Incobotulinum booster injections in patients with spasticity and dystonia after stroke

Background.\u2013 Previous results in patients injected with abobotulinum toxin A and onabotulinum toxin A have shown that injection intervals shorter than 2 months may increase the risk for neutralising antibody formation and treatment non-response. As a result, for the last 10 years, we have adopted longer intervals to treat patients with spasticity and/or dystonia secondary to stroke. It has been showed that incobotulinum toxin A does not induce neutralising antibodies. Observations.\u2013 Methods.\u2013 Ten patients with spasticity and/or dystonia due to stroke underwent a booster injection one month after the first injection. The clinical results were compared to those previously obtained in the same 10 patients using a single injection. Secondary dystonia was evaluated using the Unified Dystonia Rating Scale (UDRS), while spasticity was evaluated according to the Modified Ashworth Scale (MAS). Results.\u2013 They showed that the booster injection protocol induced an improvement in 8 subjects. In the remaining 2 subjects, we did not find any difference between the results obtained using the single and the booster injection protocols. Conclusions.\u2013 The use of a booster injection improve the clinical outcome in patients with spasticity and/or dystonia after stroke, allowing an optimal treatment of those muscles that poorly responded to the first injection

Ferromagnetic resonance assisted optomechanical magnetometer

The resonant enhancement of mechanical and optical interaction in optomechanical cavities enables their use as extremely sensitive displacement and force detectors. In this work we demonstrate a hybrid magnetometer that exploits the coupling between the resonant excitation of spin waves in a ferromagnetic insulator and the resonant excitation of the breathing mechanical modes of a glass microsphere deposited on top. The interaction is mediated by magnetostriction in the ferromagnetic material and the consequent mechanical driving of the microsphere. The magnetometer response thus relies on the spectral overlap between the ferromagnetic resonance and the mechanical modes of the sphere, leading to a peak sensitivity better than 900 pT Hz$^{-1/2}$ at 206 MHz when the overlap is maximized. By externally tuning the ferromagnetic resonance frequency with a static magnetic field we demonstrate sensitivity values at resonance around a few nT Hz$^{-1/2}$ up to the GHz range. Our results show that our hybrid system can be used to build high-speed sensor of oscillating magnetic fields

Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766).

Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and noncatalytic proteins, as robust proximal biomarkers are rarely known. To confirm that our recently discovered chemical probe 1 (CCT251236) binds the putative transcription factor regulator pirin in living cells, we developed a heterobifunctional protein degradation probe. Focusing on linker design and physicochemical properties, we generated a highly active probe 16 (CCT367766) in only three iterations, validating our efficient strategy for degradation probe design against nonvalidated protein targets

Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1a kinase-endoribonuclease

A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease

The NAMPT inhibitor FK866 reverts the damage in spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.</p> <p>Methods</p> <p>We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.</p> <p>Results</p> <p>Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.</p> <p>We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.</p> <p>Conclusions</p> <p>Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.</p

Influence of temperature and surfactants on the solubilization of hexachlorobutadiene and hexachloroethane

The solubilization of hexachlorobutadiene (HCBD) and hexachloroethane (HCA) in water as a function of temperature and in the presence of surfactants was investigated in order to predict their fate in groundwater and to increase their recovery. HCBD and HCA solubility data were experimentally determined at five temperatures in the range from (285.15 to 318.15) K. Thermodynamic parameters for dissolution (ΔsolG°, ΔsolH°, and ΔsolS°) have been calculated in order to propose a physical explanation of the minimum solubility observed between 293.15 and 298.15 K for both compounds. The solubilization process appeared to be influenced by the network of water molecules rather than by physical and chemical properties of HCBD or HCA, due to an opposite effect of temperature onto Brownian motion, which increases with temperature, and hydrogen-bond network, which collapses with temperature. Concerning the influence of surfactants, determination of the micelle–water partition coefficients (Kmw) and the molar solubilization ratio (MSR) has shown that the solubilization per micelle was more important for nonionic surfactants Triton X-100 and Tween 80 than for anionic SDBS. Also, the increase of solubility was 1 order of magnitude higher for liquid HCBD than for crystalline HCA irrespective of surfactant

Manual linear movements to assess spasticity in a clinical setting

In a clinical setting, where motor-driven systems are not readily available, the major difficulty in the assessment of the stretch reflex lies in the control of passive limb displacement velocity. A potential approach to this problem arises from the use of manual sinusoidal movements (made by continuous alternating flexions and extensions) paced by an external stimulus. Unfortunately, there are conditions in which sinusoidal movements induce interfering phenomena such as the shortening reaction or postactivation depression. In the present paper, a novel manual method to control the velocity of passive linear movements is described and the results obtained from both healthy subjects and spastic patients are reported. This method is based on the synchronisation of movements with tones played by a metronome at different speeds. In a first set of experiments performed in healthy subjects, we demonstrated consistent control of velocity during passive limb movements using this method. Four joints usually examined during muscle tone assessment were tested: wrist, elbow, knee and ankle joints. Following this, we conducted a longitudinal assessment of the stretch reflex amplitude in wrist flexor muscles in patients with spasticity treated with botulinum toxin type A. The evaluators were not only able to vary the movement velocity based on the metronome speed, but also could reproduce the respective speeds two weeks later, despite the changing degree of hypertonia. This method is easy to perform in a clinical setting and hardware requirements are minimal, making it an attractive and robust procedure for the widespread clinical assessment of reflex hypertonia