Intestinal parasitic infections in homosexual men.
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Homosexuality↗
Biomedical subjects
L Bossi
Publications and source records attributed to L Bossi.
Alterations of GABA-mediated synaptic transmission in human epilepsy.
Although animal models consistently indicate that gamma-amino-butyric acid (GABA) synaptic function (GABA levels, synthesis, uptake and/or receptors) is decreased in seizure states, there is little evidence to date in support of such a hypothesis for human epilepsy. This chapter presents the results of an in-depth study of the activity of the GABA-synthesizing enzyme L-glutamic acid decarboxylase (GAD) in brain tissue removed during neurosurgical resection for intractable epilepsy. The tissue studied is unique in that identified (by stereo EEG) foci were excised (rather than large blocks of tissue containing mixtures of foci and nonepileptic material) and compared with nonepileptic (stereo EEG and morphological definitions) tissue from the same patients. In patients in which there was no indication of a tumor, GAD activity in the foci was low in more than 50% of the patients examined. Furthermore, when the population distribution of GAD was compared in epileptic versus nonepileptic tissue fragments from all patients, the peak distribution of epileptic tissue fragments occurred at much lower GAD activities than for the nonepileptic fragments (0-20 versus 41-80 nmol CO2/mg protein X hr, respectively). A small subgroup of epileptic fragments occurred with a normal GAD distribution, indicating that the presence of an epileptic focus was not invariably associated with low GAD activity. When the low levels of GABA "A" binding sites in these epileptic tissue fragments are taken into consideration in combination with the low GAD levels, then it can be estimated that 60 to 70% of the present patient population had deficient GABAergic transmission in epileptic foci as compared to nonepileptic brain tissue from the same patients. It follows that the GABA hypothesis of human epilepsy is not an exclusive or unitary hypothesis, and some patients appear to have normally functioning GABA synapses (as assessed biochemically) in epileptogenic areas. Thus, other neurotransmitter and neurohumoral systems certainly play a role in the epileptic process.
Animals↗
[Stroke and post-ictal states].
Strokes and their sequelae are currently a major medical and social problem. Hence prevention is fundamental. The treatment of evident stroke whether general therapy, target treatment of the cerebral oedema, or specific treatment of the cerebral haemorrhage or thromboembolism is therefore equally important, though subject to controversy. In a case series of 1015 strokes, paramedical assistance and early physiokinesitherapy proved decisive. Specific treatment of the ischaemia using Buflomedil together with computerised EEG monitoring also looks promising.
Brain Edema↗
[Buflomedil and nicergoline in the targeted treatment of acute cerebral ischemia. Randomized comparative double blind study].
Acute cerebral ischaemia may take considerable advantages of an adequate intensive therapy associated with a specific treatment of cerebral oedemas, especially in terms of mortality-rate reduction. Moreover, target treatment of acute cerebral ischaemia may produce excellent results in severe cases selected by means of EEG-chronospectrography. Double-blind, randomized comparison between nicergolin and buflomedil especialls showed that the latter reduces mortality three times as much as nicergolin, and leads to a 200% increment in the complete recovery of the "functio laesa", limited to those cases, which showed an appreciable improvement following EEG-chronospectrographical survey.
Acute Disease↗
Clinical activity of GABA agonists in neuroleptic- and L-dopa-induced dyskinesia.
It is well known that the therapeutic effect of neuroleptics is counterbalanced by the property of these drugs to induce serious neurological side-effects mainly represented by tardive dyskinesia. Several reports indicate that at the experimental level GABA agonists interact with dopamine neurons with effects on behavior, stereotyped and dyskinetic movements induced by either lesions or dopamine agonists. This action on dopamine-related events provides a basis for a possible therapeutic action of GABA agonists in dyskinesia. Previous results with the GABA agonists muscimol and THIP in tardive dyskinesia have not been encouraging. The present paper deals with clinical results obtained with the new GABA agonist progabide both in neuroleptic-induced dyskinesia and in L-dopa-induced dyskinesia from five studies conducted on a total of 57 patients. Twenty-nine patients suffering from neuroleptic-induced dyskinesia have been treated in three studies (two open, one double-blind cross over) with progabide at doses from 900 to 2400 mg/day; clinical evaluation and EMG testing are in favor of a therapeutic effect of progabide on dyskinesia. Twenty-eight patients with L-dopa dyskinesia have been studied in two double blind trials. At variance with studies in tardive dyskinesia progabide was not effective in this kind of dyskinesia but an increase in the "on" time has been observed in both studies. Attempts to treat tardive dyskinesia with various pharmacological tools are reviewed and discussed, showing that at present no established effective treatment exists for this frequent complication of neuroleptic use. The possible mechanism of action of progabide in dyskinesia is discussed in the light of its pharmacological properties. These results suggest that progabide can be useful in the treatment of neuroleptic-induced dyskinesia.
Antipsychotic Agents↗
Conformational change in the DNA associated with an unusual promoter mutation in a tRNA operon of Salmonella.
We describe two novel types of mutations which decrease transcription of a tRNA operon in Salmonella typhimurium. One mutation consists of a 3 bp deletion at position -70 from the transcription start site. The second mutation is a single bp insertion between the -10 region and the transcription start site. The region around position -70 shows unusual physical properties. DNA fragments carrying the wild-type version of this region exhibit abnormally low electrophoretic mobility in polyacrylamide gels. This anomalous electrophoretic behavior is corrected if gels are run at high temperature or if the fragments contain the 3 bp deletion at -70. Our results indicate the existence of an unusual DNA conformation, probably involving DNA bending, in the region preceding the tRNA operon promoter. This structure is apparently disrupted by the 3 bp deletion. The transcriptional defect of the -70 mutant suggests a role for the unusual conformation in promoter function.
Base Sequence↗
Suppressor sufJ: a novel type of tRNA mutant that induces translational frameshifting.
We describe the DNA sequence change responsible for the creation of a frameshift-suppressor gene in Salmonella typhimurium. The suppressor, sufJ, results from a base-pair insertion in the gene coding for a threonine transfer RNA (tRNA3Thr). Unlike previously studied frameshift suppressor mutations, the sufJ insertion does not fall within the sequence corresponding to the tRNA anticodon. The insertion (a G.C base pair) occurs within a run of three G.C base pairs in that region of the gene coding for one strand of the anticodon stem. In the secondary structure of the mature tRNA, the net result is that an extra, unpaired cytidine residue is pushed into the anticodon loop, thus increasing the size of the loop to eight nucleotides. These findings are discussed in connection with the peculiar "three-out-of-four" method of reading by the sufJ suppressor. A unifying model is presented accounting for the contrasting decoding behaviors of tRNAs with eight-nucleotide-long anticodon loops.
Alleles↗
Progabide treatment in severe epilepsy: a double-blind cross-over trial versus placebo.
Twenty therapy-resistant epileptic patients entered a double-blind, randomized, two-period, cross-over trial comparing progabide (19.3-36 mg/kg/day) and placebo as add-on drugs to standard therapy. Each period lasted 6 weeks with a gradual crossover during 4 days. Five patients were dropped because of reasons unrelated to treatment. Among the 15 patients who completed the study, seven had partial, six primary generalized, and two secondary generalized epilepsies. Preexisting antiepileptic drugs (AEDs) ranging from one to three per patient (mean 2.2 AEDs/patient) were maintained unchanged during the trial. Efficacy was assessed biweekly by means of total seizure counts, counts of each seizure type, and global clinical judgment. At the same time intervals, safety was assessed by means of reports of adverse events, clinical and neurological examination, laboratory tests, and measurement of plasma concentrations of progabide and associated AEDs. According to the clinical global judgment, eight patients were considered improved during progabide treatment. Seizures were reduced in 14 of 15 patients during the progabide as compared with the placebo period. During the progabide period, the reduction of the total seizure count was 45 and 58% in two patients and 88-97% in six patients. A significant reduction of the total seizure number was observed in the progabide period as compared with the placebo period, both in the whole patient group (p less than 0.01) and in the two subgroups of patients with generalized (p less than 0.01) and partial (p less than 0.05) epilepsies.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Somatomotor manifestations in temporal lobe seizures.
Some authors include somatomotor manifestations (SMM) among the clinical features of temporal lobe seizures in man; however, data are limited and conflicting. This study describes 101 seizures recorded during stereo-EEG explorations in 50 patients, selected on the basis of the demonstration of onset in temporal lobe structures (stereo-EEG) and the presence of lateralized SMM and/or secondary generalization (SG). SMM and SG were present in about 20% of our population of patients with temporal seizures explored with stereo-EEG, and were only rarely observed during the first 10 s (early SMM) of the seizures (less than 10%). Seizures characterized by early SMM were generally induced by electrical stimulation or chemical activation and only exceptionally spontaneous. In all cases the ictal electrical discharge also involved at an early stage extratemporal structures such as the rolandic operculum, the parietal lobe, or contralateral temporal structures. In most cases (greater than 90%) SMM represented a late (greater than 10 s) event in the ictal symptomatology. The face and the upper limb were by far the most frequently involved segments. Thirty-eight percent of seizures ended up in SG. The associated ictal symptomatology was rather poor and differed from our previous findings in temporal lobe seizures: oroalimentary automatisms were relatively rare, whereas an impairment of consciousness was observed in more than 50% of seizures. The critical electrical discharge had a long duration and always involved extratemporal structures in one or both hemispheres. The involvement of the central region could be demonstrated in all patients with deep electrodes in that region. In conclusion, SMM are not characteristic of temporal lobe seizures, and their presence indicates spreading of the critical discharge beyond the temporal lobe.
Adolescent↗
Management of pain after thoracotomy: a technique of multiple intercostal nerve blocks.
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Humans↗
The expression of prokaryotic tRNA genes in frog oocytes.
A tRNA gene cluster in Salmonella typhimurium includes the genes for tRNAArg, tRNAHis, tRNA1Leu and tRNAPro. DNA clones were constructed with different portions of this tRNA gene cluster. These clones were microinjected into the nuclei of Xenopus laevis oocytes and assayed for expression. Two of the bacterial tRNA genes (tRNAArg and tRNAPro) are transcribed at high rates and the primary transcripts are processed into mature tRNAs. Transcription and processing are largely independent of whether the two genes are injected individually or as part of a tRNA gene cluster. A third tRNA gene (tRNA1Leu) is expressed less efficiently. Synthesis of this tRNA is totally abolished by a deletion removing 22 bp in the first half of the tRNA1Leu coding sequence. The expression of the fourth tRNA gene (tRNAHis) is very inefficient and dependent upon the gene organization within the injected DNA. No significant tRNA synthesis is detected upon injection of a clone containing only the tRNAHis gene. Evidence is presented suggesting that the impaired expression of the tRNAHis gene is not caused by inefficient transcription, but rather by defective processing of the primary transcript. The prokaryotic tRNAs synthesized in the oocytes show a modification pattern that is specific of eukaryotic tRNAs. Overall, our results are consistent with the hypothesis that the intragenic signals for eukaryotic tRNA gene transcription have appeared early in evolution for reasons other than gene expression.
Animals↗
Context effects: translation of UAG codon by suppressor tRNA is affected by the sequence following UAG in the message.
The efficiency of various suppressor tRNAs in reading the UAG amber codon has been measured at 42 sites in the lacI gene. Results indicate that: (1) for all suppressors, efficiency is not an a priori value; rather, it is determined at each site by the specific reading context of the suppressed codon; (2) the degree of sensitivity to context effects differs among suppressors. Most affected is amber suppressor supE (su2), whose activity varies over a 20-fold range depending on context; (3) context effects are produced by residues present at the 3' side of the UAG codon. The most important role appears to be played by the base that is immediately adjacent to the codon. When this base is a purine, the amber codon is suppressed more efficiently than when a pyrimidine is in the same position. Superimposed on this initial pattern, the influence of bases further downstream to the UAG triplet can be detected also. The possibility is discussed that context effects are produced by the whole codon following UAG in the message.
Base Sequence↗
The hisR locus of Salmonella: nucleotide sequence and expression.
In S. typhimurium, the hisR locus is defined by mutations causing reduced levels of the histidine transfer RNA. As a preliminary step in the analysis of the hisR mutants, a 972 bp DNA fragment containing the histidine tRNA gene from wild-type Salmonella was cloned and completely sequenced. This analysis revealed the existence of a tRNA gene cluster which, in addition to the tRNAHis gene, includes the genes for tRNALeu1, tRNAPro1 and a tentative tRNAArgCGG. All four tRNA genes are present as single copies and are separated by spacer sequences ranging from 20 to 53 bp in length. The gene cluster is efficiently transcribed in vitro by E. coli RNA polymerase and yields a transcript, approximately 480 nucleotides long, which contains all four tRNA sequences. This tetrameric precursor can be processed to 4S RNA in vitro with a wild-type Salmonella extract, but not with an extract prepared from a hisU (RNase P) mutant. Using portions of the tRNA gene cluster as specific hybridization probes, various processing intermediates were shown to accumulate in vivo in the hisU mutant. Most of these RNAs are monomeric precursors only a few nucleotides longer than the respective mature tRNA species.
Base Sequence↗
New suppressors of frameshift mutations in Salmonella typhimurium.
Several new types of suppressor mutants have been isolated. These were identified among revertants of mutants originally generated by mutagens other than the acridine-derived ICR191. The new suppressors correct mutations other than those with runs of C or G which are recognized by the previously described suppressors. Several frameshift mutations are corrected by more than one suppressor type. Apparently, the DNA base sequence near these mutant sites includes sites of action for several distinct suppressor types.
Base Sequence↗
Genetic characterization of the sufj frameshift suppressor in Salmonella typhimurium.
A new suppressor of +1 frameshift mutations has been isolated in Salmonella typhimurium. This suppressor, sufJ, maps at minute 89 on the Salmonella genetic map between the argH and rpo(rif) loci, closely linked to the gene for the ochre suppressor tyrU(supM). The suppressor mutation is dominant to its wild-type allele, consistent with the suppressor phenotype being caused by an altered tRNA species. The sufJ map position coincides with that of a threonine tRNA(ACC/U) gene; the suppressor has been shown to read the related fourbase codons ACCU, ACCC, ACCA.--The ability of sufJ to correct one particular mutation depends on the presence of a hisT mutation which causes a defect in tRNA modification. This requirement is allele specific, since other frameshift mutations can be corrected by sufJ regardless of the state of the hisT locus.--Strains carrying both a sufJ and a hisT mutation are acutely sensitive to growth inhibition by uracil; the inhibition is reversed by arginine. This behavior is characteristic of strains with mutations affecting the arginine-uracil biosynthetic enzyme carbamyl phosphate synthetase. The combination of two mutations affecting tRNA structure may reduce expression of the structural gene for this enzyme (pyrA).
Base Sequence↗
Plasma levels of primidone and its metabolite phenobarbital: effect of age and associated therapy.
The effects of age and associated therapy on plasma primidone (PRM) and derived phenobarbital (PB) concentrations, and on plasma concentrations-to-PRM dose ratios (L/D ratio) were evaluated retrospectively from 408 consecutive PRM and derived PB determinations in 238 chronically treated epileptic patients (153 children and adolescents between 5 months and 15 years of age and 85 adults between 16 and 55 years of age). The correlation between PRM administered and both plasma PRM and derived PB levels was significant; the correlation between PRM and PB plasma levels was also significant, but the scatter of values for the linear regressions was such that the relationship had no predictive value. Significant differences in mean plasma PRM and PB L/D ratios were found between patients aged 0-3 years, 4-9 years, 10-15 years, and adults (16-55 years), with higher values in the older groups. The PB/PRM concentration ratios were significantly lower in children than in adolescents and adults. Concomitant treatment with carbamazepine affected PRM disposition and led to increased L/D ratios for PB and decreased L/D ratios for PRM, whereas phenytoin increased the L/D ratios for PB without any significant change in the L/D ratios for PRM. The variability in the results indicates the need for routine monitoring of PRM and derived PB plasma levels, particularly in pediatric populations, in order to tailor the dose to each patient.
Adolescent↗
Double-blind crossover trial of progabide versus placebo in severe epilepsies.
In this double-blind, two-period, crossover trial with randomized treatment assignment, progabide (+/- 30 mg/kg/day) and placebo were compared as add-on to standard therapy in 20 "therapy-resistant" epileptic patients (11 males, nine females; age range, 7-47 years). The duration of each treatment period was 6 weeks. Crossover was performed gradually over 3-4 days. Twenty-four patients entered the study: three dropped out for reasons unrelated to progabide effects; one dropped out during the placebo period because of increased seizure frequency. Of the 20 patients who completed the study, 14 had partial, two partial plus secondary generalized, and four generalized seizures. Preexisting antiepileptic treatment consisted of one antiepileptic drug (AED) in three, two AEDs in eight, three AEDs in five, and four AEDs in four patients (mean, 2.5 AEDs/patient). The following parameters were recorded at biweekly intervals: (a) efficacy parameters--total seizure count, counts of each seizure type, and global clinical judgment; (b) safety parameters--adverse drug effects, brief clinical and neurological examinations, and laboratory tests; and (c) plasma concentrations of progabide and of the associated AEDs. Twelve patients were considered to be improved (p less than 0.01) with progabide by global clinical judgment compared with two patients improved with placebo. Nine patients of 20 had a 48-100% reduction of total seizure count in the verum period, leading to a significant reduction of total seizure number and of complex partial seizures in the verum period as compared with the placebo period (p less than 0.05). Adverse effects were reported or observed in 10 patients during the progabide period and in five patients in the placebo period. The side effects were generally mild and consisted of somnolence in four cases and of tremors, dry mouth, troubles of equilibrium, anorexia, euphoria, depression, and anxiety in individual patients; a 15-20% reduction of the progabide dose was required in two cases only. No treatment-related alterations in results of laboratory tests were observed.
Adolescent↗
Indications for the use of gamma-aminobutyric acid (GABA)-agonists in convulsant disorders.
From studies using pharmacological models of convulsive disorders and also from the neurochemical analysis of epileptogenic tissue removed during neurosurgical resection (cortectomy), there is strong evidence that at least a subgroup of epileptic disorders may be linked (among other things) to a deficit in GABAergic neurotransmissions. This deficit may be found at the level of GABA synthesis or at the GABA-recognition site; whether these GABA neurons are lost or are dysfunctional is not yet answered. This suggests that GABA-agonists will be of potential use in epilepsy. GABA-agonists (progabide, SL 75102, muscimol, THIP) for the classical GABA-recognition sites as well as other compounds active at sites in the GABA-receptor macromolecular complex (eg, diazepam and phenobarbital) exhibit a wide range of anticonvulsant effects in different animal models and species. However, for some of these compounds (eg, muscimol) secondary central effects occur at the same dose level as the anticonvulsant actions, and for others (eg, THIP) such secondary effects may limit the use to certain types of seizures. This problem may be related to the high affinity of such compounds for the GABA recognition site as compounds with a more moderate affinity (eg, progabide, SL 75102) have a wider margin between anticonvulsant and secondary central effects in rodents. Clinical results using progabide suggests that the GABA hypothesis of convulsive disorders has indeed a rational foundation as a significant percent of refractory or unresponsive epileptic patients with different types of seizures (eg, complex partial or primary generalized) have a significant clinical improvement with this GABA-agonist.
Animals↗