a single blinded randomized pilot study of botulinum toxin type a combined with non pharmacological treatment for spastic foot

OBJECTIVE: To explore the effect of treatment after botulinum toxin type A combined with treatments for the spastic foot. DESIGN: Single-blind, randomized trial, with 3-month follow-up. SUBJECTS: Twenty-three chronic hemiplegic adult patients with spastic equinus foot. METHODS: Following botulinum toxin type A injection at the medial and lateral gastrocnemius, patients were assigned randomly to 3 groups, and treated with taping, electrical stimulation or stretching. They were evaluated before treatment (t0), and at 10 (t1), 20 (t2) and 90 (t3) days after treatment. Outcome measures were: Modified Ashworth Scale; passive range of motion at the ankle; measurement of muscle action potential at the gastrocnemius medialis; and measurement of maximum ankle dorsiflexion angle in stance using gait analysis. RESULTS: The group treated with electrical stimulation performed better at t1 on the Modified Ashworth Scale. The taping and electrical stimulation groups performed better in all outcome measures at t3. The taping group performed better mainly for maximum ankle dorsiflexion angle in stance. The stretching group showed a less durable result, with some worsening at the t3 evaluation compared with the assessment performed before treatment. CONCLUSIONS: This pilot study indicates that combining botulinum toxin type A administration for the ankle plantar flexors with taping and electrical stimulation might be beneficial

Weak KAM for commuting Hamiltonians

For two commuting Tonelli Hamiltonians, we recover the commutation of the Lax-Oleinik semi-groups, a result of Barles and Tourin ([BT01]), using a direct geometrical method (Stoke's theorem). We also obtain a "generalization" of a theorem of Maderna ([Mad02]). More precisely, we prove that if the phase space is the cotangent of a compact manifold then the weak KAM solutions (or viscosity solutions of the critical stationary Hamilton-Jacobi equation) for G and for H are the same. As a corrolary we obtain the equality of the Aubry sets, of the Peierls barrier and of flat parts of Mather's $\alpha$ functions. This is also related to works of Sorrentino ([Sor09]) and Bernard ([Ber07b]).Comment: 23 pages, accepted for publication in NonLinearity (january 29th 2010). Minor corrections, fifth part added on Mather's $\alpha$ function (or effective Hamiltonian

Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics

Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage

Existence and multiplicity for elliptic problems with quadratic growth in the gradient

We show that a class of divergence-form elliptic problems with quadratic growth in the gradient and non-coercive zero order terms are solvable, under essentially optimal hypotheses on the coefficients in the equation. In addition, we prove that the solutions are in general not unique. The case where the zero order term has the opposite sign was already intensively studied and the uniqueness is the rule.Comment: To appear in Comm. PD

Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β

We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics

Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide

It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue

Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain

The immune response in the brain has been widely investigated and while many studies have focused on the proinflammatory cytotoxic response, the brain’s innate immune system demonstrates significant heterogeneity. Microglia, like other tissue macrophages, participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review examines the mechanisms that lead to reduction of self-toxicity and to repair and restructuring of the damaged extracellular matrix in the brain. Part of the resolution process involves switching macrophage functional activation to include reduction of proinflammatory mediators, increased production and release of anti-inflammatory cytokines, and production of cytoactive factors involved in repair and reconstruction of the damaged brain. Two partially overlapping and complimentary functional macrophage states have been identified and are called alternative activation and acquired deactivation. The immunosuppressive and repair processes of each of these states and how alternative activation and acquired deactivation participate in chronic neuroinflammation in the brain are discussed

GPR126 is a specifier of blood-brain barrier formation in the mouse central nervous system

Data availability. RNA sequencing data are available through the European Molecular Biology Laboratory–European Bioinformatics Institute (EMBL-EBI) ArrayExpress BioStudies portal with accession number E-MTAB-13914. All supporting data are provided in the Supporting Data Values file.The blood-brain barrier (BBB) acquires unique properties to regulate neuronal function during development. The formation of the BBB, which occurs in tandem with angiogenesis, is directed by the Wnt/β-catenin signaling pathway. Yet the exact molecular interplay remains elusive. Our study reveals the G protein–coupled receptor GPR126 as a critical target of canonical Wnt signaling, essential for the development of the BBB’s distinctive vascular characteristics and its functional integrity. Endothelial cell–specific deletion of the Gpr126 gene in mice induced aberrant vascular morphogenesis, resulting in disrupted BBB organization. Simultaneously, heightened transcytosis in vitro compromised barrier integrity, resulting in enhanced vascular permeability. Mechanistically, GPR126 enhanced endothelial cell migration, pivotal for angiogenesis, acting through an interaction between LRP1 and β1 integrin, thereby balancing the levels of β1 integrin activation and recycling. Overall, we identified GPR126 as a specifier of an organotypic vascular structure, which sustained angiogenesis and guaranteed the acquisition of the BBB properties during development.This study was supported by the European Research Council (ERC; 742922) and AIRC (18683 and 21320) to ED; ITN BtRAIN (675619) and CARIPLO Foundation (2016-0461) to MG; and AIRC (26183) and Horizon 2020 (964481) to DI. KB was funded by the Francis Crick Institute (FC001751). AP is funded by the Engineering and Physical Sciences Research Council (EP/S030964/1). SS was supported by the ERC (grant 101002280) and AIRC (grant 24415). MDG is supported by the Armenise Harvard Foundation, ERC (101116224), and AIRC (27564). MI is supported by the ERC (725038), AIRC (19891 and 22737), and Italian Ministry for University and Research (INF-ACT and PRIN 2022FMESXL)