[TIBOLA: an emerging clinically polymorphous rickettsiosis]. / TIBOLA : une rickettsiose en expansion, cliniquement polymorphe.

BACKGROUND: TIBOLA (tick-borne lymphadenopathy) is a rickettsiosis caused chiefly by R. slovaca, transmitted by a Dermacentor tick. We report five cases. PATIENTS AND METHODS: Three patients were diagnosed at the initial inflammatory stage (facial oedema, necrotic eschar, lymphadenopathy, fever) and two at the stage of sequelae (alopecia and fatigue). Microbiological evidence was present in only one case. DISCUSSION: TIBOLA is a form of rickettsiosis that is currently spreading in Europe. Clinical diagnosis is often made late because of the mild symptoms and the lack of knowledge among clinicians concerning the condition. Microbiological tests (serology, PCR, culture of eschar or serum samples) are negative in one third of cases. The reference treatment consists of antibiotics effective against intracellular bacteria, cyclines and macrolides.

Geometrical dependence of decoherence by electronic interactions in a GaAs/GaAlAs square network.

We investigate weak localization in metallic networks etched in a two-dimensional electron gas between 25 and 750 mK when electron-electron (e-e) interaction is the dominant phase breaking mechanism. We show that, at the highest temperatures, the contributions arising from trajectories that wind around the rings and trajectories that do not are governed by two different length scales. This is achieved by analyzing separately the envelope and the oscillating part of the magnetoconductance. For T > or approximately 0.3 K we find L phi env proportional T(-1/3) for the envelope and L phi osc proportional, T(-1/2) for the oscillations, in agreement with the prediction for a single ring [T. Ludwig and A. D. Mirlin, Phys. Rev. B 69, 193306 (2004); 10.1103/PhysRevB.69.193306C. Texier and G. Montambaux, Phys. Rev. B 72, 115327 (2005); 10.1103/PhysRevB.72.115327C. Texier, Phys. Rev. B76, 153312 (2007)10.1103/PhysRevB.76.153312]. This is the first experimental confirmation of the geometry dependence of decoherence due to e-e interaction.

Consideration on calibration and correction factors of an Hp10 chamber for different radiation qualities and angles of incidence.

This paper presents the characterisation performed at IRSN (France) of an H(p)(10) chamber in terms of calibration coefficient and correction factors for the radiation qualities of ISO narrow spectrum series. The chamber response, expressed in H(p)(10) using conversion coefficients h(p)(K)(10; N, alpha) listed in ISO 4037-3 in the energy range from 30 to 1250 keV and for angles of incidence between 0 and 70 degrees, was found to be within approximately 10%. However, for photon energies <30 keV, an overresponse of the chamber that could reach 100% was observed. Nevertheless, this overresponse was reduced to 25% using the conversion coefficients estimated at Physikalisch-Technische Bundesanstalt (PTB). This implies that the X-ray spectra produced by the IRSN X-ray units are very similar to those produced by PTB, both containing a little bit more high-energy photons than the spectra used in ISO 4037-3. The dose rate dependence of the chamber tested by gamma radiation from (60)Co sources was found to be within 2% in the range of 0.3 mSv h(-1) to 1 Sv h(-1). The H(p)(10) chamber can measure directly the conventional true value of H(p)(10) after calibration by a reference laboratory, and can be used for transferring H(p)(10) reference quantities from a reference laboratory.

Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy.

BACKGROUND: Allergen-derived (T cell epitope) peptides may be safer for immunotherapy than native allergen, as they do not cross-link immunoglobulin (Ig)E. However, HLA polymorphism results in multiple potential epitopes. Synthetic peptides of phospholipase (PL) A(2) were selected for a peptide vaccine, on the basis of binding affinity for commonly expressed HLA-DR molecules. OBJECTIVE: To evaluate treatment with an HLA-DR-based PLA(2) peptide vaccine in subjects with mild honeybee allergy in an open, controlled study. METHODS: Twelve volunteers with allergy to bee venom received nine intradermal injections of PLA(2) peptides, with six untreated subjects serving as controls. Outcome was assessed by the size of the late-phase cutaneous reaction to allergen, peripheral blood mononuclear cell (PBMC) proliferation, cytokine release, and expression of genes associated with immune regulation. RESULTS: Subjects receiving peptides showed a decrease in the magnitude of the late-phase cutaneous reaction to bee venom compared with controls (P=0.03). The proliferation of venom-stimulated PBMCs decreased in treated subjects compared with controls (P=0.01). Peptide treatment reduced the production of IL-13 by PLA(2)-stimulated PBMCs (P<0.01) and IFN-gamma (P<0.01), and increased the production of IL-10 (P=0.02). Transcription of the suppressor of cytokine signalling (Socs)3 gene was significantly increased following therapy. A transient, but modest, increase in allergen-specific IgG was also observed. CONCLUSION: HLA-DR-based T cell epitopes modify surrogate markers associated with successful immunotherapy and induction of immune regulation, supporting the concept that this form of treatment may be efficacious in human allergic disease.

Criticality accident dosimetry systems: an international intercomparison at the SILENE reactor in 2002.

In criticality accident dosimetry and more generally for high dose measurements, special techniques are used to measure separately the gamma ray and neutron components of the dose. To improve these techniques and to check their dosimetry systems (physical and/or biological), a total of 60 laboratories from 29 countries (America, Europe, Asia) participated in an international intercomparaison, which took place in France from 9 to 21 June 2002, at the SILENE reactor in Valduc and at a pure gamma source in Fontenay-aux-Roses. This intercomparison was jointly organised by the IRSN and the CEA with the help of the NEA/OCDE and was partly supported by the European Communities. This paper describes the aim of this intercomparison, the techniques used by the participants and the two radiation sources and their characteristics. The experimental arrangements of the dosemeters for the irradiations in free air or on phantoms are given. Then the dosimetric quantities measured and reported by the participants are summarised, analysed and compared with the reference values. The present paper concerns only the physical dosimetry and essentially experiments performed on the SILENE facility. The results obtained with the biological dosimetry are published in two other papers of this issue.

Reference dosimetry measurements for the international intercomparison of criticality accident dosimetry SILENE 9-21 June 2002.

An international intercomparison of criticality accident dosimetry systems took place in the SILENE reactor, in June 2002. Participants from 60 laboratories irradiated their dosemeters (physical and biological) using two different configurations of the reactor. In preparation for this intercomparison, the leakage radiation fields were characterised by spectrometry and dosimetry measurements using the ROSPEC spectrometer associated with a NE-213 scintillator, ionisation chambers, GM counters, diodes and thermoluminescence dosemeters (TLDs). For this intercomparison, a large area was required to irradiate the dosemeters both in free air and on phantoms. Therefore, measurements of the uniformity of the field were performed with activation detectors and TLDs for neutron and gammas, respectively. This paper describes the procedures used and the results obtained.

Direct measurement of the phase-coherence length in a GaAs/GaAlAs square network.

The low temperature magnetoconductance of a large array of quantum coherent loops exhibits Altshuler-Aronov-Spivak oscillations with a periodicity corresponding to 1/2 flux quantum per loop. We show that the measurement of the harmonics content provides an accurate way to determine the electron phase-coherence length L(phi) in units of the lattice length with no adjustable parameters. We use this method to determine L(phi) in a square network realized from a 2D electron gas in a GaAs/GaAlAs heterojunction, with only a few conducting channels. The temperature dependence follows a power law T(-1/3) from 1.3 K to 25 mK with no saturation, as expected for 1D diffusive electronic motion and electron-electron scattering as the main decoherence mechanism.

[Obstetrical analgesia and anaesthesia in multiple sclerosis]. / Analgésie et anesthésie obstétricale chez les patientes atteintes de sclérose en plaques.

OBJECTIVES: The use of epidural analgesia and anaesthesia is controversial in patients with multiple sclerosis (MS) due to the potential neurotoxicity of local anaesthetics. The aim of this study was to evaluate the place and the safety of epidural obstetrical analgesia in these patients. PATIENTS AND METHODS: A consecutive series of 19 patients with MS was studied over 4 years, recording the type of anaesthesia and the obstetric and neurologic observations during the pregnancy and post-partum. RESULTS: Ten patients had epidural analgesia. One patient had a caesarean section under epidural anaesthesia. Five patients relapsed during the post-partum period. Only one of them had an epidural for a spontaneous vaginal delivery, without any evidence of a causal relationship. Spinal anaesthesia is generally not advocated in the presence of MS due to concerns relating to the stronger local anaesthetics required and was therefore not used. CONCLUSION: The results confirm that epidural analgesia is innocuous in this context. The important points are the precise evaluation of the existing neurological symptoms and the sparing of local anaesthetics thanks to the addition of opioids.

Waste ecocompatibility in storage and reuse scenarios: global methodology and detailed presentation of the impact study on the recipient environments.

In 1995, the ADEME launched a research program called "Waste Ecocompatibility" in order to define a reliable methodology for measuring the impact of waste in storage or reuse scenarios. The French concept of "Ecocompatibility" is defined as the situation where the pollutant flux from waste disposed of or used in specified conditions is compatible with the environmental acceptance of the receiving environments. The chief feature of this definition is to integrate the evaluation of the three following terms: pollutants emission from the waste, transport of the pollutants from the waste to the receptor cells and the environmental acceptance of the receiving environments. The "Waste Ecocompatibility" program consisted of a literature survey and an experimental part. The literature study aimed to determine factors and waste characteristics to be considered for a reliable ecocompatility assessment, to provide an overview of the available tools for measuring those factors and characteristics and to propose a first approach of the methodology. In the framework of the experimental program, this approach was then applied to three theoretical scenarios to validate the laboratory tools (comparative study of laboratory and field results) and to calibrate the global methodology. This paper deals with the results of the experimental program concerning the impact study on receiving environments: impact on plants and microorganisms living in soil, impacts on soil fauna and aquatic fauna. In other papers we intend to present the operational methodology for the assessment of waste ecocompatibility. It includes bio-assays at laboratory scale (microcosms), pilot scale (mesocosms) and in situ experiments (experimental prairie). To limit the use of in situ experiments other research works are necessary to validate bio-assays at laboratory or pilot scale.

Study of the photon radiation performance of electronic personal dosemeters.

Following the specifications and test methods given by international standards IEC-61526 and ISO 4037, the dosimetry department of the IPSN studied the photon radiation performance of seven recent electronic personal dosemeters: The personal dosimetric performance of each piece of equipment was tested with X and gamma radiation between 12 keV and 1.25 MeV.

Complementarity and redundancy of the binding specificity of HLA-DRB1, -DRB3, -DRB4 and -DRB5 molecules.

The second HLA-DR molecules, which are encoded by loci different from HLA-DRB1 are weakly polymorphic. Predominant alleles such as HLA-DRB3*0101, HLA-DRB4*0101 and HLA-DRB5*0101 are therefore interesting targets to define antigenic peptides with major impact for the entire population. Strikingly, they have been poorly investigated. Thus we have characterized peptides from the major bee venom allergen that bind efficiently to these molecules and compared them to peptides specific for preponderant HLA-DRB1 molecules. Interestingly, DRB5*0101 and DRB1*0701 molecules share four binding peptides and use some identical anchor residues. Similarities are also found between DRB3*0101 and its haplotype-associated molecules DRB1*0301 and DRB1*1301. In sharp contrast, DRB4*0101 exhibits a unique binding specificity, which results from particular structural features of its peptide binding site. Ybeta81 seems to alter the amino acid preferences of the P1 pocket, while Rbeta71, Ebeta74, Nbeta26 and Cbeta13 confer to the P4 pocket a unique topology. Our results show that the two HLA-DR molecules expressed in most haplotypes studied here have mostly complementary binding patterns. Only haplotype HLA-DR52 exhibits peptide binding redundancies. Finally our results document functional similarities among HLA-DR molecules and allow us to propose peptide sequences that might be useful for bee venom immunotherapy.

Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules.

We obtained a lytic CD4 T-cell clone that recognized an antigen presented by HLA-DRB1*1101 on the tumor cells of a melanoma patient who enjoyed an unusually favorable clinical evolution. The antigen appeared to be shared between several melanoma cell lines. To identify the encoding gene, we used a new method, based on the cotransfection into human embryonal kidney cell line 293 of a cDNA library from the tumor together with a cDNA clone encoding the class II transactivator, which induces the expression of HLA class II molecules. The product of the gene coding for the antigenic peptide is EphA3, a member of the Eph family of tyrosine kinase receptors, which mediate the repulsion of neural cells by cells carrying the ligand Ephrins on their surface. EphA3 is expressed at a high level in the retina and fetal brain, at a lower level in several normal tissues, and not at all in hematopoietic cells, the only cells that constitutively express HLA class II molecules. It is overexpressed in several types of tumors, including melanoma, lung carcinoma, and sarcoma. On the basis of this pattern of expression, EphA3 may be a source of tumor-specific antigens recognized on tumor cells that express HLA class II molecules. Anti-EphA3 T cells may have participated in a tumor rejection response in the patient, because the cells of metastases collected several years later than the metastasis used to characterize the antigen had lost expression of HLA-DR or EphA3, therefore escaping recognition by these lymphocytes.

HLA-DR restricted peptide candidates for bee venom immunotherapy.

T cell epitopes containing peptides have been recently proposed as an alternative to conventional immunotherapy of allergic diseases because they are expected to be better tolerated than allergen extracts. A principal limitation to their clinical use is that they present an important diversity, which primarily results from the polymorphism of HLA class II molecules. In Caucasian populations, however, seven alleles of the most expressed molecules (namely DRB1*0101, DRB1*0301, DRB1*0401, DRB1*0701, DRB1*1101, DRB1*1301, and DRB1*1501) predominate. Peptides from allergens that would efficiently bind to them should be potential candidates for specific immunotherapy. In this paper, we have determined the peptides present in the major bee venom allergen by investigating the capacity of synthetic peptides that encompass its whole sequence to bind to each allele. Several efficient binders have been identified and are either allele-specific or common to several HLA-DR molecules. Interestingly enough, the 81-97 sequence is universal in the sense that it binds to all studied molecules. This sequence is surrounded by several active regions, which make the 76-106 sequence particularly rich of binding determinants and a good candidate for specific immunotherapy. Statistical analyses of the binding data also provide an overview of the preponderant HLA-DR alleles specificity.

On the diversity and heterogeneity of H-2(d)-restricted determinants and T cell epitopes from the major bee venom allergen.

One of the main limitations of using synthetic peptides for immunotherapy in allergic patients is the difficulty to delineate the immunodominant T cell epitopes which are necessarily dependent on HLA molecules. We have thus addressed the question of the role of MHC II molecules in immunodominant epitopes selection in the particular case of the major bee venom allergen (API m1). To exhaustively and easily explore it, we used BALB/c mice whose H-2 haplotype is associated with high IgE and IgG responses to API m1. By means of extensive sets of synthetic peptides, we investigated the specificity of polyclonal T cells and monoclonal hybridomas from mice immunized with API m1 and delineated four immunodominant regions, restricted to either the I-E(d) or the I-A(d) molecule. All the peptides were also tested for their capacity to bind to immunopurified MHC II molecules. Eight determinants of high affinity were identified. They clustered into three distinct regions and were largely overlapping. They included all the immunodominant epitopes, but half of them were not capable of stimulating T cells. Strikingly, interacting surfaces with either the TCR or MHC II molecule greatly differed from one determinant to another. In one case, we observed that flanking regions exerted a particular action on T cell stimulation which prevented the fine epitope localization. Our results underline the diversity and complexity of MHC II-restricted determinants and T cell epitopes from the major bee venom allergen, even in a single haplotype. These data also participate in the development of alternative approaches to conventional immunotherapy.

On the immunogenic properties of retro-inverso peptides. Total retro-inversion of T-cell epitopes causes a loss of binding to MHC II molecules.

Retro-inversion is considered an attractive approach for drug and vaccine design since it provides the modified peptides with higher resistance to proteolytic degradation. We therefore investigated in detail the effect of retro-inversion on the immunological properties of synthetic peptides. We have synthesized retro-inverso analogues of MHC II restricted peptides that thus contained the correct orientation of the side chains but an inverse main chain. Retro-inversion made the peptides unable to compete in I E(d) or I A(d) binding tests, demonstrating a very low, if any, capacity to bind to MHC II molecules. These results confirm previous structural data that hydrogen bonds between residues of MHC II molecules and the main chain of antigenic peptides play a major interacting role. In vito experiments further showed that retro-inversion of a T-cell epitope causes its inability to either sustain in vitro T-cell stimulation or to prime specific T cells. Moreover, the retro-inverso peptide was not recognized by antibodies raised against the native peptide and did not elicit antibodies when injected into BALB/c mice. Retro-inverso peptides appear to be poor immunogens as a result of their weak capacity to bind to MHC II molecules. As an advantage, they are not expected to trigger undesirable humoral responses such as hypersensitivity or allergic disease. These results also provide a molecular explanation regarding the weak immunogenicity of D-amino acids containing polypeptides.