Synthesis and pharmacological activity of the N-terminal dermorphin tetrapeptide analogs with CH2-NH peptide bond isosteres

The synthesis of pseudotetrapeptides H-Tyr-D-Ala-Phe-NH-(CH₂)₂-NH₂ (1a), H-Tyr-D-Ala-Phe-ψ(CH₂-NH)-Gly-NH₂ (2a), H-Tyr-D-Ala-ψ(CH₂-NH)-Phe-Gly-NH₂ (3a), and H-Tyr-ψ(CH₂-NH)-D-Ala-Phe-Gly-NH₂ (4a), representing the N-terminal tetrapeptide sequence of dermorphin, in which amide bonds are replaced by CH₂-NH bond, is described. N-acetyl-Tyr and desamino-Tyr pseudopeptide analogs (1-4b), (1-3c) are also described. The analogs were assayed in binding studies based on displacement of μ and δ-receptor selective radiolabels from rat brain membrane and in a bioassay using guinea pig ileum (GPI). Pseudopeptides in which the C-terminal (1a) or D-Ala-Phe (3a) amide bond are substituted, exhibit higher μ-affinities and μ-receptor selectivity than the corresponding Phe-Gly or Tyr-D-Ala analogs (2a, 4a). Acetyl-and desamino-Tyr pseudopeptide analogs (1-4b) and (1-3c) did not exhibit μ and δ-opioid receptor affinity at nM concentration. The relevance of the single peptide replacement and of its association to acetylation or amino group elimination of Tyr, is discussed on the basis of a receptor model for μ and δ opioids.     

Frequency and prognostic value of HLA antigens in osteosarcoma patients

A homogeneous group of 53 Caucasian subjects with high-grade osteosarcoma (OS) was typed for HLA-A and B locus antigens. Although no significant differences in the distribution of these antigens were found in comparison with 425 local controls, a trend towards an increase of HLA-B18 and decrease of HLA-B21 was observed. All the patients underwent amputation plus adjuvant chemotherapy and among the 29 patients with a follow-up longer than one year, 9 out of 10 subjects with HLA-A3 antigens developed metastases within a few months. None of the OS patients had the HLA-A3, B7 haplotype which is present in linkage-disequilibrium in the control population.     

Digestion by pancreatic juice of a beta-casomorphin-containing fragment of buffalo beta-casein

Degradation by pig pancreatic juice of a beta-casomorphin-containing fragment (tryptic peptide corresponding to residues 49–68 of buffalo beta-casein) was investigated. The FAB/MS (fast atom bombardment mass spectrometry) technique was used to identify the fragments produced by the concerted action of pancreatic proteases. Pancreatic juice, under our experimental conditions, is not able to release beta-casomorphins or morphiceptin from the tryptic peptide sequence. Furthermore, the present report shows that the rapid hydrolysis of a peptide bond by a single protease can prevent the cleavage of peptide bonds by a different protease. Therefore the formation of some peptides in the gastrointestinal tract can depend on the protease ratio.     

Potential Distributions Generated By Point Stimulation in a Myocardial Volume:

Potential Patterns in a 3-D Cardiac Depolarization Model, introduction: We present simulations of extracellular potential patterns elicited by delivering ectopic stimuli to a parallelepipedal slab of ventricular tissue represented as an anisotropic bidomain incorporating epiendocardial fiber rotation.
Methods and Results: Simulations were based on an eikonal model that determines wave-front shapes throughout the slab at every time instant during the depolarization phase, coupled with an approximate model of the action potential profile. The endocardial face of the slab was in contact with blood and the composite volume was surrounded by an insulating medium. The effect of a simplified Purkinje network was also studied. Results: (1) For all pacing depths, except endocardial pacing, a central negative area and two potential maxima were observed at QKS onset in all intramural planes parallel to the cpicardium. In all planes, the axis joining the two maxima was approximately aligned with the direction of fibers in the plane of pacing. Endocardial pacing generated a different pattern, but only when blood was present; (2) During later stages of excitation, outflowing currents (from the wavefront toward the resting tissue) were always emitted, at all intramural depths, only from those portions of the wavefront that spread along fibers. At any given instant, the position of the two potential maxima in a series of planes parallel to the epicardium and intersecting the wavefront rotated as a function of depth, following the rotating direction of intramural fibers. Purkinje involvement modified the above patterns.
Conclusion: Epicardial and endocardial potential maps provided information on pacing site and depth and on subsequent intramural propagation by reflecting the clockwise or counterclockwise rotation of the deep positivity. Results may be applicable to epicardial and endocardial potential maps recorded at surgery or from endocavitary probes.     

Duplex-Doppler assessment of cirrhosis in patients with chronic compensated liver disease

Portal venous flow velocity (PFV) was measured with duplex-Doppler equipment in 50 normal subjects and in 117 patients with suspected chronic liver disease who showed no evidence of decompensation such as ascites, hepatic encephalopathy, jaundice or oesophageal bleeding. All the patients underwent percutaneous liver biopsy which demonstrated non-cirrhotic liver disease in 58 cases (CH-patients: steatosis 8, persistent chronic hepatitis 8, active chronic hepatitis 42) and liver cirrhosis in the other 59 cases (LC-patients). The normal subjects and the CH-patients had similar values of max-PFV and mean-PFV (max-PFV 26.7±3.2 and 25.7±3.4 cm/s respectively; mean-PFV 22.9±2.8 and 22.4±3.8 cm/s respectively). The LC-patients’ values (max-PFV 19.3±3.5; mean-PFV 16.9±2.9) were significantly lower than those of the normal subjects (P<0.001) and of the CH-patients (P<0.001). Considering the normal max-PFV to be in the range 20–33.1 cm/s (mean±2 s.d. of the normal subjects, 95% confidence limits), max-PFV was reduced in 0/50 normal subjects, 1/58 CH-patients and 39/59 LC-patients (66.1% sensitivity; 98.2% specificity). In conclusion, the duplex-Doppler measurement of PFV is of great interest in the diagnostic study of patients with suspected chronic compensated liver disease and in the early diagnosis of cirrhosis. A low max-PFV is a reliable pointer to liver cirrhosis, whereas a normal max-PFV indicates a non-cirrhotic liver disease but is less probative. Each centre should standardize normal PFV values in order to establish their own threshold value for diagnosing liver cirrhosis.     

Internal Cardioversion of Chronic Atrial Fibrillation in Patients

Transvenous internal cardioversion of chronic AF using a right atrium (RA) coronary sinus (CS) vector requires more energy than cardioversion of paroxysmal AF. Chronic AF is not terminated in 25% of patients using biphasic shocks up to 10 J. We therefore evaluated efficacy, safety, and tolerability of internal cardioversion using a "unipolar' configuration (RA to skin patch) and biphasic shocks in patients with long-lasting AF and different heart disease. In each patient, biphasic R have synchronous shocks were delivered between a large defibrillating surface area electrode in the RA and a skin patch in the left prepectoral position. Defibrillation protocol started with a test shock of 0.4 J. Shocks were repeated and increased until termination of AF or a maximum of 34 J. Sedation was used when the patient described the shock as painful. This study included 11 patients with a mean age of 67 ± 8 years (range 56–83). AF duration was ± 1 month in all patients with a mean duration of 11 ± 11 months (range 2–36). Underlying heart disease was present in all patients and the mean left atrial dimension was 43 ± 9 mm (range 26–57). AF was terminated in 10 of 11 patients (91 %) with a mean delivered energy of the successful shocks of 18.7 ± 8.7 J (median energy 16.9 J; range 7.3–32.5) and a mean leading edge voltage of 564 ± 129 V. The mean shock impedance at the defibrillation threshold was 71 ± 13 Ω, (range 59–103). A total of 131 shocks were delivered without any complication and proarrhythmia episodes. We conclude that low energy "unipolar" internal cardioversion is a simple, safe, and effective technique for termination of chronic AF in patients with heart disease. The procedure is often tolerated under light sedation.