Marc Renaud

Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen

OBJECTIVES We evaluated the parameters influencing CD4 cell reconstitution after the introduction of highly active antiretroviral therapies in real life, as well as the frequency and the determinants of the discrepancies occurring between virus and CD4 cell count evolution. DESIGN AND METHODS A total of 317 pre-treated patients starting a protease inhibitor (PI)-containing regimen were prospectively followed for 2 years on an intent-to-treat basis for CD4 cell counts and viral loads. RESULTS The CD4 cell counts rapidly increased from baseline (50/mm3) by a median of 50/mm3 at month 2 (+0.72 CD4 cells/mm3/day) and up to 137/mm3 at the last follow-up (second slope: +0.16 CD4 cells/mm3/day). Two independent major factors among five parameters tested significantly affected the first phase, which was negatively correlated to the slope of CD4 cell decline before PI initiation, and was positively correlated to baseline CD4 cell counts (P = 0.0001); the second phase was mostly affected by the mean viral load reduction over time (P = 0.0001). Paradoxical CD4 cell reconstitution (15% of cases) was defined by a rapid or slow CD4 cell increase contrasting with a minor or strong viral reduction, respectively. The role of previous CD4 cell decline and the low effect of viral load reduction during the first 2 months explain the early paradoxical CD4 cell responses. The major influence of viral load reduction on the long-term reconstitution, however, reduces such paradoxical responses at 2 years. CONCLUSIONS Early paradoxical CD4 cell reconstitution after the introduction of a PI are explained by the major influence of previous disease progression on the early CD4 cell increase, whereas the magnitude of viral load reduction over time reduces such paradoxical evolutions in the long term.

Restoration of the immune system with anti-retroviral therapy

Clinical benefits of highly active anti-retroviral treatments (HAART) are increasingly evidenced by resolving opportunistic infections and malignancies, as well as declining hospitalization and mortality rates [1]. This suggests that potent and sustained suppression of viral replication, at least to some extent, is associated with reconstitution of the immune system even in adult patients treated at advanced stages of the disease. Increased susceptibility to opportunistic infections and tumors mainly results from the loss of memory CD4+ T cell reactivity against recall antigens which is an early event in HIV disease progression. Primary responses of naive CD4+ T cells against new pathogens are suppressed even earlier in the course of HIV disease, and the progressive depletion in naive CD4+ T cells reflects profound alterations in T cell regeneration capacities. Previous studies revealed that monotherapy with ritonavir, a protease inhibitor, resulted in a slight improvement in memory CD4+ T cell responses to recall Ags only when detectable prior to onset of therapy, suggesting that the loss of CD4+ T cell reactivity might be irreversible at advanced stages of the disease [2]. In contrast our group demonstrated more recently that restoration in CD4+ T cell reactivity to specific antigens was feasible when HAART was administered in progressors [3]. Here we address some of the questions raised by immune restoration with HAART when administered at advanced stages of the disease.

Manipulability analysis for mobile manipulators

We extend the standard definition of manipulability to the case of a nonholonomic mobile manipulator built from an n joint robotic arm and a nonholonomic mobile platform. The effects of mounting the arm on a nonholonomic platform are shown through the analysis of the manipulability thus defined. Applications of criteria inherited from manipulability considerations are given to justify design and to generate the controls of our system.

Allelic repertoire of the human MICB gene.

A distinct family of major histocompatibility complex (MHC) class I genes has recently been identified within the human MHC. Members of this MHC class I chainrelated gene (MIC) family are dispersed over the 2 megabase HLA class I region (Bahram et al. 1994; Bahram and Spies 1996a; Campbell and Trowsdale 1997). The MICA and MICB transcripts in this family carry full-length openreading frames encoding typical MHC class I-like polypeptide chains with three (α1–3) extracellular domains, a transmembrane, and a cytoplasmic segment (Bahram et al. 1994; 1996a, b; Bahram and Spies 1996a). MICA and MICB are quite similar, sharing more than 90% similarity, but are very distantly related (having less than 30% overall similarity) to other MHC-I genes (Bahram et al. 1994; Bahram and Spies 1996a). MICC, MICD, and MICE are pseudogenes due to debilitating mutations or deletions (Bahram and Spies 1996b). This mirrors the composition of the HLA class I gene family, in which six functional genes (HLA-A to G) are interspersed between 12 pseudogenes or gene fragments (Geraghty 1993). MICs are conserved across mammalian evolution, which defines them as a second lineage of MHC class I genes (Bahram et al. 1994). Unlike typical MHC class I genes, MIC are not responsive to type I and II interferons but are regulated by cell stress through upstream heat shock response elements (Bahram et al. 1994; Groh et al. 1996). Generation of monoclonal antibodies demonstrated that MICA is a membrane-bound single-chain glycoprotein, expressed almost exclusively in the gastrointestinal epithelium (Groh et al. 1996). These data raised the possibility that MICA may serve as restriction elements for intestinal intra-epithelial T lymphocytes. In light of the astonishing degree of HLA polymorphism, it was important to measure the extent of MIC allelic variation (Parham and Ohta 1996). Recent work unveiled a relative high degree of polymorphism in the MICA gene, with 16 alleles reported thus far (Fodil et al. 1996). Remarkably, none of the amino acid replacements coincided with the well-defined HLA polymorphic residues concentrated at peptide or T-cell receptor contact sites (Bjorkman and Parham 1990). Interestingly, superimposition of MICA variable residues on an HLA-A2 tridimensional structure revealed their preferential positioning along the periphery of the putative antigen binding cleft, leaving an apparently invariant ligand binding site (Fodil et al. 1996). The close proximity of MICA to HLA-B warranted examination of the possible role of these alleles in MHC class I-associated disorders (Dausset and Svejgaard 1977). In fact, one transmembrane variant of MICA is preferentially associated with Behçet’s disease at a significantly higher rate than is the previously implicated HLA-B51 gene (Mizuki et al. 1997). Given these encouraging results, we embarked on defining potential MICB alleles. The allelic repertoire of MICB was evaluated using genomic DNA from 33 HLA homozygous typing cell lines (HTCL) collected during the 10th International Histocompatibility Workshop (Tsuji et al. 1992) and purchased from the European Collection of Animal Cell Cultures (England). These were, BM14, BM15, BM92, BTB, DBB, DEU, DHIF, DKB, EHM, EJ32B, FPAF, HOM2, JESTHOM, JO528239, JVM, KAS116, LWAGS, OMW, PF97387, PITOUT, PMG075, RSH, SA, SCHU, SPACH, TAB089, TEM, TISI, VAVY, WT24, YAR, SP0010, and The nucleotide sequence data reported in this paper have been submitted to the EMBL/GenBank nucleotide sequence databases and have been assigned the accession numbers U95729 (MICB002), U95730 (MICB003), U95731 (MICB004), U95732 (MICB005), U95733 (MICB006), U95734 (MICB007)

Quasi-minimal computation of the dynamic model of a robot manipulator utilizing the newton-euler formalism and the notion of augmented body

Real-time dynamic control of robot manipulators requires on-line computation of the dynamic model that expresses the generalized forces to be applied to their joints, as a function of their generalized coordinates, velocities and accelerations. To do this, this paper presents a method of computation of this model that uses a quasiminimal number of elementary arithmetical operations and that can be applied systematically to robot manipulators with a simple kinematic chain structure and revolute and/or prismatic joints. To reach this quasi-minimal number, use if primarily made of the following : * a computation that is intrinsic rather than extrinsic, analytical rather than numerical and iterative rather than developed ; * the Newton-Euler formalism rather than the Lagrangian one and * the notion of augmented body, generalized to this type of structure. An example demonstrates that the computation of the dynamic model of an industrial robot manipulator with six revolute joints (the most complicated case in practice) can be effected with less than 300 arithmetical operations (adds and multiplies).

Kinematic control of wheeled mobile manipulators

We propose a generic scheme to solve the kinematic control problem of wheeled mobile manipulators when the operational motion is imposed. We generalize the Additional Task Method to solve the control problem of these redundant nonholonomic systems.

Planning point to point paths for nonholonomic mobile manipulators

Deals with path planning for mobile nonholonomic manipulators. The system is composed of a nonholonomic mobile platform and a simple kinematic chain holonomic arm. We propose strategies for planning paths between two points in the generalized and operational spaces. Redundancy and optimization criteria are key elements of the approach. Applications follow for a planar system in the case of point to point tasks.

A near Minimum Iterative Analytical Procedure for Obtaining a Robot-Manipulator Dynamic Model

The dynamic control synthesis of robot manipulators requires a great number of arithmetic operations, and it cannot be effected in real time unless this number is reduced. This paper presents a systematic analytical procedure for obtaining the dynamic model necessary for the dynamic control synthesis. This procedure which uses a Lagrangian formulation is applicable to all manipulators having a simple kinematic chain structure with revolute and/or prismatic joints.

Kinematic modelling of wheeled mobile manipulators

We propose a systematic modelling of the nonholonomic mobile manipulators built from a robotic arm mounted on a wheeled mobile platform. It extends the fundamental notions of nonholonomy, mobility and maneuverability to the case of these hybrid holonomic/nonholonomic systems. It offers unambiguous definitions and models to the designer of kinematic control laws.

Time-optimal motions for a torque controlled wheeled mobile robot along specified paths

This paper deals with the problem of finding the time-optimal motion along a predefined path that satisfies the non-holonomic rolling without slipping constraint for a class of wheeled mobile robots described by their dynamical model. Admissible paths are first described. Then, an algorithm is proposed that gives the optimal motion.