Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.     

Effects of ACh on the electric activity of rostral ventrolateral medullary neurons of rat in vitro

Extracellular single-unit discharges were obtained from 165 spontaneously active neurons within the region of the rostral ventrolateral medulla (RVLM) by glass microelectrode from 89 brain slices of the Sprague-Dawley rats. The units could be divided into three types: regular (61.8%), irregular (24.2%) and silent (14%). Acetylcholine (ACh, 0.1, 0.3 mumol/L) showed four kinds of effects on spontaneous discharges of RVLM neurons: excitatory, inhibitory, biphasic and non-responsive, counting respectively 41.8%, 20%, 3% and 35.2% of the neurons tested. The excitatory effect of ACh was dose-dependent. The effects, either excitatory or inhibitory, of ACh (n = 49) were mostly blocked by atropine (0.3 mumol/L, n = 42). The excitatory effect of ACh (n = 14) could be blocked mainly by selective antagonist of M1 receptor, pirenzepine (PZ, 30 nmol/L, n = 9), but not by selective antagonist of M2 receptor, methoctramine (MT) and AFDX-116. The inhibitory effect of ACh (n = 10) could be blocked mostly by M2 receptor antagonist MT (30 nmol/L, n = 7); and this inhibitory effect (n = 9) could be blocked mostly by another M2 receptor antagonist AFDX-116 (30 nmol/L, n = 6), but not by M1 receptor antagonist PZ.     

Polynomial-complexity deadlock avoidance policies for sequentialresource allocation systems

The development of efficient deadlock avoidance policies (DAPs) for sequential resource allocation systems (RASs) is a problem of increasing interest in the scientific community, largely because of its relevance to the design of large-scale flexibly automated manufacturing systems. Much of the work on this problem existing in the literature is focused on the so-called single-unit RAS model, which is the simplest model in the considered class of RASs. Furthermore, due to a well-established result stating that, even for single-unit RASs, the computation of the maximally permissive DAP is intractable (NP-hard), many researchers (including our group) have focused on obtaining good suboptimal policies which are computationally tractable (scalable) and provably correct. In the first part of the paper, it is shown, however, that for a large subset (in fact, a majority) of single-unit RASs, the optimal DAP can be obtained in real-time with a computational cost which is a polynomial function of the system size (i.e., the number of resource types and the distinct route stages of the processes running through the system). The implications of this result for the entire class of single-unit RASs are also explored. With a result on the design of optimal DAPs for single-unit RASs, the second part of the paper concentrates on the development of scalable and provably correct DAPs for the more general case of conjunctive RASs     

Infinite-dimensional convex optimization in optimal and robustcontrol theory

Many engineering problems can be shown to be equivalent to solving semidefinite programs (SPs), i.e., convex optimization problems involving linear matrix inequalities (LMIs). Powerful computation tools are available for such problems in the finite-dimensional case. However, the problems arising in optimal and robust control theory are often infinite dimensional, and so adequate computation tools are not available. The key to tackling such problems with finite computation tools is to have a primal-dual formulation of the problem without duality gap. In this paper we study infinite-dimensional SPs and present a lifting technique to recast SPs as parameterized linear programs (LPs). This enables the wealth of theoretical tools available for infinite-dimensional LPs to be extended to infinite-dimensional SPs. In particular, we develop some new sufficient conditions for the lack of a duality gap for infinite-dimensional SPs and give an exact characterization of the primal and dual problems for these cases. Both primal and dual problems are formed as infinite-dimensional SP problems, with finite truncations to each giving upper and lower bounds, respectively, on the exact solution to the infinite-dimensional problem. Thus, these results can form the basis of practical computation schemes for infinite-dimensional problems, which require only finite-dimensional computation tools. To illustrate the power of these tools we apply the results to two previously unsolved optimization problems, namely minimizing the l₁ norm of a closed-loop system subject to bounds on the frequency response magnitude at a finite number of points and/or bounds on the H₂ norm     

New advances on a posteriori error on constitutive relation in f.e. analysis

This paper deals with error estimators based on residuals on the constitutive relation which have been developed for the past 20 years at Cachan. Especially in the case of elasticity, these error estimators can become poor in situations where the material and the mesh are strongly anisotropic. The crucial point herein is the construction of equilibrated stress fields from the computed finite element solution. Therefore, in this paper, the approach and in particular this last point are re-examined. Several important modifications are introduced in the concepts and basic techniques. Hence, a new generation of error estimators which seem to be extremely robust upon initial applications has been generated.     

The held out wings (how) Drosophila gene encodes a putative RNA-binding protein involved in the control of muscular and cardiac activity

In an attempt to identify genes that are involved in Drosophila embryonic cardiac development, we have cloned and characterized a gene whose function is required late in embryogenesis to control heart rate and muscular activity. This gene has been named held out wings (how) because hypomorphic mutant alleles produce adult animals that have lost their ability to fly and that keep their wings horizontal at a 90 degree angle from the body axis. In contrast to the late phenotype observed in null mutants, the How protein is expressed early in the invaginating mesoderm and this expression is apparently under the control of twist. When the different mesodermal lineages segregate, the expression of How becomes restricted to the myogenic lineage, including the cardioblasts and probably all the myoblasts. Antibodies directed against the protein demonstrate that How is localized to the nucleus. how encodes a protein containing one KH-domain which has been implicated in binding RNA. how is highly related to the mouse quaking gene which plays a role at least in myelination and that could serve to link a signal transduction pathway to the control of mRNA metabolism. The properties of the how gene described herein suggest that this gene participates in the control of expression of as yet unidentified target mRNAs coding for proteins essential to cardiac and muscular activity.     

Effect of dynamic strain ageing on the tensile properties of a modified 9Cr–1Mo steel

Tensile testing of a modified 9Cr–1Mo steel in two microstructural conditions (710T– normalized at 1100°C, tempered at 710°C, and 550T – normalized at 1100°C tempered at 550°C) in the temperature range 25–450°C, under strain rates of 2.3×10-5–2.3×10-3s-1, exhibited serrated flow curves, with serrations appearing almost at the onset of deformation and disappearing before ultimate strengths were attained. The serrated flow curves (characteristics of dynamic strain ageing) were accompanied by increased ultimate strengths, loss of ductility and negative strain-rate sensitivity, relative to the ambient temperature properties. However, the increase in ultimate strength and the reduction in ductility were much larger for 710T specimens, as compared to 550T ones. In the dynamic strain ageing regime, the work-hardenability of 710T specimens increased rapidly while that of 550T specimens remained practically unaffected. Based on the microstructural consideration and the observed activation energy of 45 kJ mol-1, it is proposed that serrations are initiated by a nitrogen atmosphere formation on the waiting dislocations by a pipe diffusion mechanism, and they disappear by diffusion to the precipitate sinks during deformation. Because the fine alloy carbide precipitates in 550T specimens are more effective sinks than those of 710T ones, they can cause much faster depletion of the atmosphere, resulting in a much smaller effect of dynamic strain ageing on the tensile properties of 550T specimens.     

A fast spatial-domain method for the suppression ofexcitation-induced spurious modes in SCN TLM

An efficient method for the suppression of excitation-induced spurious modes in the symmetrical condensed node (SCN) transmission-line matrix (TLM) method is presented for the general case of dielectric, anisotropic, or lossy media in planar structures. A special mapping of the field-excitation onto the wave amplitudes of the TLM algorithm completely prevents the emanation of the spurious modes. The application of the mapping in the k-ω space can be done for waveguides with low computational effort. The method is generalized for planar structures with high spatial frequencies of the field at the discontinuities. We use precomputed field templates at the entrance of the three-dimensional (3-D) structures. The mapping is mainly done in the space domain based on the quasi-TEM propagation of the guided waves to keep the computational effort low. Instead of the four-dimensional (4-D) k-ω transformation, only independent one-dimensional (1-D) transformations to the wave coefficient of the conductors direction and ω are necessary. In the case of propagation with low dispersion, the expenditure can be further reduced to 1-D transformations with respect to ω. The efficiency of the present method is demonstrated by investigation of a coplanar waveguide and a triplate waveguide     

Tensile and flexural creep rupture tests on partially-damaged concrete specimens

Three series of novel tensile and flexural creep tests on partially-damaged concrete specimens were carried out in order to gain some insight into creep crack growth and failure of strain-softening materials. In the tests, each specimen was initially loaded to a given point in the descending branch and thus had a lower load-carrying capacity than that at the peak-point. Then, the specimen was unloaded and reloaded to sustain a load which was from 70% to 95% of its current load-carrying capacity. Experimental creep curves display a three-stage process, consisting of primary, secondary and tertiary stages, with a decreasing, constant and increasing creep rate, respectively. The secondary stage dominates the whole failure lifetime, whereas both the secondary and tertiary stages are important in terms of creep deformation. Failure life-time seems to be more sensitive to the change of load level in flexural tests rather than in tensile tests. The decrease in load-carrying capacity due to damage tends to result in a shorter failure lifetime and a lower critical load level for creep rupture. The descending branch of the static load-deflection or load-CMOD curve may be used as an envelope criterion for creep fracture.