Variations in peroxisomal catalase of neonatal rat hepatocyte subpopulations

Alcohol consumption during pregnancy is teratogenic and induces severe alterations in hepatocytes. In the hepatocyte peroxisomal system, ethanol is converted in the presence of H₂O₂ to acetaldehyde and water. Therefore, peroxisomal catalase also acts as an antioxidant defence mechanism by removing H₂O₂ and preventing the formation of hydroxyl radicals in the cell. Alterations in peroxisomal catalase after pre- and pre+postnatal alcohol exposure were investigated in the rat. The effect of pre- and postnatal exposure to ethanol on hepatocyte subpopulations was analysed in isolated hepatocytes originating from periportal, intermediate and perivenous zones. Analysis of catalase revealed that the total activity and content of this enzyme were higher in 12-day-old cells than in cells from newborns and that this increment was more pronounced in treated cells. In controls, the amount of peroxisomal catalase increased mainly in periportal cells, whereas alcohol exposure induced a significant increase in the catalase of perivenous hepatocytes. We conclude that pre- and postnatal alcohol exposure mainly affects the perivenous hepatocyte peroxisomes and that the increase in peroxisomal catalase could constitute a defence mechanism against free radical generation induced by alcohol exposure during the perinatal period.     

Stress protection by external fixation of the rabbit tibia

Osteopenia of the tibia and femur caused by an external fixator in the tibia was studied in 14 rabbits. Eight rabbits were treated with a complete unilateral external fixator in one tibia, whereas the other tibia served as control. The other 6 animals had one leg operated on with inserting of all the pins but without the frame. This technique was chosen to compare osteopenia caused by stress protection and the effect of the pins. After 6 weeks, we found a 7 percent reduction in the bone mineral content in the tibial diaphyseal segment between the pins of the external fixator and no bone loss in the tibia that were operated on with only pins. In the femurs, there was a smaller decrease in the bone mineral content: respectively 3.2 percent (complete frame) and 2.9 percent (only pins). On all the operated on tibiae, there was an increase in the bone mineral content around the pins both proximally and distally.     

Closure of the cleft palate in one or two stages: the surgical methods

The details of two consecutive groups of cleft palate patients treated with one- or two-stage palate repair are presented. The total number of patients is 237, with 128 operated in one stage, and 109 operated in two stages. In the two-stage group, the frequency of 'unintended' palatal fistulas decreased by 80%, and the use of blood transfusions was greatly reduced, but total operation time and hospital stay were longer. The results in terms of speech quality, facial growth and dental occlusion, will be reported on separately.     

Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.     

Synthesis and Evaluation of Azole-Substituted Tetrahydronaphthalenes as Inhibitors of P450 arom,P450 17, and P450 TxA2

In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH₃ substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C₁-spacer between the rings (compounds 2 – 26 ). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA₂ (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA₂ inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH₃-2-(imidazol-4-ylmethylene)-1-tetralone ( 4 ) and 7-OCH₃-2-(imidazol-4-ylmethyl)-tetralin ( 12 ) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12 , the 6-OCH₃ derivative (compound 11 ) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA₂: 2-(imidazol-1-ylmethyl)-1-tetralone ( 13 ) is a selective inhibitor of P450 TxA₂, whereas 7-OCH₃-2-(imidazol-1-ylmethyl)-tetralin ( 17 ) as well as 2-(imidazol-1-ylmethyl)-tetralin ( 16 ) and 7-OCH₃-2-imidazol-1-yl-3,4-dihydronaphthalene ( 25 ) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.     

Necrosis observed on CT enhancement is of prognostic value in soft tissue sarcoma.

Fifty-one patients with deep-seated soft tissue sarcoma of the extremities and trunk wall were examined with contrast-enhanced CT for presence of nonenhanced tumor areas (CT necrosis). After a median follow-up time of 3 years, 19 of the 41 patients with CT necrosis had developed metastases, compared to none of the 10 patients who had tumors without CT necrosis. Tumors with CT necrosis were larger than tumors without, but in tumors of similar size, absence of CT necrosis was a favorable prognostic sign.     

The echocardiographic evolution of left ventricular hypertrophy in treated hypertensive patients. A long-term follow-up]

In order to study the possible regressive changes of left ventricular hypertrophy in treated hypertensive patients and to correlate them either with the drugs they received and/or the blood pressure reduction obtained, a long-term (6 years) echocardiographic follow-up study was performed in 61 patients. B and M mode echocardiographic septum and posterior wall thickness and left ventricular mass index were measured yearly and the type of ventricular hypertrophy, asymmetric septal or concentric (symmetric), were compared before and after the follow-up. Sixteen patients received only diuretics; 14, only propranolol, and associated therapy was used in the remaining 31 patients. Average blood pressure was significantly reduced in the whole group of patients, but, individually, 30 of them achieved normal levels for the diastolic (90 mmHg), remaining it over this value in the other, although all of them experienced an average reduction 10 mmHg with therapy. Those patients with concentric hypertrophy at entry showed a significant septal, posterior wall thickness and total ventricular mass reduction during the follow-up, those with initial asymmetric septal hypertrophy, a significant septal thickness and ventricular mass reduction, and those without hypertrophy on admission, showed an average paradoxical increase in septal thickness. We conclude that left ventricular hypertrophy disappeared or decreased in 48% of the patients and that treatment seems to prevent its progression or development in the 43% of all patients. The regressive or favorable changes were significantly more frequent among patients with normal blood pressure after treatment as well as among patients treated only with propranolol in comparison to those treated only with diuretics.     

Ontogenesis of the pyramidal cell of the mammalian neocortex and developmental cytoarchitectonics: a unifying theory.

The prenatal development of the mammalian neocortex has been analyzed, with the rapid Golgi method, in a variety of experimental animals (hamster, mouse, rat, and cat) and in humans. A new developmental conception of the structural organization of the mammalian neocortex is discussed. Neocortical development begins with the establishment of the primordial plexiform layer (PPL) which precedes and is a prerequisite for the subsequent formation of the cortical plate (CP). The formation of the CP occurs, in its entirety, within the PPL. During its development, three fundamental neuronal events occur: migration, early differentiation, and late maturation. All migrating neurons, travelling on radial glial fibers, reach layer I, develop an apical dendrite, and establish contacts with its elements. These newly differentiated neurons assume similar morphology resembling embryonic pyramidal cells. As such, an early differentiation stage common to all neurons of the CP is established. During the late maturation stage, all CP neurons acquire their specific phenotypic structural and functional features. Only pyramidal neurons retain and expand their original connections with layer I while other neuronal types lose these connections. The pyramidal cell is redefined in developmental terms: the neocortex's pyramidal cell is both structurally and functionally locked into position between layer I and the cortical depth of its soma. During mammalian evolution pyramidal cells are forced to structurally and functionally elongate their apical dendrite outwardly to accommodate an increasing amount of information without losing either their original anchorage to layer I or their cortical depth. This unique property of pyramidal neurons is considered to be a mammalian innovation. Based on these observations, a unifying developmental cytoarchitectonic theory applicable to all mammals is proposed. The theory considers the CP to be a mammalian innovation and to represent a single, stratified, and expanding telencephalic nucleus. The theory envisions the mammalian neocortex as an open biological system capable of progressive expansion by the recruitment and transformation of primitive neurons from upper layer II into pyramidal cells. Hence, the number of pyramidal cell strata increases over the course of mammalian phylogeny. The developmental roles of layer I in the migration of neurons, formation of the CP, unique morphology of pyramidal cells, and overall structural organization of the mammalian neocortex are emphasized.