Effects of physiological and pathological levels of glucocorticoids on skeletal muscle glutamine metabolism in the rat

The effects of physiological and pathological concentrations of glucocorticoids were investigated using the glucocorticoid antagonist RU486 and the synthetic glucocorticoid dexamethasone, respectively. The effects of these treatments on the concentrations of glutamine and other amino acids in skeletal muscle and plasma and on the rates of release of glutamine and alanine from incubated preparations of skeletal muscle of the rat were investigated. Dexamethasone treatment increased the concentration of glutamine and the rate of release of this amino acid from incubated soleus muscle preparations. This treatment decreased the concentration of glutamine in both gastrocnemius and EDL muscles, but was without effect on the rate of glutamine release from EDL muscles. In contrast, administration of the glucocorticoid antagonist RU486 decreased the rate of glutamine release from muscle. It is concluded that glucocorticoids have marked effects on the metabolism of glutamine by skeletal muscle per se and that these hormones may be important in the control of the rate of glutamine release from muscle in both physiological and pathological conditions.     

Synthesis of antimicrobial agents. 3. Syntheses and antibacterial activities of 7-(4-hydroxypiperazin-1-yl)quinolones

A series of novel pyridone carboxylic acids having a 4-hydroxypiperazinyl group at the 7-position of norfloxacin and ciprofloxacin were prepared. The in vivo antibacterial efficacies of these compounds were superior to those of corresponding piperazinyl derivatives. From the results of the studies on the pharmacokinetic profile and toxicity, the 4-hydroxypiperazinyl derivatives were confirmed to be pharmacologically superior to corresponding piperazinyl derivatives. Thus, a 4-hydroxypiperazinyl group was revealed to be a beneficial substituent for potential use in future quinolone antibacterials.     

The experimental pharmacotherapy of the liver lesion induced by indomethacin

In experiments on albino rats it was established that three administrations of indomethacin in a dose of 0.01 g/kg body weight induced a severe damage of the liver characterized by disturbances of hepatocytic membranes, bile-producing and protein-producing functions of the liver, an enhancement of lipid peroxidation, a decrease of reduced glutathione pool. Antioxidants (tocopherol acetate, essentiale, legalon, flacumin) limit manifestations of indomethacin, hepatotoxicity, as a result of which tha functional-biochemical disorders in the liver show up to a lesser degree. During the combined use of antioxidants in indomethacin-induced lesions of the liver their hepatoprotective activity increases.     

Free-floating thrombus of the extracranial internal carotid artery

Free-floating clots of the extracranial internal carotid artery are generally considered as surgical emergencies. This retrospective study analyzes six free-floating clots diagnosed by arteriography. Three of these patients had a fixed stroke while the other three had an evolving stroke. Three patients had antecedent ocular or hemispheric transient ischemic attacks. The causes of free-floating clots in the internal carotid artery were atheromatous stenosis in two cases, ulcerated plaque in three cases, and carotid artery dissection in one. All six patients were seen late, approximately 15 hours after their neurologic accident. They were treated with intravenous heparin over a two to five week period. Repeat arteriograms demonstrated complete clot lysis in four instances, while partial lysis was seen in one case. Moderate extension of thrombus occurred in one case only. No further neurologic complications were noted during the treatment by heparin. As indicated by follow-up arteriographic findings, secondary surgery was performed for major carotid lesions and residual clots in five cases. The free-floating thrombus syndrome of the carotid artery should not be considered as a surgical emergency when discovered late in the wake of an acute neurologic accident.     

A chemically defined medium for the culture of mature oligodendrocytes

A new chemically defined medium consisting of equal parts of Dulbecco modified Eagle's and Ham's F-12 media supplemented with insulin, sodium selenite, putrescine, and D+ galactose, which allows the long-term survival of mature oligodendrocyte pure cultures, is described. Immunohistochemical staining has shown that over 90% of the cells become positive for myelin proteins shortly following subculture. Contaminating astrocytes (2%) do not survive in this medium. Biochemical data have indicated that these purified oligodendrocytes express 2'3'-cyclic nucleotide 3'-phosphohydrolase and UDP-galactose ceramide galactosyltransferase activities. Electron microscopical examination revealed that the oligodendrocytes were mostly of medium-dark type and appeared to be identical to cells cultured in serum-containing medium. The ability to maintain pure oligodendrocyte cultures in such a defined medium will allow investigations concerning exogenous and endogenous factors involved in oligodendrocyte metabolism.     

Facilitated uptake of zinc into human erythrocytes. Relevance to the treatment of sickle-cell anaemia

The ability of a number of heterocyclic metal chelators to deliver zinc into red cells, to release the liganded zinc to haemoglobin and thereby cause a left shift in the oxygen dissociation curve of intact red cells has been investigated. Incubation of neutrally charged zinc-pyrone and zinc-pyridin-2-one complexes with red cells led to the rapid accumulation of zinc within cells, whereas unliganded zinc in the form of zinc acetate, zinc chloride or zinc sulphate accumulated only slowly. The rate at which zinc was delivered to red cells by pyrone and pyridin-2-one ligands increased with increasing lipid solubility of the ligands. The uptake of zinc into both normal adult and sickle red cells was associated with a dose-dependent increase in the oxygen affinity of haemoglobin. The degree of left shift in the oxygen dissociation curve following the incubation of red cells with zinc-pyrone and -pyridin-2-one complexes suggests that these complexes may find application as agents to increase the oxygen affinity of haemoglobin in sickle cell disease and thereby decrease the probability of intravascular sickling at low tissue oxygen tensions. Ethylmaltol appears to be a particularly useful agent due to its known low toxicity.     

Short term treatment by fenofibrate enhances oxidative activities towards long-chain fatty acids in the liver of lean Zucker rats

Lean Zucker rats were dosed orally for 1 week with fenofibrate (100 mg/kg/day). Liver weights of treated rats, expressed as per cent of body weight, were increased, while protein, DNA and triacylglycerol contents were not changed to any great extent per gram of liver, but increased when expressed per whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly enhanced by fenofibrate, both per gram of liver and per total liver, while urate oxidase activity was slightly depressed when expressed per gram of liver. The activity of cytochrome c oxidase used as a mitochondrial marker was only higher when expressed per total liver. Besides, fenofibrate treatment induced a pronounced increase in the mitochondrial activities of carnitine palmitoyl- and acetyltransferases, of palmitoyl-CoA dehydrogenase and of carnitine-dependent oleate oxidation. Fenofibrate also enhanced significantly the carnitine content in liver and hepatic mitochondria. Malonyl-CoA content per gram of liver was found to be twice as high as in control rats, while the sensitivity of carnitine acyltransferase I to malonyl-CoA inhibition was hardly altered. The drug enhanced the percentage of palmitic acid in lipids of liver, but not in adipose tissues. The present data show that fenofibrate induced greater oxidative activities towards fatty acids, even in the lean animal. This stimulation could be related to the energy used for building new cells. In turn, at the same time of treatment, an enhanced fatty acid synthesis would provide specific fatty acids for the formation of new membranes. This latter effect will eventually disappear and the maintenance of a higher fatty acid oxidation may explain part of the overall hypolipaemic effect of fenofibrate.     

Reduction of reticulata neuronal activity by zolpidem and alpidem, two imidazopyridines with high affinity for type I benzodiazepine receptors

Zolpidem and alpidem, two imidazopyridines with high affinity for the type I benzodiazepine recognition site, have recently been proposed as preferential hypnotic (zolpidem) and anxiolytic (alpidem) drugs notable for the minor incidence of side-effects. To further characterize the molecular mechanism involved in the action of these drugs, we studied their effects in comparison with those of diazepam on the spontaneous electrical activity of substantia nigra pars reticulata (SNR) neurons. These cells have been shown to be extremely sensitive to various positive and negative modulators of GABAergic transmission. All three drugs consistently produced a dose-dependent (0.03-8.0 mg/kg i.v.) inhibition of the firing of SNR cells when administered as a single bolus. However, zolpidem was more potent and efficacious than diazepam or alpidem. The ID50s were 0.076, 0.492 and 0.821 mg/kg, respectively. When the drugs were injected in exponentially (ratio 2) increasing doses up to 8.0 mg/kg, the rank order for tachyphylaxis was zolpidem much greater than diazepam greater than alpidem. Since the effects of the drugs were abolished and prevented by a small dose (0.5 mg/kg i.v.) of flumazenil (Ro 15-1788), it is likely that the effects were mediated through activation of benzodiazepine receptors. The results indicate that the hypnotic, zolpidem, has a more potent inhibitory action on SNR cell activity than the anxiolytics, alpidem and diazepam.     

A modified algorithm for the management of ureteral calculi: 100 consecutive cases

We treated 100 consecutive ureteral calculi requiring intervention with a previously described algorithm. There were 16 ureteropelvic junction, and 18 upper, 22 mid and 44 lower ureteral calculi. Treatment was by a stent and extracorporeal shock wave lithotripsy in 10 ureteropelvic junction, 10 upper ureteral and 3 mid ureteral calculi, ureteroscopy and extracorporeal shock wave lithotripsy in 6 upper and 6 mid ureteral calculi, and ureteroscopy alone in 5 ureteropelvic junction, 2 upper and 12 mid ureteral calculi. All 44 lower ureteral calculi were treated successfully by ureteroscopy. Of the 100 patients studied 98 were treated by endourological methods (extracorporeal shock wave lithotripsy or ureteroscopy), while 2 required an operation (1 with a ureteropelvic junction calculus and 1 with a mid ureteral calculus). Over-all, 100 patients required a total of 125 procedures to accomplish successful stone removal. An algorithm is developed in which lower ureteral calculi are treated by ureteroscopy, mid ureteral calculi (large and dense) by stent bypass and extracorporeal shock wave lithotripsy or (lucent and fragile) by ureteroscopy, upper ureteral calculi by stent bypass and extracorporeal shock wave lithotripsy without manipulation, and impacted ureteral stones initially by ureteroscopy and, if necessary, then by extracorporeal shock wave lithotripsy.     

Giant hydronephrosis presenting as unilateral iliofemoral vein thrombosis

We report a case of left iliofemoral vein thrombosis with extension to the inferior vena cava associated with giant right hydronephrosis secondary to ureteropelvic junction obstruction. Surgery revealed marked infrarenal vena caval compression and deviation to the left side caused by the dilated right renal pelvis, with resultant kinking of the origin of the left iliac vein. It is postulated that the reduction in blood flow caused by this compression and distortion predisposed this patient to venous thrombosis.