The Role of Abstinence in the Genesis of Alcoholic Epilepsy

• 1 Ce travail concerne l'observation clinique de 241 sujets alcooliques preAsentant des crises convulsives. Trois groupes de patients ont pu eCtre distingueAes dont le plus important comporte 90% des sujets examineAs.
• 2 Dans le groupe le plus important, les crises, de type grand mal, apparaissent aG l'aCge adulte et surviennent de facLon isoleAe ou reApeAteAes en breGves seAries lors du sevrage alcoolique apreGs une peAriode d'intoxication chronique. L'E.E.G. est normal sauf dans la peAriode immeAdiatement post-critique. Des eApisodes de delirium tremens surviennent dans 1/3 des cas, toujours apreGs la fin des crises.
• 3 La moitieA environ des sujets de ce premier groupe montre une sensibiliteA anormale aG la stimulation lumineuse qui est en relation chronologique preAcise avec les crises par rapport au sevrage alcoolique et aux eApisodes de delirium.
• 4 Deux groupes plus reAduits ont eAteA isoleAs. L'un comprend 7 patients souffrant d'une eApilepsie idiopathique, qui sont devenus alcooliques apreGs le deAbut de leurs crises. L'autre comprend 21 patients alcooliques ayant preAalablement subi un traumatisme cranien; il est caracteAriseA par une grande proportion de crises focales et d'anomalies E.E.G. Dans ces deux derniers groupes les crises surviennent sous l'effet ou en dehors de l'effet de l'alcool, mais plus particulieGrement dans la premieGre condition.
• 5 En ce qui concerne l'E.E.G. aux diffeArentes eAtapes de l'intoxication alcoolique, il est normal chez les alcooliques qui preAsentent des crises eApileptiques, sauf de facLon treGs transitoire, dans les peAriodes de sevrage apreGs un abus, il est au contraire anormal chez les eApileptiques aG crises renforceAes par l'alcool. Ces constatations E.E.G. confirment l'impression clinique que l'eApilepsie alcoolique est engendreAe par l'alcool lui-meCme et infirment la notion suivant laquelle l'alcool ne ferait que preAcipiter les crises eApileptiques chez des sujets qui preAsentent des crises ou sont “constitutionnellement” preAdisposeAs aux convulsions.
• 6 Le facteur le plus important dans la geneGse de l'eApilepsie alcoolique semble eCtre le sevrage de l'alcool apreGs une peAriode d'abus chronique. Ce facteur joue un roCle eAvident dans la forme habituelle de l'eApilepsie alcoolique, mais il est aussi preAsent dans les cas d'eApilepsie idiopathique ou post-traumatique favoriseAs par l'alcool. Le meAcanisme responsable des manifestations du sevrage alcoolique est encore inconnu de facLon preAcise.

     

Atypical Case of Pott's Disease

An unusual case of Pott's Disease in an adult, Australian born, Caucasian male is reported. The typical and atypical radiological features of spinal tuberculosis are reviewed.     

Serial Lead Impedance Measurements Confirm Fixation of Helical Screw Electrodes During Pacemaker Implantation

The purpose of this study was to determine whether serial measurements of helical screw pacemaker lead impedance could reliably confirm electrode fixation in the right atrium and right ventricle. Fixation is generally assessed fluoroscopically, which can be misleading because the myocardium is radio lucent. Alternatively, because the electrical conductivity of blood is greater than that of myocardium, serial measurements of the lead impedance might be expected to show an impedance increase with appropriate fixation of the pacemaker electrode when the electrode becomes embedded in myocardial tissue. Impedance measurements were made during the placement of 23 atrial and 28 ventricular active fixation electrodes in 31 consecutive patients. Impedance measurements were recorded in unipolar and bipolar electrode configurations with the electrode free floating in the chamber, unfixed (with exposed screws) but touching the endocardial surface, and after fixation. No significant impedance differences were found between free-floating and unfixed electrode positions. With fixation, the lead impedance increased significantly in the ventricle (P = 0.0001, unipolar and bipolar) and the atrium (P = 0.0069 unipolar and 0.0052 bipolar). Typical increases, reflected by median values, were 197 ohms unipolar and 203 ohms bipolar in the ventricle and 47 ohms unipolar and 53 ohms bipolar in the atrium for electrodes with permanently exposed or retractable screw designs. Comparing serial measurements of lead impedance before and after electrode fixation is a valid electrical method of confirming appropriate fixation of helical screw electrodes.     

Comparative biological activities of potent analogues of α-melanotropin

Several α-melanotropin (α-MSH) analogues with para substituted aromatic and nonaromatic amino acids in the 7-position of the hormone were prepared and their melanotropic activities determined in the frog (Rana pipiens) and lizard (Anolis carolinensis) skin bioassays. D and L-Phe(p-NO₂), D- and L-Tyr, D- and L-Ala, and Gly were substituted in the 7-position. The use of substituted D or L-aromatic amino acids in the 7th position of the central Ac-[Nle⁴] -α-MSH_4–11 - NH₂ fragment resulted in a loss in potency relative to the corresponding phenylalanine-containing analogue. The loss in potency cannot be due entirely to steric hindrance at the melanophore receptor, since nonaromatic amino acids substituted in the 7th position of this octapeptide fragment also generally led to a loss in biological activity. We reported previously that replacement of phenylalanine-7 by its D enantiomer led to a marked increase in potency in each fragment analogue tested. Analogues containing other D amino acids in the 7th position also were more potent than their L amino acid-containing analogues with one exception: Ac-[Nle⁴, Ala⁷]-α-MSH_4–11-NH₂ was more potent than Ac-[Nle⁴, D-Ala⁷]-α-MSH_4–11-NH₂ in the frog skin bioassay. Replacement of phenylalanine-7 by glycine resulted in a large decrease in potency in both bioassays, illustrating the importance of the side chain group, in this position of α-MSH, to biological potency of the hormone.     

NMR and quenched molecular dynamics studies of superpotent linear and cyclic α-melanotropins

Conformational searching, computer simulations, synthesis and NMR are used on a variety of α melanocyte-stimulating hormone (α-MSH) analogues to understand the physical characteristics required for biological potency. Peptides I (AC-[Nle⁴,Asp⁵,d -Phe⁷,Lys¹⁰]α-MSH(4-10)-NH₂), II (Ac-c[Nle⁴,Asp⁵,d -Phe⁷,Lys¹⁰]α-MSH(4-10)-NH₂) and III (Ac-[Nle⁴,Asp⁵,d -Phe⁷,Dap¹⁰]α-MSH(4-10)-NH₂ all show very similar conformational properties (backbone and side-chain torsional angles), and all display high biological potencies. The modeling results for these compounds are supported by the NMR data. Peptide IV (Ac-c[Nle⁴,Asp⁵,d -Phe⁷,Dap¹⁰]α-MSH(4-10)-NH₂) appears to have a markedly different conformation and has decreased biological potency.     

A Comparison of the Physicochemical and Biological Properties of Mirtazapine and Mianserin

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pK_a value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the α₁-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.     

Structure-activity studies of hydrophobic amino acid replacements at positions 9, 11 and 16 of glucagon

We have designed and synthesized eight compounds 2-9 which incorporate neutral, hydrophobic amino acid residues in positions 9, 11 and 16 of the glucagon molecule: (2) [desHis¹,Va1⁹,11e^11,16] glucagon amide, (3) [desHis¹,Val^9,11,16]glucagon amide, (4) [desHis¹,Va1⁹,Leu^11,16]glucagon amide, (5) [desHis¹,Nle⁹,11e^11,16]glucagon amide, (6) [desHis¹,Nle⁹,Val^11,16]glucagon amide, (7) [desHis¹,Nle⁹,Leu^11,16]glucagon amide, (8) [desHis¹,Val⁹,Leu^11,16,Lys^17,18,Glu²¹]glucagon amide and (9) [desHis¹,Nle⁹,Leu^11,16,Lys^17,18,Glu²¹]glucagon amide. The effect of neutral, hydrophobic residues at positions 9, 11 and 16 led to good binding to the glucagon receptor. Compared to glucagon (IC₅₀= 1.5 nM), analogues 2-9 were found to have IC₅₀ values of 6.0, 6.0, 11.0, 9.0, 2.5, 2.8, 6.5 and 7.0 nM, respectively. When these compounds were tested for their ability to block adenylate cyclase (AC) activity, they were found to be antagonists having no stimulation of adenyl cyclase, with PA₂, values of 6.15, 6.20, 6.30, 7.25, 6.10, 7.30, 6.25 and 7.25, respectively. © Munksgaard 1997.