Antiepileptic effects of allopurinol on EL mice are associated with changes in SOD isoenzyme activities

We have investigated the potential antiepileptic action of superoxide dismutase (SOD) activities in the brain of the epileptic mutant EL mouse. EL mice which experienced frequent seizures (EL[s]) had abnormally low levels of SOD isoenzyme activity in the hippocampal area. Once epileptogenicity was established in these animals, activity of cyanide-sensitive Cu,Zn-SOD was maintained at significantly lower levels than in control mice. However, cyanide-insensitive Mn-SOD activity was not different from non-epileptic controls. In EL mice which had not experienced seizure provoking stimulations and exhibited no seizures (EL[ns]) there was moderately lower levels of SOD isoenzyme activities compared to controls. In spite of the low level of Cu,Zn-SOD activity in EL[s] mice, the Cu,Zn-SOD protein content was high in the hippocampus of these animals, suggesting that inactive Cu,Zn-SOD might be induced during development. After allopurinol (ALP) was given orally to EL[s] mice, Cu,Zn-SOD activities increased dramatically in the hippocampus and seizure activity was decreased. Even after 48 h, when antiepileptic action of ALP was lost, the SOD activity was maintained at the high level associated with initial ALP administration. EL[s] mice also showed DNA fragmentation in the hippocampal CA1 region and the parietal cortex, detected with in situ terminal transferase-mediated dUTP nick labeling with the aid of alkaliphosphatase or peroxidase. The degree of DNA fragmentation was less severe in EL[ns] mice. We propose that abnormalities in region specific Cu,Zn-SOD isoenzyme activity might produce free radicals, leading to DNA fragmentations and cell loss. This might contribute to hippocampal epileptogenesis in EL mice.     

Vessel boundary extraction based on a global and local deformable physical model with variable stiffness

BACKGROUND: Oligomenorrhea, defined as a menstrual cycle lasting 36 to 90 days, can be a normal condition in the first years after the menarche. When it persists or appears after a period of normal menstrual cycles, an underlying illness must be sought. AIM: To assess ovulation and causes of anovulatory cycles in women with oligomenorrhea, compared with causes of secondary amenorrhea. PATIENTS AND METHODS: One hundred one women of less the 35 years old, presenting with oligomenorrhea persisting 5 years after menarche or lasting more than two years after a period of normal menstrual cycles, were studied. Ovulation was studied measuring serial plasma progesterone during normal or induced (with intramuscular progesterone) menstrual cycles. RESULTS: Eighty nine percent of women had anovulatory oligomenorrhea. The main causes were polycystic ovarian disease in 51% and hypothalamic dysfunction in 31%. Thirty percent of women with secondary amenorrhea had polycystic ovarian disease and 14% had hyperprolactinemia. Women older than 20 years old or with more than 10 years of gynecological age had a higher frequency of polycystic ovarian disease and a lower prevalence of hypothalamic dysfunction. CONCLUSIONS: There is a high frequency of anovulatory oligomenorrheas. Therefore, this symptom deserves a thorough endocrinological assessment to uncover underlying diseases. Special attention must be paid to polycystic ovary syndrome, due to its importance in internal medicine as a risk factor for myocardial infarction, high blood pressure, and type 2 diabetes mellitus.     

A natural kinase-deficient variant of fibroblast growth factor receptor 1

A fibroblast growth factor receptor 1 variant missing 37 amino acids from the carboxy-terminal tyrosine kinase catalytic domain was discovered in human lung fibroblasts and several other human cell lines. The receptor variant binds specifically to acidic fibroblast growth factor but has no tyrosine kinase activity. It was found that cellular transfectants expressing the fibroblast growth factor receptor 1 variant are mitogenically inactive and ligand binding to the receptor causes neither receptor autophosphorylation nor phospholipase C-gamma transphosphorylation. The fibroblast growth factor receptor 1 variant therefore represents an inactive receptor for acidic fibroblast growth factor. Since both kinase and kinase-deficient receptor forms are expressed in cells, it is conceivable that the kinase-deficient receptor plays an important role in regulating cellular responses elicited by acidic fibroblast growth factor stimulation.     

Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: implications for their carcinogenicity

The present study was undertaken to provide a rationale for the marked difference in carcinogenic potential among isomeric diaminotoluenes, in relation to their ability to induce their own bioactivation through CYP1A induction, their genotoxic potential, and their ability to bind to the cytosolic aromatic hydrocarbon (Ah) receptor. Of the four possible diaminotoluenes only the 2,3- and, to a lesser extent, the 2,4-isomer induced CYP1A activity. Similarly, only these two isomers could displace [3H]T-CDD from the hepatic cytosolic Ah receptor. In the presence of Aroclor 1254- induced microsomes, 2,4- and 2,6-diaminotoluene were potent mutagens in the Ames test. Only 2,4-diaminotoluene could autoinduce its activation. Of the four isomers only 2,4-diaminotoluene is an established carcinogen and this is compatible with the present observations that it is the only isomer that stimulates its own activation through CYP1A induction, is metabolically converted to genotoxic intermediates, and binds to the Ah receptor. 2,6-Diaminotoluene is recognized as a mutagenic noncarcinogen and in the present studies it elicited a positive mutagenic response in the Ames test but failed to induce CYP1A activity and its own activation, and could not bind to the Ah receptor even at concentrations as high as 5 x 10(-4) M. The present findings demonstrate that in vitro studies are very useful tools in predicting the carcinogenic potency of isomeric chemicals.     

Secretion-capture role for apolipoprotein E in remnant lipoprotein metabolism involving cell surface heparan sulfate proteoglycans

To determine the impact of enhanced apolipoprotein (apo) E secretion on the mechanism of remnant lipoprotein uptake, rat hepatoma cells (McA-RH7777) were stably transfected with normal human apoE3 or receptor binding-defective apoE-Leiden. After a 2-h incubation, the human apoE secreted from the transfected hepatocytes was 10-12 times greater than the endogenous rat apoE. The apoE3-transfected cells bound and internalized rabbit beta-very low density lipoproteins (beta-VLDL) to a much greater degree than did apoE-Leiden-transfected cells and nontransfected cells. The apoE3-secreting cells displayed a 2-3.5-fold enhancement of cell-associated beta-VLDL compared to either the apoE-Leiden-transfected or nontransfected cells. Fluorescently labeled beta-VLDL were observed to concentrate within intracellular granules of the apoE3-transfected cells, presumably within endosomes and lysosomes. Furthermore, electron microscopy revealed that the apoE3-secreting cells displayed abundant beta-VLDL and chylomicron remnants on their cell surfaces and microvilli, in contrast to non-transfected or apoE-Leiden-secreting cells. Electron microscopy also revealed an abundance of chylomicron remnants within intracellular vesicles and multivesicular bodies of apoE3-transfected hepatocytes. Heparinase treatment (3 units/ml) completely abolished the increased association of beta-VLDL with apoE3-transfected cells but did not affect the limited association of beta-VLDL with apoE-Leiden-transfected or nontransfected cells. We established that the apoE3-enriched beta-VLDL were bound to cell surface heparan sulfate proteoglycans, as was the newly synthesized and secreted apoE3 (approximately 12% of the total secreted apoE3 was released by heparinase and suramin; 4% by heparin). In addition, reisolation of beta-VLDL by fast performance liquid chromatography after their incubation with exogenous apoE3, with medium from apoE3-secreting cells, or with the apoE3-secreting cells themselves revealed that the particles were enriched in apoE3 and displayed enhanced binding. These results suggest a secretion-capture role for apoE and indicate an important role for heparan sulfate proteoglycans on the cell surface for remnant lipoprotein metabolism.     

CD56+ NK lymphomas: clinicopathological features and prognosis

Dosing regimen is an important determinant of both drug cost and patient compliance. This retrospective analysis evaluated dosing regimens and drug acquisition costs for 101 patients identified from medical records in a large metropolitan hospital as having hypertension and/or benign prostatic hyperplasia and receiving alpha-blocker therapy with either doxazosin or terazosin. Although once-daily administration is generally recommended for both drugs, 25 (38%) of 66 patients receiving terazosin were treated twice daily compared with 6 (17%) of 35 patients treated twice daily with doxazosin. This difference was statistically significant. The average (mean +/- SD) daily treatment cost per patient for all individuals receiving terazosin during the period of the record review was $1.68 +/- 0.60. For patients treated with doxazosin, the average was $0.96 +/- 0.65-a highly statistically significant result. If all 66 patients receiving terazosin had been converted to doxazosin at the beginning of the study, annual savings would have been $17,345.00. These results demonstrate the importance of reviewing actual dosing regimens. The fact that doxazosin could be administered to a significantly higher percentage of patients once daily rather than twice daily substantially decreased its cost relative to terazosin. A once-daily treatment regimen may also enhance patient compliance, thereby improving the chances of therapeutic success.     

APC-mediated proteolysis of Ase1 and the morphogenesis of the mitotic spindle

The molecular mechanisms that link cell-cycle controls to the mitotic apparatus are poorly understood. A component of the Saccharomyces cerevisiae spindle, Ase1, was observed to undergo cell cycle-specific degradation mediated by the cyclosome, or anaphase promoting complex (APC). Ase1 was degraded when cells exited from mitosis and entered G1. Inappropriate expression of stable Ase1 during G1 produced a spindle defect that is sensed by the spindle assembly checkpoint. In addition, loss of ASE1 function destabilized telophase spindles, and expression of a nondegradable Ase1 mutant delayed spindle disassembly. APC-mediated proteolysis therefore appears to regulate both spindle assembly and disassembly.     

Evaluation of staging conformity CTNM and PTNM for lung cancer

A series of 225 consecutive lung cancer patients were prospectively randomized into study group (75 patients) and control group (150 patients), and the conformity of CTNM and PTNM staging was was evaluated. Radical mediastinal lymph node dissection was performed and in average 11.5 nodes were dissected in the study group. Only suspected metastatic lymph nodes, 3.4 in average, were dissected in the control group. CTNM classification was made according to clinical examination, chest image examination and bronchoscopy in every patient and PTNM staging was made after thoracotomy. Then the conformity of CTNM and PTNM staging was examined by Kappa value. The results showed that the Kappa value in the two groups was lower than the effective standard value of 0.4. The study group (Kappa = 0.097) was poorer than the control group (Kappa = 0.371). The principal influencing cause was that N was not well evaluated by CTNM. The principal manifestation of the staging inconsistency was that the stage of PTNM was advanced than that of CTNM. In the study group 43% of patients showed an increased stage and this occurred in 33% of the control group (P < 0.05). The results of the study show that at present the CTNM staging has not fully satisfied the needs of practice and requires to be further improved. The operative procedure which only dissects suspected involved mediastinal lymph nodes can not meet the needs of PTNM staging. In order to make PTNM staging accurately and evaluate the results of treatment for lung cancer, radical mediastinal lymph node dissection should be performed in every operable patient.