A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

Myeloproliferative neoplasms are a varied group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform into a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel inhibitor of the M2 subunit of ribonucleotide reductase. Sequential inhibition of ribonucleotide reductase with triapine and an M1 ribonucleotide reductase inhibitor (fludarabine) was noted to be safe, and led to a 29% complete plus partial response rate in myeloproliferative neoplasms. This article reports the findings of a phase II trial of triapine (105 mg/m²/day) followed by fludarabine (30 mg/m²/day) daily for 5 consecutive days in 37 patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. The overall response rate was 49% (18/37), with a complete remission rate of 24% (9/37). Overall response rates and complete remissions were seen in all disease subsets, including secondary acute myeloid leukemia, in which the overall response rate and complete remission rate were 48% and 33%, respectively. All patients with known JAK2 V617F mutations (6/6) responded. The median overall survival of the entire cohort was 6.9 months, with a median overall survival of both overall responders and complete responders of 10.6 months. These data further demonstrate the promise of sequential inhibition of ribonucleotide reductase in patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. This study was registered with clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00381550","term_id":"NCT00381550"}}NCT00381550).     

Incidence of Waldenstrom's macroglobulinemia

This study sought to determine the incidence and pattern of occurrence of Waldenstrom's macroglobulinemia, a plasmacytoid lymphocyte malignancy that involves monoclonal production of the IgM M-component type. Cases with Waldenstrom's macroglobulinemia have been reported since 1978 to the population-based cancer registry that serves western Washington state, and since 1988 to the eight other cancer registries that participate in the National Cancer Institute's Surveillance, Epidemiology, and End-Results program. Persons less than 85 years old newly diagnosed with Waldenstrom's macroglobulinemia were identified through 1989. The age-standardized annual incidence rate was 6.1 per million in white men and 2.5 per million in white women (1980 US standard). Only five cases were reported in black women, among whom the age-standardized annual incidence rate was 3.6 per million. No cases were reported among black men (5.8 cases expected, based on the rates in white men); this finding may be due to chance, underdiagnosis of Waldenstrom's macroglobulinemia in this group, or may reflect a truly low rate. Further investigation of a large, racially diverse population is required to better characterize the epidemiology of this rare disease.     

Transmission of the agent of human granulocytic ehrlichiosis by Ixodes spinipalpis ticks: evidence of an enzootic cycle of dual infection with Borrelia burgdorferi in Northern Colorado

Previous work described an enzootic cycle of Borrelia burgdorferi sensu lato (hereafter referred to as B. burgdorferi) maintained by the rodent Neotoma mexicana and the tick Ixodes spinipalpis in northern Colorado. We investigated the incidence of coinfection among rodents with the agent of human granulocytic ehrlichiosis (aoHGE). aoHGE was detected in 23.5% of 119 rodent spleens examined. Biopsy results indicated that 78 (65.5%) of the 119 rodents were positive for B. burgdorferi, whereas 22 (78.5%) of the 28 animals that harbored aoHGE were also infected with B. burgdorferi. In 14 of 25 I. spinipalpis tick pools, aoHGE was detected by amplifying both the 16s rRNA and p44 gene of aoHGE. The ability of I. spinipalpis to transmit aoHGE was examined in C3H/HeJ mice. aoHGE was detected in their blood 5 days after I. spinipalpis infestation. This study confirms that both B. burgdorferi and aoHGE can be transmitted by I. spinipalpis ticks and that there is a high incidence of coinfection in rodents, predominantly Peromyscus maniculatus and N. mexicana, that inhabit the foothills of northern Colorado.     

Hemin preferentially stimulates synthesis of alpha-globin in K562 human erythroleukemia cells

K562 human erythroleukemia cells are an established cell line derived from an adult with chronic myelogenous leukemia. Hemin stimulates their synthesis of embryonic and fetal hemoglobins. We have found that their globin synthetic pattern depends on the concentration of added hemin. Clone RA6 was cultured with 0--100 microM hemin and the globin synthetic pattern determined by 3H-leucine incorporation and analysis of 3H-globins by polyacrylamide gel electrophoresis in Triton X acid urea followed by fluorography and densitometry. The higher the hemin concentration, the greater the synthetic rate of each type of globin. However, the relative increase was greatest for alpha-globin. We propose that the differential dependence of alpha synthesis on added hemin is a reflection of translational inefficiency of alpha messenger RNA and that this property is exposed when the translational capacity of the cell is limited by hemin deficiency. We suggest that the differential dependence of alpha-chain synthesis on added hemin in clone RA6 is evidence of an intrinsic deficiency in heme synthesis.     

Accuracy of a Digital Weight Scale Relative to the Nintendo Wii in Measuring Limb Load Asymmetry

[Purpose] The aim of the present study was to investigate the accuracy of a digital weight scale relative to the Wii in limb loading measurement during static standing. [Methods] This was a cross-sectional study conducted at a public university teaching hospital. The sample consisted of 24 participants (12 with osteoarthritis and 12 healthy) recruited through convenient sampling. Limb loading measurements were obtained using a digital weight scale and the Nintendo Wii in static standing with three trials under an eyes-open condition. The limb load asymmetry was computed as the symmetry index. [Results] The accuracy of measurement with the digital weight scale relative to the Nintendo Wii was analyzed using the receiver operating characteristic (ROC) curve and Kolmogorov-Smirnov test (K-S test). The area under the ROC curve was found to be 0.67. Logistic regression confirmed the validity of digital weight scale relative to the Nintendo Wii. The D statistics value from the K-S test was found to be 0.16, which confirmed that there was no significant difference in measurement between the equipment. [Conclusion] The digital weight scale is an accurate tool for measuring limb load asymmetry. The low price, easy availability, and maneuverability make it a good potential tool in clinical settings for measuring limb load asymmetry.Key words: Accuracy, Digital weight scale, Nintendo Wii Fit     

Serologic evidence that factor IX inhibitor in the plasma of hemophilia B patients detects factor IX on normal red cells

BACKGROUND: Patients with hemophilia B lack factor IX (F IX). These patients may become alloimmunized after the transfusion of F IX concentrates and may develop F IX inhibitors, which have been characterized as polyclonal IgG4 alloantibodies. Two cases in which F IX inhibitors caused difficulty in compatibility testing and antibody identification were encountered. It was hypothesized that, because F IX is present in normal plasma, it might be adsorbed by red cells in vivo and then be detected during antibody screening tests with serum containing F IX inhibitors. CASE REPORT: Sera from two African American half-brothers with hemophilia B were incompatible with all common and rare red cell phenotypes tested in the anti-human globulin test, but did not react with each other's red cells. The brothers' red cell antibodies were neutralized with both normal plasma and a commercially available F IX concentrate, which indicated that the red cell incompatibility was most probably caused by their F IX inhibitors. Red cells from an unrelated patient with hemophilia B and a very low titer of F IX inhibitor were tested against the half-brothers' sera and did not react. The compatible red cells from one of the half-brothers and the unrelated patient with hemophilia B adsorbed F IX from normal plasma or F IX concentrate after 37 degrees C incubation; this rendered them incompatible with the plasma containing F IX inhibitor from the other half-brother. CONCLUSION: F IX appears to be present on normal red cells and may be detected during compatibility and antibody identification procedures when serum or plasma containing F IX inhibitors is tested.