Conformation of model,alanine and proline containing tetrapeptides in water

CD spectra of model alanine and prolyl-alanine tetrapeptides were measured at different _pH values. An analysis of the spectra shows that proline in position 2 or 4 of a tetrapeptide favours folding of the peptide chain, and unfolding when it is in position 3. Changes in CD spectra evidence growing amounts of the β-turn conformation upon increasing ^pH, independent of proline position in the peptide chain.     

Standard and intermediate risk acute lymphoblastic leukemia in Poland: A report of the Polish Children's Leukemia/Lymphoma Study Group

A total of 527 children with acute lymphoblastic leukaemia (ALL) from the most frequent risk groups: standard risk group (SRG) and intermediate risk group (IRG) were treated between 1987 and 1991 according to an intensified treatment program (based on the BFM protocol) including the use of an intermediate dose of methotrexate in the IRG. A comparison of the treatment results in this group from 513 children treated between 1981 and 1987 indicates that the chance for a 6 year event-free survival has increased to 73% (previously 55%).     

Single residue modifications of the delta opioid receptor selective peptide, [d-Pen2,d-Pen5]-enkephalin (DPDPE)

Six analogs of the highly delta opioid receptor selective, conformationally restricted, cyclic peptide [d -Pen²,d -Pen⁵]enkephalin, Tyr-d -Pen-Gly-Phe-d -PenOH (DPDPE), were synthesized and evaluated for opioid activity in rat brain receptor binding and mouse vas deferens (MVD) smooth muscle assays. All analogs were single amino acid modifications of DPDPE and employed amino acid substitutions of known effects in linear enkephalin analogs. The effect on binding affinity and MVD potency of each modification within the DPDPE structural framework was consistent with the previous reports on similarly substituted linear analogs. Conformational features of four of the modified DPDPE analogs were examined by ¹H NMR spectroscopy and compared with DPDPE. From these studies it was concluded that the observed pharmacological differences with DPDPE displayed by diallyltyrosine¹-DPDPE ([DAT¹]DPDPE) and phenylglycine⁴-DPDPE ([Pgl⁴]DPDPE) are due to structural and/or conformational differences localized near the substituted amino acid. The observed enhanced μ receptor binding affinity of the carboxamide terminal DPDPE-NH₂ appears to be founded solely upon electronic differences, the NMR data suggesting indistinguishable conformations. The observation that the α-aminoisobutyric acid substituted analog [Aib³]DPDPE displays similar in vitro opioid behavior as DPDPE while apparently assuming a significantly different solution conformation suggests that further detailed conformational analysis of this analog will aid the elucidation of the key structural and conformational features required for action at the δ opioid receptor.     

Opioid receptor affinity and selectivity effects of second residue and carboxy terminal residue variation in a cyclic disulfide-containing opioid tetrapeptide

The previously described cyclic, delta opioid receptor-selective tetrapeptide H-Tyr-d -Cys-Phe-d -Pen-OH, where Pen, penicillamine, is β,β-dimethylcysteine, was modified at residues 2 and 4 by varying combinations of d - and l -Cys and d - and l -Pen, and effects on mu and delta opioid receptor binding affinities and on potency in the mouse vas deferens (MVD) smooth muscle assay were evaluated. A comparison was drawn between consequences of alterations in this series of analogs and those of analogous modifications in the related cyclic pentapeptide series which includes the highly delta receptor-selective [d -Pen²,d -Pen⁵]enke-phalin, DPDPE. Unlike effects observed in the cyclic pentapeptide series, the mu receptor binding affinities of the cyclic tetrapeptides are not dramatically influenced by substitution of Pen for Cys at residue 2. Conversely, while binding of the pentapeptides is only slightly affected by alteration of the chirality of the carboxy-terminal residue, modification of stereochemistry at the carboxy terminus in the tetrapeptides critically alters binding behavior at both mu and delta sites. In contrast with the pentapeptide series, the tetrapeptides appear to be highly dependent upon primary sequence for binding and activity, as only the lead compound binds with high affinity to the delta site. Results suggest that the less flexible cyclic tetrapeptides, lacking the Gly³ residue, display more stringent structural requirements for binding and activity than do the corresponding cyclic pentapeptides.     

Implantable Cardioverter‐Defibrillator in Patients With Hypertrophic Cardiomyopathy: Efficacy and Complications of the Therapy in Long‐Term Follow‐up

ICD in Hypertrophic Cardiomyopathy Patients. Introduction: Although implantable cardioverter‐defibrillators (ICDs) are used in sudden cardiac death (SCD) prevention in high‐risk patients with hypertrophic cardiomyopathy (HCM), long‐term results as well as precise risk stratification are discussed in a limited number of reports. The aim of the study was to assess the incidence of ICD intervention in HCM patients with relation to clinical risk profile. Methods and Results: We studied 104 consecutive patients with HCM implanted in a single center. The mean age of study population was 35.6 (SD, 16.2) years with the average follow‐up of 4.6 (SD, 2.6) years. ICD was implanted for secondary (n = 26) and primary (n = 78) prevention of SCD. In the secondary prevention group, 14 patients (53.8%) experienced at least 1 appropriate device intervention (7.9%/year). In the primary prevention (PP) group appropriate ICD discharges occurred in 13 patients (16.7%) and intervention rate was 4.0%/year. Nonsustained VT was the only predictive risk factor (RF) for an appropriate ICD intervention in the PP (positive predictive value 22%, negative predictive value 96%). No significant difference was observed in the incidence of appropriate ICD discharges between PP patients with 1, 2, or more RF. Complications of the treatment included: inappropriate shocks (33.7%), lead dysfunction (12.5%), and infections: 4.8% of patients. Four patients died during follow‐up. Conclusion: ICD therapy is effective in SCD prevention in patients with HCM, although the complication rate is significant. Nonsustained ventricular tachycardia seems to be the most predictive RF for appropriate device discharges. Number of RF did not impact the incidence of appropriate ICD interventions. (J Cardiovasc Electrophysiol, Vol. 21, pp. 883‐889, August 2010)     

Comparison of conformational properties of proline and threonine residues

The conformational role of Thr was investigated by ¹³C-n.m.r. and CD methods using a following series of tetrapeptides: Thr-Ala-Ala-Ala, Ala-Thr-Ala-Ala, Ala-Ala-Thr-Ala and Ala-Ala-Ala-Thr. It was found that introduction of Thr in every position of the tetraalanine peptide chain distinctly influences conformational equilibria of the peptides. An increase of β-turn forms in conformational equilibria is induced by ionization of the terminal carboxyl group, independent of threonine position in the peptide chain. Threonine in position 1 or 3 of the peptide chain seems to have some importance for β-turn formation in acid solution.