Effectiveness of mammographic screening for breast cancer in women aged over 50 years in Japan.

The optimal age for effective screening of subjects for breast cancer by mammography in Japan was studied based on the results of two mammographic screening systems (systems I and II) in Tokushima Prefecture. System I consisted of visit screening using a bus equipped with a mammographic apparatus. System II consisted of central screening performed at Tokushima Health Screening Center. The examinees numbered 2,500 and 3,707 in systems I and II, respectively. There was a significant difference between the two screening systems in the age distribution of the examinees. The detection rates of breast cancer were 0.6% and 0.24% in systems I and II, respectively, which are 2-5 times higher than that (0.12%) obtained by conventional screening using physical examination alone. The detection rate increased especially in the sixth and seventh decades of life. The sensitivity of mammography screening was 93.3% in system I and 81.1% in system II. Higher sensitivity (100%) than that (73%) of screening by physical examination was obtained in women aged over 50. The proportion of stage I was 60% in system I and 66.7% in system II, compared with 32-65% in the United States and Europe. The rates of no nodal involvement were high, being 77.8% and 83.3% in systems I and II, respectively, compared with 57-71% in other countries. Breast-conserving therapy was applied to 18 of the 24 patients with breast cancer detected by the two screening systems. In addition, in Wolfe's classification of mammograms, the proportion of DY (mammary dysplasia) pattern was remarkably low, being 3.2% in the sixth decade and 0.8% in the seventh decade, compared with 16.6% in women aged 49 years. These results indicate that mammographic screening is effective in women aged over 50 years in Japan, as has been found in other countries.

Morphological changes in hepatic Ito cells after parenteral treatment with carmellose sodium in rats.

Carmellose sodium (1.5%), dissolved in physiological saline, was given for 4 days via oral, subcutaneous or intraperitoneal routes. In the rats treated with carmellose sodium by the parenteral route, hepatic sinusoidal component cells and free macrophages were swollen. The degree of the swelling was more severe in the rats treated by the intraperitoneal route than by the subcutaneous route. The swollen sinusoidal component cells which engulfed the carmellose sodium-related substance were classified as Kupffer's cells or Ito cells by immunohistochemical reaction. Ito cells were isolated from a 5-week-old rat and were cultured in Dulbecco's modified Eagle's medium (DMEM). Some of the Ito cells which were cultured in DMEM containing 0.3% carmellose sodium showed phagocytic properties; vesicles in their cytoplasm and other Ito cells which were cultured in DMEM containing India ink contained some carbon particles.

[Repeated dose toxicity studies of taltirelin tetrahydrate(TA-0910) by oral administration to rats].

Four-, 13- and 52-week repeated dose toxicity studies of taltirelin tetrahydrate(TA-0910), a thyrotropin-releasing hormone(TRH) analogue, were carried out in rats. Through the three studies, TA-0910 solution was administered orally at doses of 3, 30 and 300 mg/kg/day. The animals receiving TA-0910 showed hyperlocomotion, grooming and wet dog shaking which were attributable to the central effects similar to those of TRH, but there was no death nor obvious deterioration of health caused by the treatment. Body weights decreased in males of 300 mg/kg group, and food consumption was on the upward trend in females in 300 mg/kg group. In 13- and 52-week studies, females receiving 300 mg/kg showed elongated estrous cycle, although it was not an evident change. Blood examinations revealed increases in erythrocyte count, hemoglobin and hematocrit in 300 mg/kg group. Reductions in serum(plasma) proteins and lipids, and drug-metabolizing enzyme activity of the liver were regarded as non-specific changes, as they were sporadic and slight in 300 mg/kg group. Salivary gland and adrenal weights increased in 300 mg/kg group. For the thyroid, weights increased in 300 mg/kg group in the 4- and 13-week studies, and increases of microfollicles and cell debris were observed microscopically in each treated group in the 52-week study. These changes seemed to be related with hormonal action of TA-0910, but the effects on animals were judged slight from plasma TSH and thyroid hormone levels after 4 weeks of dosing. The non-toxic dose was estimated to be 30 mg/kg/day, through the rat repeated dose toxicity studies. All the above changes were alleviated or abolished by 4-week recovery period.

Oncogenicity studies of taltirelin tetrahydrate (TA-0910) by oral (GAVAGE) administration in CD-1 mice and CD rats.

Oncogenicity studies of taltirelin tetrahydrate (TA-0910), a new thyrotropin-releasing hormone (TRH) analogue, were carried out on CD-1 mice and CD rats. Groups of 60 male and 60 female CD-1 mice received TA-0910, by oral gavage, at dosages of 5, 15 or 50 mg/kg/day. Treatment continued for a minimum period of 104 weeks. Groups of 55 male and 55 female CD rats received TA-0910, by oral gavage, at dosages of 20, 60 or 200 mg/kg/day. Treatment continued for a minimum period of 90 or 94 weeks for males and females, respectively. Of the treatment-related behavioral changes noted, the majority were considered to be directly related to the known pharmacological activity of the test substance and, as such, to be of questionable direct toxicological significance. In mice, there was no evidence of a treatment-related effect on the incidence of neoplasms. In rats, slightly higher incidences of pituitary adenoma, in males given 60 or 200 mg/kg/day, and thyroid follicular adenoma, in females given 200 mg/kg/day, were noted. However, in neither case was statistical significance attained in pair-wise comparisons, and the incidences were within expectation from background data. There was no evidence of any oncogenic potential of TA-0910 in these studies.

Toxicokinetics of phenobarbital in rats with DL-ethionine-induced liver injury.

The toxicokinetic parameters of phenobarbital (PB) were assessed in a female rat model of liver disease. In a preliminary study to determine the optimum dose of DL-ethionine (ET) for creating liver damage, intraperitoneal injection of 250, 500, or 1,000 mg/kg of ET was done for 4 days. ET treatment caused an increase in serum GOT and GPT activity and a decrease in the serum glucose concentration. In the liver, triglycerides and free fatty acids were increased and glucose and S-adenosylmethionine (SAM) were decreased. Histologic examination revealed diffuse fatty degeneration of the hepatocytes. These findings accorded with those already reported as characteristic of ET intoxication. The toxicokinetic parameters for PB were determined after oral or intravenous administration of 100 mg/kg of PB to rats with ET (500 mg/kg, i.p.)-induced hepatotoxicity. After oral administration of PB, prolongation of the Tmax, increased AUC0-infinity, and decreased ke and CL values were noted in ET-treated rats. When PB was given intravenously, the AUC0-infinity was increased while the values of alpha, beta and CL were decreased. A high level of urinary excretion of PB persisted for 48 hr. Protein binding of PB was unchanged in ET-treated animals, but the extent of bioavailability of PB tended to increase. These results indicate that elimination of PB was impaired in the ET-treated rats.

Cytofluorometric determination of nuclear DNA in heart muscles of patients with muscular dystrophy.

The degree of DNA-polyploidy of cardiac muscle cells was investigated by cytofluorometry in 4 cases of progressive muscular dystrophy (DMP) and 2 cases of myotonic dystrophy (DM), and the results were compared with those for non-dystrophic hearts of normal or increased weight. The heart muscle cells from all patients with these forms of dystrophy showed marked nuclear DNA hyperploidy reaching 16c, irrespective of cardiac hypertrophy or atrophy. In the non-dystrophic group, DNA hypertrophy corresponding to that of dystrophy was only detected in cases of marked cardiac hypertrophy exceeding a weight of 400 g. The wasting of the respiratory musculature, deformity of the thorax and cardiac muscular atrophy appeared to be the principal factors causing DNA polyploidy in patients with muscular dystrophy.

Paraganglioma of the cauda equina: an ultrastructural and immunohistochemical study of two cases.

The ultrastructural and immunohistochemical features of 2 paragangliomas arising in the cauda equina are described. In both cases the tumor cells were arranged in small nests or cords and contained characteristic neurosecretory granules, lamellar stacks of rough endoplasmic reticulum (RER), and some well-developed Golgi apparatuses in their cytoplasm. The cells varied in electron density; the darker cells, occasionally resembling sustentacular cells, were probably dehydrated light cells because they contained a few neurosecretory granules. Sustentacular cells were difficult to identify by electron microscopy, but irregularly distributed S-100 protein and glial fibrillary acidic protein (GFAP) were found in these cells by immunostaining. Many tumor cells contained abundant neurofilaments. Curiously, a few cytokeratin-positive cells were found in 1 case. On microscopic examination, a small area of ganglioneuroma was found associated with the paraganglioma in 1 case. Ganglionic differentiation was concluded to be frequent in paragangliomas of the cauda equina region as in duodenal paragangliomas.

Fiber type differentiation and myosin expression in regenerating rat muscles.

The relation between fiber type differentiation and the expression of slow and fast myosin isoforms was examined in regenerating rat muscles after injection of a myotoxic agent, bupivacaine. The histochemical myosin ATPase reaction for fiber typing demonstrated that immature type 2C fibers differentiated into type 1, 2A and 2B fibers. Slow and fast myosin isoforms were demonstrated immunohistochemically using antibodies raised against myosins extracted from the slow-twitch soleus and fast-twitch tensor fasciae latae muscles of mature guinea pigs (anti-SOL, anti-TFL). The results showed that immature type 2C fibers destined to differentiate into type 1 fibers first reacted with anti-TFL only, and later reacted with both anti-TFL and anti-SOL, whereas those destined to differentiate into type 2A and 2B fibers reacted with anti-TFL only throughout regeneration. The significance of the myosin isoforms that react with anti-TFL in immature type 2C fibers was discussed.