Late-onset globoid cell leukodystrophy

During the past 12 years, ten cases of globoidcell leukodystrophy (GLD) have been followed up: seven of these patients were affected by the late infantile form. The authors point out the clinical aspects and the course of these patients and stress the high frequency of this form of GLD in Sicily.     

Effects of centrally administered neuropeptide Y (NPY) and NPY13–36 on the brain monoaminergic systems of the rat

Summary The effects of centrally administered NPY on the brain monoamine systems were investigated in the rat. Neuropeptide Y (0.2–5.0 nmol), its C-terminal 13–36 amino acid (a.a.) fragment, NPY_13–36 (0.4–10.0 nmol), or saline were injected into the right lateral cerebral ventricle of unrestrained rats. After l h the animals were decapitated, and the brains were taken out. Two cortical regions (frontal and parietal), the striatum, the hypothalamus, and the brain stem were dissected out. The tissue contents of noradrenaline (NA), dopamine (DA) and serotonin (5-HT), as well as of their major metabolites, 3-methoxy-4-hydroxy-phenylethylené glycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxy-indole acetic acid (5-HIAA) were measured. The most consistent finding was a dose-related increase of both DA and DOPAC levels after treatment with NPY. This effect was reproduced by NPY_13–36 in cortical tissue, whereas, in the sub-cortical regions, NPY_13–36 only reproduced the effects of NPY on the DOPAC levels. Less consistent effects were found on the NA systems, in which NA levels showed a tendency to increase following low, and decrease after high doses of NPY. These effects were largely reproduced by NPY_13–36. In addition, NPY increased tissue levels of MHPG in frontal cortical tissue in a dose-related manner. The brain 5-HT systems were not affected.     

Effects of chronic antidepressant treatment on α1- and α2-adrenoceptors in the rat anococcygeus muscle

Summary The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the ₂-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the ₁-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied.Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic ₁-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic ₂-adrenoceptors to xylazine. These results show that the adaptative changes of -adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize ₁-adrenoceptors.     

Amoeboid Microglial Cells and not Astrocytes Synthesize TNF-alpha in Swiss Mouse Brain Cell Cultures

The role of tumour necrosis factor (TNF-alpha) in brain physiology and pathology has been the focus of several studies. However, the source of this lymphokine in the central nervous system and the regulation of its synthesis is still poorly understood. We have therefore used purified astrocytes and brain macrophages in culture to compare the abilities of these two cell types to synthesize TNF-alpha and its mRNA. We find that, in the Swiss mouse, no significant TNF activity or TNF-alpha mRNA are produced by astrocytes, even following activation with lipopolysaccharides (LPS). On the other hand, purified microglial cells express a cytotoxic activity able to kill TNF-sensitive LM cells. Part of this activity is released into the culture medium and part remains bound to the membrane after mild paraformaldehyde treatment, demonstrating the existence in the culture of the soluble and membrane-bound forms of TNF activity. The fact that amoeboid microglial cells, and not astrocytes, are the actual source of TNF in brain cultures was further demonstrated by Northern blot analysis and in situ hybridization using a TNF-alpha specific oligonucleotide probe. The definition of the cell type which, in the CNS, is responsible for TNF synthesis will allow the regulation of this lymphokine to be analysed and opens the way for a better understanding of the interactions between amoeboid microglial cells and the other cell types which make up the nervous system.     

Atrial natriuretic peptides in canine hypoxic pulmonary vasoconstriction

STUDY OBJECTIVE--The aim of the study was to investigate whether atrial natriuretic peptides have a physiological role in regulation of the pulmonary circulation. DESIGN--Plasma concentrations of immunoreactive atrial natriuretic peptide and guanosine-3',5'-cyclic monophosphate (cGMP) were measured during evaluation of pulmonary vascular tone by multipoint pulmonary arterial pressure-cardiac index (Ppa/Q) relationships. SUBJECTS--Experimental animals were 17 mongrel dogs of either sex, 21-35 kg weight, anaesthetised with pentobarbitone. MEASUREMENTS and MAIN RESULTS--Measurements of Ppa/Q relationships and atrial natriuretic peptide/cGMP were made during hyperoxia (Fio2 0.4) and hypoxia (Fio2 0.1). Hypoxic pulmonary vasoconstriction, defined as hypoxia induced increase in pulmonary artery pressure over the entire range of Q studied from 2-5 litre.min-1.m-2, was elicited in nine dogs ("responders"). In the other eight dogs, hypoxia did not change pulmonary artery pressure over the entire range of Q studied ("non-responders"). At neither the highest nor the lowest Q in hyperoxia did atrial natriuretic peptide and cGMP concentrations differ between these two groups, nor did acute reduction in Q affect the concentrations in either group. At the highest Q, plasma atrial natriuretic peptide increased in hypoxia from 11(SEM 2) to 15(3) pmol.litre-1 in the responders (p less than 0.05), and from 15(2) to 20(2) pmol.litre-1 in the non-responders (p less than 0.05). However at the lowest Q, atrial natriuretic peptide was increased in non-responders only, from 17(3) to 23(4) pmol.litre-1 (p less than 0.05). CGMP did not vary significantly in any experimental condition. CONCLUSIONS--Hypoxia slightly increased plasma atrial natriuretic peptides without any relationship with associated pulmonary haemodynamic changes. These data do not support the hypothesis that atrial natriuretic peptides play a physiological role in the regulation of the pulmonary circulation in dogs.     

"Hemicrania Episodica"-A New Type of Headache or a Pre-Chronic Stage of Hemicrania Continua?

For seventeen years, a young man suffered from headaches of one to three days duration occurring once every six or seven days and totally disappearing between episodes. These were strictly unilateral (always on the left side), and were absolutely responsive to indomethacin. They differ clinically from the other two indomethacin-responsive headaches described up to now: Hemicrania Continua (HC) and Chronic Paroxysmal Hemicrania (CPH). He has a sister suffering from HC. Similar to HC, but unlike CPH, topical tyramine in our patient's eyes resulted in anisocoria before, but not after, indomethacin treatment. Our case differs from HC, however, in its time pattern; it could either be a pre-chronic stage of HC or a new type of headache. It seems unlikely that a time pattern that has remained unchanged for 17 years will become continuous, as in HC, in the future, and thus it is possible that our patient represents a case of a new type of headache that we propose to name "Hemicrania Episodica." In any case, it seems probable that this type of headache, although clinically different, may share a common pathogenic basis with HC.     

The use of macrolides in respiratory tract infections

Macrolides have enjoyed continued use for over 40 years, being increasingly used for the treatment of respiratory tract infections. Newer macrolides have been introduced that show improved absorption after oral administration, better gastrointestinal tolerance, and delivery of increased amounts of drug to the infection site. Macrolides are commonly used in community-acquired pneumonia, as well as in atypical pneumonia and legionellosis. The newer macrolides, in comparative studies, have been shown to be as affective as the conventional therapies for treating acute otitis media, acute sinusitis and acute pharyngitis, with a low incidence of side-effects. However, dosing can be simplified because of their unique pharmacokinetic properties. Limitations in the use of macrolides for respiratory infections include rather marginal activity in the most severe cases of Haemophilus influenzae infections, lack of activity against Klebsiella and other coliforms, which precludes their use as single agents in the therapy of pneumonia in patients with significant underlying disease or in the elderly, and development of resistance in streptococci and staphylococci.     

Hydrolysis of Carbonates,Thiocarbonates, Carbamates,and Carboxylic Esters of α-Naphthol, β-Naphthol,and p-Nitrophenol by Human,Rat, and Mouse Liver Carboxylesterases

Thirty carbonates, thiocarbonates, carbamates, and carboxylic esters of -naphthol, -naphthol, and p-nitrophenol were synthesized and tested as substrates for liver carboxylesterases from the crude microsomal fractions of human and mouse, and purified isozymes, hydrolases A and B, from rat liver microsomes. The carbonates, thiocarbonates, and carboxylic esters of -naphthol were cleaved more rapidly than the corresponding -naphthol isomers by the mammalian liver esterases. -Naphthyl esters of acetic, propionic, and butyric acids were among the best substrates tested for these enzymes. The majority of the substrates was consistently hydrolyzed at higher rates by hydrolase B compared with hydrolase A, although the Michaelis–Menten constant (K _m) values of selected substrates differed widely with these two isozymes. Malathion was a 15-fold better substrate for hydrolase B than for hydrolase A. Compared with the corresponding carboxylates, the carbonate moiety of - and -naphthol and p-nitrophenol lowered the specific activities of the enzymes by about fivefold but improved stability under basic conditions. The optimum pH of mouse liver esterase with the acetate, methylcarbonate, and ethylthiocarbonate of -naphthol was between pH 7.0 and pH 7.6. Human and mouse liver microsomal esterase activities were about five orders of magnitude lower than the esterase activities of purified rat liver hydrolase B. A relationship between the catalytic activity of the enzymes and the lipophilicity of the naphthyl substrates indicated that (i) in the - and -naphthyl carbonate series, an inverse relationship between enzyme activity and lipophilicity of the substrates was observed, whereas (ii) in the -naphthyl carboxylate series, an increase in enzyme activity with increasing lipophilicity of the substrates up to a log P value of about 4.0 was observed, after which the enzyme activity decreased.     

Inhibition of two imidazole antimycotics, eberconazole and clotrimazole, by different components of Candida albicans serotype B membrane protoplasts

The inhibitory activity of different components from Candida albicans membrane protoplasts against clotrimazole and eberconazole was studied. The phospholipid fraction had the most inhibitory activity and the antimycotic activity of eberconazole was more affected than that of clotrimazole.     

Evidence for an Interaction Between the β-Blocker Pafenolol and Bile Salts in the Intestinal Lumen of the Rat Leading to Dose-Dependent Oral Absorption and Double Peaks in the Plasma Concentration–Time Profile

Pafenolol is a -blocker with unusual oral absorption properties. The blood concentration–time profile exhibits two peaks, and the bioavailability is low and dose dependent because of incomplete and nonlinear intestinal uptake. We addressed the question whether the intestinal absorption of pafenolol was affected by bile depletion in the gut lumen of rats. Further, the hypothesis that variable gastric emptying accounts for double peaks in blood was tested by duodenal administration of pafenolol. Following intraduodenal administration to rats with intact bile secretion, double peaks were observed in the blood concentration–time curve. The bioavailability was 6.8 ± 0.7% for the low dose (1 µmol/kg) and increased significantly to 28 ± 10% following the high duodenal dose (25 µmol/kg). These blood concentration–time profiles exclude interrupted gastric emptying as cause of the twin peaks. In bile duct-cannulated rats the intestinal absorption of the low dose (1 µmol/kg) was still poor (F = 10.7 ± 5.5%) and the blood concentration–time profile contained two peaks. Following administration of a high duodenal dose (25 µmol/kg) to rats with an almost bile-free small intestine, the absorption rate increased and the double-peak phenomenon disappeared in five of seven rats, while the bioavailability increased significantly, to 62 ± 27%. These results suggest that the low bioavailability of pafenolol is due to a complexation between bile and pafenolol in the gut lumen, preventing intestinal uptake in the major part of the small intestine. Further, such complex formation in the intestinal lumen may be the underlying mechanism of the double peaks observed in the blood concentration–time profile.