Attenuation of pathological tremors by functional electrical stimulation II: Clinical evaluation

In this study we evaluated a technique for tremor suppression with functional electrical stimulation (FES), the technical details of which were described in the previous paper. Three groups of patients were investigated: those with essential tremor, parkinsonian tremor, and cerebellar tremor associated with multiple sclerosis. In each group, tremor was attenuated by significant amounts (essential tremor: 73%; parkinsonian tremor: 62%; cerebellar tremor: 38%). These attenuations were in good accord with predictions based on the dynamic analyses and filter designs derived in the previous paper. With filters “tuned” to the lower mean tremor frequency encountered in the cerebellar patients, more attenuation was possible in this group as well. We identified some practical limitations in the clinical application of the technique in its present form. The most important was that in daily use, only one antagonist pair of muscles can realistically be controlled. At first sight, this restricts the usefulness of the system to patients with single-joint tremors. However, the concomitant use of mechanical orthoses may broaden the scope of application.     

The linear mitochondrial plasmid pAL2-1 of a long-lived Podospora anserina mutant is an invertron encoding a DNA and RNA polymerase

The molecular characterization of an additional DNA species (pAL2-1) which was identified previously in a long-lived extrachromosomal mutant (AL2) of Podospora anserina revealed that this element is a mitochondrial linear plasmid. pAL2-1 is absent from the corresponding wild-type strain, has a size of 8395 bp and contains perfect long terminal inverted repeats (TIRs) of 975 bp. Exonuclease digestion experiments indicated that proteins are covalently bound at the 5 termini of the plasmid. Two long, non-overlapping open reading frames, ORF1 (3,594 bp) and ORF2 (2847 bp), have been identified, which are located on opposite strands and potentially encode a DNA and an RNA polymerase, respectively. The ORF1-encoded polypeptide contains three conserved regions which may be responsible for a 3–5 exonuclease activity and the typical consensus sequences for DNA polymerases of the D type. In addition, an amino-acid sequence motif (YSRLRT), recently shown to be conserved in terminal proteins from various bacteriophages, has been identified in the amino-terminal part of the putative protein. According to these properties, this first linear plasmid identified in P. anserina shares all characteristics with invertrons, a group of linear mobile genetic elements.     

Über die jahreszeitlich bedingten änderungen der Empfindlichkeit der Froschlunge gegenüber Acetylcholin

Zusammenfassung Die Empfindlichkeit des Froschlungenpräparates, das im Winter auf Acetylcholinkonzentrationen von 110¹⁶ und darunter anspricht, nimmt in den Sommermonaten um mehrere Zehnerpotenzen ab. Da für die Verwertung des Präparates zur Bestimmung derartig kleiner A.Ch.-Konzentrationen die genaue Kenntnis dieser Empfindlichkeitsänderung notwendig ist, wurde die Umstellung des Präparates während der Monate September und Oktober durch tägliche Versuche verfolgt. Es zeigte sich, daß die Umstellung im September beginnt, besonders rasch in der zweiten Oktoberhälfte fortschreitet und Ende Oktober bereits beendet ist. Dabei steigt die Kontraktionshöhe bei der A.Ch.-Konzentration 110⁴ auf das Doppelte, bei 110¹² auf das Zehnfache. Die Konzentration 110¹⁶, die im Sommer keine sichtbare Wirkung hatte, bewirkt noch eine Verkürzung der Lungen um fast 10%. Auch die Verhältniszahlen, d. h. das Verhältnis der Kontraktionshöhe einer A.Ch.-Konzentration 110^x zur Kontraktionshöhe auf einen Prüfreiz 110⁴, die im Sommer recht niedrig lagen, wuchsen stetig an. Die ursprüngliche Größe und Konstanz der Verhältniszahlen ist im letzten Drittel des Oktober wieder erreicht.     

Cyclosporine A inhibits acetylcholinesterase activity in selected parts of the rat brain

Cyclosporine A (CsA) is the major immunosuppressive drug used for organ and neural transplantation and the therapy of selected autoimmune diseases. We investigated the effect of CsA on the activity of acetylcholinesterase (AChE) in the frontal cortex, hippocampus, septum, and basal ganglia. AChE was determined spectrophotometrically with acetylthiocholine as substrate and 5,5-bis-2-nitrobenzoic acid as chromogen. CsA was administered in single doses of 20 or 45 mg/kg perorally; in the case of the higher dose we also performed a repeated administration of CsA in three consecutive doses separated by 24 h intervals. Both lower and higher doses of CsA decreased AChE activity in the frontal cortex and hippocampus to practically the same extent. On the contrary, AChE activity was more diminished in the case of the higher dose of CsA used in the septum and basal ganglia. Repeated administration of the higher dose of CsA did not lead, with the exception of the hippocampus, to a further decrease in AChE activity in the brain structures observed. These findings contribute to rare evidence concerning the interaction of CsA and the cholinergic system in the brain.     

Carriers for drugs and enzymes based on copolymers of allyl glycidyl ether with acrylamide

Copolymerization of acrylamide with allyl glycidyl ether yielded water soluble polymers containing an epoxy group; addition of a crosslinking agent, N,N′-methylenebis(acrylamide), to the copolymerization mixtures resulted in the formation of similar though water insoluble polymers. Condensation of a potent beta-adrenergic antagonist Alm? H, which contains a reactive amino group, with a polymer containing an epoxy group yeilded a pharmacologically active polymer. The polymer containing the epoxy group was also converted, by reaction with sodium thiosulfate and subsequent reduction, into a mecapto groups containing polymer which was also water soluble. The latter polymer was converted by condensation with a beta-adrenergic antagonist Alm? COCH₂Br, which contains a reactive bromoacetamido group, into a pharmacologically active polymer.     

Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.