Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML

Relapse after autologous bone marrow transplantation for chronic myelogenous leukemia (CML) can be due either to the persistence of leukemia cells in systemic tissues following preparative therapy, or due to the persistence of leukemia cells in the autologous marrow used to restore marrow function after intensive therapy. To help distinguish between these two possible causes of relapse, we used safety-modified retroviruses, which contain the bacterial resistance gene NEO, to mark autologous marrow cells that had been collected from patients early in the phase of hematopoietic recovery after in vivo chemotherapy. The cells were then subjected to ex vivo CD34 selection following collection and 30% of the bone marrow were exposed to a safety-modified virus. This marrow was infused after delivery of systemic therapy, which consisted of total body irradiation (1,020 cGy), cyclophosphamide (120 mg/kg), and VP-16 (750 mg/m2). RT PCR assays specific for the bacterial NEO mRNA, which was coded for by the virus, and the bcr-abl mRNA showed that in two evaluable CML patients transplanted with marked cells, sufficient numbers of leukemia cells remained in the infused marrow to contribute to systemic relapse. In addition, both normal and leukemic cells positive for the retroviral transgenome persisted in the systemic circulation of the patients for at least 280 days posttransplant showing that the infused marrow was responsible for the return of hematopoiesis following the preparative therapy. This observation shows that it is possible to use a replication-incompetent safety-modified retrovirus in order to introduce DNA sequences into the hematopoietic cells of patients undergoing autologous bone marrow transplantation. Moreover, this data suggested that additional fractionation procedures will be necessary to reduce the probability of relapse after bone marrow transplantation in at least the advanced stages of the disease in CML patients undergoing autologous bone marrow transplantation procedures.     

Assessing Environmental Risks: Lessons From Superfund

This essay analyzes the use of risk assessment in Superfund, the controversial American hazardous waste cleanup programme. We argue that risk assessment has been used in three ways in discussing policy options in this programme: as a metric for assessing performance; as a means for resolving conflicts; and as a tool for comparing different environmental initiatives. Use of risk reduction as an analytical tool in European efforts to clean up hazardous waste sites is discussed. We conclude that while risk assessment has potential utility for each of these applications, there are also accompanying technical and political difficulties.     

Renal length in sickle cell disease: observations from a cohort study

Renal length has been measured by ultrasound in 237 subjects with homozygous sickle cell (SS) disease, 147 with sickle cell-hemoglobin C (SC) disease, and in 78 age-matched controls with a normal hemoglobin (AA) genotype. As expected, renal length increased with age in all genotypes but mean length was significantly greater in SS disease compared with SC disease (mean difference 4.3 mm after adjustment for height) and significantly greater in both genotypes than in AA controls (SS/AA difference 9.2 mm, SC/AA difference 5.0 mm after adjustment for height). Examination of relationships between renal length and some hematological indices (hemoglobin, fetal hemoglobin, reticulocyte counts, alpha thalassemia status) in SS or SC disease showed only a significant negative correlation with hemoglobin and positive correlation with reticulocyte count in SS disease. Further analysis suggested that the stronger relationship was between renal length and high reticulocyte count. The mechanism of renal enlargement is unknown although glomerular hypertrophy and increased renal blood volume are likely contributors.     

Batch-means control charts for autocorrelated data

Modern statistical process control must often cope with large quantities of highly autocorrelated data. Alwan and Radson (1992) proposed the monitoring of autocorrelated processes by plotting the averages of small batches of data separated by skipping observations. Using results for the AR(1) process, we show that generally better performance can be achieved with no skipping and much larger batch sizes. The resulting batch-means charts derive from methods used in simulation output analysis and can be implemented easily with common digital control systems.     

Mechanisms of virus assembly probed by Raman spectroscopy: the icosahedral bacteriophage P22

A microdialysis flow cell has been developed for time-resolved Raman spectroscopy of biological macromolecules and their assemblies. The flow cell permits collection of Raman spectra concurrent with the efflux of small solute molecules into a solution of macromolecules and facilitates real-time spectroscopic detection of structural transitions induced by the effluent. Additionally, the flow cell is well suited to the investigation of hydrogen-isotope exchange phenomena that can be exploited as dynamic probes of viral protein folding and solvent accessibility along the assembly pathway. Here, we describe the application of the Raman dynamic probe to the maturation of the icosahedral capsid of bacteriophage P22, a double-stranded DNA virus. The P22 virion is constructed from a capsid precursor (procapsid) consisting of 420 coat subunits (gp5) in an outer shell and a few hundred scaffolding subunits (gp8) within. Capsid maturation involves expulsion of scaffolding subunits coupled with shell expansion at the time of DNA packaging. Raman static and dynamic probes reveal that the scaffolding subunit is highly alpha-helical and highly thermolabile, and lacks a typical hydrophobic core. When bound within the procapsid, the alpha-helical fold of gp8 is thermostabilized; however, this stabilization confers no apparent protection against peptide NH-->ND exchange. A molten globule model is proposed for the native scaffolding subunit that functions in procapsid assembly. Accompanying capsid expansion, a small conformational change (alpha-helix-->beta-strand) is also observed in the coat subunit. Domain movement mediated by hinge bending is proposed as the mechanism of capsid expansion. On the basis of these results, a molecular model is proposed for assembly of the P22 procapsid.     

Pulmonary Wegener''s disease mimicking tuberculosis]

We report a case of early Wegener's disease mimicking tuberculosis in a 36 year old man. Lungs are solely affected for 6 months. Unusual appearance of radiographic features with large apical excavations explain the delai for the diagnosis. We discuss morphological features in the lungs and kidney.     

Structural properties and electrical behaviour of thin silicon oxynitride layers

Thin SiO₂ and SiO_xN_y layers were grown on silicon using Rapid Thermal Processing (RTP) in either O₂ or N₂O ambient. Subsequent annealing or nitridation was performed in order to improve the electrical stability. The composition of the films, in particular the incorporation of nitrogen and hydrogen, has been studied. We obtained the distribution of states at the Si/insulator interface through the evaluation of CV measurements and investigated the charge trapping in the layers analysing the voltage–time behaviour during Fowler–Nordheim constant current injection. Furthermore, assuming a trap assisted tunneling mechanism, the influence of near interface trap states on the current voltage characteristic was used to derive an effective insulator state distribution.     

Inflammatory myofibroblastic tumor in children

The authors presented the cases of two children with inflammatory myofibroblastic (IMF) tumor and reviewed the literature to facilitate the preoperative recognition, delineate the clinical features, and describe the natural history of this entity. The first child had IMF tumor arising from the mesentery of the small intestine. He presented with an abdominal mass associated with severe inflammatory response manifested by fever, impaired growth, thrombocytosis, and microcytic, hypochromic anemia. After surgical resection, his fever resolved and his growth rate and the laboratory abnormalities normalized. Five months after initial diagnosis, the fever, anemia, and thrombocytosis recurred along with two tumors arising from the omentum and the abdominal soft tissue. After the second surgery, he remains free of recurrent disease for 30 months. The second child presented with a lung mass that was radiologically indistinguishable from pulmonary sequestration. After surgical resection, she remains free of recurrent disease for 18 months. IMF tumor should be considered in any solid tumor that occurs in association with a chronic inflammatory response. IMF tumor should also be considered in the differential diagnosis of pulmonary sequestration.