Toxicokinetics of methylmercury and mercuric chloride in mouse embryos in vitro.
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Abnormalities, Drug-Induced↗
Biomedical subjects
Y Kajiwara
Publications and source records attributed to Y Kajiwara.
Combined effects of low-level methylmercury and x-radiation on the developing mouse cerebellum.
The effects of low-level methylmercury and x-radiation in combination on the developing mouse cerebellum were studied. Pregnant BALB/cJcl mice were divided into two groups. Dams of a group were orally given 9 micrograms Hg/g body weight of methylmercuric chloride on d 17 of pregnancy. The other dams were not treated. They were allowed to give birth, and the male pups were exposed to a single x-radiation at doses of 0.125 or 0.5 Gy on the day following birth. Sham-exposed pups were also prepared. The pups were killed at various postexposure periods, and their cerebella were removed and processed for microscopy and mercury analysis. Mercury was retained in the pup cerebellum at levels of 4-8 micrograms/g for 4 d and then lowered. Appearance and incidence of cell death in the external granular layer (EGL) were similar in groups exposed to 0.125 Gy alone or 0.125 Gy and methylmercury in combination. Fourteen percent of cells in the EGL were killed by exposure to 0.5 Gy with or without methylmercury. Restoration of the EGL from the damage was slightly retarded by methylmercury, but by 10 d of age these cerebella overtook the normal ones in development. These findings indicate that methylmercury does not modify the apoptotic cell death caused by x-radiation in the EGL but retards the tissue restoration from the damage.
Animals↗
Strain difference of the mouse in manifestation of hydrocephalus following prenatal methylmercury exposure.
Genetic background may influence susceptibility to hydrocephalus. In the present experiment we compared the manifestation of hydrocephalus following prenatal methylmercury exposure among strains of mice which sporadically develop or never develop spontaneous hydrocephalus. Pregnant mice of the B10.D2 congenic strain were given a single oral dose of 10 mg/kg methylmercuric chloride on one of days 14 through 17 of pregnancy and allowed to give birth and rear their litters. The incidence of grossly apparent hydrocephalus in the offspring at 30 days of age following treatment on day 14, 15, 16, or 17 of pregnancy was 67, 88, 75, and 48%, respectively; that of sham-treated and untreated offspring was 5 and 4%, respectively. In addition, there were some brains showing slight dilatation of the lateral ventricles. Pregnant females of C57BL/10 (B10) or DBA/2 (D2) strain were also treated with 10 mg/kg methylmercury on day 15 of pregnancy. The incidence of hydrocephalus at 30 days of age in untreated and dosed B10 mice was 0.8 and 54%, respectively. Hydrocephalus failed to develop in D2 mice. The hydrocephalus is a communicating type. Occlusion of the cerebral aqueduct with glial reaction and caudal displacement of the cerebellum are considered to be secondary changes. The results indicate that the susceptibility to methylmercury-induced hydrocephalus is under genetic control in mice.
Animals↗
Juvenile granulosa cell tumor in a three-year-old infant. An immunohistochemical and ultrastructural study.
A three-year-old female infant with a juvenile granulosa cell tumor of the ovary and precocious pseudopuberty is presented. Laboratory tests revealed elevated levels of serum and urinary estrogen. Histological examinations showed an immature follicular pattern surrounded by theca-like stromal tissue. The immunohistochemical localization of estradiol, estriol, progesterone and testosterone was studied by indirect immunoperoxidase staining of cryostat sections. All of these steroid hormones were localized mainly in stromal cells and in some follicular cells. Electron microscopic examination revealed three types of tumor cell, i.e. polygonal cells, spindle cells and transitional cells. Well developed smooth endoplasmic reticulum, mitochondria with tubulovesicular cristae, and lipid droplets in the cytoplasm, which are typical features of steroid synthesis, were conspicuous mainly in the last type of cell. Such transitional cells almost corresponded to steroid-positive cells. These cells were considered to have a close relationship to theca gland cells of developed ovarian follicles and to have mainly participated in steroid synthesis in the present tumor. In addition, some spindle cells showed features of myofibroblasts, such as intracytoplasmic filaments, dense body-like structures, and pinocytotic vesicles. These features suggest that the cells might all be derived from the same progenitor of ovarian mesenchyme.
Child, Preschool↗
Inhibitory activity and protein binding of L-lysine derivatives as angiotensin converting enzyme inhibitors.
Four compounds 1a-4a containing one L-lysine residue in the molecule including a diastereomer mixture of lisinopril (N-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline) and N epsilon-carbobenzoxy-L-lysine derivatives 1b-4b of each of the four compounds were synthesized to compare the angiotensin converting enzyme (ACE) inhibitory activities in vitro and in vivo. They all showed high ACE inhibitory activity in vitro (IC50 = 0.14-42 nmol/l). A marked difference, however, was observed in inhibition of the pressor response to angiotensin I between 1a-4a (high activity) and 1b-4b (low activity). The binding of these compounds to human serum proteins in vitro was investigated by means of equilibrium dialysis and ultracentrifugation. Compounds 1b-4b showed higher levels of binding to serum albumin than that of the corresponding compounds 1a-4a, and the percentage of binding ranged from 20.1 to 89.1%. Furthermore, the inhibitory activity of compounds 1b-4b in vitro was decreased by the addition of albumin in a concentration-dependent manner. These results suggested that the difference in the protein binding rate of compounds is one of the important factors influencing the inhibitory activity in vivo.
Angiotensin-Converting Enzyme Inhibitors↗
Hypotensive and hemodynamic effects of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline.
The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.
Administration, Oral↗
Synthesis and angiotensin converting enzyme inhibitory activity of N-carboxymethyldipeptides with omega-(4-piperidyl)alkyl group.
The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing 1(S)-carboxy-omega-(4-piperidyl)alkyl group at the N-terminal of the dipeptide is described. These 1-carboxy-omega-(4-piperidyl)alkyl derivatives possess greater or equivalent in vitro potency and in vivo efficacy than captopril and enalapril. The length (n) of the carbon chain in the omega-(4-piperidyl)alkyl moiety was varied from two to six to investigate the optimal structure for long-acting ACE inhibitors. 1-[N-[1(S)-Carboxy-6-(4- piperidyl)hexyl]-L-alanyl]-(2a,3a beta, 7a beta)-octahydro- 1H-indole-2-carboxylic acid (9b), the most potent member of the series, had an in vivo area under the curve (AUC) of 685, which was calculated by the inhibition of angiotensin I-induced pressor response vs. time curves (0 to 8 h) after p.o. administration.
Angiotensin-Converting Enzyme Inhibitors↗
Pharmacological properties of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline.
AB-47 (N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline) is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor with omega-aminoalkyl group. AB-47 was slightly more potent than enalaprilat in inhibiting rabbit lung ACE. The ACE inhibition and bradykinin (BK) potentiation by AB-47 in guinea-pig ileal longitudinal muscle were as potent as with enalaprilat. In conscious rat, AB-47 (i.v.) inhibited angiotensin I (A-I)-induced pressor response and augmented BK-induced depressor response more potently and in a long-lasting manner than enalaprilat. Furthermore, AB-47 exhibited higher selectivity for ACE inhibition than for BK inactivation and higher selectivity than enalaprilat and captopril. The inhibition of A-I-induced pressor response by AB-47 (p.o.) was as potent as that of enalapril. These results suggest that AB-47 is a highly potent, long-lasting and relatively A-I-selective ACE inhibitor.
Angiotensin-Converting Enzyme Inhibitors↗
Platelet protein phosphatases and their endogenous substrates.
One p-nitrophenyl phosphate phosphatase (A) and five protein phosphatases (B, C, D, E, F) with neutral pH optimum (7.0-7.5) were partially purified from human platelets. Protein phosphatases were activated by Mn2+ (B-F), Mg2+ (D, F) or Ca2+ (F) but all of them had substantial activity even in the presence of EDTA. The activity of phosphatase D was predominant when assayed in the presence of EDTA. Phosphatase F was significantly enhanced by Ca2+ and calmodulin and therefore considered to be calcineurin. Without strict substrate specificity, all protein phosphatases (B-F) dephosphorylated phosphoproteins like actin binding protein, 47k protein and myosin light chain. Thus, it was suggested that protein phosphatases might play a role in the down regulation of platelet function not only in the resting but agonist-stimulated platelets.
Blood Platelets↗
[A case of giant cavernous hemangioma with hemoperitoneum due to blunt abdominal trauma; CT findings].
A 55-year-old woman with a giant cavernous hemangioma in the liver with hemoperitoneum due to blunt abdominal trauma was reported. CT findings of the liver at first thought to be hepatic injuries. But serial studies revealed that the CT findings were dependent on giant cavernous hemangioma and apart from hepatic injury.
Abdominal Injuries↗
[Possible mechanisms of hematoma formation in the urinary tracts in a patient with idiopathic thrombocytopenic purpura].
A 30-year-old female was admitted to our hospital complaining of hematuria and right flank pain in September, 1987. She had been diagnosed idiopathic thrombocytopenic purpura in 1980, and had similar symptoms before. Hematoma in the right ureter was demonstrated by retrograde pyelography and CT-scanning, and these symptoms improved within one month. Each activity of plasma clotting factors was within normal limits. Enzymatic studies of the urine revealed low values of plasmin-, urokinase-, and kallikrein-like activities in both excerbation and remission. These hemorrhagic tendencies might have been the result of marked thrombocytopenia: After bleeding into the urinary tracts began, the bleeding would tend to form hematoma because of elevated clotting activity; then hematoma would grow due to decreased urine fibrinolytic activities. This suggested that a decline of fibrinolysis in urine might have a promoting effect on the process of hematoma formation.
Adult↗
[A case of gastric cancer (IIb) on the submucosal tumor (leiomyoma) of the stomach].
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Adenocarcinoma↗
[Trends in the incidence of uterine cancer in Nagasaki city, with special reference to previous atomic bomb exposure, 1973-1982].
An epidemiological study has been conducted to elucidate the trend in the incidence of uterine cancer, a with a reference also to previous A-bomb exposure. Studied were 783 cases (345 exposed and 438 nonexposed) of uterine cancer that were handled from 1973 to 1982. The incidence rate of cervical cancer was significantly higher among the population who came into Nagasaki city within two weeks after exposure. A comparison between the incidence rate of '73-'77 and '78-'82 revealed a decreasing trend of cervical cancer and an increasing trend of corpus cancer. The increasing rate of corpus cancer was higher in the younger group of a-bomb survivors (less than 59 years old) than in the other survivors.
Adult↗
Synthesis and angiotensin converting enzyme inhibitory activity of N-carboxymethyldipeptides with an omega-aminoalkyl group.
A series of novel L-alanyl- and L-lysyl-L-proline derivatives having an omega-amino-1-carboxyalkyl group was prepared, and assayed for their inhibitory activity against angiotensin converting enzyme (ACE). The dicarboxylic acids possesing S,S,S configuration showed potent in vitro ACE inhibitory activity with IC50 values of 0.68-1.4 nmol/l. The length of the carbon chain in the omega-aminoalkyl moiety was varied from 6 to 9 to investigate the optimal structure for long-acting ACE inhibitors. The most prolonged activity in vivo was observed with N-[8-amino-1(s)-carboxyoctyl]-L-alanyl-L-proline upon i.v. and p.o.
Alkylation↗
Primary malignant lymphoma of the rectum.
A rare case of a primary malignant lymphoma of the rectum in a 7 year old girl is presented. Although rectal polyps in children are usually benign juvenile polyps, a rare possibility of malignancy should be kept in mind. An adequate histological examination is essential.
Child↗
Synthesis and angiotension converting enzyme inhibitory activity of L-lysyl-N-substituted glycine derivatives.
The synthesis and biological activity of novel L-lysyl-N-substituted glycine derivatives which exhibit in vitro and in vivo angiotensin converting enzyme (ACE) inhibition, are described. Particularly, N-[N alpha-(1-carboxy-3-phenylpropyl)-L-lysyl]-N-(4-phenylcyclohexyl)glycine (11e), N-[N alpha-(1-carboxy-3-cyclopentylpropyl)-N epsilon-carbobenzoxy-L- lysyl]-N-cyclopentyl glycine (9h) and N-[N alpha-[1(S)-carboxy-3-cyclohexylpropyl]-L-lysyl]-N-cyclopentyl glycine (19a) showed a strong inhibitory activity at IC50 as low as 0.65, 0.64 and 0.11 nmol/l, respectively. The most potent activity in vivo was observed with the compound 19a after i.v. administration in the rat.
Angiotensin I↗
[Successful treatment of an infant with fulminant hepatitis by factor VII concentrate].
A 2-month-old boy was admitted to our hospital because of poor sucking and jaundice. There were no abnormalities during the whole period of pregnancy and at birth. His mother was a HBeAb positive HBsAg carrier, but prophylactic maneuver such as anti-HB immunoglobulin and HB vaccine was not performed on him at birth. Physical examination on admission revealed mild disturbance of consciousness. The laboratory findings showed marked increments of serum bilirubin, GOT, GPT, and NH3, and prolongation of prothrombin time, activated partial thromboplastin time and hepaplastin test. Thus, he was diagnosed as fulminant hepatitis and treated with exchange transfusion once or twice a day. Biochemical data improved gradually, but hypocoagulable states remained unchanged. At that time we decided to use Factor VII concentrate, because we found that, among several coagulation factors, factor VII activity decreased most rapidly after exchange transfusion. The alternate therapy of exchange transfusion and Factor VII concentrate improved his coagulation abnormality without any side effects. Our experience suggests that the combination therapy of exchange transfusion and Factor VII concentrate may be useful for management of fulminant hepatitis, particularly for uncontrollable coagulopathy.
Acute Disease↗
Studies on myosin light chain phosphorylation in intact platelets, utilizing a cell-penetrating thiol protease inhibitor.
By employing a cell penetrating thiol protease inhibitor, EST: ethyl(+)-(2S,3S)-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)buty lcarbamoyl]- 2-oxiranecarboxylate, the role of calpain, a major thiol protease in platelets, on 20K protein (myosin light chain) phosphorylation was examined in intact human platelets. EST dose-dependently inhibited 20K phosphorylation in platelets stimulated by thrombin, ionomycin or collagen. Phosphopeptides mapping revealed the phosphorylation by these agonists was rendered only by the action of myosin light chain kinase (MLCK). However, in TPA (12-O-tetradecanoylphorbol-13-acetate) stimulated platelets, EST did not inhibit 20K phosphorylation which was mediated by the action of C-kinase. [Ca2+]i determined by the use of quin-2 was elevated after the stimulation of thrombin, ionomycin or collagen but not TPA. Thus, it was suggested that calpain enhances MLCK activity on 20K phosphorylation in intact platelets following the stimulation by the agonist which elevates [Ca2+]i.
Blood Platelets↗