The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy

A definite diagnosis of pure small fiber neuropathy (SFN) relies on specific diagnostic testing, such as skin biopsy, quantitative sensory testing (QST), and nociceptive evoked potentials, which require considerable resources that may not be widely available. Accordingly, diagnostic tools with easy implementation in non-specialist centers are warranted to identify patients who require second-level diagnostic tests. In this study, we aimed to test the accuracy of the Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN-SIQ) in diagnosing pure SFN. We enrolled 86 patients with suspected pure SFN. In these patients, we calculated the diagnostic accuracy of the SFN-SIQ using a combination of clinical examination, QST, and skin biopsy as a reference standard. We found that the SFN-SIQ showed an excellent ability to discriminate between patients with and without pure SFN, with 86% sensitivity and 70% specificity in the diagnosis of pure SFN. Our study providing the diagnostic yield of the SFN-SIQ for pure SFN diagnosis suggests that this questionnaire might be used to screen patients with suspected SFN and identify those requiring second-level diagnostic tests such as QST, skin biopsy, or nociceptive evoked potentials

Pain associated with COVID-19 vaccination is unrelated to skin biopsy abnormalities

Previous clinical observations raised the possibility that COVID-19 vaccination might trigger a small-fibre neuropathy.Objectives:In this uncontrolled observational study, we aimed to identify small fibre damage in patients complaining of generalized sensory symptoms and pain after COVID-19 vaccination.Methods:We collected clinical data, including a questionnaire for assessing autonomic symptoms (Composite Autonomic Symptom Score-31), and investigated quantitative sensory testing (QST) and skin biopsy in 15 prospectively enrolled patients with generalized sensory symptoms and pain after COVID-19 vaccination. Nine patients complaining of orthostatic intolerance also underwent cardiovascular autonomic tests.Results:We found that all patients experienced widespread pain, and most of them (11 of 15) had a fibromyalgia syndrome. All patients had normal skin biopsy findings, and in the 9 patients with orthostatic intolerance, cardiovascular autonomic tests showed normal findings. Nevertheless, 5 patients had cold and warm detection abnormalities at the QST investigation.Conclusions:In our study, most patients complaining of generalized sensory symptoms and pain after COVID-19 vaccination had clinical and diagnostic test findings compatible with a fibromyalgia syndrome. Although the abnormal QST findings we found in 5 patients might be compatible with a small-fibre neuropathy, they should be cautiously interpreted given the psychophysical characteristics of this diagnostic test. Further larger controlled studies are needed to define precisely the association between small fibre damage and COVID-19 vaccination

Polymer-Lipid Hybrid Membranes as a Model Platform to Drive Membrane-Cytochrome c Interaction and Peroxidase-like Activity

Controllable attachment of proteins to material surfaces is very attractive for many applications including biosensors, bioengineered scaffolds or drug screening. Especially, redox proteins have received considerable attention as a model system not only to understand the mechanism of electron transfer in biological systems, but also the development of novel biosensors. However, current research attempts suffer from denaturation of the protein after its attachment to solid substrates. Here, we present how lipid, polymer and hybrid membranes based on mixtures of lipids and copolymers on a solid support provide a more favorable environment to drive selective and functional attachment of a model redox protein, cytochrome c (cyt c). Polymer membranes provided chemical versatility to support covalent attachment of cyt c, whereas lipid membranes provided flexibility and biocompatibility to support insertion of cyt c through its hydrophobic part. Hybrid membranes combine the most promising characteristics of both lipids and polymers and allowed attachment of cyt c with both covalent attachment and insertion driven by hydrophobic interactions. We then investigated the effect of different attachment strategies on the accessibility and peroxidase-like activity of cyt c, in the presence of different membranes. The real-time combination of cyt c with the planar membranes was investigated by quartz crystal microbalance with dissipation. It was possible to selectively drive the insertion of cyt c into a specific lipid domain of hybrid membranes. In addition, protein accessibility and its functionality were dependent on the specificity of the combination strategy: covalent conjugation of cyt c to polymer and hybrid membranes promoted higher accessibility and supported higher peroxidase-like activity. Taking together, the combination of biomolecules with planar membranes can be modulated in such a way to improve the accessibility of the biomolecules and their resulting functionality for the development of efficient âEuro�active surfacesâEuro�

Tailoring a Solvent-Assisted Method for Solid-Supported Hybrid Lipid-Polymer Membranes

Combining amphiphilic block copolymers and phospholipids opens new opportunities for the preparation of artificial membranes. The chemical versatility and mechanical robustness of polymers together with the fluidity and biocompatibility of lipids afford hybrid membranes with unique properties that are of great interest in the field of bioengineering. Owing to its straightforwardness, the solvent-assisted method (SA) is particularly attractive for obtaining solid-supported membranes. While the SA method was first developed for lipids and very recently extended to amphiphilic block copolymers, its potential to develop hybrid membranes has not yet been explored. Here, we tailor the SA method to prepare solid-supported polymer-lipid hybrid membranes by combining a small library of amphiphilic diblock copolymers poly(dimethyl siloxane)-poly(2-methyl-2-oxazoline) and poly(butylene oxide)- block -poly(glycidol) with phospholipids commonly found in cell membranes including 1,2-dihexadecanoyl- sn -glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphoethanolamine, sphingomyelin, and 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine- N -(glutaryl). The optimization of the conditions under which the SA method was applied allowed for the formation of hybrid polymer-lipid solid-supported membranes. The real-time formation and morphology of these hybrid membranes were evaluated using a combination of quartz crystal microbalance and atomic force microscopy. Depending on the type of polymer-lipid combination, significant differences in membrane coverage, formation of domains, and quality of membranes were obtained. The use of the SA method for a rapid and controlled formation of solid-supported hybrid membranes provides the basis for developing customized artificial hybrid membranes

Recent Advances in Hybrid Biomimetic Polymer-Based Films: from Assembly to Applications

Biological membranes, in addition to being a cell boundary, can host a variety of proteins that are involved in different biological functions, including selective nutrient transport, signal transduction, inter- and intra-cellular communication, and cell-cell recognition. Due to their extreme complexity, there has been an increasing interest in developing model membrane systems of controlled properties based on combinations of polymers and different biomacromolecules, i.e., polymer-based hybrid films. In this review, we have highlighted recent advances in the development and applications of hybrid biomimetic planar systems based on different polymeric species. We have focused in particular on hybrid films based on (i) polyelectrolytes, (ii) polymer brushes, as well as (iii) tethers and cushions formed from synthetic polymers, and (iv) block copolymers and their combinations with biomacromolecules, such as lipids, proteins, enzymes, biopolymers, and chosen nanoparticles. In this respect, multiple approaches to the synthesis, characterization, and processing of such hybrid films have been presented. The review has further exemplified their bioengineering, biomedical, and environmental applications, in dependence on the composition and properties of the respective hybrids. We believed that this comprehensive review would be of interest to both the specialists in the field of biomimicry as well as persons entering the field

Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or raltitrexed.

Despite the introduction of several novel anticancer agents almost 50% of colorectal cancer (CRC) patients die for cancer suggesting the necessity of new therapeutical approaches. In this study we demonstrated that the HDAC inhibitor vorinostat exerted potent antiproliferative effect in a panel of mut- and wt-p53 human CRC cell lines. Moreover, in combination with 5-fluorouracil modulated by folinic acid (5FU-FA) or with Raltitrexed (RTX), both commonly used in the treatment of this disease, it showed a clear schedule-dependent synergistic antiproliferative interaction as demonstrated by calculating combination indexes. Only simultaneous, or 24 h pretreatment with vorinostat followed by either agent, produced synergistic effect paralleled by evident cell cycle perturbations with major S-phase arrest. Moreover, we provided for the first time evidences that vorinostat can overcome resistance to both 5FU and RTX. Downmodulation of Thymidilate synthase (TS) protein induced by vorinostat within 24 h, represented a key factor in enhancing the effects of both drugs in sensitive as well as resistant tumor cells. Furthermore, p53, whose wild-type expression is critical for sensitivity to 5FU and RTX, was upregulated by vorinostat in wt- and downregulated in mut-p53 cells, suggesting an additional mechanism of the antiproliferative synergistic interactions observed. Overall these data add new insights in the mechanism of vorinostat antitumor effect and suggested that the association of vorinostat plus 5FU-FA and/or RTX should be clinically explored

Brushing the surface: cascade reactions between immobilized nanoreactors

Functionalization of hard or soft surfaces with, for example, ligands, enzymes or proteins, is an effective and practical methodology for the development of new applications. We report the assembly of two types of nanoreactors based upon poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PDMS-b-PMOXA) diblock copolymers as scaffold, uricase and lactoperoxidase as bio-catalysts located within the nanoreactors, and melittin as the biopores inserted into the hydrophobic shell. The nanoreactors were immobilized on poly(2-hydroxyethyl methacrylate)-co-poly(2-aminoethyl methacrylate hydrochloride) (PHEMA-co-P(2-AEMA·HCl) brushes-grafted wafer surfaces by utilizing the strong supramolecular interactions between biotin and streptavidin. The (PHEMA-co-P(2-AEMA·HCl) brushes on silicon surfaces were prepared by a surface initiating atom transfer radical polymerization (ATRP) "graft-from" technique. Cascade reactions between different surface-anchored nanoreactors were demonstrated by converting Amplex Red to the fluorescent probe resorufin by using the H2O2 produced from uric acid and H2O. The detailed properties of the nanoreactors on the functionalized surface including the binding behaviours and cascade reactions were investigated using emission spectroscopy, transmission electron microscopy (TEM), light scattering (LS), atomic force microscopy (AFM) and a quartz crystal microbalance (QCM-D). The results are proof-of-principle for the preparation of catalytically functional engineered surface materials and lay the foundation for applying this advanced functional surface material in biosensing, implanting and antimicrobial materials preparation

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex

In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested. In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system. HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS. HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system. Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans

Cr(III) Complexes Bearing a β-Ketoimine Ligand for Olefin Polymerization: Are There Differences between Coordinative and Covalent Bonding?

β-ketoimines are extensively applied for the synthesis of organometallic complexes intended as (pre)catalysts for a variety of chemical transformations. We were interested in the synthesis of two Cr complexes bearing a simple bidentate β-ketoimine (L), with different ligand binding modes, as well as their application as a precatalyst in the polymerization of olefins. Complex 1 (L2CrCl3) was obtained by direct reaction of L with CrCl3(THF)3, while, for the synthesis of complex 2 (LCrCl2), the ligand was first deprotonated with nBuLi, giving the β-ketoiminato ligand L─Li+, and then reacted with CrCl3(THF)3. Characterization of the complexes proved that the Cr(III) ion is coordinatively bonded to L in 1, while it is covalently bonded to L in 2. The complexes were then used as precatalysts for the polymerization of ethylene and various cyclic olefins. Upon activation with methylaluminoxane, both the complexes exhibited poor activity in the polymerization of ethylene, whilst they exhibit good productivity in the polymerization of cyclic olefins, affording semicrystalline oligomers, without a significant difference between 1 and 2. To gain more insight, we investigated the reaction of the complexes with the Al-cocatalyst by IR and UV-Vis spectroscopies. The results proved that, in case of 1, the Al-activator deprotonates the ligand, bringing to the formation of an active species analogous to that of 2