In order to reveal the precursor lesion of hepatocellular carcinoma, a histopathologic study was performed on 141 cases of liver cirrhosis with or without hepatocellular carcinoma. Exclusive of primary or metastatic hepatocellular carcinoma nodules, 94 nodular lesions (greater than 5 mm) were detected in 53 cirrhotic livers. They consisted of 83 large regenerative nodules and 11 dysplastic nodules. Besides some common features with those observed in the former type, the dysplastic nodules presented increased cytoplasmic basophilia, nuclear and nucleolar enlargement, nuclear crowding, occasional microacinar formation and proliferation of the hepatocytes within fibrous septa. These changes were not substantial enough to allow the diagnosis of hepatocellular carcinoma. In one case, however, malignant transformation of hepatocytes was suspected because of their pattern of extranodular outgrowth. It is important to recognize these subtle abnormalities in order to define premalignant hepatic lesions. A possible connection between benign large regenerative nodules and dysplastic nodules is also discussed.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

Dopamine metabolism in the central nervous system after discontinuation of L-dopa therapy in patients with Parkinson disease.

The dopamine turnover rate in the central nervous system (CNS) of parkinsonian patients was studied by means of the intravenous probenecid test during drug holiday (DH) and alternate day L-dopa therapy (ADDT). After L-dopa therapy was stopped, the dopamine turnover rate decreased more rapidly in patients with the marked wearing-off phenomenon than that in patients without fluctuation of symptoms. The lumbar CSF concentrations of L-dopa and 3-O-methyldopa of patients with and without wearing-off phenomenon were similar during L-dopa therapy. DH improved the effect of L-dopa on parkinsonian symptoms; it did not affect, however, the metabolism of exogenous L-dopa. The dopamine turnover rate in the CNS before L-dopa therapy or on on-days did not differ between patients tolerating and those not tolerating ADDT. However, it was significantly lower on off-days in patients not tolerating ADDT than in those tolerating ADDT. The relationship between dopamine storage in the CNS and the response to L-dopa therapy is discussed.

Adult↗

PubMedDate not supplied

Effect of clomiphene on rat zygotes.

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Animals↗

PubMedDate not supplied

Posttraining administration of gastrin-releasing peptide improves memory loss in scopolamine- and hypoxia-induced amnesic mice.

We examined memory improvement with respect to the effects of gastrin-releasing peptide (GRP) in male C57BL/6J mice under conditions of experimentally induced amnesia. GRP was administered following training in a one-trial passive avoidance test. In Experiment 1, the drug scopolamine (1 or 2 mg/kg, ip) was used to induce amnesia prior to training, and GRP (32 nmol/kg, ip) or saline (control) was administered immediately after training. Results indicate that GRP at this dose improved memory only when the dosage of scopolamine was relatively low (1 mg/kg). In Experiment 2, CO2-induced amnesia was employed. Mice were placed in a chamber filled with CO2 or air (control) immediately after acquisition training. Subsequently, they were administered either saline or GRP (32 nmol/kg, ip). Significantly longer light-dark latency was observed in all mice that received GRP (both experimental and control groups). In total, our results indicate that the effect of GRP at this dose on the improvement of impaired memory is dependent on the degree of impairment. Furthermore, because CO2-induced hypoxia is known to decrease acetylcholine release in the brain, our results also suggest that GRP and its receptor may interact with the cholinergic system in the central nervous system.

Acetylcholine↗

PubMedDate not supplied

Effects of prenatal and postnatal exposure to styrene dimers and trimers on reproductive function in rats.

Styrene dimers and trimers (SDT) were evaluated for reproductive toxicity in Sprague-Dawley rats. SDT was administered orally to rats at doses of 0, 0.04, 0.2, and 1.0 mg/kg from day 6 of gestation through day 21 after delivery. Clinical signs, including pregnancy and lactation, and changes in body weight and food consumption were assessed. All dams underwent a gross necropsy examination. The brain, liver, kidney, ovary, uterus, thyroid gland, and pituitary were weighed. Offspring were evaluated for the effects of the test compound on viability, growth, anogenital distance, preputial separation and vaginal opening, behavioral function, estrous cycling, mating, and fertility. There were no test compound-related clinical signs or effects on body weight or food consumption in dams during any phase of the study. In addition, no abnormalities in delivery or lactation, including gestation length, were noted in any dam. No dose-dependent changes were observed in pup viability or growth. There were no adverse effects of SDT on any developmental landmark, learning, memory, or estrous cycling in offspring. The number of days to inseminations in the 0.2 mg/kg group was significantly greater than that in the control group, but was independent of dose. No test compound-related necropsy findings were seen in either the dams or the offspring. No compound-related histopathologic findings were noted in the reproductive tissues of either the male or female offspring. No compound-related alterations in sperm motion or density were detected in the offspring. Thyroid stimulating hormone levels in the male offspring of the 0.2 mg/kg and 1.0 mg/kg groups were significantly higher than those in the controls, whereas thyroid hormone (T(3), T(4)) levels in these groups were comparable to the controls. In addition, the thyroid glands of males in all groups were similar histologically. These results indicate that SDT administered at doses as high as 1.0 mg/kg (1000 times the estimated human daily intake) did not produce reproductive toxicity in dams or offspring.

Animals↗

PubMedDate not supplied

Reproductive effects of nonylphenol in rats after gavage administration: a two-generation study.

The potential reproductive toxicity of nonylphenol (NP) was assessed in a two-generation reproductive toxicity study. Groups of 25 male and female Crj:CD (SD) IGS rats were given NP by gavage at levels of 2, 10, or 50 mg/kg, and 25 males and females were given corn oil as controls. No adverse changes in clinical signs were observed in any rats throughout the study. Significant increases in the liver, kidney and pituitary gland weights in males, and decreases in thymus weight in males and in ovary weight in females were observed in the 50 mg/kg group. NP did not affect sperm characteristics or the estrous cycle at any dose administered. A significant increase in the TSH level was observed in males in the 50 mg/kg group. No adverse effects of NP on reproduction were found. At necropsy, no treatment-related alterations were observed in any organs including the reproductive tissues in any group. Histopathologic changes were found in the liver of male and female rats and kidneys of males in the 50 mg/kg group. The viability of offspring from postnatal day 0 to 4 in the 50 mg/kg group was reduced as compared with that in the controls, although growth was not affected by NP administration. On postnatal day 22, an increase in the serum FSH level and decrease in T(3) level for males, and decreases in LH and TSH levels and an increase in T(3) levels for females were observed in the 50 mg/kg group. NP did not affect the timing of preputial separation, while vaginal opening was accelerated in the 50 mg/kg group. No adverse changes were found in behavior or learning in the offspring of NP-treated groups. There were no treatment-related changes in any reproductive parameter, including estrous cycle, mating, fertility, delivery, and lactation, except for significant decreases in the numbers of implantation sites and live pups, and a significant decrease in ovary weight in the 50 mg/kg group. Kidney and liver weight were increased in males in the 50 mg/kg group. Histopathologic examination revealed changes in the liver of males and females of the 50 mg/kg group. No treatment-related changes were observed in the sperm characteristics. Hormone data should be interpreted cautiously until the findings are repeated and confirmed by further studies. These results of NP suggested that the no observed adverse effect level (NOAEL) on reproductive capacity is 50 mg/kg/day or greater in parent animals, and 10 mg/kg/day in the next generation under the present experimental condition.

Administration, Oral↗

PubMedDate not supplied

The role of the protein C-thrombomodulin system in physiologic anticoagulation during cardiopulmonary bypass.

Changes in the protein C-thrombomodulin (PC-TM) system in relation to other coagulofibrinolytic parameters were examined in 25 patients undergoing open heart surgery. Although all patients were given heparin, a decrease in antithrombin III (ATIII) and progressive increase in thrombin-ATIII complex (TAT) and fibrinopeptide A (FPA) levels were noted during cardiopulmonary bypass, which indicated that heparinization did not completely inhibit the formation of thrombin and its function. C1-inactivator (INA) resistant fibrinolytic activity increased markedly during CPB, in parallel with the change of tissue plasminogen activator antigen (t-PA;Ag), which indicates that fibrinolytic activity during CPB is mainly of extrinsic origin caused by t-PA. Protein C antigen (PC;Ag), protein S antigen (PS;Ag), and thrombomodulin antigen (TM;Ag) were all decreased significantly during CPB. This is considered to reflect the activation and consumption of the PC-TM system in response to generated thrombin. Furthermore, enhancement of the extrinsic fibrinolytic system is easily explained by the action of activated PC, which counteracts plasminogen activator inhibitor (PAI-1), to cause enhancement of t-PA activity.

Adult↗

PubMedDate not supplied

Interstitial tumour cell invasion in small hepatocellular carcinoma. Evaluation in microscopic and low magnification views.

In order to study the process of hepatocellular carcinoma (HCC) development, and to search for a clue to histologic diagnosis of well-differentiated HCC (wd-HCC), interstitial invasion in small HCC was evaluated. The study material consisted of 35 cases of HCC that were smaller than 3 cm that comprised 17 cases of wd-HCC, 18 cases of moderately or poorly differentiated classical HCC (cl-HCC), and 20 cases of large regenerative nodules (LRN). Interstitial invasion was microscopically classified into three patterns: (i) crossing type, in which HCC was invading across fibrous septa of tumour nodules; (ii) longitudinal type, in which tumour cells were growing longitudinally within fibrous septa; and (iii) irregular type, in which the portal area was irregularly invaded by HCC. The crossing type was found in two cases (12%) of wd-HCC and 10 cases (56%) of cl-HCC while the longitudinal type was observed in 16 cases (94%) of wd-HCC and eight cases (44%) of cl-HCC. The irregular type was frequently seen in wd-HCC (15 cases, 88%), and cl-HCC (12 cases, 67%). No interstitial invasion was observed in LRN. Interstitial invasion could be recognized even in the low magnification view of histological specimens, with a detection rate of 59% (10 cases) in wd-HCC and 72% (13 cases) in cl-HCC. These results suggest that evaluation of interstitial invasion is useful in diagnosing wd-HCC independent of cellular atypia. In addition, such invasive growth is revealed to play an important role in destroying original hepatic architecture during its developmental process from the early to advanced stages.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

UV-dependent quinolone-induced human erythrocyte membrane lipid peroxidation: studies on the phototoxicity of Y-26611, a new quinolone derivative.

Quinolone antibacterial drugs are widely used as oral therapeutic agents. However, in some patients they cause ultraviolet (UV)-dependent dermatitis. Using lipid peroxidation as an index of phototoxicity, we studied the effects of a new quinolone derivative, Y-26611 together with ofloxacin, sparofloxicin and lomefloxacin on washed human erythrocyte suspensions. Irradiation of erythrocytes with UV-A or UV-B for 60 min. in the presence of Y-26611 (30-600 micrograms/ml) strong dose dependent lipid peroxidation, up to 17.01 nmoles/ml was induced. Under identical conditions, lipid peroxidation induced by up to 600 micrograms/ml ofloxacin, sparofloxacin or lomefloxacin were 0.94, 3.36 and 2.98 nmoles/ml respectively. The lipid peroxidation was entirely dependent on both UV as well as the drug. The lipid peroxidation responses to drug+UV could completely be inhibited by sodium azide (hydroxyl radical, HO. and single oxygen, 1O2 scavenger) or by phenyl N-tert-butylnitrone (PBN, HO. and superoxide anion radical, O2- scavenger). It is likely that reactive oxygen species generated by interaction between UV-sensitized drug molecules and oxygen molecules mediate erythrocyte membrane lipid peroxidation. The method used in this study is rapid and convenient for screening drugs for UV-dependent cytotoxicity.

4-Quinolones↗

PubMedDate not supplied

The expression of presenilin 1 mRNA in skin fibroblasts and brains from sporadic Alzheimer's disease.

We examined the expression of presenilin 1 (PS-1) mRNA in cultured skin fibroblasts taken from living patients with Alzheimer's disease (AD) and human brains taken postmortem from AD patients by RT-PCR analysis. The donors of fibroblasts consisted of 28 cases with AD and 19 neurological patient without dementia (CTL). The brains came from 17 cases with AD and 23 cases with CTL. We found that PS-1 mRNA levels in skin fibroblasts of AD patients were significantly higher than those of CTL patients (p < 0.0001). Moreover, we found that PS-1 mRNA levels in human brains with AD were significantly higher than in those with CTL (p < 0.0001). These findings suggest that high levels of PS-1 mRNA in AD may play an important role in developing AD and that the examination of PS-1 mRNA in skin fibroblasts may be helpful for the diagnosis of AD.

Aged↗