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The charge density wave (CDW) instability, usually occurring in low-dimensional metals, has been a topic of interest for longtime. However, some very fundamental aspects of the mechanism remain unclear. Recently, a plethora of new CDW materials, a substantial fraction of which is two-dimensional or even three-dimensional, has been prepared and characterised as bulk and/or single-layers. As a result, the need for revisiting the primary mechanism of the instability, based on the electron–hole instability established more than 50 years ago for quasi-one-dimensional (quasi-1D) conductors, has clearly emerged. In this work, we consider a large number of CDW materials to revisit the main concepts used in understanding the CDW instability, and emphasise the key role of the momentum dependent electron–phonon coupling in linking electronic and structural degrees of freedom. We argue that for quasi-1D systems, earlier weak coupling theories work appropriately and the energy gain due to the CDW and the concomitant periodic lattice distortion (PLD) remains primarily due to a Fermi surface nesting mechanism. However, for materials with higher dimensionality, intermediate and strong coupling regimes are generally at work and the modification of the chemical bonding network by the PLD is at the heart of the instability. We emphasise the need for a microscopic approach blending condensed matter physics concepts and state-of-the-art first-principles calculations with quite fundamental chemical bonding ideas in understanding the CDW phenomenon in these materials. [ABSTRACT FROM AUTHOR]

An editorial is presented which argues on complementary value of preclinical and clinical radiobiology research projects to rationalize the therapeutic use of radiopharmaceuticals. It presents the views on relevant preclinical models for radiobiology, recommendations on dosimetry in preclinical models and dose–effect relationship and quantitative radiobiological models.

Targeted radionuclide therapy (TRT) is used to treat disseminated or metastatic tumours in which conventional external beam radiotherapy (EBRT) would have unacceptable side effects. Unlike EBRT, TRT delivers low doses at a continuous low dose rate. In EBRT, the effect increases progressively with the dose rate, and biological effects (tumour control and normal tissue damage) are related to the dose according to a sigmoid curve model. This model is part of the so-called quantitative radiobiology that is mostly based on the target cell theory, according to which cell death is due to (lethal) radiation hits to vital cellular targets. This model was developed for EBRT, but was adapted to low dose-rate situations by including a parameter that reflects the time needed to repair tissue damage. However, a growing body of evidence indicates that the model should take into account also the biological effects, which are due to intercellular communications (bystander effects) and amplify the effects of radiation, as well as the immune system. Moreover, extranuclear targets must be considered, although induced intracellular and intercellular signalling pathways may ultimately result in DNA damage. It is likely that bystander effects and immune response always contribute to the overall response to TRT at different levels, and that dose and dose rate are key parameters in controlling their real contribution. We hypothesize that the dose rate is the key determinant in the balance between the physical and DNA-centred response on one side, and the biological response that integrates all subcellular compartments and intercellular signalling pathways on the other side. [Display omitted] [ABSTRACT FROM AUTHOR]

Targeted radionuclide therapy (TRT) is used to treat disseminated or metastatic tumours in which conventional external beam radiotherapy (EBRT) would have unacceptable side effects. Unlike EBRT, TRT delivers low doses at a continuous low dose rate. In EBRT, the effect increases progressively with the dose rate, and biological effects (tumour control and normal tissue damage) are related to the dose according to a sigmoid curve model. This model is part of the so-called quantitative radiobiology that is mostly based on the target cell theory, according to which cell death is due to (lethal) radiation hits to vital cellular targets. This model was developed for EBRT, but was adapted to low dose-rate situations by including a parameter that reflects the time needed to repair tissue damage. However, a growing body of evidence indicates that the model should take into account also the biological effects, which are due to intercellular communications (bystander effects) and amplify the effects of radiation, as well as the immune system. Moreover, extranuclear targets must be considered, although induced intracellular and intercellular signalling pathways may ultimately result in DNA damage. It is likely that bystander effects and immune response always contribute to the overall response to TRT at different levels, and that dose and dose rate are key parameters in controlling their real contribution. We hypothesize that the dose rate is the key determinant in the balance between the physical and DNA-centred response on one side, and the biological response that integrates all subcellular compartments and intercellular signalling pathways on the other side. [Display omitted] [ABSTRACT FROM AUTHOR]

Vanadium dioxide exhibits a first order metal to insulator transition (MIT) at 340 K (TMI) from a rutile (R) structure to a monoclinic (M1) structure. The mechanism of this transition interpreted as due either to a Peierls instability or to a Mott-Hubbard instability is controversial since half a century. However, in the last twenty years the study of chemical and physical properties of VO2 and of its alloys, benefits of a renewed interest due to possible applications coming from the realization of devices made of thin films. We describe in this review the structural, electronic and magnetic properties of the different metallic (R) and insulating (M1, T, M2) phases of VO2, of its solid solutions and under constraint. We present in a synthetic manner the various phase diagrams and their symmetry analysis. This work allows us to revisit older interpretation and to emphasize in particular the combined role of electron-electron interactions in the various phase of VO2 and of structural fluctuations in the MIT mechanism. In this framework we show that the phase transition is surprisingly announced by anisotropic one-dimensional (1D) structural fluctuations revealing chain like correlations between the V due to an incipient instability of the rutile structure. This leads to an unexpected critical dynamics of the order-disorder (or relaxation) type. We describe how the two-dimensional (2D) coupling between these 1D fluctuations, locally forming uniform V4Å zig-zag chains and V-V pairs, stabilizes the M2 and M1 insulating phases. These phases exhibit a 1D electronic anisotropy where substantial electron-electron correlations conduct to a spin-charge decoupling. The spin-Peierls ground state of M1 is analyzed via a mechanism of dimerization, in the T phase, of the spin 1/2 V4Å zigzag Heisenberg chains formed in the M2 phase. This review summarizes in a critical manner the main results of the large literature on fundamental aspects of the MIT of VO2. It is completed by unpublished old results. Interpretations are also placed in a large conceptual frame which is also relevant to interpret physical properties of other classes of materials. [ABSTRACT FROM AUTHOR]

This contribution is a tribute to André Guinier and to the scientific school he created. We show how his thesis work allowed one to develop new X-ray scattering techniques of investigation of matter both at small and large scattering Bragg angles. In parallel to his pioneering experimental work, André Guinier introduced a well-adapted formalism allowing a precise characterization of various types of local order in the matter. These findings, which have been extended by his own students, have seed an "X-ray scattering" school of international reputation, which remains very active today. Here, we cover in detail the birth of this school from 1940 to 1980. Then, we outline the evolution of researches of the team he founded at the "Laboratoire de physique des solides" of Paris-Sud University until the beginning of the 21st century, when investigations using synchrotron radiation have revolutionized the study of the structure of the matter. [ABSTRACT FROM AUTHOR]

Significance: Radiation therapy (from external beams to unsealed and sealed radionuclide sources) takes advantage of the detrimental effects of the clustered production of radicals and reactive oxygen species (ROS). Research has mainly focused on the interaction of radiation with water, which is the major constituent of living beings, and with nuclear DNA, which contains the genetic information. This led to the so-called target theory according to which cells have to be hit by ionizing particles to elicit an important biological response, including cell death. In cancer therapy, the Poisson law and linear quadratic mathematical models have been used to describe the probability of hits per cell as a function of the radiation dose. Recent Advances: However, in the last 20 years, many studies have shown that radiation generates "danger" signals that propagate from irradiated to nonirradiated cells, leading to bystander and other off-target effects. Critical Issues: Like for targeted effects, redox mechanisms play a key role also in off-target effects through transmission of ROS and reactive nitrogen species (RNS), and also of cytokines, ATP, and extracellular DNA. Particularly, nuclear factor kappa B is essential for triggering self-sustained production of ROS and RNS, thus making the bystander response similar to inflammation. In some therapeutic cases, this phenomenon is associated with recruitment of immune cells that are involved in distant irradiation effects (called "away-from-target" i.e., abscopal effects). Future Directions: Determining the contribution of targeted and off-target effects in the clinic is still challenging. This has important consequences not only in radiotherapy but also possibly in diagnostic procedures and in radiation protection. [ABSTRACT FROM AUTHOR]

The strong socio-economic growth of Quito has led to significant projects of inter-basin transfers, intensifying high-altitude resources mobilization in environmentally sensitive areas and with accelerated melting of glaciers. In order to study various future scenarios, we propose modelling of the climate/glacier/hydrology/water resources management continuum, applied to Andean basins. Using the tool Water Evaluation and Planning (WEAP21), we developed: (1) semi-distributed hydro-climate modelling with monthly data using regional homogenization (vector method); (2) glacier modelling of water production and inter-annual evolution; (3) modelling in hydrological units depending on land cover; and (4) water management modelling distinguishing water rights, allocation and use. In this paper, we mainly present results of monthly hydrological calibrations (1963–2006), studying, in particular, the equifinality of various parameter settings. We show flexibility, robustness and limits of the proposed modelling, contributing to identification of uncertainties for evaluation of future scenarios. [ABSTRACT FROM AUTHOR]

We review salient structural and electronic features associated with the concomitant Peierls–charge density wave (CDW) instabilities observed in most one-dimensional (1D) inorganic and organic electronic conductors. First of all, the genesis of these concepts is placed in an historical perspective. We then present basic experimental facts supporting the general description of these 1D electron–phonon coupled systems developed in the 1970s. In this framework we shall consider in particular the role of 1D fluctuations on both lattice and electronic degrees of freedom, and of the inter-chain Coulomb coupling between CDWs in stabilizing in 3D the Peierls transition at finite temperature. We also clarify, in relation with experimental findings, the various conditions of adiabaticity of the electron–phonon coupling. Finally we illustrate by recent structural measurements the pioneering work of Jacques Friedel on CDW elasticity and plasticity and CDW pinning to defects through the appearance of Friedel oscillations. [ABSTRACT FROM AUTHOR]

A first-principles density functional theory study of the Bechgaard salts (TMTSF)2ClO4 and (TMTSF)2NO3, with special emphasis on the anion ordering transition, is reported. It is found that the main effect of the anion ordering on the band structure occurs through the deformations induced in the TMTSF layers and not through the Coulomb potential of the anions, as it has been almost invariably assumed. It is shown that the anion ordering in (TMTSF)2ClO4 leads to a modulation of the dimerization in successive chains and to a noteworthy polarization of the two partially filled bands around the Fermi level into either the TMTSF A or TMTSF B donors. The calculated anion ordering half gap ΔAO is found to be small but definitely non-nil, ~14 meV. The suppression of the SDW instability in the relaxed samples is attributed to the deterioration of the Fermi surface nesting in the anion ordered phase. The possible nodal structure of the superconducting gap is discussed in relation with the newly calculated split Fermi surface. Anion ordering in (TMTSF)2NO3 leads to a smaller half gap, 8.9 meV. The anion ordering in this salt leads to a larger charge transfer between the two donors but to a smaller polarization of the two partially filled electron and hole bands. The weak influence of anion ordering into the low-temperature physics of this salt is related to the different periodicity of the anion ordering which leaves the nested parts of the Fermi surface almost unaltered. [ABSTRACT FROM AUTHOR]

Abstract: We review 35 years of structural studies of quasi-1D organic conductors during which the concepts of 2k F and 4k F BOW and CDW have been elaborated. In strongly correlated quarter filled band systems these instabilities give rise to SP, DM and CO ground states. We relate these structural features to the instabilities of the 1D electron gas. To stabilize the different ground states the nature of the electron-phonon coupling has to be considered together with the coupling of the organic stacks with the anion sublattice. New results concerning the classification of the SP phase in connection with the adiabatic or antiadiabatic phonon field and its competition with the CO are also introduced. [Copyright &y& Elsevier]

α-(BEDT-TTF)213 exhibits a metal to insulator transition around 135 K that has been ascribed to charge ordering in the donor layers containing three different donors (A-A dimers, B and C). First-principles density-functional theory (DFT) calculations provide a description of the electronic structure of this system in agreement with the presently available experimental information above and below the transition. A new mechanism of the charge ordering transition in which the anions play a major role is proposed. It is shown that lowering the temperature induces a differentiation of the two I zigzag chains which leads to an increase/decrease of the donor-anion hydrogen bonding with the two initially identical A donors. This induces a redistribution of holes mostly affecting the A donors (thus becoming inequivalent A, A'), giving rise to the charge ordering. The interrelation between the strength of the hydrogen bonding with the anions and the concentration of holes in the HOMOs involves a subtle polarization mechanism among the a and n electron densities of the donors. The redistribution of holes leads to the opening of a band gap via the modulation of the site potential of donors A/A' and the increased band mixing because of the symmetry lowering. [ABSTRACT FROM AUTHOR]

Changes in intracortical inhibition have been detected by means of paired-pulse transcranial magnetic stimulation (TMS) based on electromyographic recordings in many neurological or psychiatric disorders, including amyotrophic lateral sclerosis (ALS). By contrast, inhibitory responses have been generally overlooked in single motor unit (MU) studies in patients with ALS. The aim of this study was to investigate the TMS-induced inhibitory responses of single MUs in peristimulus time histograms and the changes observed with time. For this purpose, 263 MUs were tested in 10 ALS patients in two to four recording sessions. Upon subdividing the data into epochs corresponding to mean disease durations of 12, 20, 32, 43, and 168 months, we found that inhibitory responses occurred more frequently than normal throughout the course of the disease and were stronger than normal during the first year after disease onset. This finding argues against the hypothesis that loss of inhibition may be part of the pathogenic process in ALS. Muscle Nerve 39: 310-317, 2009 [ABSTRACT FROM AUTHOR]

Background: Q fever is characterized by its clinical polymorphism; neurological involvement has occasionally been described. In the course of acute Q fever, neurological manifestations may include aseptic meningitis, encephalitis or encephalomyelitis, and peripheral neuropathy. Objective: To review and evaluate cases of acute Q fever with neurological symptoms diagnosed in our laboratory. Methods: A total of 1269 acute Q fever cases were recorded from January 1985 to January 2000 in our laboratory and were reviewed for neurological complications. Patients were considered to have acute Q fever when serological procedures showed Coxiella burnetii phase II titers of 1:200 or higher for IgG and 1:50 or higher for IgM. Those patients who underwent a lumbar puncture for cerebrospinal fluid analysis or who had abnormal neurological symptoms were selected for this study. We describe the clinical, epidemiological, and biological lectures of these cases. We also review the literature and compare our cases with those previously reported. Results: Among the 45 patients selected, 14 were excluded because they had normal cerebrospinal fluid and no neurological symptoms. Two were excluded because there were no clinical or epidemiological data. Three maj or clinical syndromes were observed: meningoencephalitis or encephalitis in 17 cases; meningitis in 8; and myelitis and peripheral neuropathy in 4. Encephalitic signs were not specific, but behavior or psychiatric disturbances were common. Conclusions: Q fever should be included in the differential diagnosis of acute neurological disease in a patient with a fever. Serological testing should be performed in cases of meningoencephalitis, lymphocytic meningitis, and peripheral neuropathy, including Guillain-Barré syndrome and myelitis. [ABSTRACT FROM AUTHOR]

Abstract. Radiobiological studies have shown for some time that the effects of ionising radiation on cells are mainly explained by modification of the DNA. Numerous studies over the past 50 years have accumulated clear evidence of the cause-effect relationship between damage to DNA and the cytotoxic and mutagenic effects of ionising radiation. However, the path from irradiation of the cells to the induction of biological effects comprises several complex steps. The first step involves interactions between the radiation and the cellular environment. These consist of physical and chemical reactions which produce ions, excited molecules and radical species. Excitations and ionisations are complete in about 10[sup -15] s, and are followed by a chemical thermal equilibrium of the species produced within 10[sup -12] s. These species then diffuse from their site of production and provoke alterations to a variety of cellular components. This damage is detected by cellular surveillance systems, which in turn activate signalling cascades, gene transcription and enzyme recruitment, which participate in the cellular response. In most cases, cell cycle arrest occurs, allowing, according to the biological relevance of the DNA damage, either a process of DNA repair or programmed cell death (apoptosis). The accuracy of the DNA repair which is performed depends on the complexity of the DNA lesion and on the DNA repair machinery fidelity itself. Improper DNA repair can lead to mutation, chromosome aberration, genetic instability, oncogenic transformation and, ultimately, cell death. [ABSTRACT FROM AUTHOR]

Owing to the low sensitivity of clinical signs in assessing upper motor neuron (UMN) involvement in ALS, there is a need for investigative tools capable of detecting abnormal function of the pyramidal tract. Transcranial magnetic stimulation (TMS) may contribute to the diagnosis by reflecting a UMN dysfunction that is not clinically detectable. Several parameters for the motor responses to TMS can be evaluated with different levels of significance in healthy subjects compared with ALS patients. The central motor conduction time, however, is not sensitive in detecting subclinical UMN defects in individual ALS patients. The amplitude of the motor evoked potential (MEP), expressed as the percentage of the maximum wave, also has a low sensitivity. In some cases, the corti- comotor threshold is decreased early in the disease course as a result of corti-comotor neuron hyperexcitability induced by glutamate. Later, the threshold increases, indicating a loss of UMN. In our experience, a decreased silent period duration appears to be the most sensitive parameter when using motor TMS in ALS. TMS is also a sensitive technique for investigating the corticobulbar tract, which is difficult to study by other methods. TMS is a widely available, painless and safe technique with a good sensitivity that can visualize both corticospinal and corticobulbar tract abnormalities. The sensitivity can be improved further by taking into account the several MEP parameters, including latency and cortical silent period decreased duration. (ALS 2000; 1(suppl 2):S45-S49). [ABSTRACT FROM AUTHOR]

Bulbar and pseudobulbar symptoms are diagnostic criteria of amyotrophic lateral sclerosis (ALS). One of the earliest symptoms of bulbar involvement is voice deterioration. Until now voice assessment in ALS patients has been done mainly by perceptual analysis. The objective parameters, including acoustic measures, one aerodynamic measure and the maximal phonation time, have been measured only in a few small series of patients. The first purpose of this prospective study was to determine which vocal parameters discriminate ALS patients with bulbar involvement from control patients. The second was to identify sensitive parameters for early detection of voice deterioration due to bulbar involvement in pre-symptomatic ALS patients. The voices of 63 female ALS patients, including 40 with bulbar symptoms (sALS patients) and 23 without bulbar symptoms (aALS patients), were studied using an objective voice analysis system that allows simultaneous analysis of acoustic and aerodynamic parameters. Measurements were compared with those obtained in 40 normal female subjects (control patients). Five of eight acoustic parameters were significantly different among the three groups: jitter, coefficient of variation for frequency, shimmer, number of harmonics, and maximum phonatory frequency range. Three aerodynamic parameters, phonatory airflow, cycle-to-cycle variation for phonatory airflow, and coefficient of variation for phonatory airflow were significantly different between sALS patients and control patients. No aerodynamic parameter allowed discrimination between aALS patients and control patients. This study shows that acoustic parameters are more sensitive than aerodynamic parameters for early detection of bulbar involvement. Nevertheless, the measurements used can predict bulbar involvement in 73% of those in the sALS group, but only in 52% of those in the aALS group. [ABSTRACT FROM AUTHOR]

Bulbar and pseudobulbar symptoms are diagnostic criteria of amyotrophic lateral sclerosis (ALS). One of the earliest symptoms of bulbar involvement is voice deterioration. Until now voice assessment in ALS patients has been done mainly by perceptual analysis. The objective parameters, including acoustic measures, one aerodynamic measure and the maximal phonation time, have been measured only in a few small series of patients. The first purpose of this prospective study was to determine which vocal parameters discriminate ALS patients with bulbar involvement from control patients. The second was to identify sensitive parameters for early detection of voice deterioration due to bulbar involvement in pre-symptomatic ALS patients. The voices of 63 female ALS patients, including 40 with bulbar symptoms (sALS patients) and 23 without bulbar symptoms (aALS patients), were studied using an objective voice analysis system that allows simultaneous analysis of acoustic and aerodynamic parameters. Measurements were compared with those obtained in 40 normal female subjects (control patients). Five of eight acoustic parameters were significantly different among the three groups: jitter, coefficient of variation for frequency, shimmer, number of harmonics, and maximum phonatory frequency range. Three aerodynamic parameters, phonatory airflow, cycle-to-cycle variation for phonatory airflow, and coefficient of variation for phonatory airflow were significantly different between sALS patients and control patients. No aerodynamic parameter allowed discrimination between aALS patients and control patients. This study shows that acoustic parameters are more sensitive than aerodynamic parameters for early detection of bulbar involvement. Nevertheless, the measurements used can predict bulbar involvement in 73% of those in the sALS group, but only in 52% of those in the aALS group. [ABSTRACT FROM AUTHOR]

Mutations in the FIG4 gene have been identified in various diseases, including amyotrophic lateral sclerosis, Parkinson's disease, and Charcot–Marie–Tooth 4 J (CMT4J), with a wide range of phenotypic manifestations. We present eight cases of CMT4J patients carrying the p.Ile41Thr mutation of FIG4. The patients were categorized according to their phenotype. Six patients had a pure CMT; whereas, two patients had a CMT associated with parkinsonism. Three patients had an early onset and exhibited more severe forms of the disease. Three others experienced symptoms in their teenage years and had milder forms. Two patients had a late onset in adulthood. Four patients showed electrophysiological evidence of conduction blocks, typically associated with acquired neuropathies. Consequently, two of them received intravenous immunoglobulin treatment without a significant objective response. Interestingly, two heterozygous patients with the same mutations exhibited contrasting phenotypes, one having a severe early-onset form and the other experiencing a slow disease progression starting at the age of 49. Notably, although 7 out of 8 patients in this study were compound heterozygous for the p.Ile41Thr mutation, only one individual was found to be homozygous for this genetic variant and exhibited an early-onset, severe form of the disease. Additionally, one patient who developed the disease in his youth was also diagnosed with hereditary neuropathy with pressure palsies. Our findings provide insights into the CMT4J subtype by reporting on eight heterogeneous patient cases and highlight the potential for misdiagnosis when conduction blocks or asymmetrical nerve conduction study results are observed in patients with FIG4 mutations. [ABSTRACT FROM AUTHOR]

Non-targeted effects, including bystander and systemic effects, play a crucial role during Auger targeted radionuclide therapy. Here, we investigated whether small extracellular vesicles (sEVs) produced by irradiated cells could contribute to the bystander cytotoxic effects in vitro and also to therapeutic efficacy in vivo, after their injection in tumor xenografts. B16F10 melanoma donor cells were exposed to radiolabeled antibodies (Auger radioimmunotherapy, RIT) for 48 h or to X-rays (donor cells). Then, donor cells were incubated with fresh medium for 2 h to prepare conditioned medium (CM) that was transferred onto recipient cells for bystander effect assessment, or used for sEVs enrichment. Resulting sEVs were incubated in vitro with recipient cells for determining bystander cytotoxicity, or injected in B16F10 melanoma tumors harbored by athymic and C57BL/6 mice. In vitro analysis of bystander cytotoxic effects showed that CM killed about 30–40% of melanoma cells. SEVs isolated from CM contributed to this effect. Moreover, the double-stranded DNA (dsDNA) content was increased in sEVs isolated from CM of exposed cells compared to control (not exposed), but the difference was significant only for the X-ray condition. These results were supported by immunodetection of cytosolic dsDNA in donor cells, a phenomenon that should precede dsDNA enrichment in sEVs. However, sEVs cytotoxicity could not be detected in vivo. Indeed, in athymic and in immunocompetent mice that received four intratumoral injections of sEVs (1/day), tumor growth was not delayed compared with untreated controls. Tumor growth was slightly (not significantly) delayed in immunocompetent mice treated with sEVs from X-ray-exposed cells, and significantly with sEVs purified from CM collected after 48 h of incubation. These results highlight the need to determine the optimal conditions, including radiation absorbed dose and sEVs collection time, to obtain the strongest cytotoxic effects. This study demonstrates that sEVs could play a role during Auger RIT through bystander effects in vitro. No systemic effects were observed in vivo, under our experimental conditions. However, X-rays experiments showed that sEVs collection time might be influencing the nature of sEVs, a parameter that should also be investigated during Auger RIT. [ABSTRACT FROM AUTHOR]

In view of the conflicting results about the links between lower and upper motor neuron (LMN, UMN) dysfunction in amyotrophic lateral sclerosis (ALS), we undertook this study to correlate their changes over time. Single motor units (MUs) were characterized by their macro-MU potentials, twitch amplitude, and excitatory responses to transcranial magnetic stimulation (TMS). Ten ALS patients were studied 2 to 4 times and their data were subdivided into epochs corresponding to mean disease duration of 12 (58 MUs), 20 (60 MUs), 32 (50 MUs), 43 (40 MUs), and 168 months (55 MUs). The MU size increased and the contractile effectiveness and the excitatory response rates decreased significantly with time. The contractile effectiveness of MUs producing normal excitatory responses decreased with time, whereas a gradual loss of excitatory responses was observed among MUs with normal electromechanical properties. Since no correlation was found between UMN and LMN dysfunction, we conclude that UMN and LMN probably degenerate independently in ALS. Muscle Nerve, 2008 [ABSTRACT FROM AUTHOR]

To study the relative importance of upper motor neuron (UMN) dysfunction in the weakness of amyotrophic lateral sclerosis (ALS) and to compare the sensitivity of several transcranial magnetic stimulation (TMS) parameters as means of assessing UMN impairment in ALS, we used TMS to evaluate one upper limb of 63 patients. The triple-stimulation technique (TST) and silent period (SP) were found to be the most frequently abnormal parameters (55.6% and 47.6%, respectively), without significant difference in their diagnostic sensitivity. The SP was found to be a useful parameter in patients with suspected or possible ALS. A positive correlation was found between weakness and the TST amplitude ratio, indicating that weakness may partly be caused by UMN dysfunction. Thus, the TST provides a quantitative tool for assessing UMN conduction failure. When used in association with the SP, the TST provides a sensitive diagnostic tool for use on ALS patients. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

Purpose: This in vitro study aims at evaluating the effect of the combination of pentoxifylline (PTX) and trolox (Tx), the water-soluble analogue of α-tocopherol, on the oxidative state and DNA damage in dermal microvascular endothelial cells exposed to doses up to 10 Gy of ionizing radiation. Materials and methods: Confluent primary cultures of dermal endothelial cells were gamma irradiated at 3 and 10 Gy, and 0.5 mM of both drugs, PTX and Tx, was added either before (15 min) or after (30 min or 24 h) irradiation. Reactive oxygen species (ROS), measured by the dichlorodihydrofluorescein diacetate assay, and DNA damage, assessed by the comet and micronucleus assays, were measured at different times after exposure (0 – 21 days). Results: The PTX/Tx treatment decreased the early and delayed peak of ROS production by a factor of 2.8 in 10 Gy-irradiated cells immediately after irradiation and the basal level by a factor of 2 in non-irradiated control cells. Moreover, the level of DNA strand breaks, as measured by the comet assay, was shown to be reduced by half immediately after irradiation when the PTX/Tx treatment was added 15 min before irradiation. However, unexpectedly, it was decreased to a similar extent when the drugs were added 30 min after radiation exposure. This reduction was accompanied by a 2.2- and 3.6-fold higher yield in the micronuclei (MN) frequency observed on days 10 and 14 post-irradiation, respectively. Conclusion: These results suggest that oxidative stress and DNA damage induced in dermal microvascular endothelial cells by radiation can be modulated by early PTX/Tx treatment. These drugs acted not only as radical scavengers, but they were also responsible for the increased MN frequency in 10 Gy-irradiated cells. Thus, these drugs may cause a possible interference with DNA repair processes. [ABSTRACT FROM AUTHOR]

Purpose: The deleterious processes triggered by heavy ions on DNA were studied through the determination of the yield of a series of oxidized bases. Emphasis was placed on the estimation of the respective contribution of direct ionization and indirect effects, mostly by comparison with low linear energy transfer (LET) ?-rays. Material and Methods: DNA samples and human monocytes were exposed either to ?-rays emitted by a 60 Co source or to 12 C 6+ or 36 Ar 18+ ions. The levels of thymidine and 2'-deoxyguanosine oxidation products were determined by liquid chromatography coupled to tandem mass spectrometry subsequently to DNA digestion into nucleosides. Results: The yields of thymidine lesions were similar to those of 8-oxo-7,8-dihydro-2'-deoxyguanosine within isolated DNA exposed either to ?-rays or argon ions. Addition of spermine and Tris aimed at minimizing the indirect effect modified this ratio to the same extent with both types of radiation. In cells, the level of radiation-induced base damage was found to be correlated with the radiolytic yield of °OH that depends on the LET of the particle. In addition, radiation-induced thymidine and 2'-deoxyguanosine lesions were produced in similar amounts. In contrast, oxidation of 2'-deoxyguanosine was the main process when ionization was triggered in cellular DNA by ultraviolet laser-induced biphotonic processes. Conclusions: Predominant oxidation of 2'-deoxyguanosine is expected to be the hallmark of direct DNA ionization. The observation that thymidine and 2'-deoxyguanosine are equally damaged rules out a major contribution of the direct ionization in radiation-induced base damage to both isolated and cellular DNA by heavy ions. Dependence of the yield of lesions on the LET provides further support for this conclusion. [ABSTRACT FROM AUTHOR]

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders.Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients.Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to quantitatively compare five commercial dosimetric software platforms based on the analysis of clinical datasets of patients who benefited from peptide receptor radionuclide therapy (PRRT) with 177Lu‐DOTATATE (LUTATHERA®). Methods: The dosimetric analysis was performed on two patients during two cycles of PRRT with 177Lu. Single photon emission computed tomography/computed tomography images were acquired at 4, 24, 72, and 192 h post injection. Reconstructed images were generated using Dosimetry Toolkit® (DTK) from Xeleris™ and HybridRecon‐Oncology version_1.3_Dicom (HROD) from HERMES. Reconstructed images using DTK were analyzed using the same software to calculate time‐integrated activity coefficients (TIAC), and mean absorbed doses were estimated using OLINDA/EXM V1.0 with mass correction. Reconstructed images from HROD were uploaded into PLANET® OncoDose from DOSIsoft, STRATOS from Phillips, Hybrid Dosimetry Module™ from HERMES, and SurePlan™ MRT from MIM. Organ masses, TIACs, and mean absorbed doses were calculated from each application using their recommendations. Results: The majority of organ mass estimates varied by <9.5% between all platforms. The highest variability for TIAC results between platforms was seen for the kidneys (28.2%) for the two patients and the two treatment cycles. Relative standard deviations in mean absorbed doses were slightly higher compared with those observed for TIAC, but remained of the same order of magnitude between all platforms. Conclusions: When applying a similar processing approach, results obtained were of the same order of magnitude regardless of the platforms used. However, the comparison of the performances of currently available platforms is still difficult as they do not all address the same parts of the dosimetric analysis workflow. In addition, the way in which data are handled in each part of the chain from data acquisition to absorbed doses may be different, which complicates the comparison exercise. Therefore, the dissemination of commercial solutions for absorbed dose calculation calls for the development of tools and standards allowing for the comparison of the performances between dosimetric software platforms. [ABSTRACT FROM AUTHOR]

Here, the first accurate study is presented of the room‐temperature and 100 K structures of one of the first organic spin liquids, κ‐(BEDT‐TTF)2Ag2(CN)3. It is shown that the monoclinic structure determined previously is only the average one. It is shown that the exact structure presents triclinic symmetry with two non‐equivalent dimers in the unit cell. But surprisingly this does not lead to a sizeable charge disproportionation between dimers. The difference from the analogue compound κ‐(BEDT‐TTF)2Cu2(CN)3 which also presents a spin liquid phase is discussed in detail. The data provided here show the importance of the anionic layer and in particular the transition metal position in the process of symmetry breaking. The possible impact of the symmetry breaking, albeit weak, on the spin‐liquid mechanism and the influence of various disorders on the physical properties of this system is also discussed. [ABSTRACT FROM AUTHOR]

Introduction: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a debilitating autoimmune neuropathy that is treated with intravenous immunoglobulin (IVIG). The aim of this retrospective study was to investigate the efficacy and safety of the sucrose-free IVIG Octagam® (Octapharma AG, Lachen, Switzerland) in patients with CIDP. Methods: Data from 47 patients who received at least one dose of Octagam were collected from the records of 11 centres in France. Efficacy was assessed using Overall Neuropathy Limitation Scale (ONLS). Safety was evaluated using adverse event rates. Results: Data from 24 patients who were IVIG naïve (n = 11) or had stopped IVIG ≥ 12 weeks before initiation of Octagam therapy (washout group; n = 13) were included in the efficacy analysis. At 4 months post-initiation of Octagam treatment, 41.7% of patients had improved their functional status (decrease of ≥ 1 ONLS score) with a significant change in the ONLS score from baseline (– 0.42; p = 0.04; signed test). Functional status was reduced in only two patients: one patient in the IVIG-naïve group and one patient in the IVIG-washout group. All 47 patients were included in the safety analysis, which showed that Octagam was well tolerated, with a frequency of 0.04 adverse events per Octagam course. The most common adverse drug reaction was headache. Conclusions: These real-life results are consistent with the efficacy and safety of IVIG reported in randomised controlled studies. A long-term prospective study of Octagam in patients with CIDP is warranted. Funding: Octapharma, France SAS. [ABSTRACT FROM AUTHOR]

Highlights • Avalglucosidase alfa (neoGAA) had a well-tolerated safety profile in LOPD patients. • Respiratory and functional capacities were stable or improved in most patients. • Postinfusion, avalglucosidase alfa in plasma fell monoexponentially (t 1/2z ∼1.0 h). • AUC for avalglucosidase alfa in plasma was 5–6 × higher for the 20 vs 5 mg/kg group. • Safety/exploratory efficacy data support further avalglucosidase alfa development. Abstract This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t 1/2z ∼1.0 h). AUC was 5–6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulin (IVIg) is the gold‐standard for maintenance treatment of multifocal motor neuropathy (MMN). This phase III, randomised, double‐blind, multi‐centre, active‐control, crossover study, aimed to evaluate the non‐inferiority of IqYmune® relative to Kiovig®, primarily based on efficacy criteria. Twenty‐two adult MMN patients, treated with any brand of IVIg (except Kiovig® or IqYmune®) at a stable maintenance dose within the range of 1 to 2 g/kg every 4 to 8 weeks, were randomised to receive either Kiovig® followed by IqYmune®, or IqYmune® followed by Kiovig®. Each product was administered for 24 weeks. The primary endpoint was the difference between IqYmune® and Kiovig® in mean assessments of modified Medical Research Council (MMRC) 10 sum score (strength of 5 upper‐limb and 5 lower‐limb muscle groups, on both sides, giving a score from 0 to 100) during the evaluation period (non‐inferiority margin of Δ = 2). A linear mixed model analysis demonstrated the non‐inferiority of IqYmune® relative to Kiovig®, independently of the covariates (value at baseline, treatment period, and treatment sequence). The estimated "IqYmune® − Kiovig®" difference was −0.01, with a 95% confidence interval (CI) −0.51 to 0.48. The number of adverse reactions (ARs) and the percentage of patients affected were similar for the two products: 39 ARs in 10 patients with IqYmune® vs 32 ARs in 11 patients with Kiovig®. No thromboembolic events nor haemolysis nor renal impairment were observed. In this first clinical trial comparing two IVIg brands for maintenance treatment of MMN, efficacy and tolerability of both brands were similar. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to assess the usefulness of motor unit number index (MUNIX) technique in Charcot-Marie-Tooth disease and test the correlation between MUNIX and clinical impairment. Methods MUNIX technique was performed in the abductor pollicis brevis (APB), the abductor digiti minimi (ADM) and the tibialis anterior (TA) muscles in the nondominant side. A MUNIX sum score was calculated by adding the MUNIX of these 3 muscles. Muscle strength was measured using the MRC (medical research council) scale. Disability was evaluated using several functional scales, including CMT neuropathy score version 2 (CMTNSv2) and overall neuropathy limitation scale (ONLS). Results A total of 56 CMT patients were enrolled. The MUNIX scores of the ADM, APB and TA muscles correlated with the MRC score of the corresponding muscle (p < 0.01). The MUNIX sum score correlated with the clinical scales CMTNSv2 ( r   =  −0.65, p < 0.01) and ONLS ( r   =  −0.57, p < 0.01). Conclusion MUNIX correlates with muscle strength and clinical measurements of disability in patients with CMT disease. Significance The MUNIX technique evaluates motor axonal loss and correlates with disability. The MUNIX sum score may be a useful outcome measure of disease progression in CMT. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary inclusion body myopathy (hIBM) refers to a group of clinically and genetically heterogeneous diseases. The overlapping histochemical features of hIBM with other genetic disorders lead to low diagnostic rates with targeted single-gene sequencing. This is true for the most prevalent form of hIBM, GNEpathy. Therefore, we used whole-exome sequencing (WES) to determine whether a cohort of clinically suspected GNEpathy patients undiagnosed by targeted GNE analysis could be genetically characterized.Methods: Twenty patients with hIBM but undiagnosed by targeted GNE sequencing were analyzed by WES before data filtering on 306 genes associated with neuromuscular disorders.Results: Seven patients out of 20 were found to have disease-causing mutations in genes associated with hIBM or genes allowing for hIBM in the differential diagnosis or associated with unexpected diagnosis.Discussion: Next-generation sequencing is an efficient strategy in the context of hIBM, resulting in a molecular diagnosis for 35% of the patients initially undiagnosed by targeted GNE analysis. Muscle Nerve 56: 993-997, 2017. [ABSTRACT FROM AUTHOR]

Objective To identify factors associated with efficacy of rituximab (RTX) infusions in patients with anti-myelin associated glycoprotein (MAG) neuropathy. Methods 33 patients with anti-MAG neuropathy treated with RTX were retrospectively evaluated. All patients underwent neurological, biological, and electrophysiological examinations. Good response was defined as an improvement of at least one point of the Overall Neuropathy Limitation Scale (ONLS) at 6 months or at the last follow-up. Disease evolution was defined as sub-acute if the ONLS increased by at least 2 points the year before therapy. Results Ten patients (30%) were improved 6 months after RTX and 6/20 (30%) at the last follow-up (mean 42 months). Response to RTX was significantly associated with subacute evolution and proximal weakness of the lower limbs at the onset of disease. Improvement was not correlated with electrophysiological data and anti-MAG antibodies titers. Discussion This study suggests that RTX may be efficacious in a sub-population of patients with anti-MAG neuropathy, particularly in those with proximal weakness of the lower limbs or sub-acute evolution. [ABSTRACT FROM AUTHOR]

Introduction: The diagnostic sensitivity of repetitive nerve stimulation (RNS) in patients with myasthenia gravis (MG) varies as a function of the number of muscles or the choice of muscles studied.Methods: By exploring 12 muscles bilaterally, we evaluated the global sensitivity of RNS at rest, the sensitivity in different clinical forms, and the sensitivity of different combinations of muscles studied.Results: The global sensitivity of RNS was 82%, and specificity was 100%. The sensitivity in the MG subgroups was as follows: ocular (O) = 67%; oculobulbar (OB) = 86%; and generalized (G) = 89%. The most sensitive muscles were the anconeus in group O, orbicularis oculi (OO) or nasalis in group OB, and the trapezius in group G. Maximum sensitivity was obtained by exploring OO, trapezius, and anconeus bilaterally.Conclusions: We recommend bilateral exploration of at least 3 muscles, a facial muscle, trapezius, and anconeus. Muscle Nerve 55: 532-538, 2017. [ABSTRACT FROM AUTHOR]

The article offers information on the multidisciplinary field of molecular radionuclide therapy (MRT) that allows specific irradiation of localized and disseminated disease and mentions improvements in radiochemistry, radiopharmacy, and dosimetry of MRT agents. It proposes several topics to understand therapeutic radiopharmaceutical of MRT including determining the role of radiopharmaceutical and target distribution and the role of the tumor microenvironment and systemic reactions.

Abstract: The one-dimensional (1D) strongly correlated BaVS3 undergoes a series of unexplained phase transitions. Among them it undergoes a metal-insulator (MI) transition associated with a charge density wave (CDW) instability. We show that this CDW ground state is very sensitive to chemical substitutions and/or sulfur deficiency. Substitutions of V with of Nb, Ti or Ba with K in probably sulfur deficient samples leads to a completely different ground state. This ground state is characterized by a short range structural modulation with the incommensurate wave vector , which could be due to a CDW taking place in a differently filled band. [Copyright &y& Elsevier]

Aims: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with 125I [125I-mAbs]). Results: We showed that the cytotoxicity of 125I-mAbs targeting the cell membrane of p53+/+ HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. 125I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ⅛ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca2+ fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2'-deoxyuridine to the nucleus was comparable to that of 125I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by 125I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. Innovation: Low-energy Auger electrons, such as those emitted by 125I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with 125I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. Conclusion: Our findings describe the mechanisms involved in the efficacy of 125I-mAbs targeting the cancer cell surface. [ABSTRACT FROM AUTHOR]

Background: In myotonic dystrophy type 1 (DM1), only one FDG-PET study used statistical parametric mapping (SPM) showing frontal reduced FDG-uptake. Our aim was to 1) identify the FDG-PET area with the most severe reduced FDG-uptake using SPM8 in a larger group of patients 2) assess potential correlation between CTG-numbers and FDG-PET.Methods: FDG-PET was performed in 24 patients and compared to 24 controls. Pearson's correlation was used to analyse correlation.Results: SPM8 revealed Brodmann area 8 as the area with the most severe reduced FDG-uptake. Weak, although not statistically significant, correlation was observed between CTG-numbers and reduced FDG-uptake in Brodmann area 8.Conclusion: In DM1, Brodmann area 8 is the area with the most severe reduced FDG-uptake on FDG-PET. Brodmann area 8 reduced FDG-uptake is correlated -although weakly- to CTG-repeat numbers. [ABSTRACT FROM AUTHOR]

A correction to the article "An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A," by Shahram Attarian and colleagues is presented.

Objective To determine the test–retest reliability of motor unit number index (MUNIX) technique and to explore if the MUNIX sumscore could be related with disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Methods The MUNIX technique was unilaterally assessed in the abductor digiti mini (ADM), the abductor pollicis brevi (APB) and the tibialis anterior (TA) muscles two different times by two blinded examiners. The MUNIX sumscore was calculated by adding the results of the ADM, APB and TA muscles. Results 14 CIDP patients were enrolled. The intraclass correlation coefficient (ICC) was great for inter and intra variability for ADM muscles (0.8 and 0.81), TA muscles (0.86 and 0.89) and MUNIX sumscore (0.76 and 0.83). The MUNIX sumscores from the first and second evaluations were strongly correlated ( r = 0.83, p < 0.001). The MUNIX sumscore was significantly correlated with MRC testing ( r = 0.71, p < 0.01), overall neuropathy limitation scale (ONLS) ( r = −0.70, p < 0.001), rasch-built overall disability scale (R-ODS) ( r = 0.71, p < 0.001). Conclusions The MUNIX technique has a good reproducibility and the MUNIX sumscore is related to the disability. Significance The MUNIX technique estimates the axonal loss and the number of functional motor units. The MUNIX sumscore may be a good instrument to evaluate the CIDP patients during their follow-up. [ABSTRACT FROM AUTHOR]

Background Patients with inflammatory sensory neuronopathy (SNN) may benefit from immunomodulatory or immunosuppressant treatments if administered timely. Knowing the temporal profile of neuronal loss in dorsal root ganglia will help to ascertain whether a final diagnosis may be reached before the occurrence of irreversible neuronal injuries. Thus, we addressed the evolution of neuronal loss in SNN by using sensory nerve action potentials (SNAPs) as a surrogate marker of neuron degeneration. Methods Eighty-six patients with acute/subacute inflammatory SNN (paraneoplastic, associated with dysimmune diseases, or idiopathic) were retrospectively studied. The monthly SNAP reduction was determined and normalized with the lower limit of normal. Disability progression was expressed by the modified Rankin score and correlated with SNAP reduction. Results The monthly SNAP reduction was similar in the four limbs although the median nerve was less severely affected. The monthly SNAP reduction was very severe within the first two months of evolution, began to slow down after seven months, and stabilized after ten months. It was tightly correlated with disability progression. Kaplan–Meier analysis showed that the median time until matching the diagnostic criteria of SNN was 8.5 months. Within this period, 42% of nerves remained excitable. Conclusions Developing treatment aiming at the stabilization of SNN is possible within the first 8 months of evolution. An improvement of the disease is possible if patients are treated within two months, which needs an early referral to an expert center and ENMG testing of the radial and ulnar nerves, which are most sensitive to changes. [ABSTRACT FROM AUTHOR]

Hypohidrosis is a frequent and early symptom in patients with Fabry disease. Studies have reported improved sweating in patients treated with enzyme-replacement therapy. A new method, Sudoscan, has been developed that is noninvasive, is quantitative, and can quickly evaluate sweat gland function. It is based on the electrochemical reaction between sweat chlorides and stainless-steel electrodes in contact with the palms and soles. The aim of our study was to evaluate the Sudoscan as a tool to assess sudomotor dysfunction in patients with Fabry disease. Consecutive patients were prospectively recruited who had a diagnosis of Fabry disease, which had been confirmed genetically and/or by measurement of α-galactosidase activity in leukocytes. Healthy controls, matched (1:1) for age and sex, were also enrolled. Test results were expressed immediately as electrochemical skin conductance (ESC, µS) for hands and feet. Sudomotor dysfunction was considered absent, moderate, or severe if the ESC measured on the feet was >60 µS, between 60 and 40 µS, or <40 µS, respectively. Among the 18 patients, 11 had hypohidrosis or anhidrosis. Hand and feet ESCs were significantly lower in patients compared to their controls (P=0.0015 and P=0.0047, respectively). Among patients, 8/18 (44.5%) had a sudomotor dysfunction, moderate in three and severe in five cases. Hand and feet ESCs were significantly lower in those with hypohidrosis/anhidrosis compared to those without (P=0.0014 and P=0.0056, respectively). This study showed that Sudoscan provided a quick, noninvasive, and quantitative measurement of sudomotor function in Fabry disease patients. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed three patients with pure motor neuronopathy followed for more than four years in our center. The patients presented a rapidly progressive lower motor neuron syndrome (LMNS) over the course of a few weeks leading to a severe functional impairment. The neurological symptoms preceded the diagnosis of a breast adenocarcinoma and a thymoma in the first two patients, one of them with anti-CV2/CRMP5 antibodies. Cancer was not detected in the third patient who had circulating anti-Hu antibodies. A final diagnosis of paraneoplastic syndrome was made after investigations for alternative causes of lower motor neuron syndrome. Early diagnosis, combined treatment of the underlying cancer, and immunomodulatory treatment led to neurological improvement of the disease in two out of the three cases in which the cancer was diagnosed. Cases of subacute LMNS with rapid progression may occur as an expression of a paraneoplastic neurological syndrome. Identification of these syndromes is important, as the treatment of underlying malignancy along with immunomodulatory treatment may result in a favorable long-term outcome of these potentially fatal diseases. [ABSTRACT FROM AUTHOR]

Introduction: In this study we analyzed the effects of a rehabilitation method based on the use of vibratory proprioceptive assistance (VPA) in subjects with facioscapulohumeral muscular dystrophy.Methods: Eight subjects were given 1 month of mechanical vibratory treatment that consisted of 8 sessions of 40-min stimulation on the more affected side. During each session, illusory movements were induced as follows: sensations of extension or flexion of the forearm or elevation of the arm via vibration applied to the distal tendon of the biceps brachialis (BB), triceps brachialis (TB), or pectoralis major muscles (PM), respectively, and of elevation of the arm with extension or flexion of the forearm via vibration of PM+BB or PM+TB, respectively.Results: Treatment led to a significant increase in the amplitude of voluntary shoulder flexion, constant score, and self-rated health.Conclusion: VPA may serve as a rehabilitation method for reducing the deleterious effects of decline in motor activities. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n=4), 0.05 (n=3), 0.15 (n=3), or 0.3(n=7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. [ABSTRACT FROM AUTHOR]