Solid-phase synthesis of neurokinin A antagonists

During the preparation of the NK-2 selective tachykinin antagonist MEN 10208 (Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH₂) and its analogs by the solid-phase method employing the Boc strategy routinely used in our laboratory, we encountered difficulties in the coupling of hydrophobic amino acids D-Trp and Val. To study the coupling problems several syntheses of MEN 10208 and analogs were carried out with different activation strategies. These syntheses yielded considerable amounts of deletion sequences even though a negative Kaiser test was obtained after each coupling. Inaccessibility of the free amino group of the growing peptide due to steric hindrance of the hydrophobic residues during coupling, and for the ninhydrin complex during the Kaiser test, may account, at least in part, for the unsatisfactory synthetics results and for the false-negative ninhydrin tests. Repetition of each synthesis with the Fmoc strategy on a newly developed DOD resin for peptide amides using the DCC/HOBt chemistry gave superior results in terms of the yield and purity of the crude peptides. Therefore, the Fmoc strategy appears to offer advantages over the Boc method for the preparation of these peptides containing hydrophobic amino acids.     

Changes in Morphology of the Paced QRS Complex Related to Atrial Contraction

A patient with 2:1 AV block underwent temporary ventricuJar pacing. AU the paced stimuli resuited in ventricular capture, but a marked variability in morphology of the paced QRS complexes occurred. Two different types of paced QRS complex (labeled A and B) were recognized. Type B complexes were manifest only when the pacing stimulus was preceded hy a sinus P wave within a time interval ranging from 0.15 to 0.52 sec. The P wave-induced changes in morphology of the paced QRS complexes were interpreted as due to displacement of the pacing ventricular lead caused by atrial systole.     

A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract

Summary. The only genetic disorder with elevated serum ferritin levels so far described is hereditary HLA-related haemochromatosis. On the other hand, hereditary cataract is both genotypically as well as phenotypically heterogenous, and no specific locus or any useful marker has been yet identified. We studied two Italian families in whom a combination of elevated serum ferritin not related to iron overload and congenital nuclear cataract is transmitted as an autosomal dominant trait. Affected individuals have normal serum iron and transferrin saturation, but high serum ferritin. Red cell counts are normal and venesection therapy rapidly produces iron-deficiency anaemia.
This genetic disorder, which is characterized by hyperferritinaemia, differs from hereditary HLA-related haemochromatosis mostly for the absence of iron overload. A gene responsible for the congenital nuclear cataract likely maps on chromosome 19q close to the ferritin L-subunit gene. Within families with autosomal dominant congenital cataract, serum ferritin might be an early marker of disease.     

Irregular Sinus Parasystole Due to Intermittency and Modulation of Parasystolic Activity

Intermittent Sinus Parasystole. A case of intermittent sinus parasystole in which the parasystolic focus is protected from the dominant sinus rhythm only during the second half of its intrinsic cycle is reported. In addition, a modulating (i.e., electrotonic) effect is often clearly exerted from the dominant rhythm upon the focus during the protected period. Coexistence of both modulation and intermittency in sinus parasystole, as well as a modulating effect limited to the second part of the parasystolic cycle, have not been previously reported.     

Myoglobin structure and regulation of solvent accessibility of heme pocket

The effects of heme removal on the molecular structure of tuna and sperm whale myoglobin have been investigated by comparing the solvent accessibility to the heme pocket of the two proteins with that of the corresponding apoproteins. Although the heme microenvironment of tuna myoglobin is more polar than that of sperm whale myoglobin, the accessibility of solvent to heme is identical in the two proteins as revealed by thermal perturbation of Soret absorption. The removal of heme produces loss of helical folding and increase of solvent accessibility but the effects are rather different for the two proteins. More precisely, the loss of helical structure upon heme removal is 50% for tuna myoglobin and 15% for sperm whale myoglobin; moreover, the solvent accessibility of the heme pocket of tuna apomyoglobin is 2–3-fold greater than that of sperm whale apomyoglobin. These results have been explained in terms of the lack of helical folding in segment D, the structural organization of which may have a relevant effect in regulating the accessibility of ligands to the heme. The effects produced by charged quenchers reveal that the ligand path from the surface of the molecule to the ion atom of the heme involves a positively charged residue which may reasonably be identified as Arg-45 (sperm whale myoglobin) or Lys-41 (tuna myoglobin) on the basis of recent X-ray crystallographic information.     

Determinants of Efficacy of Atrial Pacing in Preventing Atrial Fibrillation Recurrences

Atrial Pacing in Atrial Fibrillation. Introduction: Several studies have shown that single or dual site atrial pacing is effective in reducing he frequency of recurrent atrial fibrillation (AF) in selected patients. However, it is still unclear what the best predictors are of long-term efficacy of atrial pacing. Methods and Results: Forty-seven patients with paroxysmal AF requiring demand pacing underwent electrophysiologic study and dual chamber pacemaker implant. After 4 months of follow-up, patients were divided into two groups according to the presence (group 1) or absence (group 2) of symptomatic AF recurrences. Atrial pacing markedly reduced AF recurrences in all patients. Twenty-four patients were free of arrhythmia. The basal state conduction times (CT_s) and the incremental conduction times (ICT_s), during programmed electric stimulation between the high right atrium (HRA) and the coronary sinus ostium (CS_os) but not between the HRA and the His-bundle region, were significantly longer in group 1. There was no statistical difference in the effective refractory period (ERP) recorded at the HRA, the low right atrium (LRA), and the CS_s between the two groups, whereas the differences between the greatest and least recorded ERPs measured from the HRA, LRA, and CS_os (δERP) were significantly greater in group 1 patients. Two parameters were selected by discriminant multivariate analysis, namely δCT_os (ICT-CT between HRA and CS_os and δERP. The first bad a greater relative importance in predicting AF recurrence (r²= 0.33 and r²= O.1, respectively). Conclusion: Single site atrial pacing is effective in reducing AF recurrences, with decreasing efficacy in patients with greater right atrial conduction delay and wider refractoriness dispersion.