing system using CB6F1 rasH2-Tg (rasH2-Tg) mice. Chloroform was administered to rasH2-Tg males at doses of 28, 90, or 140 mg/kg and rasH2-Tg females at 24, 90, or 240 mg/kg by oral gavage for 26 weeks. Wild-type (non-Tg) male and female mice received doses of 140 mg/kg and 240 mg/kg, respectively. N-methyl-N-nitrosourea was administered to rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. In both the rasH2-Tg and non-Tg mice, there was no significant increase in the incidence of neoplastic lesions by chloroform treatment. The incidence of hepatocellular foci in the rasH2- and non-Tg females receiving 240 mg/kg was increased. Forestomach tumors and malignant tumors occurred in most of the rasH2-mice in the positive control group. Swelling or vacuolation of hepatocytes, a toxic change induced by chloroform, occurred in both the rasH2-Tg and non-Tg mice. It is concluded that chloroform, a putative human noncarcinogen, did not show evidence of carcinogenic potential in the present study using rasH2-Tg mice. This study suggests that the rasH2-Tg mouse model may not be appropriate for detecting nongenotoxic carcinogens. However, the sensitivity of rasH2-Tg mice to nongenotoxic carcinogens should be assessed with consideration of the results from the other ILSI-HESI project studies.     

Immunohistochemical expressions of cytokeratins, mucin core proteins, p53, and neuroendocrine cell markers in epithelial neoplasm of appendix

Epithelial neoplasms of appendix are infrequent, and their pathological features are not fully characterized. We collected 33 cases of appendiceal tumors and examined immunohistochemically the expression of cytokeratins (CK, CK7, and CK20), mucin core protein (MUC1, MUC2, MUC5AC, and MUC6), E-cadherin, chromogranin A, and p53 protein. Gene analysis of TP53 was also conducted on exons 5 to 8. Clinically, mucinous tumors were predominant in females. Immunohistochemically, all the tumors expressed CK20, whereas CK7 was positive in one third of the cases. Similarly, MUC2 was expressed in all the tumors, whereas MUC1 and MUC5AC were detected in about a half of the cases. Although chromogranin A-positive cells are generally sparse in normal appendix, they were more common in mucinous tumors than in nonmucinous tumors. Contrary to the previous data reported (Mod Pathol 2002;15:599-605), mucinous carcinoma exhibited a higher frequency of p53-positive cells (mean 29%) compared with mucinous adenoma (2.8%) (P < .001), whereas nonmucinous tumors showed high levels of p53-positive cells to similar extent (51%-67%) in both adenoma and carcinoma. The high expression of p53 protein coincided with the presence of mutations in multiple sites of TP53 gene in mucinous tumors. This is the first report that characterized the immunophenotypic profile of appendiceal epithelial neoplasms with an emphasis of a higher frequency of p53 positivity in mucinous carcinoma cases compared with mucinous adenoma in the appendix.     

Histamine downregulates CD14 expression via H2 receptors on human monocytes

Lipopolysaccharide (LPS) binds to LPS-binding protein (LBP) in plasma and is delivered to the cell surface receptor CD14 on human monocyte. LPS is transferred to the transmembrane signaling receptor toll-like receptor (TLR) 4. In the present study, the effect of histamine on the expression of CD14 on human monocytes was investigated. Histamine concentration- and time-dependently decreased the expression of cell surface CD14, whereas histamine did not decrease mRNA for CD14 nor increase soluble CD14 (sCD14). The inhibitory effects of histamine on CD14 expression were antagonized by H2-receptor antagonist, but not by H1 and H3/H4 antagonist. The effects of selective H2-receptor agonists, 4-methylhistamine and dimaprit, on CD14 expression mimicked that of histamine indicating that histamine regulated CD14 expression through the stimulation of H2-receptors. The pretreatment with histamine partially inhibited the LPS-induced TNF-alpha production in human peripheral blood mononuclear cells (PBMC). Such inhibition might be due to the down-regulation of CD14 expression on monocytes by histamine.     

Expression of gastrin-releasing peptide (GRP) in the bovine uterus during the estrous cycle

Gastrin-releasing peptide (GRP) has been proposed as a novel regulatory peptide in the reproductive tract. We previously demonstrated that GRP immunoreactivities are found predominantly in the uterine gland epithelial cells of nonpregnant and pregnant cows. The present study focused on the distribution of GRP immunoreactivity and the expression of GRP mRNA in the bovine endometrium during the estrous cycle. Tissues were collected from 21 uterine horns and bodies during the estrous cycle. RT-PCR showed the expected GRP mRNA fragments (284 bp) in the tissues from all stages of the cycle. In situ hybridization results ascertained the expression of the GRP mRNA in the uterine gland epithelial cells and superficial epithelial cells of the endometrium. Positive staining of GRP immunoreactivity in the uterine gland epithelial cells was detected in both the uterine horn and body from all stages of the cycle. In metestrus and diestrus stages, GRP was also detected in the superficial epithelial cells of horn, but not in the body. The degrees of GRP mRNA expression and intensities of GRP immunoreactivity in the endometrium increased from proestrus to diestrus stages. These findings suggest that GRP may be important both in the endometrial remodeling during the estrous cycle and in the implantation and development of blastocysts.     

Memory phenotype CD8(+) T cells in IL-15 transgenic mice are involved in early protection against a primary infection with Listeria monocytogenes

We recently constructed IL-15 transgenic (Tg) mice using cDNA encoding a secretable isoform of the IL-15 precursor protein under the control of an MHC class I promoter. The IL-15 Tg mice exhibited resistance against a primary infection with Listeria monocytogenes. The numbers of memory CD8(+) T cells were markedly increased in the IL-15 Tg mice following Listeria infection accompanied by sustained IL-15 production. The increased CD44(+)CD8(+) T cells in the infected IL-15 Tg mice were not specialized to recognize Listeria-specific antigen but produced a large amount of IFN-gamma in response to bystander stimulation exogenous IL-15 in combination with IL-12. Furthermore, Listeria-specific Th1 response by CD4(+) T cells was significantly augmented in the IL-15 Tg mice compared with control mice following Listeria infection. In vivo depletion of the CD8(+) T cells by anti-CD8 monoclonal antibody and adoptive transfer of the T cells from naive IL-15 Tg mice indicated that the CD8(+) T cells functioned not only to eliminate bacteria at the early stage of infection but also to promote Th1 response to L. monocytogenes. Overexpression of IL-15 shed light on a novel role of memory CD8(+) T cells in early protection and promotion of Th1 response against a primary infection with L. monocytogenes.     

Glucose uptake by individual skeletal muscles during running using whole-body positron emission tomography

The purpose of this study was to examine, by positron emission tomography (PET), the distribution of [¹⁸F]fluoro-deoxy-glucose ([¹⁸F]FDG) uptake by human muscles during 35?min of running. Thirteen healthy male subjects were studied, seven of whom participated in the exercise study. Running intensity was kept constant such that the subjects' heart rates were maintained at between 140 and 150?beats per minute. [¹⁸F]FDG [62.9 (14.8)?MBq, mean (SD)] was injected after 15?min of running. PET imaging was started immediately after the running ended. The ratio of [¹⁸F]FDG uptake by muscles in runners to that in control subjects (r-c ratio) varied from three to six for the muscles of the foot and leg below the knee joint. The r-c ratio of the medial head of the gastrocnemius (MG) was higher than that of its lateral head (LG). The r-c ratio of the rectus femoris (RF) was lower than that of the other three muscles of the quadriceps femoris (QF). The r-c ratio of inactive muscles located above the waist was approximately 0.7. These results suggest that, during the moderate running of this study: (1) glucose uptake by muscles of the foot and leg below the knee joint clearly increases, (2) the r-c ratio differs significantly among the skeletal muscles, which act synergistically, and (3) glucose uptake by inactive skeletal muscles decreases.