Malignant and benign ovarian neoplasms among atomic bomb survivors, Hiroshima and Nagasaki, 1950-80.

For 1950-80, 194 ovarian cancer cases were ascertained among the 70,030 females of the Radiation Effects Research Foundation's Life-Span Study E-85 sample, and 106 autopsied cases with benign ovarian neoplasms were ascertained among all 3,046 autopsies performed in the same sample. On the basis of microscopic review, 66% of the cancer and 84% of the benign tumor cases were classified by histologic type. The age-adjusted ovarian cancer incidence rates showed a statistically significant increase with increased exposure dose, both in the entire exposed group (P less than .01) and in the microscopically reviewed subset (P less than .01). This dose response was only significant (P less than .01) in the latter half of the study period, 1965-80. The radiation effect was higher in the younger age group at the time of the bomb (ATB) for the specific attained age or was adjusted for attained age. In general, relative risk (greater than or equal to 100 rad vs. 0 rad) did not differ by attained age, except for the youngest age group, less than 20 years old ATB, where the relative risk tended to decrease with increased attained age, although cases were few in number and follow-up study was necessary. Estimated minimum latent period for radiation-induced ovarian cancer seemed to be 15-20 years. The proportion of autopsied cases with benign ovarian tumor increased with increasing exposure dose, both in the entire series of cases (P less than .05) and in the microscopically reviewed subset. Statistical significance, however, was not achieved in the latter group (P greater than .10). The distribution of histologic types of both cancer and benign tumor of the ovary did not vary significantly with radiation dose. The data are consistent with the hypothesis that radiation injury of the ovaries and secondary excess of gonadotropic hormones are important causative factors in the development of ovarian neoplasms.

Effects of nicotine on the functions of human polymorphonuclear leukocytes in vitro.

Effects of nicotine on migration, extracellular release of lysosomal enzymes, and superoxide anion (O-2) production of human polymorphonuclear leukocytes (PMN) were studied. Nicotine (5 X 10(-6) to 5 X 10(-4) M) had no effect on random migration, chemotaxis to fMet-Leu-Phe, nor on chemokinesis induced by fMet-Leu-Phe. Nicotine, however, inhibited both extracellular release of lysosomal enzymes from PMN and O-2 production of PMN, both of which were induced by fMet-Leu-Phe and cytochalasin B. The inhibition of enzyme release and O-2 production by nicotine was not affected by atropine, hexamethonium, or acetyl beta-methylcholine, suggesting a direct action of nicotine on PMN functions. It is presumed that nicotine does not affect PMN migration to inflammatory sites, but inhibits the microbicidal functions of PMN. Exposure to PMN to nicotine introduced into the body by smoking could suppress their functions. This might result in harmful influences on the host defense mechanism, including antitumor function.

Measurement of active phagocytosis by polymorphonuclear leukocytes by fluorescence liberation from phagocytized microspheres.

Phagocytosis by polymorphonuclear leukocytes (PMN) was determined by a newly developed technique based on measurement of liberation of a fluorescence substance from PMN phagosomes; 4-methylumbelliferyl-beta-D-glucuronide (4MUGL), which is a substrate of beta-glucuronidase in lysosome, was conjugated with a microsphere, and 4-methylumbelliferone (4MU) liberated from phagocytized 4MUGL-microspheres was measured. The microspheres were composed of glyceryl-methacrylate having a diameter of 2.0 micron. Liberating activity of six kinds of 4MUGL-microspheres containing various amounts of amino and carboxyl groups was compared. Among these six kinds of 4MUGL-microspheres, four kinds showed activity similar to that of morphological phagocytosis. These four kinds of 4MUGL-microspheres liberated 4MU into the extracellular fluid from PMN during phagocytosis. Furthermore, they were recognized as a substrate of purified beta-glucuronidase. 4MUGL-MS610 showed the highest liberating activity among the four kinds of microspheres. Optimal conditions for phagocytosis by PMN were determined using 4MUGL-MS610. Total liberation of 4MU from the microspheres increased almost linearly with incubation time with PMN from 0 to 60 min and was linear with 4MUGL-MS in concentrations up to 4 X 10(8) microspheres/ml. This liberation was parallel to phagocytosis in a dose-dependent fashion. During 10-min incubation 20.4% of 4MU was liberated from 4MUGL-microspheres with phagocytosis. Seventy-five percent of the liberated 4MU was distributed in the extracellular fluid. 4MU distributed in the extracellular fluid was not attributable to hydrolysis of unphagocytized microspheres by beta-glucuronidase extracellularly leaked from PMN by phagocytosis. Also phagocytized 4MUGL-MS610 by PMN was observed by scanning electron microscopy. These results indicate that 4MU was liberated from 4MUGL-MS by hydrolysis due to beta-glucuronidase released into phagosomes with phagocytosis by PMN. Sensitivity of this assay was limited to about 50 pmol/ml, being less than 0.5-1 microsphere phagocytized into one cell.

Age-related decline in lysosomal enzyme release from polymorphonuclear leukocytes after N-formyl-methionyl-leucyl-phenylalanine stimulation.

Aging is assumed to decrease lysosomal enzyme release from polymorphonuclear leukocytes (PMN). A synthetic chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe) was utilized to stimulate enzyme release of PMN from 45 human subjects, 21 males and 24 females, ranging in age from 22-83 yr old. Results of the studies showed no sex differences in the stimulation of enzyme release for either age group. However, stimulation was found to significantly decline in both males and females over 50 yr old compared to subjects under 50 yr old. The linear formulae for beta-glucuronidase, beta-galactosidase and lysozyme in male subjects were Y = 6.5X + 617.2, Y = -1.9X + 311.5 and Y = -1.9X + 327.3 with correlation coefficient of -0.685, -0.352 and -0.401, respectively. The linear formulae in females were Y = -5.2X + 536.6, Y = -3.0X + 340.6 and Y = -1.7X + 333.6 with correlation coefficient of -0.582, -0.303 and -0.462, respectively. These findings suggest that there was an age-related decline of response to the stimulant, fMet-Leu-Phe.

Unilateral thickening of placental fetal veins.

Unilateral muscular thickening (ULT) was observed in the wall of the fetal veins on the placental surface beneath the amnion. The maternal facing wall of the fetal veins was thin, and protruded into the amniotic sac. The ratio of the thickness of the maternal facing to the fetal facing wall was 4:1 to 3:1 in the fetal veins. ULT was found to develop after 17 weeks of gestation and was not observed in the small veins less than 1.0 mm in diameter or in the veins located in the deep portion of the chorionic plate. The intimal thickening was not recognized and there was no lipid deposition in ULT. ULT was found in every one of 110 mature placentae and was assumed to be a normal histological finding.

Pulmonary yellow hyaline membranes in neonates.

The recent increase in the occurrence of pulmonary yellow hyaline membranes correlates with improved therapy for premature infants with the respiratory distress syndrome and with their prolonged survival. We compared the clinicopathologic features in 54 cases with pulmonary yellow hyaline membranes with those in 56 cases with conventional hyaline membranes seen during the same interval at Magee-Womens Hospital. Kernicterus, intraventricular hemorrhage, intrahepatic bile stasis, pulmonary hemorrhages, and disseminated intravascular coagulation were significantly frequent in the yellow hyaline membrane group. Clinical problems of hypoglycemia, hypocalcemia, jaundice, and endotracheal hemorrhages and also treatment with endotracheal intubation, ventilatory assistance, and phototherapy were much more common in the yellow hyaline membrane cases. The yellow pigment was identified as unconjugated bilirubin by histochemical and biochemical techniques. A plausible hypothesis for the pathogenesis is presented wherein intrapulmonary hemorrhages lay an important role. The frequent association of yellow membranes and kernicterus in premature infants at relatively low serum levels of bilirubin is significant.

Pharmacological properties of YM-21095, a potent and highly specific renin inhibitor.

A novel renin inhibitor, YM-21095 [2RS), (3S)-3-[N alpha-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-buthyl]-L- histidil-amino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-but anol), has been synthesized in our laboratories. The aim of this study was to evaluate the pharmacological properties of YM-21095 in in vitro and in vivo experiments. YM-21095 inhibited human renin with an IC50 value of 4.7 x 10(-10) mol/L. YM-21095 was also a potent inhibitor against squirrel monkey renin, but less effective against renins from dog, rabbit, and rat. The effect of YM-21095 is highly specific for renin, since it did not inhibit cathepsin D, pepsin, or angiotensin converting enzyme up to a concentration of 10(-4) mol/L. YM-21095 was resistant to proteolytic actions of the enzymes (pepsin, chymotrypsin, trypsin) and squirrel monkey tissue homogenates (liver, kidney, small intestine). Intravenous infusion of YM-21095 (0.1 to 100 micrograms/kg/min) decreased mean blood pressure and inhibited plasma renin activity in a dose-dependent manner with no effect on heart rate in anesthetized sodium-depleted and sodium-replete squirrel monkeys. The hypotensive effect of YM-21095 in sodium-depleted squirrel monkeys was about ten times as potent as that in sodium-replete squirrel monkeys. Oral administration of YM-21095 to conscious sodium-depleted squirrel monkeys produced dose-related decreases of systolic blood pressure. We conclude that YM-21095 is a potent and highly specific inhibitor of primate renin and produces a blood pressure lowering effect.

Specificity of the fatty acyl moieties of diacylglycerol for the activation of calcium-activated, phospholipid-dependent protein kinase.

The specificity of the fatty acyl moieties of diacylglycerol for the activation of Ca2+-activated, phospholipid-dependent protein kinase was investigated. Diacylglycerol has been previously shown to activate this enzyme by increasing the affinity for Ca2+ and phospholipid, both of which are indispensable for the enzyme activation. Diacylglycerols containing at least one unsaturated fatty acid at either position 1 or 2 are fully active in this capacity, irrespective of the chain length of the other fatty acyl moiety in the range tested, C2 to C18. Diacylglycerols containing two saturated fatty acids such as dipalmitin and distearin are far less effective. Mono- and triacylglycerols and free fatty acids are totally inactive, indicating that the diacylglycerol structure is essential.

Inhibitory effect of a novel non-steroidal aromatase inhibitor, YM511 on the proliferation of MCF-7 human breast cancer cell.

The proliferation of MCF-7, human breast cancer cell line, was stimulated by testosterone and estradiol. The aromatase activity in MCF-7 cells, which catalysed the conversion of testosterone to estradiol, was inhibited by a novel non-steroidal aromatase inhibitor, YM5111, with the IC50 of 0.2 nM, indicating that its inhibitory activity was 5.5 times more potent than that of CGS 16949A. YM511 inhibited the proliferation of MCF-7 stimulated by testosterone but did not inhibit the cell proliferation stimulated by estradiol. The IC50 values of YM511 for cell growth and DNA synthesis were 0.13 nM and 0.18 nM, respectively, demonstrating that YM511 was about 3-5 times more potent than CGS 16949A and had no anti-estrogenic or cytotoxic activity. YM511 significantly inhibited testosterone-stimulated transcriptional activation of estrogen-responsive element (ERE) in MCF-7 cells transfected transiently with ERE-luciferase reporter plasmid. The IC50 of YM511 for transactivation was 0.36 nM, suggesting that its inhibitory potency was comparable to the inhibition of aromatase activity of MCF-7 cells. These data may indicate that the inhibition by YM511 of cell proliferation of MCF-7 is attributed to the decreased production of estrogen due to the inhibition of aromatase activity. YM511 may be useful in the treatment of estrogen-dependent cancers.

The potent and selective inhibition of estrogen production by non-steroidal aromatase inhibitor, YM511.

YM511 inhibited aromatase activities in microsomes from rat ovary and human placenta competitively (IC50s: 0.4 and 0.12 nM, respectively). YM511 was about 3 times more potent than other aromatase inhibitors, such as CGS 16949A, CGS 20267 and R 76713. YM511 decreased the contents of estradiol stimulated by pregnant mare's serum gonadotropin in rat ovary with an ED50 of 0.002 mg/kg, indicating that YM511 was equipotent to CGS 20267 and 3 times more potent than the other two inhibitors. Serum estradiol levels in female rats were reduced by YM511 at 0.01 mg/kg into the ovariectomized range. YM511 at 1 mg/kg for 2 weeks decreased rat uterine weight to levels comparable to ovariectomy, showing it was 10 times more potent than other inhibitors. But the maximal inhibitory effect of tamoxifen failed to reach ovariectomized level. YM511 slightly inhibited production of other steroid hormones in vitro and in vivo. The IC50s of YM511 for aldosterone and cortisol production from adrenal cells were from 5500 to 9800 times higher than that for rat ovarian aromatase and 130,000 times higher for testosterone production, indicating that YM511 is a highly specific aromatase inhibitor. The data suggest that YM511 may be a potent and selective agent for suppressing estrogen-dependent action without affecting serum levels of other steroid hormones.

Placental cavities.

OBJECTIVE: To study placental cavities by gross and microscopic examination and ultrasonography and their frequency with various epidemiologic factors and intervillous thrombosis. METHODS: After formalin fixation, interval sections of 567 placentas were prepared to search for cavities and intervillous thrombosis. Cavities were subjected to histologic and ultrasonographic examinations. RESULTS: Frequency of cavities with diameter of 1 cm or more was 34.9% in 567 mature placentas. Frequency of cavities was significantly higher in heavy, thick placentas associated with male fetuses. Histologic examination revealed villus laceration in cavities and syncytial cells, isolated chorionic villi, or air bubbles in placental fetal veins. All 82 placentas with cavities showed villus lacerations in the cavities and air bubbles in the fetal veins. Intervillous thromboses in fetal lobules were located only in the cavities. Cavities were first found by ultrasonography at a mean gestational age of 30.9 +/- 3.8 weeks. Ultrasonography did not always differentiate accurately between intervillous thrombosis and cavities. CONCLUSION: Placental cavities were found significantly more often in heavy, thick placentas associated with male fetuses. Strong uterine contractions during placental detachment could produce villus laceration in cavities, following contamination by air bubbles and isolated villus tissue in the fetal veins. Placental cavities are vulnerable to villus laceration. Intervillous thrombosis occurred only in cavities.

Blood gas analysis of placental and uterine blood during cesarean delivery.

OBJECTIVE: To measure blood gases in uterine venous blood and maternal and fetal blood from the placenta, and to characterize gas exchange in the intervillous space. METHODS: Blood gas measurements were performed immediately after collecting placental and uterine blood from the subchorial and marginal lakes, from the chorionic vein and artery in the placenta in utero, and from the uterine vein during 12 cesarean deliveries. RESULTS: The mean oxygen pressure (PO2) values of the chorionic vein and subchorial lake were 28.7 +/- 6.0 and 29.9 +/- 7.5 mmHg, respectively, with a difference of 1.2 mmHg. The individual data for PO2 of the chorionic vein exceeded those of the subchorial lake in five subjects and were almost equal in two of the 12 subjects. The mean values of carbon dioxide pressure (PCO2) and bicarbonate were greater in the chorionic vein than in the subchorial lake, but the mean pH values were the same in the two groups. The mean values of blood gas analysis were not different between subchorial and marginal lakes with similar blood composition. The mean PO2 of the uterine vein in ten subjects was 45.9 mmHg, significantly higher than that of the subchorial lake. CONCLUSIONS: The human placenta may be defined as a multivillous model with a high degree of oxygen transfer. Arteriovenous anastomoses are suspected in the pregnant uterus beyond 37 weeks' gestation. Subchorial and marginal lakes contain similar admixed blood, which circulates and performs gas exchange.

Elevation of ratio of urinary N-acetylneuraminlactose to free sialic acid in some advanced cancer patients.

We estimated the levels of free sialic acid and sialylated oligosaccharides excreted in the urine of normal donors (n = 10) and patients with gastric cancer (n = 6) and colorectal cancer (n = 4). The total sialic acid level in cancer patients was similar to that in normal donors. However, the ratios of glycosidically bound sialic acids to free sialic acid were higher in some advanced cancer patients than in the normal donors. A major component of sialylated oligosaccharides was N-acetylneuraminyl alpha (2-->3) lactose. The elevation of the urinary ratio of this sialylated oligosaccharide to free sialic acid observed in some advanced cancer patients in this study may reflect the elevation of sialyltransferase activity in tumor tissues.

Giant hornet (Vespa mandarinia) venomous phospholipases. The purification, characterization and inhibitory properties by biscoclaurine alkaloids.

Two species of giant hornet phospholipase B (PLB), alpha and beta, were purified from the venom of Vespa mandarinia. The purification procedure was simplified by two steps of column chromatographies, Sephadex G-100 and SP-Sepharose. The molecular sizes of PLB alpha and beta were 29.5 and 26.0 kDa, respectively. The isoelectric point of alpha and beta enzymes were pH 10.6 and 10.7, respectively. The temperature optimum for egg yolk lecithin was a broad peak at 40-60 degrees C for both enzymes. Amino acid compositions of both enzymes were high contents of aspartic acid, glycine, leucine, lysine and other aliphatic amino acids. Cystine was similar amounts to other species of phospholipases (PLs). The K(m) values of alpha and beta enzymes were 8.29 and 7.53 mg/ml for egg yolk lecithin, respectively. In the catalytic specificity for L-alpha-phosphatidylcholine-beta-oleoil-gamma-palmitoil, the K(m) values of alpha enzyme for gamma-palmitoil and beta-oleoil residues were 0.528 and 1.392 mM, respectively. While the K(m) values of beta enzyme for gamma-palmitoil and beta-oleoil residues were 7.91 and 2. 68 mM, respectively. Both alpha and beta enzymes were inhibited strongly by cepharanthine. The lecithin hydrolysis of alpha enzyme was competitively inhibited, but beta enzyme was uncompetitive. Cepharanthine also inhibited noncompetitively PLA(2)s of bovine pancreas, bee venom and Naja mossambica mossambica.

Monocyte chemotactic and activating factor/monocyte chemoattractant protein-1-mediated histamine release from human nasal mucosa.

OBJECTIVES: To demonstrate the existence and localization of monocyte chemotactic and activating factor or monocyte chemoattractant protein-1 (MCAF/MCP-1) in human nasal mucosa and to verify its activity as a histamine-releasing factor. DESIGN: Detection of MCAF/MCP-1 in culture supernatants of nasal mucosa using Western blot analysis and assay of histamine release from basophils induced by these culture supernatants. Detection of MCAF/MCP-1 expression in nasal mucosa of patients with perennial allergic rhinitis using immunohistochemistry. PATIENTS: Twenty-one patients with house dust mite allergy, 7 nonallergic patients, and 5 patients with chronic inflammatory sinusitis participated in the study. All the allergic patients had positive test results for mite nasal allergy, detected by a clinical history, a nasal provocation test, and determination of specific mite IgE antibodies by a radioallergosorbent test. RESULTS: In Western blot analysis of supernatants of explant culture of human nasal mucosa, the band corresponding to approximately 13 to 15 kd was observed. This band was considered to be MCAF/MCP-1. These supernatants induced histamine release from basophils (approximately 3%-5% in net histamine release), and anti-MCAF/MCP-1 antibody inhibited this histamine-releasing activity. Immunoreactivity of MCAF/MCP-1 was observed in the nasal submucosa but not in the epithelium. Immunoreactive cells of MCAF/MCP-1 were also stained with the antibody, which recognizes monocytes and macrophages. CONCLUSIONS: These results suggest that MCAF/MCP-1, which is produced constantly by monocytes and macrophages and is stored in human nasal mucosa, possibly participates in the protracted histamine release from basophils and in the pathogenesis of perennial allergic rhinitis.

Spectrophotometric determination of trace sulphate in rain and snow after preconcentration with 2-aminoperimidine on a membrane filter.

A simple and precise preconcentration technique, based on collecting a precipitate on a membrane filter and dissolving the filter and precipitate in an organic solvent, has been applied to the spectrophotometric determination of trace sulphate in rain and snow. The sulphate is precipitated with 2-aminoperimidine and the resulting compound is dissolved in nitric acid, made alkaline with sodium hydroxide and then adsorbed on tetradecyldimethylbenzylammonium nitrate. The precipitate is then collected on a membrane filter and both precipitate and filter are dissolved in dimethylsulphoxide (DMSO). The absorbance of the DMSO solution is measured at 550 nm against a reagent blank. The molar absorptivity is 2.1 x 10(4) 1 . mole(-1) . cm(-1) and the coefficient of variation for six measurements is < 1.5%. The detection limit (S/N = 3) is 0.06 mug of sulphate in 5 ml of sample solution.

New sulfamoylphenethylamines, potent alpha 1-adrenoceptor antagonists.

The (+)-isomer of amosulalol, a combined alpha- and beta-adrenoceptor antagonist, was one log unit order more potent and less potent than the (-)-isomer in blocking alpha 1- and beta 1-adrenoceptors, respectively, in anaesthetized rats. Nine newly synthesized desoxy compounds derived from amosulalol and its analogues were found to possess potent alpha 1-adrenoceptor blocking activity and to be practically devoid of beta 1-adrenoceptor blocking activity. Among the desoxy derivatives, YM-12617 was more potent than prazosin in blocking alpha 1-adrenoceptors in anaesthetized rats and in reducing blood pressure, total peripheral resistance and left ventricular work in anaesthetized dogs.

Regional differences in homicide patterns in five areas of Japan.

This article describes regional differences in the homicide patterns which occurred in Sapporo City and the surrounding area, and in Akita, Ibaraki, Chiba and Toyama prefectures in Japan. Information collected from each case of homicide included factors such as age, sex of the victim and assailant, causes of death, disposition of the offender, relationship between assailant and victim, reasons for criminal action, et al. The statistical features of homicidal episodes among the five different regions showed considerable variation, as follows. The mean death rates for homicide (number of victims per 100,000 of population) during the period 1986-1995 were 0.44 (Sapporo), 0.8 (Akita), 0.58 (Toyama), 0.7 (Ibaraki) and 0.75 (Chiba), respectively. Close family relationship between the victim and assailant was observed in the homicidal acts which occurred in Sapporo, Akita and Toyama. Assailant's relationship to victim was commonly extra-familial in Ibaraki and Chiba-neighboring megalopolis Tokyo, where some events of murder by a foreigner occurred. Homicide by female assailant, murder by mentally abnormal killers and homicide-suicide events were closely associated with family members. And these factors contributed to the considerable number of victims in Sapporo, Akita and Toyama. But, this close family relationship of the victim to the assailant did not correspond with the elevation in the number of deaths, and it was rather inversely related to the higher death rates recognized in Ibaraki and Chiba. This comparative study suggested that rapid urbanization considerably affects regional differences in homicide patterns.

Tracheal aspiration cytology in neonates with respiratory distress: histopathologic correlation.

This report evaluates the use of tracheal aspiration cytology in the differential diagnosis of respiratory distress in neonates by correlating cytologic features with histopathologic findings in 72 infants who died and were autopsied at Magee-Womens Hospital. It is concluded that the common causes of respiratory distress in neonates, including hyaline membrane disease (conventional and yellow), pneumonia, aspiration syndrome, pulmonary hemorrhage and bronchopulmonary dysplasia, may be diagnosed in adequate smears by this easily accessible, noninvasive, safe and repetitive method.

Acute cerebellar hemorrhage in a patient with Klinefelter syndrome: XXY karyotype obtained postmortem from cells from pericardial fluid.

A case of Klinefelter syndrome and a spontaneous cerebellar hemorrhage in a 12-year-old boy is presented. Autopsy revealed that the hemorrhage was due to the rupture of a dilated artery in an arteriovenous malformation in the right cerebellar hemisphere. The small, undescended testes exhibited partial atrophy of the seminiferous tubules. Postmortem chromosome analysis of cells from the pericardial fluid demonstrated a 47, XXY karyotype. He had previous surgical treatment for bilateral thumb polydactyly and patent ductus arteriosus. In juvenile cases of sudden death with overlapping morphological dysgenesis, postmortem karyotyping may provide important diagnostic information.