Tumor Induction by Azoxymethane (AOM) and 2-Amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in F344 Rat Gastric Mucosa Featuring Intestinal Metaplasia Caused by X-irradiation

Male F344 5-week-old rats were X-irradiated, and 16 weeks after the first dose. azoxymethane (AOM) was injected or 2-amino-l-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) was given by intragastric intubation. Tumors in the pylorus of the glandular stomach were observed in 4 out of the 29 animals receiving X-rays + AOM and in 4 out of the 25 animals receiving X-rays + PhIP, 12 months after administration. No such lesions were found in the chemical or X-ray alone groups. Intestinal metaplasia and some induced tumors were positive for CDX2. It was concluded that the presence of intestinal metaplasia may increase sensitivity to the induction of gastric tumors by colon carcinogens

Damage of the Mouse Testis by Tritiated Water and <137>^Cs-γ-Rays

Tritiated water at 23.2, 46.3 or 92.5 MBq/animal and ^Cs-γ-rays at 9.5 Gy (equivalent 370 MBq) or lower doses were administered to 6-week old male C3H/HeNCrj and C57BL/6NCrj mice, as well as FI Crj: B6C3F1 (C3H × C57BL) progeny. Each set of six to ten animals were autopsied 30 days after the first irradiation. Testis weights were decreased dose dependently, relative values being highest in the C3H and lowest in the C57BL case, with B6C3F1 intermediate. Vacuolization in seminiferous tubules appeared in the 23.2 MBq group and increased with the dose. Focal pyknosis and karyomegaly were found at 46.3 MBq, while primary and secondary spermatocytes and spermatids disappeared with 92.5 MBq. Only a few spermatogonia and Sertoli cells remained after exposure to 9.5 Gy ^Cs-γ-rays. Sizes of seminiferous tubules were decreased dose dependently, with no strain differences. When male B6C3F1 mice were irradiated with Cs-γ-rays at 0.119 (equivalent 4.63 MBq tritiated water) or 2.38 Gy (equivalent 92.5 MBq tritiated water), body weights and size of the seminiferous tubules were decreased at both doses, and the larger dose also caused reduction of testis weight and abnormal sperm. However, all changes except for the alteration in weights had disappeared 1 month after the final irradiation. It is considered that the size of seminiferous tubules may be a good parameter for radiation damage in the testis

Effects of Weaning by Surrogate Mothers (ACI) on Tumor Development in SD Rats Treatedwith Methylnitrosourea (MNU) and/or N-Methyl-N-nitro-N-nitrosoguanidine (MNNG)

In this experiment, MNU was administered, followed by MNNG, to assess effects ofsurrogate mothering on tumor. One or two day old male SD pups were treated with or without30mg/kg body weight of methylnitrosourea (MNU) and nursed by SD or ACI surrogate mothersfor 5 weeks. When 6-weeks-old they were then treated with 100ppmN-methyl-N-nitro-N-nitrosoguanidine (MNNG) or tap water for 16 weeks. The tumor incidencein the MNNG alone group was significantly lower than with MNU alone or MNU+MNNG (p<0.01).Kidney or nerve tumors mainly developed in the MNU group, gastric tumors in the MNNG group,and the two combined in the MNU+MNNG group. The incidence and mean number of tumors didnot significantly differ between the two weaning groups. However, mean survival time withthe ACI surrogate mothers after treatment with MNU was increased as compared with the SDmother group. Cumulative development of tumors in the ACI surrogate mother group was alsodelayed (p<0.05). Similar results were obtained with MNU+MNNG and MNNG alone. The presentexperiment suggested that tumor induction might be effected by components of the mother'smilk

Low-Dose Intravenous Alteplase in Wake-Up Stroke

Background and Purpose—We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods—This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0–1). Results—Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68–1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06–12.58]; P>0.999), respectively. Conclusions—No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions

Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system

Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine‐rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand‐independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of RET(C618F) in organogenesis, we generated a knock‐in mouse line conditionally expressing RET(C618F) cDNA by the Ret promoter. The RET(C618F) allele can be made to be Ret‐null and express mCherry by Cre‐loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain‐of‐function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis

Radioprotective Effects of Miso (Fermented Soy Bean Paste) Against Radiation in B6C3Fl Mice : Increased Small Intestinal Crypt Survival, Crypt Lengths and Prolongation of Average Time to Death

The radioprotective effect of miso, a fermentation product from soy bean, was investigated with reference to the survival time, crypt survival and jejunum crypt length in male B6C3F1 mice. Miso at three different fermentation stages (early-, medium- and long-term fermented miso) was mixed in MF diet into biscuits at 10% and was administered from 1 week before irradiation. Animal survival in the long-term fermented miso group was significantly prolonged as compared with the short-term fermented miso and MF cases after 8 Gy of 60Co-γ-ray irradiation at a dose rate of 2Gy min-1. Delay in mortality was evident in all three miso groups, with significantly increased survival. At doses of 10 and 12 Gy X-irradiation at a dose rate of 4 Gy min-1 the treatment with long-term fermented miso significantly increased crypt survival. Also the protective influence against irradiation in terms of crypt lengths in the long-term fermented miso group was significantly greater than in the short-term or medium-term fermented miso and MF diet groups. Thus, prolonged fermentation appears to be very important for protection against radiation effects