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We use the resonant dipole-dipole interaction between Rydberg atoms and a periodic external microwave field to engineer XXZ spin Hamiltonians with tunable anisotropies. The atoms are placed in one-dimensional (1D) and two-dimensional (2D) arrays of optical tweezers. As illustrations, we apply this engineering to two iconic situations in spin physics: the Heisenberg model in square arrays and spin transport in 1D. We first benchmark the Hamiltonian engineering for two atoms and then demonstrate the freezing of the magnetization on an initially magnetized 2D array. Finally, we explore the dynamics of 1D domain-wall systems with both periodic and open boundary conditions. We systematically compare our data with numerical simulations and assess the residual limitations of the technique as well as routes for improvement. The geometrical versatility of the platform, combined with the flexibility of the simulated Hamiltonians, opens up exciting prospects in the fields of quantum simulation, quantum information processing, and quantum sensing., This work is supported by the European Union (EU) Horizon 2020 research and innovation program “Programmable Atomic Large-Scale Quantum Simulation” (PASQuanS) under Grant Agreement No. 817482, the Agence National de la Recherche (ANR, project RYBOTIN), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy EXC2181/1-390900948 (the Heidelberg STRUCTURES Excellence Cluster), within the Collaborative Research Center SFB1225 (ISOQUANT), the DFG Priority Program 1929 “GiRyd” (DFG WE2661/12-1), and by the Heidelberg Center for Quantum Dynamics. C.H. acknowledges funding from the Alexander von Humboldt foundation, T.F. from a graduate scholarship of the Heidelberg University (LGFG), and D.B. from the Ramón y Cajal program (RYC2018-025348-I). F.W. is partially supported by the Erasmus+ program of the EU. We also acknowledge support by the state of Baden-Württemberg through Baden-Württemberg high performance computing (bwHPC) and the DFG through Grant No. INST 40/575-1 FUGG (JUSTUS 2 cluster).

Early allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as primary treatment modality for patients with chronic myeloid leukemia (CML). This concept has been challenged by transplantation mortality and improved drug therapy. In a randomized study, primary HSCT and best available drug treatment (IFN based) were compared in newly diagnosed chronic phase CML patients. Assignment to treatment strategy was by genetic randomization according to availability of a matched related donor. Evaluation followed the intention-to-treat principle. Six hundred and twenty one patients with chronic phase CML were stratified for eligibility for HSCT. Three hundred and fifty four patients (62% male; median age, 40 years; range, 11-59 years) were eligible and randomized. One hundred and thirty five patients (38%) had a matched related donor, of whom 123 (91%) received a transplant within a median of 10 months (range, 2-106 months) from diagnosis. Two hundred and nineteen patients (62%) had no related donor and received best available drug treatment. With an observation time up to 11.2 years (median, 8.9 years), survival was superior for patients with drug treatment (P = .049), superiority being most pronounced in low-risk patients (P = .032). The general recommendation of HSCT as first-line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first.

IRSN has been asked by SNCF (French Railways) to carry out measurements in order to establish the values of ambient dose equivalents H*(10) in the vicinity of shipments of radioactive materials to assess the external exposure to ionising radiation to which employees may be subjected during the carriage of radioactive goods. Detailed dosimetric characterisations of the wagons have been made and the external exposure at different stages of the work that is done by the employees have been measured in terms of H*(10). For the study presented in this paper, and corresponding to a used fuel shipment composed of UO2 and UO2-PuO2, it has been observed that the photon and neutron doses are very similar. In addition, the order of magnitude of the total dose integrated by an employee who would carry out 100 times the series of essential operational tasks, has been found to be approximately 250 microSv. This value is compared with those observed for other previously investigated shipments involving the exposure to photon fields only. Language: en

This paper presents the results of measurements made with the electronic personal neutron Saphydose-N during the four campaigns of the European contract EVIDOS (EValuation of Individual DOSimetry in mixed neutron and photon radiation fields). These measurements were performed at Institute for Radiological Protection and Nuclear Safety (IRSN) in France (C0), at the Krümmel Nuclear Power Plant in Germany (C1), at the VENUS Research Reactor and the Belgonucléaire fuel processing plant in Belgium (C2) and at the Ringhals Nuclear Power Plant in Sweden (C3). The results for Saphydose-N are compared with reference values for dose equivalent.

Although defects in the weight bearing area of the heel can be covered by local flaps, radiodermatitis is a contraindication to these flaps. Thin free flaps, as grafted fascial or muscles flaps and thin fasciocutaneous flaps, are usually the option of choice in these particular defects. These reconstructions are prone to shearing strains resulting in ulceration, hypertrophic scars and hyperkeratosis. The authors present a retrospective study of the reconstruction of six small heel defects with the fasciocutaneous temporal free flap performed between 1996 and 2001. The mean size of the defect was 20 cm 2 . All arterial anastomoses were performed end to side on the posterior tibial artery. Despite the flap thinness, swelling was present during 12–25 months and one debulking had to be performed. With a mean follow-up of 32 months, all flaps regained protective sensibility after 7 months. No sliding of the flaps could be noted but there was one transient hyperkeratosis. Although the amount of hair on the transferred flaps decreased spontaneously with time, laser hair removal was performed in two patients for psychological reasons. In conclusion, it seems that in selected cases where local flaps are contraindicated, the fasciocutaneous temporal free flap can offer an excellent alternative for heel reconstruction. Due to its particular architecture, it resembles the complex tissue of the sole of the foot resulting in fewer complications and maintenance of flap durability.

Chronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201+ (HLA-A*0201+) individuals, response after interferon-α (IFN-α) was shown to be associated with the emergence of CML-specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)–derived nonapeptide. In contrast, imatinib potently induces remissions from CML by specific inhibition of the ABL tyrosine kinase. Here, we explored molecular regulations associated with CML responses under different treatment forms using cDNA-array. Expression of MBN was found to be down-regulated in remission under imatinib therapy (0 of 7MBN+ patients). In contrast, MBNtranscription was readily detectable in the peripheral blood in 8 of 8 tested IFN-α patients in complete remission (P = .0002). IFN-α–dependent MBNtranscription was confirmed in vitro by stimulation of peripheral blood mononuclear cells (PBMCs) with IFN-α and by IFN-α–mediated activation of the MBN promoter in reporter gene assays. Finally, with the use of HLA-A*0201–restricted,MBN-specific tetrameric complexes, it was demonstrated that all of 4 IFN-α–treated patients (100%), but only 2 of 11 imatinib patients (19%), in complete hematological or cytogenetic remission developed MBN-specific cytotoxic T cells (P = .011). Together, the induction of MBNexpression by IFN-α, but not imatinib, may contribute to the specific ability of IFN-α to induce an MBN-specific T-cell response in CML patients. This also implies that the character of remissions achieved with either drug may not be equivalent and therefore a therapy modality combining IFN-α and imatinib may be most effective.

Die chronische myeloische Leukamie (CML) stellt eine Modellerkrankung fur Diagnostik und Therapie neoplastischer Erkrankungen dar. Die zu Grunde liegende zytogenetische Aberration, die Philadelphia-Translokation, mit der BCR-ABL-Genfusion sowie der mehrstufige Verlauf mit der stabilen, therapeutisch gut zu beeinflussenden chronischen Phase, der Akzelerationsphase und der Blastenphase ermoglichen die Ubertragung molekularzytogenetischer Erkenntnisse in die klinisch-therapeutische Anwendung.

Individual neutron dosimetry represents one of the current difficulties in the field of radiological protection of workers. Since March 1999, the regulatory requirements in France for active (i.e. operational) dosimetry have been those of ICRP Publication 60, applicable from May 2000, necessitating the introduction of a new generation of neutron dosemeters. Over the last few years, the Institute for Nuclear Safety and Protection has been studying an individual electronic dosemeter for neutrons based on a semiconducting detector, capable of meeting the specifications laid down by a neutron dosimetry work group, including members from all the main players in the French nuclear industry. In 1998, the IPSN began transferring technology to the Saphymo company which, by the end of 2001, will be marketing Saphydose-n, the first individual dosemeter for neutrons which complies with IEC Standard 1323. This dosemeter is of compact design and can assess the individual dose equivalent H p (10) in mixed neutron and gamma radiation fields. It will be usable in any nuclear facility without prior knowledge of the average neutron spectrum or of the neutron-gamma ratio. It will be possible to connect the Saphydose-n dosemeter to any of the existing gamma deserter terminals to read the dose data and recharge the batteries.

Selective Inhibition of Tyrosine Kinases – a New Therapeutic Principle in Oncology Tyrosine kinases are enzymes that regulate mitosis, differentiation, migration, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CML) represents an ideal target for a therapy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-phenylpyrimidine derivative STI571 was rationally designed to inhibit ABL and BCR-ABL tyrosine kinase activities through competitive ATP-binding pocket interactions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. STI571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases with ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell factor receptor CD117, the product of the proto-oncogene c-kit. Inhibition of c-kit in vivo results in an immediate metabolic change of the tumor cells, detectable by positron emission tomography. Since c-kit overexpression is inhibited in small-cell lung cancer cell lines, a study with STI571 as second-line therapy of c-kit-positive small-cell lung cancer is in progress. Clinical studies are ongoing in malignancies associated with an enhanced activity of the PDGF-R, such as highgrade glioma, prostate cancer and leukemias with rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors.

La dosimetrie individuelle des neutrons constitue une des difficultes actuelles de la radioprotection des travailleurs. La dosimetrie dite active (operationnelle) est reglementaire depuis mars 1999 ; les valeurs des seuils recommandees par la CIPR 60 applicables en mai 2000 rendent necessaire la mise en place d'une nouvelle generation de dosimetres neutrons. L'Institut de protection et de surete nucleaire (IPSN) a mene, au cours de ces dernieres annees, l'etude d'un dosimetre electronique individuel pour les neutrons satisfaisant aux specifications d'un cahier des charges defini par le groupe de travail " dosimetrie neutrons " reunissant les principaux acteurs du cycle nucleaire francais. Courant 1998, l'IPSN a engage un transfert de technologie vers la societe Saphymo ; celle-ci commercialisera fin 2000 le premier dosimetre individuel electronique pour les neutrons, le Saphydose-n, repondant a la norme CEI 1323. Ce dosimetre, d'un encombrement reduit, permettra d'evaluer l'equivalent de dose individuel Hp(10) dans des champs mixtes neutron-gamma. Il pourra etre utilise dans toutes les installations du cycle electronucleaire, sans connaissance prealable de l'energie moyenne du spectre des neutrons et du rapport neutron-gamma. Le dosimetre Saphydose-n pourra etre raccorde aux bornes existantes des dosimetres gamma pour la lecture des informations et pour la charge des accumulateurs.

In in£ammation and wound healing, dynamic changes in cell adhesion and migration are fundamental properties of the cells involved. Disturbed interaction of leukocytes with microvascular endothelial cells has been proposed to be a central pathogenic factor in chronic venous insu⁄ciency. This disease may therefore serve to elucidate dysregulated modulation of adhesion molecule expression in conditions of chronic in£ammation and impaired wound healing. In this study, we determined how the expression of ICAM-1/VCAM-1 on endothelial cells and their ligands LFA-1/VLA-4 on leukocytes is modulated in skin of progressing stages of chronic venous insu⁄ciency. Immunohistochemical staining of skin biopsies revealed an increase in the expression of ICAM-1 and VCAM-1 on endothelial cells in an early stage of venous disease such as stasis dermatitis. Such protein expression correlated with an increase of corresponding mRNA in skin biopsies. Expression of these CAMs on endothelial cells was accompanied by the occurrence of a marked perivascular in¢ltration of leukocytes, which expressed increased levels of LFA-1 and VLA-4. In progressing stages of chronic venous insu⁄ciency, characterized by hyperpigmentation and lipodermatosclerosis, which precede skin ulceration, all these CAMs remained upregulated on endothelial cells and in¢ltrating leukocytes. Our ¢ndings indicate that following an initial peak expression during stasis dermatitis, vascular ICAM-1 and VCAM-1 expression is not downmodulated to baseline levels, but remains upregulated. This possibly promotes tissue damage by a perpetuated, upregulated in£ux of activated leukocytes, ¢nally leading to skin ulceration. Key words: chronic venous insu⁄ciency; adhesion molecules; endothelial cells; leukocytes.

The barley Rar1 gene is an essential component of the race-specific, Mla-12-specified powdery mildew resistance reaction. As part of a map-based cloning strategy designed to isolate Rar1, five barley yeast artificial chromosomes (YACs) have been identified, ranging in size from 300 to 1100 kb. PCR-based YAC end-specific markers have been established and were employed to construct a local YAC contig. Four out of five YAC clones were found to be non-colinear with the source DNA. High-resolution genetic mapping of the YAC ends demonstrated that the set of five overlapping YAC clones encompasses the barley Rar1 gene.

The Mla-12-mediated resistance in barley against Erysiphe graminis f. sp. hordei requires for its function the Rar1 gene. High-resolution genetic mapping was accomplished by inspecting more than 4000 plants segregating for Rar1 within an 0.7-cM interval containing the target gene. Marker enrichment in the target region was carried out by an amplified fragment length polymorphism (AFLP)-based search for polymorphic loci using bulked DNA templates from resistant and susceptible recombinants adjacent to Rar1. RFLP markers closely linked to Rar1 were used to investigate the relationship between physical and genetical distances by PFGE Southern analysis, indicating the physical linkage of two genetically separated RFLP loci. Comparative mapping of Rar1-linked RFLP probes in barley and rice identified a break of collinearity in the orthologous chromosome segments.

Neutral atoms are promising candidates for the realization of entangled states involving up to a few tens of particles. To generate such states, one approach consists in using the dipole blockade mechanism, which results from the strong dipole-dipole interactions between Rydberg atoms.Following this approach, this thesis describes the design and the characterization of an experimental apparatus allowing to manipulate single 87Rb atoms trapped in microscopic optical tweezers, and to excite them towards Rydberg states. A stable electrostatic environment and controlled electrodes enable the fine manipulation of these states. Using two optical tweezers separated by a few microns, we demonstrate the Rydberg blockade between two single atoms, and we observe their collective excitation.Finally, by operating in the partial blockade regime, we develop a method allowing to measure the van der Waals interaction ∆E = C6 /R6 between two atoms separated by a controlled distance R. The C6 coefficients obtained for various Rydberg states agree well with ab initio theoretical calculations, and we observe the dramatic increase of the interaction with the principal quantum number n of the Rydberg state.

A review of the development of electronic neutron dosemeters is given, with an assessment of their characteristics. Comment is made on necessary lines for future development.

new method using one PN junction covered with a hydrogenous converter ( 10 B-loaded) is proposed for individual neutron dosimetry. This method is based on a pulse shape analysis to discriminate the photon signal from the neutron signal. This method allows drastic reduction of the photon sensitivity (by a factor of 1000). Additionally, when using a photon correction factor, the photon response becomes negligible. By applying a neutron correction factor to the low energy events, the gap in neutron sensitivity for intermediate energy can be partly filled. Lead shields used to surround the detector allow the remaining photon sensitivity to be decreased by a factor of two. An especially designed hydrogenous moderator placed at the top of the detector allows the neutron sensitivity to be increased by a factor of two for 250 keV neutron energy.

Different options were investigated in the development of active neutron dosemeters for personnel and area monitoring. In particular, two different classes of detectors, superheated emulsions and silicon diodes, were studied as radiation sensors for such devices. The detectors were analysed with respect to their neutron sensitivity and their overall suitability for practical dosimetry. Superheated emulsions proved adequate in terms of their dose equivalent response and their photon discrimination: future work should now focus on the development of a rugged device. Significant improvements were also achieved with the diode sensors, although more research will be necessary for the design ofa simple, single structure readily usable as a neutron dosemeter.

This paper deals with the design and fabrication of three new dosimetric sensors to be used in personal radiation monitoring. The first two sensors, double diode and streamer chamber, are based on the same particle detection principle, the last is a multicellular tissue-equivalent proportional counter. Each dosimetric sensor has a preferential range of applications. The double diode dosemeter, called DIAC, is the least sensitive, but can be reduced to the size of an 'electronic credit card' weighing a few 10s of grams. Two versions of the streamer chamber have been developed, the first corresponding to a personal device called DINE and the second to an ambient device called DANE. These two sensors are much more sensitive than the DIAC. The last sensor, studied in the SDOS laboratory, is a multicellular proportional counter called MC-TEPC. Giving both the dose and the dose equivalent quantities, it is more suitable for a good evaluation of the radiation risk but many problems due to gas aging have to be solved.

HISTORY AND CLINICAL FINDINGS: A 60-year-old woman presented with night-sweats and increasing weakness. Physical examination revealed no abnormalities. For 27 years she had been treated for Philadelphia-positive chronic myeloid leukemia (CML). Because of progressive disease treatment with the tyrosine kinase inhibitor imatinib (STI571, Glivec (R)) had been started 9 months before. She had achieved complete hematological remission within 8 weeks, but not a cytogenetic response. INVESTIGATIONS: Elevated WBC count (26.7/nl) with a differential displaying typical features of acceleration in bone marrow aspirate confirmed CML in accelerated phase. Sequencing of the ATP binding site of the BCR-ABL gene, which - at protein level - is the target for imatinib, revealed the clonal selection of cells harboring a point mutation leading to the exchange of amino acid 253 from tyrosine to histidine. This was considered to be the cause of resistance to imatinib. TREATMENT AND COURSE: Dose increase of imatinib up to 600 mg daily and administration of cytarabine did not overcome resistance. Imatinib therapy was discontinued; hematologic remission was induced by oral therapy with hydroxyurea and mercaptopurine. In the course of the following 6 months a gradual decrease of the resistant clone from 100 % down to lower than the detection limit of the method was demonstrated. CONCLUSIONS: Clonal mutations are often the cause of resistance to imatinib therapy. They can be detected by sequencing of the ATP binding site of BCR-ABL in specialized laboratories. This case shows that discontinuation of imatinib therapy can significantly reduce the mutated (resistant) clone and thereby restore sensitivity to imatinib.

Clinical trials underestimate the age of chronic myeloid leukemia (CML) patients. Incidence and median age of Ph/BCR-ABL-positive CML and other chronic myeloproliferative disorders in a representative area in Germany

Ultra-cold atomic systems provide a new setting where to investigate the role of long-range interactions. In this paper we will review the basics features of those physical systems, in particular focusing on the case of Chromium atoms. On the experimental side, we report on the observation of dipolar effects in the expansion dynamics of a Chromium Bose-Einstein condensate. By using a Feshbach resonance, the scattering length characterising the contact interaction can be strongly reduced, thus increasing the relative effect of the dipole-dipole interaction. Such experiments make Chromium atoms the strongest candidates at present for the achievement of the strong dipolar regime. On the theoretical side, we investigate the behaviour of ultra-cold dipolar systems in the presence of a periodic potential. We discuss how to realise this situation experimentally and we characterise the system in terms of its quantum phases and metastable states, discussing in detail the differences with respect to the case of zero-range interactions., 30 pages, 17 figures, to be published in the Proceedings of the Workshop "Dynamics and Thermodynamics of Systems with Long Range Interactions" (Assisi, July 2007), AIP Conference Proceedings

Clonal cytogenetic aberrations of the Philadelphia chromosome (Ph) positive hematopoiesis have been associated with the natural evolution of CML to advanced disease. Clonal aberrations of Ph negative metaphases have been described after treatment with interferon alpha or imatinib in a minority of patients (pts) with cytogenetic response. Conflicting data suggest selection of preexisting clones vs. induction of aneuploidy by tyrosine kinase inhibitors. The prognostic impact of aberrations in the Ph negative hematopoiesis for the individual pts remains to be determined. Dasatinib is a multitargeted agent inhibiting both ABL and SRC tyrosine kinases. The efficacy and safety of dasatinib has been demonstrated in phase I and II studies in pts with Ph positive CML after failure of imatinib therapy. We sought to evaluate the effect of dasatinib on Ph positive clones with additional cytogenetic aberrations and the frequency of novel aberrations in Ph positive and Ph negative metaphases during dasatinib therapy. 71 pts (40 m, 31 f) with Ph positive CML after failure of imatinib therapy have been evaluated. Median age was 58 years (range, 28–78), median time from diagnosis 73 months (range, 14–231). Pts were in chronic phase (CP, n=50), accelerated phase (AP, n=6), myeloid (n=8) or lymphoid (n=7) blast crisis (BC). Pretreatment consisted of imatinib (n=71), hydroxyurea (n=48), interferon alpha (n=49), cytosine arabinoside (n=11) and nilotinib (n=2). Dasatinib therapy was commenced at a dose of 100–140 mg/day, median duration of dasatinib therapy was 9 months, (range, 1–16). Prior to dasatinib therapy, 22 pts (31%) demonstrated additional chromosomal aberrations in the Ph positive clone indicating BCR-ABL independent mechanisms of resistance. Of these, 8 pts were in CP (16%), 5 in AP (83%), and 9 in BC (60%). In 35 pts (49%), BCR-ABL mutations associated indicating a BCR-ABL dependent mechanism of resistance were observed. 9 pts (13%) showed both clonal evolution and BCR-ABL mutations. Two pts (3%) had trisomy 8 as an aberration of the Ph negative clone at baseline. During dasatinib therapy, 33 pts (46%) achieved major cytogenetic remission, 26 (37%) being complete. From pts with clonal evolution, 3 (14%) achieved a major with 2 (9%) complete cytogenetic remissions. Novel aberrations of the Ph positive clone appeared during dasatinib therapy in 6 pts (8%), aberrations of the Ph negative clone in 3 pts (4%). In total, 5/71 pts (7%) showed clonal aberrations of Ph negative metaphases after consecutive imatinib/dasatinib therapies. None of these pts had morphological indications for secondary neoplastic changes, like myelodysplasia or acute leukemia. In conclusion, dasatinib was efficacious in pts with clonal cytogenetic aberrations as a marker of BCR-ABL independent imatinib resistance. However, cytogenetic response was delayed compared to pts without additional aberrations. Preexisting clonal aberrations of the Ph negative hematopoiesis were uncovered by a simultaneous gradual elimination of the Ph positive clone. In addition, a minority of pts demonstrated novel aberrations in Ph negative cells. The prognostic significance of aneuploidy of the Ph negative hematopoiesis remains to be evaluated by long term observation.

This paper mainly aims at presenting the measurements and the results obtained with the electronic personal neutron dosemeter Saphydose-N at different facilities. Three campaigns were led in the frame of the European contract EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields'). The first one consisted in the measurements at the IRSN French research laboratory in reference neutron fields generated by a thermal facility (SIGMA), radionuclide ISO sources (241AmBe; 252Cf; 252Cf(D2 O)\Cd) and a realistic spectrum (CANEL/T400). The second one was performed at the Krümmel Nuclear Power Plant (Germany) close to the boiling water reactor and to a spent fuel transport cask. The third one was realised at Mol (Belgium), at the VENUS Research Reactor and at Belgonucléaire, a fuel processing factory. © 2006 Oxford University Press.

EVIDOS is an EC sponsored project that aims at an evaluation and improvement of radiation protection dosimetry in mixed neutron/photon fields. This is performed through spectrometric and dosimetric investigations during different measurement campaigns in representative workplaces of the nuclear industry. The performance of routine and, in particular, novel personal dosemeters and survey instruments is tested in selected workplace fields. Reference values for the dose equivalent quantities, H*(10) and Hp(10) and the effective dose E, are determined using different spectrometers that provide the energy distribution of the neutron fluence and using newly developed devices that determine the energy and directional distribution of the neutron fluence. The EVIDOS project has passed the mid-term, and three measurement campaigns have been performed. This paper will give an overview and some new results from the third campaign that was held in Mol (Belgium), around the research reactor VENUS and in the MOX producing plant of Belgonucléaire. © 2006 Oxford University Press.

This work describes spectral distributions of neutrons obtained as function of energy and direction at four workplace fields at the Krümmel reactor in Germany. Values of personal dose equivalent Hp(10) and effective dose E are determined for different directions of a person's orientation in these fields and readings of personal neutron dosemeters - Especially electronic dosemeters - Are discussed with respect to Hp(10) and E. © 2006 Oxford University Press.

In recent years IRSN has developed tissue-equivalent proportional counters (TEPCs) for neutron monitoring. A detector with a multi-element geometry was studied for personal dosimetry purposes. The determination of the personal dose equivalent using a multi-element TEPC requires to calculate the mean chord length of the charged particles in the counter gas. This paper presents the results of the simulations using the MCNPX code and explains the influence of the gas parameters on the mean chord length and the consequences on the dose equivalent response. © The Author 2005. Published by Oxford University Press. All rights reserved.

In nuclear medicine departments, where radioactive sources are manipulated, the personnel can receive large radiation doses to the skin of their hands. For performing detailed characterisations and dose optimisations of these workplaces, active extremity dosemeters can be used as complementary tools to passive hand monitoring. Active extremity dosimetry is still a subject of research. In this context, IRSN has started a research and development programme. As a first step, a hospital workplace study has been performed using thermoluminescence dosemeters and has shown, in agreement with previous works, that the pads of the fingers, points that are very difficult to instrument, receive the largest doses. Numerical studies have now started, with the aim of calculating the dose equivalent gradients through the hands, in order to optimise the locations of the detectors.

Gender-related aspects in chronic myeloid leukemia (CML) have not been studied well. We therefore analyzed 856 patients with Ph/BCR-ABL-positive CML from the German randomized CML-studies I (interferon alpha (IFN) vs hydroxyurea (HU) vs busulfan) and II (IFN+HU vs HU alone). The median observation time was 8.6 years. A total of 503 patients (59%) were male. Female patients were older (51 vs 46 years; P

Tissue-equivalent proportional counters (TEPC) allow the measurements of the absorbed dose and the ambient dose equivalent for neutron fields. A device based on this approach, called NAUSICAA ( 1 , 2 ) , has already been developed by IRSN to be used in high energy neutron fields for space applications. The response of this detector underestimates significantly the dose equivalent at low energies (several hundred keV) which represent the major component of neutron fields at workplaces in the nuclear industry. A counter with a similar geometry (cylindrical detector) and a lower gas pressure was studied in order to simulate a I pm biological site. In 2003, the performance of the device was further improved by adding a small amount of 3 He to the tissue-equivalent gas (propane based) in order to increase the response for the lower energies of neutrons. Three amplification circuits were used to cover lineal energy range from 10 - 1 to 10 4 keV μm - 1 . Tests were performed in monoenergetic neutron and source fields. This paper presents the experimental results obtained with this change.

Since 1993, the Institute for Radiological Protection and Nuclear Safety (IRSN) has lead, in association with Electricité de France (EDF), a R&D study of a neutron personal electronic dosemeter. This dosemeter, called 'Saphydose-N', is manufactured by the SAPHYMO company. This paper presents first the optimisation of some detector components using Monte Carlo calculations, and second the test of the manufactured Saphydose-N under radiation following the IEC 1323 standard's recommendations for active personal neutron dosemeters. The measurements with the manufactured dosemeter were performed on the one hand at PTB (Physikalisch-Technische Bundesanstalt) in mono-energetic neutron fields and, on the other hand at IRSN in neutron fields generated by a thermal facility (SIGMA), radionuclide ISO sources and a realistic spectrum (CANEL/T400). The manufactured dosemeter Saphydose-N was also tested during measurement campaigns of the European programme EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields') at different nuclear workplaces. The study showed that Saphydose-N complies with the recommendations of standard IEC 1323 and can be used at any workplace with no previous knowledge of the neutron field characteristics. © Oxford University Press 2004; all rights reserved.

We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.

A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) alpha-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1-34%; n=7) cytogenetic remission after 3-20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82-7.8) in patients with subsequent relapse and 0.075% (range 0-3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL0.1% as best molecular response are in continuous remission, while 6/13 patients (46%) with ratios/=0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL0.1% are associated with continuous remission.

Telomeres are composed of TTAGGG repeats and associated proteins. In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence. In previous studies, we described substantial and disease stage-specific telomere shortening in peripheral blood (PB) leukocytes from patients with chronic myeloid leukemia (CML). Here, we sought to determine whether age-adjusted telomere length in PB granulocytes (deltaTEL(gran)) is associated with response to treatment with the selective tyrosine kinase inhibitor imatinib. A total of 517 samples from 206 patients in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) before and up to 706 days after initiation of imatinib therapy (median: 144 days) were analyzed by quantitative fluorescence in situ hybridization of interphase cells in suspension (Flow-FISH); telomere fluorescence was expressed in molecular equivalents of soluble fluorochrome units (MESF). Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean +/- SE; -1.5 +/- 0.3 kMESF) compared to samples from patients treated for more than 144 days (-0.8 +/- 0.3 kMESF, p = 0.035). In patients with repeated measurements, a significant increase in telomere length under treatment was observed. Median telomere length in major remission was found to be significantly longer compared to patients without response to treatment measured either by cytogenetics (n = 246, p < 0.05), interphase FISH (n = 204, p = 0.002), or quantitative RT-PCR (n = 371, p < 0.05). In conclusion, the increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph- cells in the PB of patients with CML.

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between long arms of chromosomes 9 and 22 that produces the Philadelphia chromosome. The resulting chimeric BCR-ABL fusion gene is thought to be the molecular cause of the disease. Typical symptom is the marked expansion of myeloid cells that mature normally. The natural history of CML is progression from chronic phase to a rapidly fatal blast crisis within three to five years. Blast crisis is often preceded by an accelerated phase in which increasing doses of initial therapy are required. Treatment options have become more complex in recent years, allogeneic stem cell transplantation is still the only curative option. Recent data show that interferonalpha prolongs life in CML patients, as compared to chemotherapy. New therapies based on the causative molecular abnormality of CML are showing great promise. Imatinib (formerly STI571; Glivec) is an orally administered selective inhibitor of the BCR-ABL tyrosine kinase. Preliminary results from three international phase 11 studies are promising with good hematological and cytogenetical response rates and manageable side effects. Combination with cytostatic drugs may help to overcome the problem of secondary resistance in advanced disease. Longterm observation is required to demonstrate whether imatinib will prolong life in comparison with other methods of treatment.

Telomeres are composed of TTAGGG repeats and associated proteins.[1][1] In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence.[2][2] In previous studies, we and others described substantial and disease stage–specific

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.

Over the past few years, the Institute for Radiation Protection and Nuclear Safety (IRSN) has been studying a personal electronic neutron dosemeter and an ambient electronic neutron dosemeter based on experimental microdosimetric principles using low pressure proportional counters. The results obtained in 2000 and in 2001 with the cylindrical tissue-equivalent proportional counter developed for use in radiation protection and filled with a low pressure tissue-equivalent gas (propane based) are presented here.