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During the last decade, improvements in network, software, and hardware capabilities have leveraged the development of rich Internet applications (RIAs) that offer new and better user experiences. This new deal in the landscape of Internet technologies led us to reconsider the integration of telecommunication on the web. Instead of creating yet another artificial bridge between Internet and various telecommunication architectures, we tried to design a brand new communication model adapted to the intrinsic properties of the web. We implemented a prototype built on an innovative container-based mechanism which provides this new web-telco infrastructure with a high degree of flexibility and a complete adaptability to its environment. Then we defined open interfaces to guarantee fine-grained control and personalization of the communication sessions. Finally, we tested this new approach through a live experimental platform in order to measure the impact of our model in real conditions. To date, the experiments have provided compelling results which demonstrate a real interest from end users and new opportunities for services providers and telecom operators.

We have discovered an X-ray-selected galaxy cluster with a spectroscopic redshift of 1.753. The redshift is of the brightest cluster galaxy (BCG), which is coincident with the peak of the X-ray surface brightness. We also have concordant photometric redshifts for seven additional candidate cluster members. The X-ray luminosity of the cluster is (3.68 +- 0.70) x 1043 erg s-1 in the 0.1-2.4 keV band. The optical/IR properties of the BCG imply that its formation redshift was [?]5 if its stars formed in a short burst. This result continues the trend from lower redshift in which the observed properties of BCGs are most simply explained by a single monolithic collapse at very high redshift instead of the theoretically preferred gradual hierarchical assembly at later times. However, the models corresponding to different formation redshifts are more clearly separated as our observation epoch approaches the galaxy formation epoch. Although our infrared photometry is not deep enough to define a red sequence, we do identify a few galaxies at the cluster redshift that have the expected red sequence photometric properties.

When applied to the linear advection problem in dimension two, the upwind finite volume method is a non consistent scheme in the finite differences sense but a convergent scheme. According to our previous paper [Bouche et al., SIAM J. Numer. Anal.43(2005) 578–603], a sufficient condition in order to complete the mathematical analysis of the finite volume scheme consists in obtaining an estimation of order p, less or equal to one, of a quantity that depends only on the mesh and on the advection velocity and that we called geometric corrector. In [Bouche et al., Hermes Science publishing, London, UK (2005) 225–236], we prove that, on the mesh given by Peterson [SIAM J. Numer. Anal.28(1991) 133–140] and for a subtle alignment of the direction of transport parallel to the vertical boundary, the infinite norm of the geometric corrector only behaves like h1/2where his a characteristic size of the mesh. This paper focuses on the case of an oblique incidence i.e.a transport direction that is not parallel to the boundary, still with the Peterson mesh. Using various mathematical technics, we explicitly compute an upper bound of the geometric corrector and we provide a probabilistic interpretation in terms of Markov processes. This bound is proved to behave like h, so that the order of convergence is one. Then the reduction of the order of convergence occurs only if the direction of advection is aligned with the boundary.

We study the growth of dark matter halos in the concordance LCDM cosmology using several N-body simulations of large cosmological volumes. We construct merger trees from the Millennium and Millennium-II Simulations, covering the ranges 109-1015 M in halo mass and 1-105 in merger mass ratio. Our algorithm takes special care of halo fragmentation and ensures that the mass contribution of each merger to halo growth is only counted once. This way the integrated merger rate converges and we can consistently determine the contribution of mergers of different mass ratios to halo growth. We find that all resolved mergers, up to mass ratios of 105:1, contribute only [?]60% of the total halo mass growth, while major mergers are subdominant, e.g., mergers with mass ratios smaller than 3:1 (10:1) contribute only [?]20% ([?]30%). This is verified with an analysis of two additional simulation boxes, where we follow all particles individually throughout cosmic time. Our results are also robust against using several halo definitions. Under the assumption that the power-law behavior of the merger rate at large mass ratios can be extrapolated to arbitrarily large mass ratios, it is found that, independent of halo mass, [?]40% of the mass in halos comes from genuinely smooth accretion of dark matter that was never bound in smaller halos. We discuss possible implications of our findings for galaxy formation. One implication, assuming as is standard that the pristine intergalactic medium is heated and photoionized by UV photons, is that all halos accrete >40% of their baryons in smooth "cold" T [?] 104 K gas, rather than as warm, enriched, or clumpy gas or as stars.

ABSTRACTThe next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.

BACKGROUND Mutations in the gene encoding mitofusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. OBJECTIVE To describe MFN2 mutations and associated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). DESIGN Direct sequencing of the MFN2 gene and clinical investigations of patients with MFN2 mutations. SETTING Molecular genetics laboratory of a university hospital and the Limoges National Referral Center for Rare Peripheral Neuropathies. PATIENTS One hundred fifty index patients with HMSN and a median motor nerve conduction velocity of 25 m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. MAIN OUTCOME MEASURES Results of genetic analyses and phenotypic observations. RESULTS Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduction velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with heterozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients underwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. CONCLUSIONS MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.Arch Neurol. 2009;66(12):1511-1516--

We analyze the physical conditions in the low-ionization component of starburst outflows (in contrast to the high-ionization wind fluid observed in X-rays), based on new Keck/LRIS spectroscopy of partially resolved absorption troughs in near-ultraviolet and optical spectra of Ultraluminous Infrared Galaxies. The large velocity width and blueshift present in seven atomic transitions indicate a macroscopic velocity gradient within the outflowing gas. The separation of the Mg II 2796, 2803 (and Fe II 2587, 2600) doublet lines in these data constrains the gas kinematics better than previous studies of the heavily blended Na I 5892, 5898 doublet. The identical shape of the Mg II 2796 absorption troughs to that of the normally weaker transition at 2803 A (after accounting for emission filling) requires both transitions be optically thick at all outflow velocities. The fraction of the galactic continuum covered by the outflow at each velocity therefore dictates the shape of these absorption troughs. We suggest that the velocity offset of the deepest part of the troughs, where the covering factor of low-ionization gas is near unity, reflects the speed of a shell of swept-up, interstellar gas at the time of blowout. In a spherical outflow, we show that the fragments of this shell, or any clouds that expand adiabatically in rough pressure equilibrium with the hot wind, expand slowly relative to the geometrical dilution, and the covering fraction of low-ionization gas decreases with increasing radius. Our measurement of a covering factor that decreases with increasing velocity can therefore be interpreted as evidence that the low-ionization outflow is accelerating, i.e., absorption at higher velocity comes from gas at larger radii. We also present measurements of Cf (v) in four species, place an upper limit of ne [?] 3000 cm-3 on the density of the outflowing gas, and discuss lower limits on the mass outflow rate.

We have developed a new method to extract halo merger rates from the Millennium Simulation. First, by removing superfluous mergers that are artifacts of the standard friends-of-friends (FOF) halo identification algorithm, we find a lower merger rate compared to previous work. The reductions are more significant at lower redshifts and lower halo masses, and especially for minor mergers. Our new approach results in a better agreement with predictions from the extended Press-Schechter model. Second, we find that the FOF halo finder overestimates the halo mass by up to 50% for halos that are about to merge, which leads to an additional [?]20% overestimate of the merger rate. Therefore, we define halo masses by including only particles that are gravitationally bound to their FOF groups. We provide new best-fitting parameters for a global formula to account for these improvements. In addition, we extract the merger rate per progenitor halo, as well as per descendant halo. The merger rate per progenitor halo is the quantity that should be related to observed galaxy merger fractions when they are measured via pair counting. At low-mass/redshift, the merger rate increases moderately with mass and steeply with redshift. At high enough mass/redshift (for the rarest halos with masses a few times the "knee" of the mass function), these trends break down, and the merger rate per progenitor halo decreases with mass and increases only moderately with redshift. Defining the merger rate per progenitor halo also allows us to quantify the rate at which halos are being accreted onto larger halos, in addition to the minor and major merger rates. We provide an analytic formula that converts any given merger rate per descendant halo into a merger rate per progenitor halo. Finally, we perform a direct comparison between observed merger fractions and the fraction of halos in the Millennium Simulation that have undergone a major merger during the recent dynamical friction time, and find a fair agreement, within the large uncertainties of the observations. Our new halo merger trees are available at http://www.mpe.mpg.de/ir/MillenniumMergerTrees/.

High signal-to-noise, representative spectra of star-forming galaxies at z [?] 2, obtained via stacking, reveal a high-velocity component underneath the narrow Ha and [N II] emission lines. When modeled as a single Gaussian, this broad component has FWHM [?] 1500 km s-1; when modeled as broad wings on the Ha and [N II] features, it has FWHM [?] 500 km s-1. This feature is preferentially found in the more massive and more rapidly star-forming systems, which also tend to be older and larger galaxies. We interpret this emission as evidence of either powerful starburst-driven galactic winds or active supermassive black holes (SMBHs). If galactic winds are responsible for the broad emission, the observed luminosity and velocity of this gas imply mass outflow rates comparable to the star formation rate. On the other hand, if the broad-line regions of active black holes account for the broad feature, the corresponding black holes masses are estimated to be an order of magnitude lower than those predicted by local scaling relations, suggesting a delayed assembly of SMBHs with respect to their host bulges.

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Recent observations of UV/optically selected, massive star-forming galaxies at z [?] 2 indicate that the baryonic mass assembly and star formation history is dominated by continuous rapid accretion of gas and internal secular evolution, rather than by major mergers. We use the Millennium Simulation to build new halo merger trees and extract halo merger fractions and mass accretion rates. We find that, even for halos not undergoing major mergers, the mass accretion rates are plausibly sufficient to account for the high star formation rates observed in z [?] 2 disks. On the other hand, the fraction of major mergers in the Millennium Simulation is sufficient to account for the number counts of submillimeter galaxies (SMGs), in support of observational evidence that these are major mergers. When following the fate of these two populations in the Millennium Simulation to z = 0, we find that subsequent mergers are not frequent enough to convert all z [?] 2 turbulent disks into elliptical galaxies at z = 0. Similarly, mergers cannot transform the compact SMGs/red sequence galaxies at z [?] 2 into observed massive cluster ellipticals at z = 0. We argue therefore, that secular and internal evolution must play an important role in the evolution of a significant fraction of z [?] 2 UV/optically and submillimeter-selected galaxy populations.

We present a simple set of kinematic criteria that can distinguish between galaxies dominated by ordered rotational motion and those involved in major merger events. Our criteria are based on the dynamics of the warm ionized gas (as traced by Ha) within galaxies, making this analysis accessible to high-redshift systems, whose kinematics are primarily traceable through emission features. Using the method of kinemetry (developed by Krajnovic and coworkers), we quantify asymmetries in both the velocity and velocity dispersion maps of the warm gas, and the resulting criteria enable us to empirically differentiate between nonmerging and merging systems at high redshift. We apply these criteria to 11 of our best-studied rest-frame UV/optical-selected z [?] 2 galaxies for which we have near-infrared integral-field spectroscopic data from SINFONI on the VLT. Of these 11 systems, we find that >50% have kinematics consistent with a single rotating disk interpretation, while the remaining systems are more likely undergoing major mergers. This result, combined with the short formation timescales of these systems, provides evidence that rapid, smooth accretion of gas plays a significant role in galaxy formation at high redshift.

This paper describes the surplus value of a quadrupole‐orthogonal acceleration TOF mass spectrometer, coupled to a liquid chromatographic separation system, for the unequivocal identification and structural elucidation of an unknown compound in the field of designer drugs. In a patient sample set (blood, tissues, vitreous humor, etc.), analyzed with a dedicated liquid chromatographic–fluorescence detection method for the determination of methylenedioxy amphetamine, methylenedioxy methamphetamine, and methylenedioxy ethylamphetamine (MDEA), a “strange” inexplicable peak appeared at a retention time not corresponding to any of our reference materials. Based on the identical excitation and emission wavelengths in detection, and a retention behavior comparable to MDEA, it was assumed that this unknown compound was an isomer of the recreational drug MDEA. With a simple and straightforward methodological crossover between LC fluorescence detection and LC‐MS/MS, additional information for structural elucidation was easily obtained. Chromatographic separation was achieved on a Hypersil BDS C18 column (fluorescence detection part) and on a Hypersil BDS phenyl column (mass spectrometric detection part). MS showed that the unknown compound's molecular mass was identical to that of MDEA, and, in addition, its fragmentation pattern too proved quite similar to that of MDEA. A thorough literature overview and study of the fragmentation pattern by means of the MS/MS spectrum led to an evidence‐based hypothesis of 3,4‐methylenedioxyN,N‐dimethylamphetamine (MDDM) being the unknown compound. To confirm this hypothesis, MDDM was synthesized and its presence in our biological sample was finally demonstrated by co‐injection with alternatively synthesized MDDM and MDEA. This application shows the synergism between LC and MS in the elucidation of unknown compounds, nevertheless emphasizing the essence of chromatographic separation when dealing with isomers.

We test the reliability of a method to measure the mean halo mass of absorption-line systems such as damped Lya absorbers (DLAs). The method is based on measuring the ratio of the cross-correlation between DLAs and galaxies to the autocorrelation of the galaxies themselves, which is (in linear theory) the ratio of their bias factor b. We show that the ratio of the projected cross- and autocorrelation functions [wdg(rth)/wgg(rth)] is also the ratio of their bias factor, irrespective of the galaxy distribution, provided that one uses the same galaxies for wdg(rth) and wgg(rth). Thus, the method requires only multiband imaging of DLA fields and is applicable to all redshifts. Here, we focus on z = 3 DLAs. We demonstrate that the method robustly constrains the mean DLA halo mass using smoothed particle hydrodynamics (SPH) cosmological simulations that resolve DLAs and galaxies in halos of mass Mh [?] 5.2 x 1010 M. If we use the bias formalism of Mo & White with the DLA and galaxy mass distributions of these simulations, we predict an amplitude ratio wdg/wgg of 0.771. Direct measurement of these correlation functions from the simulations yields wdg/wgg = bDLA/bgal = 0.73 +- 0.08, in excellent agreement with that prediction. Equivalently, inverting the measured correlation ratio to infer the (logarithmically) averaged DLA halo mass yields [?]log MDLA(M)[?] = 11.13img2.gif, in excellent agreement with the true value in the simulations: log MDLA(M) = 11.16 is the probability-weighted mean mass of the DLA host halos in the simulations. The cross-correlation method thus appears to yield a robust estimate of the average host halo mass, even though the DLAs and the galaxies occupy a broad mass spectrum of halos and massive halos contain multiple galaxies with DLAs. If we consider subsets of the simulated galaxies with high star formation rates (representing Lyman break galaxies [LBGs]), then both correlations are higher, but their ratio still implies the same DLA host mass, irrespective of the galaxy subsamples, i.e., the cross-correlation technique is also reliable. The inferred mean DLA halo mass, [?]log MDLA[?] = 11.13img2.gif, is an upper limit, since the simulations do not resolve halos less massive than ~1010.5 M. Thus, our results imply that the correlation length between DLAs and LBGs is predicted to be at most ~2.85 h-1 Mpc, given that z = 3 LBGs have a correlation length of r0 [?] 4 h-1 Mpc. While the small size of current observational samples does not allow strong conclusions, future measurements of this cross-correlation can definitively distinguish models in which many DLAs reside in low-mass halos from those in which DLAs are massive disks occupying only high-mass halos.

The influence of specific antibodies on molecular and cellular mechanisms of activation, detoxification and biological activity of the ubiquitous carcinogen benzo[a]pyrene (B[a]P) was investigated using a monoclonal antibody. The antibody was shown to decrease cellular uptake and metabolic activation of B[a]P as demonstrated by higher recovery of unmetabolized B[a]P and decreased formation of end-point phenol metabolites in two types of target cells. Furthermore, strong antibody reactivity with 7,8-diol-B[a]P provided a second chance for interrupting metabolic activation by sequestration of this intermediate metabolite in the extracellular space. The biological relevance of B[a]P and 7,8-diol-B[a]P redistribution by antibody was demonstrated by reversion of B[a]P-induced inhibition of proliferation of human peripheral blood lymphocytes and by inhibition of CYP 1A1 induction in HepG2 cells. Remarkably, the antibody was still protective against B[a]P-induced immunotoxicity even after delayed addition, suggesting a more important role of metabolites in immunotoxicity than has been appreciated so far. Although B[a]P is activated to 7,8-diol-B[a]P in the same cells that are inhibited by this metabolite, the antibody completely restored lymphocyte proliferation indicating that extracellular trapping of the 7,8-diol-B[a]P is biologically highly effective. Thus, repartitioning of both B[a]P and its metabolites by the antibody may reduce their effective concentration in susceptible target organs and therefore relieve overloaded DNA repair mechanisms and inhibit carcinogen-induced P450 induction. These in vitro data also suggest that a natural or prophylactic antibody response against carcinogens may be associated with a reduced risk of cancer.

Lewis–Sumner syndrome (LSS) is a dysimmune peripheral nerve disorder, characterized by a predominantly distal, asymmetric weakness mostly affecting the upper limbs with sensory impairment, and by the presence of multifocal persistent conduction blocks. The nosological position of this neuropathy in relation to multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is still debated. We report the clinical, biological and electrophysiological features, the course and the response to treatment in 23 LSS patients. The initial symptoms started in the distal part of an upper limb in 70% of patients. They were sensorimotor in 65% and purely sensory in 35% of patients. A cranial nerve involvement was observed in 26% of patients and a distal limb amyotrophy in 52%. The CSF protein level was normal in 67% of patients and mildly elevated in the remainder. None had serum anti-GM1 antibodies. There were multiple motor conduction blocks (average of 2.87/patient), predominantly located in the forearm, whereas demyelinating features outside the blocked nerves were rare. Abnormal distal sensory potentials were found in 87% of patients. The electrophysiological pattern suggests a very focal motor fibre demyelination sparing the nerve endings, whereas sensory fibre involvement was widespread. The course was chronic progressive in 71% of patients and relapsing–remitting in the others. During the follow-up study (median duration of 4 years), half of the patients progressed with a multifocal pattern and the distribution of the motor deficit remained similar to the initial presentation. The other patients showed a progression to the other limbs, suggesting a more diffuse process. Fifty-four percent of the patients treated with intravenous immunoglobulin showed an improvement, compared with 33% of the patients treated with oral steroids. Overall, 73% of patients had a positive response to immune-mediated therapy. LSS may be distinguished from MMN by the presence of sensory involvement, the absence of serum anti-GM1 antibodies and, in some cases, a positive response to steroids. In some of the patients in our study, LSS evolved into a more diffuse neuropathy sharing similarities with CIDP. Others had a clinical course characterized by a striking multifocal neuropathy, which suggests underlying mechanisms different from CIDP. Overall, whatever the clinical course, LSS responded to immune-mediated treatment in a manner similar to CIDP.

We present our results on the cross-correlation of Lyman break galaxies (LBGs) around three damped Lya absorbers (DLAs) at zabs [?] 3 from deep [mI,AB(sky) [?] 27.6 mag arcsec-2] UBVI KPNO 4 m/MOSAIC images. The large area of the MOSAIC images, 0.31 deg2 or ~65 x 65 himg1.gif Mpc comoving at redshift z = 3, allows us to probe the clustering of LBGs on scales up to 20 Mpc comoving. Our survey covers a total of 1 deg2 and contains ~3000 LBGs with photometric redshifts between 2.8 and 3.5. Using the redshift likelihood distributions with mI as a prior, we selected LBGs within a redshift slice of width Wz = 0.15 (corresponding to sz, the uncertainty in photometric redshifts) centered on the redshift of the absorbers. Within that redshift slice, we find that the DLA-LBG cross-correlation wdg is wdg = (1.62 +- 1.32) x wgg, where wgg is the LBG autocorrelation. This corresponds to a correlation length of r0 = 5 +- 4.5 h-1 (comoving) (or r0 = 7 +- 6.8 himg1.gif Mpc). The cross-correlation is most significant on scales 5-10 Mpc. Through Monte Carlo simulations, we find that wdg is significantly greater than zero at the greater than 95% level. In three other redshift slices that do not contain a DLA, we do not find any evidence of clustering. A larger sample will enable us to discriminate between wdg/wgg < 1 and wdg/wgg > 1, i.e., to test whether DLA halos are more or less massive than LBG halos.

We present results on the clustering of Lyman break galaxies (LBGs) around a probable damped Lya absorption line cloud (DLA) at zabs = 2.974 from deep UBVI images of the field containing the quasar APM 08279+5255 (zem = 3.91). The large area covered by our images, 0.31 deg2 or ~40 x 40 Mpc comoving at redshift z = 3, and their depth, mI,AB(sky) [?] 27.6 mag arcsec-2, allow us to identify ~450 LBG candidates brighter than IAB = 24.80 at 2.75 < z < 3.25 both close (50 kpc) to the DLA line of sight and up to 20 Mpc (comoving) from the DLA, i.e., physically unrelated. LBG candidates were identified using photometric redshift techniques that include the I magnitude as a prior estimate in addition to the colors. The two are combined using Bayes's theorem. This helps to break the degeneracies that occur in a pure spectral template fitting scheme. The overall rms is sz [?] 0.15 at z ~ 3 based on our analysis of photometric redshifts in the HDF-N. From the redshift likelihood distributions, we selected LBG galaxies within a redshift slice of width Wz = 0.15([?] sz) centered on the redshift of the DLA zabs. Within that redshift slice, we find an enhancement of galaxies near the DLA using both the surface density (S/Sg [?] 3) and an estimator of the three-dimensional spatial overdensity (n/img1.gifg ~ 5 +- 3). The surface overdensity S/Sg is significant at the more than 95% significance level on scales 2.5 < rth < 5 Mpc comoving. The overdensity cannot be related to the QSO environment since the QSO is at zem = 3.91. These results imply that some DLA could reside in high-density regions. We search within 45'' from the line of sight for galaxies responsible for the DLA and find one candidate with zphot = 3.03 that is 26'' (145 kpc physical) away. From its magnitude I = 24.65 +- 0.2, its luminosity is MI,AB = -21.35. Due to its large impact parameter, however, this galaxy is not a likely candidate for the absorber.

Although edible vaccines seem to be feasible, antigens of human pathogens have mostly been expressed in plants that are not attractive for human consumption (such as potatoes) unless they are cooked. Boiling may reduce the immunogenicity of many antigens. More recently, the technology to transform fruit and vegetable plants have become perfected. We transformed carrot plants with Agrobacterium tumefaciensto generate plants (which can be eaten raw) transgenic for an immunodominant antigen of the measles virus, a major pathogen in man. The hemagglutinin (H) glycoprotein is the principle target of neutralizing and protective antibodies against measles. Copy numbers of the H transgene were verified by Southern blot and specific transcription was confirmed by RT-PCR. The H protein was detected by western blot in the membrane fraction of transformed carrot plants. The recombinant protein seemed to have a 8% lower molecular weight than the viral protein. Although this suggests a different glycosylation pattern, proper folding of the transgenic protein was confirmed by conformational-dependent monoclonal antibodies. Immunization of mice with leaf or root extracts induced high titres of IgG1 and IgG2a antibodies that cross-reacted strongly with the measles virus and neutralized the virus in vitro. These results demonstrate that transgenic carrot plants can be used as an efficient expression system to produce highly immunogenic viral antigens. Our study may pave the way towards an edible vaccine against measles which could be complementary to the current live-attenuated vaccine.

To report patients with neuralgic amyotrophy (NA) and abnormal sensory nerve action potentials (SNAP).

Co-evolving mechanisms of immune clearance and of immune suppression are among the hallmarks of measles. B cells are major targets cells of measles virus (MV) infection. Virus interactions with B cells result both in immune suppression and a vigorous antibody response. Although antibodies fully protect against (re)infection, their importance during the disease and in the presence of a potent cellular response is less well understood. Specific serum IgM appears with onset of rash and confirms clinical diagnosis. After isotype switching, IgG1 develops and confers life-long protection. The most abundant antibodies are specific for the nucleoprotein, but neutralizing and protective antibodies are solely directed against the two surface glycoproteins, the hemagglutinin and the fusion protein. Major neutralizing epitopes have been mapped mainly on the hemagglutinin protein with monoclonal antibodies, producing an increasingly comprehensive map of functional domains.

Electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were proposed by an Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991. Only 60% of CIDP patients fulfilled these criteria, which therefore appear poorly sensitive. We therefore sought to revise the electrophysiological criteria. We selected 40 CIDP patients and compared them with 35 patients with axonal polyneuropathy, 116 patients with Charcot‐Marie‐Tooth type 1A (CMT1A) disease, and 66 patients with immunoglobulin M (IgM) monoclonal gammopathy. The proposed electrophysiological criteria identified 90% of the CIDP patients, although 3% of patients with axonal polyneuropathy were falsely identified. For the CIDP patients, sensitivity and specificity were 90% and 97%, respectively. Of the patients with IgM monoclonal gammaglobulin of undetermined significance (MGUS) and CMT1A, 100% fulfilled these new criteria, whereas 90% and 97%, respectively, fulfilled the AAN criteria. These results suggest that the AAN criteria are more appropriate for IgM MGUS and CMT1A patients than for CIDP patients. We therefore propose new electrophysiological criteria for CIDP that appear to have better sensitivity. © 2002 American Association of Electrodiagnostic Medicine Muscle Nerve 25: 26–30, 2002

Dorsal roots have a limited regeneration capacity after transection. To improve nerve regeneration, the growth-promoting effects of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were evaluated. The proteins were continuously released by synthetic nerve guidance channels bridging a 4-mm gap in the transected dorsal root. Four weeks after lesion, the regenerated nerve cables were analyzed for the presence of myelinated and unmyelinated axons. While BDNF showed a limited effect on axonal regeneration (863 ± 39 axons/regenerated nerve, n = 6), NGF (1843 ± 482) and NT-3 (1495 ± 449) powerfully promoted regeneration of myelinated axons compared to channels releasing the control protein bovine serum albumin (293 ± 39). In addition, NGF, but not BDNF nor NT-3, had a potent effect on the regeneration of unmyelinated axons (NGF, 55 ± 1.4; BDNF, 4 ± 0.3; NT-3, 4.7 ± 0.3 axons/100 μm2; n = 6). The present study suggests that synthetic nerve guidance channels slowly and continuously releasing the neurotrophins NGF and NT-3 can overcome the limited regeneration of transected dorsal root.

Exogenous FGF-2 added to cells is internalized and part of it translocates to the nucleus of the cells. To get a better understanding of the FGF-2-induced signaling pathway, we looked for proteins associated with FGF-2 in the cytoplasm of the target cells. We first used the GST-FGF-2 to isolate cytoplasmic proteins complexes containing FGF-2 from S100 extract (supernatant 100,000g). Among the retrieved proteins, we focused our studies on RPS19, a protein of the 40S small ribosomal subunit. We showed that FGF-2 interacts directly with RPS19 in vitro. Second, we coimmunoprecipitated RPS19 and FGF-2 from a S240 extract (240,000g supernatant) prepared from FGF-2-stimulated cells and devoided of 40S ribosomal subunit. The result of these experiments suggest that a pool of free RPS19 exists in cells and that FGF-2 interacts in vivo with free RPS19.

X-linked dominant Charcot–Marie–Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this study we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age at onset was 15.4 ± 9.6 years in males (range 1–40 years) and 18.7 ± 13.1 years in females (range 1–56 years) (P = 0.22) and the duration of disease at the time of examination was 18.3 ± 14.6 years in males and 23.9 ± 13.7 years in females (P = 0.11). Males were more severely affected than females, with significantly more frequent muscle weakness, amyotrophy, proprioception loss, upper limb areflexia and pes cavus. Females were more frequently asymptomatic, whereas high functional disability scores were more frequently encountered in males. The electrophysiological studies showed that motor nerve conduction velocities in CMTX females, but not males, were heterogeneous between nerves compared with Charcot–Marie–Tooth type 1A (CMT1A) patients and controls. The terminal latency index (TLI) for the median nerve was 0.37 ± 0.08; it was similar in men and in women and a little higher than those observed in CMT1A and controls. The range of values for median TLI was wider in both male and female CMTX patients than in controls, but was similar to that of CMT1A patients, suggesting that motor conduction was relatively homogeneous within a given nerve. Twenty-seven different CX32 mutations, including missense (n = 23), nonsense (n = 2) and frameshift mutations (n = 1) and one entire deletion of the CX32 coding sequence, were observed in the 37 families. Four of these mutations are described for the first time. The phenotype of the patients, especially age at onset, is discussed in relation to the functional consequences of CX32 mutations, analysed in vitro in Xenopus oocytes and mammalian cells. CMTX patients with age at onset in the first decade mostly presented non-functional mutations, suggesting that the physiological consequences of the mutations affect age at onset in CMTX.

Despite previous intensive ground-based imaging and spectroscopic campaigns and wideband Hubble Space Telescope (HST) imaging of the z = 0.927 QSO 3C 336 field, the galaxy that hosts the damped Lya system along this line of sight has eluded detection. We present a deep narrowband Ha image of the field of this zabs = 0.656 damped Lya absorber, obtained through the F108N filter of NICMOS1 on board the HST. The goal of this project was to detect any Ha emission 10 times closer than previous studies to unveil the damped absorber. We do not detect Ha emission between 0.''05 and 6'' (0.24 and 30 h-1 kpc) from the QSO, with a 3 s flux limit of 3.70 x 10-17 h-2 ergs s-1 cm-2 for an unresolved source, corresponding to a star formation rate (SFR) of 0.3 h-2 M yr-1. This leads to a 3 s upper limit of 0.15 M yr-1 kpc-2 on the SFR density, or a maximum SFR of 1.87 M yr-1 assuming a disk of 4 kpc in diameter. This result adds to the number of low-redshift damped Lya absorbers that are not associated with the central regions of Milky Way-like disks. Damped Lya absorption can arise from high-density concentrations in a variety of galactic environments including some that, despite their high local H I densities, are not conducive to widespread star formation.

In an in vitro study, less compound A was formed when a KOH-free carbon dioxide absorbent was used. To confirm this observation we used a lung model in which carbon dioxide was fed in at 160 ml min(-1) and sampling gas was taken out for analysis at 200 ml min(-1); ventilation aimed for a PE'CO2 of 5.4 kPa. The soda lime canister temperatures in the inflow and outflow ports (Tin and Tout) were recorded. In six runs of 240 min each, a standard soda lime, Sodasorb (Grace, Epernon, France) was used and in eight runs KOH-free Sofnolime (Molecular Products, Thaxted, UK) was used. Liquid sevoflurane was injected using a syringe pump to obtain 2.1% E'. Compound A was measured by capillary gas chromatography combined with mass spectrometry. Median (range) compound Ainsp increased to a maximum of 22.7 (7.9) ppm for Sodasorb and 33.1 (20) for Sofnolime at 60 min and decreased thereafter; the difference between groups was significant (P<0.05) at each time of analysis up to 240 min. The canister temperatures were similar in both groups and increased to approximately 40 degrees C at 240 min. Contrary to expectation, compound A concentrations were greater with the KOH-free absorbent despite similar canister temperatures with both absorbents.

The aim of this randomized open-label study was to compare a bimonthly with a monthly regimen of 5-fluorouracil (5-FU) and leucovorin for the adjuvant treatment of colon and high-rectum adenocarcinoma. The bimonthly regimen was administered for 2 consecutive days every 14 days as d,L-leucovorin 200 mg/m2or L-leucovorin 100 mg/m2as a 2-hour infusion followed by 5-FU bolus of 400 mg/m2and a 600 mg/m25-FU 22-hour continuous infusion (LV5FU2). In the monthly regimen, d,L-leucovorin 200 mg/m2or L-leucovorin 100 mg/m215-minute infusion followed by a 400 mg/m215 minute 5-FU bolus was administered for 5 consecutive days every 28 days (FUFOL). Nine hundred five patients with recently resected stage B2 or C colon or high-rectum adenocarcinoma (inferior pole of the tumor subperitoneal) were recruited into the study. Patients were randomized in a 2 × 2 factorial design to receive either LV5FU2 or FUFOL for 24 or 36 weeks. Characteristics of the patients in the two different treatment groups were similar at baseline. Compliance was good. Mean 5-FU dose intensities were 930 mg/ m2/wk and 463 mg/m2/wk for LV5FU2 and FUFOL, respectively. The incidence of maximal grade III–IV toxicities for LVSFU2 and FUFOL was neutropenia 6% and 16% (P< .001), diarrhea 4% and 10% (P< .001), and mucositis 2% and 7% (P< .001), respectively. Maximum grade III–IV toxicities in the LV5FU2 treatment group were significantly lower than in the FUFOL group (10% v26%; P< .001). Although patients in the LV5FU2 group received twice the dose of 5-FU compared with those in the FUFOL group, LV5FU2 was shown to be less toxic. Efficacy data will be available in 2001.

We conducted a double-blind, placebo-controlled, study of 19 patients fulfilling eligibility criteria for multifocal motor neuropathy with persistent conduction block. They were enrolled and divided into two groups: those who had never been treated previously with intravenous immunoglobulins (IVIg) (Group 1: 10 patients) and those who presented recurrent symptoms after previously successful treatment with IVIg (Group 2: nine patients). They were randomized prospectively to receive either IVIg or placebo at a dose of 500 mg/kg/day for 5 consecutive days, once a month for 3 months. At month 4, patients found to be responders remained on the same treatment for the 3 following months, while non-responders were switched to the alternative study drug for the 3 following months. Clinical assessment was conducted with the MRC score in 28 muscles and a self-evaluation scale (five daily motor activities scored from 0 to 5). In Group 1, nine patients completed the study, of whom initially four received IVIg and five placebo; four patients responded to IVIg (two at months 4 and 7, and a further two at month 7 after switching treatment at month 4), two patients responded to placebo at months 4 and 7, and three patients did not respond to either treatment. In Group 2, nine patients completed the study. Five patients first received IVIg and all responded at months 4 and 7. Four patients first received placebo and none responded at month 4; all were then switched to IVIg and three responded at month 7. When the 18 patients were considered together, seven out of the nine patients who received IVIg first were responders at month 4, compared with two of the nine patients who received placebo first, a difference that was statistically significant (P = 0.03). On the other hand, there was no significant difference in MRC score but a significant difference in the self-evaluation score, at month 4, between IVIg patients and placebo patients. Electrophysiological studies did not show significant differences at month 4 in motor parameters between IVIg patients and placebo patients. IgM anti-GM1 titres did not change significantly in patients treated with IVIg compared with those who received placebo, between baseline, month 4 and month 7. However, of five patients who had significantly high anti-GM1 titres (>3200) at baseline, four responded to IVIg. This trial confirms that IVIg is a promising therapeutic option for multifocal motor neuropathy.

We report the clinical and electrophysiological features of six members of a French family with a dominantly inherited motor and sensory neuropathy. Mean age at onset was 33.6 ± 9.1 years. Mean age at examination was 55.5 ± 13.3 years. Clinical presentation combined symptoms of hereditary sensory and autonomic neuropathy type I (HSAN‐I) with prominent distal muscle weakness. Five male patients presented with sensory symptoms involving the distal part of the limbs, especially the legs. All but one had histories of trophic alterations, consisting of poorly healing foot ulcers. Muscle weakness and wasting were always present, often severe, and mainly affected dorsiflexion of the toes and feet. One obligate female carrier aged 65 was clinically asymptomatic. Electrophysiological findings were consistent with a distal axonal motor and sensory neuropathy. Results of linkage analysis excluded the Charcot‐Marie‐Tooth 2A (CMT2A) and CMT2B loci and suggested the possibility of a linkage to HSAN‐I locus on 9q22.1–q22.3. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1508–1514, 2000.

FGF‐2 exerts its pleiotropic effects on cell growth and differentiation by interacting with specific cell surface receptors. In addition, exogenously added FGF‐2 is translocated from outside the cell to the nucleus during G1‐S transition. In this study, we show that a single point mutation in FGF‐2 (substitution of residue serine 117 by alanine) is sufficient to drastically reduce its mitogenic activity without affecting its differentiation properties. The FGF‐2(S117A) mutant binds to and activates tyrosine kinase receptors and induces MAPK and p70S6K activation as strongly as the wild‐type FGF‐2. We demonstrate that this mutant enters NIH3T3 cells, is translocated to the nucleus, and is phosphorylated similar to the wild‐type growth factor. This suggests that FGF‐2 mitogenic activity may require, in addition to signaling through cell surface receptors and nuclear translocation, activation of nuclear targets. We have previously shown that, in vitro, FGF‐2 directly stimulates the activity of the casein kinase 2 (CK2), a ubiquitous serine/threonine kinase involved in the control of cell proliferation. We report that, in vivo, FGF‐2(WT) transiently interacts with CK2 and stimulates its activity in the nucleus during G1‐S transition in NIH3T3 cells. In contrast, the FGF‐2(S117A) mutant fails to interact with CK2. Thus, our results show that FGF‐2 mitogenic and differentiation activities can be dissociated by a single point mutation and that CK2 may be a new nuclear effector involved in FGF‐2 mitogenic activity. Bailly, K., Soulet, F., Leroy, D., Amalric, F., Bouche, G. Uncoupling of cell proliferation and differentiation activities of basic fibroblast growth factor (FGF‐2). FASEB J.14, 333—344 (2000)