Carcinogenic susceptibility to N-bis(2-hydroxypropyl)nitrosamine (DHPN) in rasH2 mice

To evaluate the susceptibility of rasH2 mice to N-bis(2-hydroxypropyl)nitrosamine (DHPN), a potent carcinogen targeting the lung, liver, thyroid, and kidney, male, 6-week old, rasH2 mice and wild-type littermates (non-Tg mice) were given DHPN in drinking water at 0, 20 or 200 ppm, and 0 or 200 ppm, respectively, for 26 weeks. The experiment using rasH2 mice given 200 ppm DHPN and non-Tg mice given 200 and 0 ppm DHPN was completed at 20 weeks, since mortality in these groups was remarkably increased due to hemangiosarcomas of the liver. Histologically, tumors developed in the lung and liver in both rasH2 and non-Tg mice treated with DHPN. In addition, proliferative lesions were observed in the forestomach, urethra, and excretory duct of salivary glands in rasH2 mice given 200 ppm DHPN. RT-PCR analysis showed no marked difference in expression of mRNAs for the transgene and the endogenous mouse ras gene between the whole lung tissue containing a neoplasm and normal lung tissue. Our results suggest that rasH2 mice are highly susceptible to DHPN, the target organs including the forestomach, salivary gland and urethra, which have not been found to develop tumors in previous long-term carcinogenicity studies of DHPN in rats and mice.     

The distribution of serotonin transporter immunoreactivity in hippocampal formation in monkeys and rats

To elucidate the anatomical distribution of the serotonergic neurotransmitter system, we identified serotonin transporter (5-HTT) in the hippocampus of rats and monkeys by immunohistochemistry. A widespread and heterogeneous distribution of 5-HTT-immunoreactive fine fibers was noted in the rat brain. However, in monkeys, punctuate 5-HTT-immunoreactive deposits and fewer fibers were observed. The species difference in 5-HTT immunohistochemical staining pattern may be caused by differences in localization of 5-HTT between species.     

Microscopic measurement of the facial nerve root exit zone from central glial myelin to peripheral Schwann cell myelin

OBJECT: The authors have attempted to define the exact borders of the root exit zone (RExZ) of the facial nerve, measure the distribution of myelin histologically, and examine the relationship between contact vessels and the RExZ. METHODS: Seventy-five facial nerves were obtained from brainstems excised from 44 adult patients at autopsy. The arteries and veins associated with the facial nerve were counted and measured. The facial nerves, associated vasculature, and adjoining portions of the brainstem were then removed en bloc. These tissues were serially sectioned and stained, and a photomicrograph of each section was obtained. The distribution of myelin on each section was measured from the upper edge of the supraolivary fossette, and the relationship between contact vessels and the RExZ examined. The lateral transitional zone of the facial nerve began 8 mm distal to the upper edge of the supraolivary fossette (root exit point [RExP]) and had a mean length of 1.9 mm. The root detachment point (RDP) of the facial nerve at the medial side was located very close to the beginning of the medial transitional zone. In more than 80% of the nerves that were examined, vascular structures compressed the central glial myelin of the nerve. CONCLUSIONS: The authors propose the use of the terms "RExP," "RDP," and "transitional zone," instead of RExZ, which cannot be well defined. The RDP appears to be a good landmark for use during microvascular decompression.     

Thirteen-week repeated dose toxicity study of wormwood (Artemisia absinthium) extract in rats

Wormwood, Artemisia absinthium, is a very bitter plant, and its extract has been used as food additives such as seasonings for food and drinks. A 13-week repeated dose toxicity study of wormwood extract was performed in both sexes of Wistar Hannover (GALAS) rats. Rats were divided into 4 groups consisting of 10 males and 10 females each, and were given water containing 0, 0.125, 0.5, or 2% wormwood extract. All rats had survived at the end of the study, and no changes indicating obvious toxicities that are attributable to the treatment of wormwood extract were observed in the body weights, hematological and serum biochemical examinations, organ weights, and histopathological examinations. Based on the results of the present study, the NOAEL (no-observed-adverse-effect-level) of wormwood extract of Wistar Hannover rats was estimated to be 2% (equivalent to 1.27 g/kg/day in males and 2.06 g/kg/day in females) or more.     

Possible mechanism on enhanced carcinogenesis of genotoxic carcinogens and unsolved mechanisms on lesser carcinogenic susceptibility to some carcinogens in rasH2 mice

The rasH2 mice are hemizygous transgenic mice carrying the human prototype c-Ha-ras gene with its own promoter region, and have been used in 6-month short-term carcinogenicity tests for pharmaceutical drugs in accordance with the recommendation of the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH). Based on the validation studies, it has been recognized that they are very susceptible to genotoxic carcinogens. To elucidate the mechanism of the enhanced carcinogenesis, spontaneous and chemically induced tumors in rasH2 mice have been subjected to molecular analyses, but the results have thus far been equivocal. This article focuses on the possible molecular mechanism of enhanced carcinogenesis in rasH2 mice, based on the results of a search in the literature. In addition, there are several reports suggesting lesser carcinogenic susceptibility of rasH2 mice to some carcinogens: Malignant lymphomas were induced by treatment with phenolphthalein in heterozygous p53 knockout mice, but not in rasH2 mice, and ethinylestradiol, uterine tumor promoter, resulted in depression of uterine proliferative lesions in rasH2 mice. In this review, the possible mechanisms of why rasH2 mice were less sensitive for these carcinogens are also discussed.     

Xenografts of human solid tumors frequently express cellular-associated isoform of vascular endothelial growth factor (VEGF) 189.

Vascular endothelial growth factor (VEGF), a major factor mediating tumor stromal angiogenesis, is expressed as five splice variants encoded by a single gene (VEGF121, VEGF145, VEGF165, VEGF189 and VEGF206). Recently, we demonstrated that the cell-associated isoform, VEGF189, plays important roles in establishment of human colon and esophageal cancer xenografts. We have established 228 xenografts originating from various human solid tumors. In this study, we investigated the expression patterns of VEGF isoforms in those tumor xenografts by RT-PCR. The isoform patterns were VEGF121/VEGF165 in 27 xenografts (11.8%) and VEGF121/VEGF165/VEGF189 in 201 (88.2%). All human solid tumor xenografts expressed VEGF189 more frequently than primary tumors reported previously. These results suggest that VEGF189 contributes to the successful xenotransplantability of various human solid tumors via augmentation of stromal vascularization.     

Prevalence of anemia according to stage of chronic kidney disease in a large screening cohort of Japanese

Background  

The prevalence of chronic kidney disease (CKD) is high in developed countries, including Japan. However, little is known about the prevalence of anemia according to the estimated glomerular filtration rate (eGFR) among Japanese.