Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance.

About 40% of patients with myelodysplastic syndromes (MDSs) present with a normal karyotype, and they are facing different courses of disease. To advance the biological understanding and to find molecular prognostic markers, we performed a high-resolution oligonucleotide array study of 107 MDS patients (French American British) with a normal karyotype and clinical follow-up through the Duesseldorf MDS registry. Recurrent hidden deletions overlapping with known cytogenetic aberrations or sites of known tumor-associated genes were identified in 4q24 (TET2, 2x), 5q31.2 (2x), 7q22.1 (3x) and 21q22.12 (RUNX1, 2x). One patient with a 7q22.1 deletion had an additional 5q31.2 deletion of the acute myeloid leukemia/MDS region, the smallest deletion identified so far and including the putative tumor suppressor (ts) genes, EGR1 and CTNNA1. One TET2 deletion was homozygous and one heterozygous, with a missense mutation in the remaining allele, further supporting its role as a ts gene. Besides these recurrent alterations, additional individual imbalances were found in 34 cases; in total, 42/107 (39%) cases had genomic imbalances. These patients had an inferior survival as compared with the rest of the patients (P=0.002). This study emphasizes the heterogeneity of MDS, but points to interesting genes that may have diagnostic and prognostic impact.

Z = 50 shell gap near 100Sn from intermediate-energy Coulomb excitations in even-mass 106-112Sn isotopes.

Rare isotope beams of neutron-deficient 106,108,110Sn from the fragmentation of 124Xe were employed in an intermediate-energy Coulomb excitation experiment. The measured B(E2,0(1)(+)-->2(1)(+)) values for 108Sn and 110Sn and the results obtained for the 106Sn show that the transition strengths for these nuclei are larger than predicted by current state-of-the-art shell-model calculations. This discrepancy might be explained by contributions of the protons from within the Z = 50 shell to the structure of low-energy excited states in this region.

Shape and structure of N=Z 64Ge: electromagnetic transition rates from the application of the recoil distance method to a knockout reaction.

Transition rate measurements are reported for the 2(1)+ and 2(2)+ states in N=Z 64Ge. The experimental results are in excellent agreement with large-scale shell-model calculations applying the recently developed GXPF1A interactions. The measurement was done using the recoil distance method (RDM) and a unique combination of state-of-the-art instruments at the National Superconducting Cyclotron Laboratory (NSCL). States of interest were populated via an intermediate-energy single-neutron knockout reaction. RDM studies of knockout and fragmentation reaction products hold the promise of reaching far from stability and providing lifetime information for excited states in a wide range of nuclei.

Ethmozine for ventricular premature complexes.

Twenty patients with an average of more than 30 ventricular premature complexes (VPCs) per hour were treated with ethmozine. Eighteen had either not responded or had adverse reactions to at least 1 other antiarrhythmic drug. Patients were treated with 200 to 300 mg 3 times daily (8.25 to 11.7 mg/kg) and were followed for up to 6 months. Three patients were withdrawn from ethmozine therapy because of unwanted effects before evaluation of efficacy. One of these patients had sustained ventricular tachycardia (VT) after a loading dose of ethmozine. Eleven of the remaining 17 patients (65%) experienced more than a 75% reduction in ventricular ectopic activity. Six patients had a smaller or no decrease in VPC frequency. Eleven of 16 patients (68%) with paired VPCs had a more than 90% reduction in paired VPC frequency. Eleven of 13 patients (84%) with VT events of 3 beats or more had more than a 90% reduction in VT events. Of the 11 patients in whom a more than 75% reduction in VPC frequency occurred, 1 patient died suddenly after 133 days of effective drug therapy. Three patients discontinued ethmozine therapy for reasons not related to the drug. Of the 6 patients in whom there was less than a 75% reduction in VPC frequency, 2 patients discontinued treatment, 1 patient because of hyperanxiety and 1 because of drug-related left anterior hemiblock. Ethmozine lengthened PR and QRS intervals but not the JT interval. Thus, ethmozine is effective and clinically useful for suppression of frequency VPCs in 50% (10 of 20 patients) of a selected population.

Assessment of the potential pharmacokinetic interaction between digoxin and ethmozine.

The potential for a pharmacokinetic interaction between the investigational antiarrhythmic drug ethmozine (moricizine HCl, the generic name that is infrequently used in existing literature) and digoxin was evaluated in nine healthy male adults. Serum and urinary digoxin concentrations were measured by radioimmunoassay following intravenous digoxin administration before and during steady-state ethmozine dosing. Plasma ethmozine levels following a single oral dose were measured before and after a single intravenous dose of digoxin. A mean elimination half-life of 45.6 hours was determined for digoxin alone, compared to 43.1 hours in combination with ethmozine. Average values for digoxin systemic clearance, apparent volume of distribution, and renal clearance were 2.87 mL/min/kg, 11.3 L/kg, and 2.44 mL/min/kg, respectively for digoxin alone, compared to 3.01 mL/min/kg, 11.3 L/kg, and 2.64 mL/min/kg, respectively for digoxin with ethmozine. A mean half-life of 2.0 hours was determined for ethmozine alone, compared with 1.8 hours following a single intravenous dose of digoxin. No change was observed in the oral pharmacokinetics of ethmozine following a single intravenous dose of digoxin, as indicated by the area under the plasma concentration versus time curve, Cmax or Tmax. These findings suggest that no pharmacokinetic interaction occurs when single intravenous doses of digoxin are co-administered with multiple oral doses of ethmozine.