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Objective: The hallmark of advanced axial SpA (axSpA) is spine ankylosis due to excessive ectopic bone formation. This prospective study aimed to describe the changes in serum levels of different regulators [sclerostin, dickkopf-1 (DKK-1)] and markers of bone formation [bone morphogenetic protein 7 (BMP-7)] over 5 years in early axSpA patients and to assess determinants of such changes., Methods: The DEvenir des Spondyloarthropathies Indifférenciées Récentes cohort is a prospective, multicentre French study of 708 patients with early (>3 months-<3 years) inflammatory back pain suggestive of axSpA. Serum levels of BMP-7, sclerostin and DKK-1 were assessed at baseline and after 2 and 5 years. Changes in bone formation regulators over time were analysed using mixed linear models., Results: Serum BMP-7 significantly increased over time, with a median relative change of 223.7% [interquartile range (IQR) 0-10 700 (0.17 pg/ml/month), P < 0.001]. Serum sclerostin significantly increased over time, with a median relative change of 14.8% [IQR -7.9-41.4% (0.001 ng/ml/month), P < 0.001]. Serum DKK-1 did not significantly change over time. Serum BMP-7 increased over time in active disease (Ankylosing Spondylitis Disease Activity Score with CRP ≥1.3, P = 0.01), but the increase was less pronounced with TNF inhibitor (TNFi) use (P < 0.001). No determinant was associated with serum sclerostin change., Conclusion: Serum BMP-7 change over 5 years was related with inflammation; it was increased in active disease, but the increase was low with TNFi use. Serum sclerostin levels significantly increased over time, but to a lesser degree than for serum BMP-7., Clinical Trial Registration: https://clinicaltrials.gov/, NCT01648907., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The frequency and consequences of anti-drug antibodies to rituximab (RTX-ADA) are not well known in RA and even less in other systemic auto-immune diseases (sAID). We aimed to evaluate the frequency, consequences and predictive factors of RTX-ADA in RA and sAID., Methods: All patients presenting with RA or other sAID treated with RTX from 2012 to 2017 in our tertiary reference centre for sAID were retrospectively studied. Patients who were tested for RTX-ADA were identified., Results: One hundred and ninety-nine patients were treated with RTX (RA: 124, other sAID: 75). Among 62/199 (31.1%) tested for RTX-ADA, 14 were positive: 3/35 RA (8.6%) and 11/27 (40.7%) other sAID, (P = 0.0047). Among the whole RTX-treated populations, the frequency of RTX-ADA was 2.4% and 14.7% (P = 0.0026) in RA and sAID, respectively. Most of the immunized patients had infusion reactions to second or subsequent RTX cycles (11/14) and loss of efficacy (2/14). Predictive factors of immunization were sAID vs RA (78.6% vs 21.4%, P = 0.026, adjusted odds ratio (OR) = 5.35[1.43-54.75]) and African ethnicity (57.1% vs 4.2%, P < 0.001, adjusted OR = 9.25 [5.08-302.12]). Associated immunosuppressive therapy did not protect against immunization. Three patients with pSS immunized against RTX were treated with ofatumumab with complete remission of their disease., Conclusion: Immunization against RTX is more frequent in other sAID than in RA. Testing for RTX-ADA must be performed in patients with infusion reactions or loss of efficacy especially if they are of African origin. Immunized patients might be treated efficiently and safely with ofatumumab. This alternative should be further evaluated for sAID., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: We compared histological and clinical profiles of primary Sjögren syndrome (pSS) small fiber neuropathy (SFN; pSS-SFN) with idiopathic SFN (i-SFN) and hereditary transthyretin amyloidosis SFN (hATTR-SFN) and described the evolution of pSS-SFN., Methods: All patients with pSS-SFN, i-SFN, and hATTR-SFN confirmed by reduced intraepidermal nerve fiber density on skin biopsy were retrospectively included, and their characteristics were compared. To analyze prognosis of pSS-SFN, patients prospectively underwent a second evaluation., Results: Fifteen pSS-SFN, 17 hATTR-SFN, and 11 i-SFN were included. Time to diagnosis SFN was longer in pSS-SFN and i-SFN than in hATTR-SFN. Painful and non-length-dependent patterns were more frequent in pSS-SFN than in hATTR-SFN. Twelve (80%) patients with pSS-SFN had a non-length-dependent pattern. Ten patients with pSS were reassessed after 3.1 years (1.7-4.7); none developed large fiber neuropathy linked to pSS., Discussion: Primary Sjögren syndrome SFN is characterized by a more frequent non-length-dependent pattern compared with i-SFN and hATTR-SFN. Primary Sjögren syndrome SFN did not evolve through large fiber neuropathy., (© 2020 Wiley Periodicals, Inc.)

Objectives: The French E3N-EPIC ( Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale - European Prospective Investigation into Cancer and Nutrition) cohort enrolled 98 995 women aged 40 to 65 years at inclusion since 1990 to study the main risk factors for cancer and severe chronic conditions in women. They were prospectively followed with biennially self-administered questionnaires collecting self-reported medical, environmental and lifestyle data. Our objective was to assess the accuracy of self-reported diagnoses of rheumatoid arthritis (RA) and to devise algorithms to improve the ascertainment of RA cases in our cohort., Design: A validation study., Participants: Women who self-reported an inflammatory rheumatic disease (IRD) were asked to provide access to their medical record, and to answer an IRD questionnaire. Medical records were independently reviewed., Primary and Secondary Outcome Measures: Positive predictive values (PPV) of self-reported RA alone, then coupled with the IRD questionnaire, and with a medication reimbursement database were assessed. These algorithms were then applied to the whole cohort to ascertain RA cases., Results: Of the 98 995 participants, 2692 self-reported RA. Medical records were available for a sample of 399 participants, including 305 who self-reported RA. Self-reported RA was accurate only for 42% participants. Combining self-reported diagnoses to answers to a specific IRD questionnaire or to the medication reimbursement database improved the PPV (75.6% and 90.1%, respectively). Using the devised algorithms, we could identify 964 RA cases in our cohort., Conclusion: Accuracy of self-reported RA is poor but adding answers to a specific questionnaire or data from a medication reimbursement database performed satisfactorily to identify RA cases in our cohort. It will subsequently allow investigating many potential risk factors of RA in women., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This review summarizes recent advances in micro- and nanopore technologies with a focus on the functionalization of pores using a promising method named contactless electro-functionalization (CLEF). CLEF enables the localized grafting of electroactive entities onto the inner wall of a micro- or nano-sized pore in a solid-state silicon/silicon oxide membrane. A voltage or electrical current applied across the pore induces the surface functionalization by electroactive entities exclusively on the inside pore wall, which is a significant improvement over existing methods. CLEF's mechanism is based on the polarization of a sandwich-like silicon/silicon oxide membrane, creating electronic pathways between the core silicon and the electrolyte. Correlation between numerical simulations and experiments have validated this hypothesis. CLEF-induced micro- and nanopores functionalized with antibodies or oligonucleotides were successfully used for the detection and identification of cells and are promising sensitive biosensors. This technology could soon be successfully applied to planar configurations of pores, such as restrictions in microfluidic channels., Competing Interests: The authors declare no conflict of interest.

This review intends to present a comprehensive analysis of the mechanical considerations for chronically-implanted neural probes. Failure of neural electrical recordings or stimulation over time has shown to arise from foreign body reaction and device material stability. It seems that devices that match most closely with the mechanical properties of the brain would be more likely to reduce the mechanical stress at the probe/tissue interface, thus improving body acceptance. The use of low Young's modulus polymers instead of hard substrates is one way to enhance this mechanical mimetism, though compliance can be achieved through a variety of means. The reduction of probe width and thickness in comparison to a designated length, the use of soft hydrogel coatings and the release in device tethering to the skull, can also improve device compliance. Paradoxically, the more compliant the device, the more likely it will fail during the insertion process in the brain. Strategies have multiplied this past decade to offer partial or temporary stiffness to the device to overcome this buckling effect. A detailed description of the probe insertion mechanisms is provided to analyze potential sources of implantation failure and the need for a mechanically-enhancing structure. This leads us to present an overview of the strategies that have been put in place over the last ten years to overcome buckling issues. Particularly, great emphasis is put on bioresorbable polymers and their assessment for neural applications. Finally, a discussion is provided on some of the key features for the design of mechanically-reliable, polymer-based next generation of chronic neuroprosthetic devices.

Optical nanotip arrays fabricated on etched fiber bundles were functionalized with DNA spots. Such unconventional substrates (3D and non-planar) are difficult to pattern with standard microfabrication techniques but, using an electrochemical cantilever, up to 400 spots were electrodeposited on the nanostructured optical surface in 5 min. This approach allows each spot to be addressed individually and multiplexed fluorescence detection is demonstrated. Finally, remote fluorescence detection was performed by imaging through the optical fiber bundle itself after hybridisation with the complementary sequence.

The use of biological-probe-modified solid-state pores in biosensing is currently hindered by difficulties in pore-wall functionalization. The surface to be functionalized is small and difficult to target and is usually chemically similar to the bulk membrane. Herein, we demonstrate the contactless electrofunctionalization (CLEF) approach and its mechanism. This technique enables the one-step local functionalization of the single pore wall fabricated in a silica-covered silicon membrane. CLEF is induced by polarization of the pore membrane in an electric field and requires a sandwich-like composition and a conducting or semiconducting core for the pore membrane. The defects in the silica layer of the micropore wall enable the creation of an electric pathway through the silica layer, which allows electrochemical reactions to take place locally on the pore wall. The pore diameter is not a limiting factor for local wall modification using CLEF. Nanopores with a diameter of 200 nm fabricated in a silicon membrane and covered with native silica layer have been successfully functionalized with this method, and localized pore-wall modification was obtained. Furthermore, through proof-of-concept experiments using ODN-modified nanopores, we show that functionalized nanopores are suitable for translocation-based biosensing.

We report on the recently emerging (laser) light-sheet-based fluorescence microscopy field (LSFM). The techniques used in this field allow to study and visualize biomedical objects nondestructively in high resolution through virtual optical sectioning with sheets of laser light. Fluorescence originating in the cross-section of the sheet and sample is recorded orthogonally with a camera. In this paper, the first implementation of LSFM to image biomedical tissue in three dimensions-orthogonal-plane fluorescence optical sectioning microscopy (OPFOS)-is discussed. Since then many similar and derived methods have surfaced, (SPIM, ultramicroscopy, HR-OPFOS, mSPIM, DSLM, TSLIM, etc.) which we all briefly discuss. All these optical sectioning methods create images showing histological detail. We illustrate the applicability of LSFM on several specimen types with application in biomedical and life sciences.

The 22q11.2 deletion syndrome is a common dominant genetic disorder characterized by a heterozygous deletion of a cluster of genes on chromosome 22q11.2. TBX1, a transcription factor belonging to the T-box gene family, is a key player in the syndrome. However, heterozygosity of Tbx1 in mouse models does not fully recapitulate the phenotypes characteristic of the disease, which may point to the involvement of other genes in the deleted chromosomal region. Hence, we investigated the contribution of the catenin ARVCF, another gene that is deleted in 22q11.2DS. During Xenopus development, ARVCF mRNA is expressed in the pharyngeal arches and depleting either ARVCF or Tbx1 results in delayed migration of the cranial neural crest cells and in defects in the craniofacial skeleton and aortic arches. Moreover, double depletion of ARVCF and Tbx1 revealed that they act cooperatively, indicating that decreased ARVCF levels may also contribute to 22q11.2DS-associated phenotypes., (Copyright © 2011 Wiley Periodicals, Inc.)

A high-density array of opto-electrochemical nanosensors is presented for remote DNA detection. It was fabricated by chemical etching of a coherent optical fibre bundle to produce a nanotip array. The surface of the etched bundle was sputter-coated with a thin ITO layer which was eventually insulated by an electrophoretic paint. The fabrication steps produced a high-density array of electrochemical nanosensors which retains the optical fibre bundle architecture and its imaging properties. A DNA probe was then immobilized on the nanosensor array surface in a polypyrrole film by electropolymerisation. After hybridisation with the complementary sequence, detection of the strepavidin-R-phycoerythrin label is performed by fluorescence imaging through the optical fibre bundle itself. Control experiments and regeneration steps have also been successfully demonstrated on this nanostructured opto-electrochemical platform.

Surface modification at the nanometer scale is a challenge for the future of molecular electronics. In particular, the precise anchoring and electrical addressing of biological scaffolds such as complex DNA nanonetworks is of importance for generating bio-directed assemblies of nano-objects for nanocircuit purposes. Herein, we consider the individual modification of nanoelectrodes with different oligonucleotide sequences by an electrochemically driven co-polymerization process of pyrrole and modified oligonucleotide sequences bearing pyrrole monomers. We demonstrate that this one-step technique presents the advantages of simplicity, localization of surface modification, mechanical, biological and chemical stability of the coatings, and high lateral resolution.

Customized pores are smart components that find challenging applications in a variety of fields including purification membranes and biosensing systems. The incorporation of recognition probes within pores is therefore a challenge, due to the technical difficulty of delimiting the area functionalized and obtaining the localized, specific chemical modification of pore walls. An innovative approach, named contactless electrofunctionalization (CLEF), is presented to overcome this problem. CLEF allows easy, one-step modification of the inner surface of a pore etched in a dielectric membrane. The pore wall is coated under the influence of an electric field created by the application of a voltage between two electrodes, located near but not in contact with the pore openings. This specific localization of the deposited material within the pore is extremely rapid. Coatings were reliably and reproducibly obtained using polypyrrole co-polymers bearing oligonucleotides, demonstrating that this technology has a promising future in the design of biosensors. Moreover, the versatility of this process allows the deposition of various electroactive entities such as iridium oxide and therefore indicates a strong potential for diverse applications involving porous materials.

Induction of protein disulfide isomerase (PDI) is validated as a main mechanism by which 4-hydroxybenzyl alcohol (4-HBA), an active principle of Gastrodia elata Blume, reduces cerebral infarct volumes in a murine model of focal brain ischemia/reperfusion. In contrast to its position isomers, i.e. 3-hydroxybenzyl alcohol (3-HBA) and 2-hydroxybenzyl alcohol (2-HBA), and to aliphatic diols (1,4-butanediol and 1,5-pentanediol), 4-HBA administered intravenously at 25 mg/kg protected mice, significantly reducing total, cortical and sub-cortical infarct volumes by 42, 28 and 55%, respectively. All compounds, 4-HBA included, were devoid of antioedematous properties. Only the stroke protective 4-HBA, but neither 3-HBA nor 2-HBA, was capable of significantly inducing PDI in intact mouse brains. Stroke protection was fully prevented by bacitracin (500 mg/kg), a known inhibitor of PDI, which, without affecting basal brain PDI levels, altered the ability of 4-HBA to induce significantly PDI in intact brains. Taken as a whole, our data indicate that stroke protection induced by 4-HBA involves PDI as a key player, making this protein a valuable target to control brain injury disorders. The fact that 4-HBA, at doses up to 200mg/kg, was devoid of neurotoxicity in the rotarod test is also a decisive element to promote the neuroprotective use of this plant compound.

A giant pseudo-polyposis lesion was diagnosed clinically and radiologically as cancer of right side of colon. The etiopathology of this lesion can probably be explained by the hemorrhagic rectocolitis that developed three years after its excision.