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Many species of aphids on spruce excrete large quantities of honeydew. As providers of carbohydrates, it is likely that they affect several ecosystem functions by fueling biological processes which are energy-limited. In a rainfall simulation experiment, we manipulated the level of aphid infestation on spruce and studied the effects of honeydew on forest-floor solution chemistry collected underneath infested and uninfested trees. A non-destructive sampling method was used to allow repeated measurements using the same forest floor during the experimental period. Although the input of dissolved organic carbon (DOC)underneath infested trees to the forest floor was considerably higher compared to uninfested trees, carbon concentrations of forest-floorleachates did not differ between treatments. Concentrations of dissolved organic nitrogen (DON), NO3-N and Ntotal of forest-floor leachates, underneath infested and uninfested trees followed a marked seasonal trend with low concentrations recorded in June and after-frost treatment of the forest floor, while the highest concentrations were recorded in July/August. Statistically significantdifferences in soil solution properties underneath infested and uninfested trees were recorded in July when honeydew-affected forest-floor leachates had lower concentrations of NH4-N, Ntotal, a lower conductivity and a higher pH. Despite a large input of honeydew, no pronounced seasonal trend was found in the carbon leachate concentrations of the forest floor (e.g. DOC, hexose-C). Discriminant function analysis showed that forest-floor leachates can be classified according to the experience of frost and nitrogen concentrations, which were affected by the honeydew of aphids. At the end of theexperiment, the number of micro-organisms present in the forest floor was not significantly different between treatments but was higher in the Oh compared to the Ol+f horizon. Microbial co [ABSTRACT FROM AUTHOR]

Anti-idiotypic antibodies (anti-Id) have been described against idiotypes expressed on various autoantibodies. Since an immunoregulatory effect has been postulated for anti-Id, modulation of the anti-Id response in autoimmune disease may be of interest. In chronic immune thrombocytopenic purpura (AITP), autoantibodies directed mainly against platelet membrane glycoprotein (GP) IIb/IIIa cause platelet destruction by Fc-mediated phagocytosis or by complement lysis. We have previously reported on the generation of two recombinant anti-GPIIb/IIIa autoantibody fragments (PDG-X, PDG-B), that are specific for conformationally intact GPIIb/IIIa and inhibit binding of autoantibodies from patients with AITP. In the present study, we show that anti-GPIIb/IIIa specificities are not limited to a single individual by isolating five additional anti-GPIIb/IIIa autoantibody fragments from a second phagemid Fab library of an unrelated healthy donor. Using soluble Fab of PDG-X and PDG-B as antigens for panning Fab phagemid libraries from healthy human individuals, we isolated anti-Id phage clones specific for PDG-X or PDG-B. In addition they inhibited the binding of PDG-X or PDG-B to GPIIb/IIIa. Amino acid sequence comparison between these specific antiId and GPIIb/IIIa was performed. Generation of these anti-Id directed against pathologically relevant anti-GPIIb/IIIa autoantibodies may represent a new suitable and specific therapeutic option for the treatment of antibody-mediated AITP. [Copyright &y& Elsevier]

Ligand exchange processes at metal complexes underpin their reactivity and catalytic applications. While mechanisms of ligand exchange at single site complexes are well established, occurring through textbook associative, dissociative and interchange mechanisms, those involving heterometallic complexes are less well developed. Here we report the reactions of a well-defined Fe-Al dihydride complex with exogenous ligands (CO and CNR, R=Me, t Bu, Xyl=2,6-Me 2 C 6 H 3 ). Based on DFT calculations we suggest that these reactions occur through a dyotropic rearrangement, this involves initial coordination of the exogenous ligand at Al followed by migration to Fe, with simultaneous migration of a hydride ligand from Fe to Al. Such processes are rare for heterometallic complexes. We study the bonding and mechanism of the dyotropic rearrangement through in-depth computational analysis (NBO, IBOs, CLMO analysis, QTAIM, NCIplot, IGMH), shedding new light on how the electronic structure of the heterometallic core responds to the migration of ligands between metal sites. The dyotropic rearrangement fundamentally changes the nature of the hydride ligands, exposing new nucleophilic reactivity as evidenced by insertion reactions with CO 2 , isocyanates, as well as isocyanides., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Nail involvement is frequent in patients with psoriasis (Pso) and psoriatic arthritis (PsA) and there is a relationship between nail involvement and inflammation of the enthesis. The main objective of the present study is to describe the ultrasound findings and clinical characteristics of nails from patients with psoriasis and psoriatic arthritis with and without nail dystrophy., Methods: A cross-sectional study including consecutive patients with PsO and PsA was carried out. The study patients were divided into 4 groups, totaling 120 participants. Group 1: patients with psoriasis vulgaris and clinically normal nails; Group 2: patients with psoriasis vulgaris and onychodystrophy; Group 3: patients with psoriatic arthritis and clinically normal nails; Group 4: patients with psoriatic arthritis and onychodystrophy; All patients were submitted to dermatological and rheumatological clinical analysis. Ultrasound examinations was performed by a single examiner, blinded to all clinical data, with ultrasound high resolution, in B-mode or gray-scale (GS), Power Doppler (PD) and Spectral Doppler., Results: A significant difference was found between the groups regarding the variable Psoriasis Area and Severity Index (PASI) (p = 0.008) and body surface area (BSA) (p = 0.005), with patients with psoriatic arthritis having lower PASI and BSA compared to patients with only cutaneous psoriasis. A positive relationship was found with the average ultrasound thickness of the nail bed and the Nail Psoriasis Severity Index (NAPSI) in correlation analysis (rho = 0.344). When we grouped patients with psoriasis and psoriatic arthritis, there was no significant difference between the cutaneous psoriasis groups and the psoriatic arthritis groups in terms of nail plate GS (p = 0.442), nail bed PD (p = 0.124)., Conclusion: Greater nail bed thickness indicates early psoriatic nail disease, as confirmed in our study correlating NAPSI with nail bed thickness. Ultrasonography is a low-cost exam, promising in the evaluation, showing that the ultrasound grayscale is consistent with those who have dystrophic nails, but it can't distinguish psoriasis from psoriatic arthritis, even in those with nail dystrophy., (© 2024. The Author(s).)

The oxidative addition of sp 2 C-H bonds of alkenes to single-site transition-metal complexes is complicated by the competing π-coordination of the C═C double bond, limiting the examples of this type of reactivity and onward applications. Here, we report the C-H activation of styrenes by a well-defined bimetallic Fe-Al complex. These reactions are highly selective, resulting in the ( E )-β-metalation of the alkene. For this bimetallic system, alkene binding appears to be essential for the reaction to occur. Experimental and computational insights suggest an unusual reaction pathway in which a (2 + 2) cycloaddition intermediate is directly converted into the hydrido vinyl product via an intramolecular sp 2 C-H bond activation across the two metals. The key C-H cleavage step proceeds through a highly asynchronous transition state near the boundary between a concerted and a stepwise mechanism influenced by the resonance stabilization ability of the aryl substituent. The metalated alkenes can be further functionalized, which has been demonstrated by the ( E )-selective phosphination of the employed styrenes.

In the design process of large adaptive mirrors numerical simulations represent the first step to evaluate the system design compliance in terms of performance, stability and robustness. For the next generation of Extremely Large Telescopes increased system dimensions and bandwidths lead to the need of modeling not only the deformable mirror alone, but also all the system supporting structure or even the full telescope. The capability to perform the simulations with an acceptable amount of time and computational resources is highly dependent on finding appropriate methods to reduce the size of the resulting dynamic models. In this paper we present a framework developed together with the company Microgate to create a reduced order structural model of a large adaptive mirror as a preprocessing step to the control system simulations. The reduced dynamic model is then combined with the remaining system components allowing to simulate the full adaptive mirror in a computationally efficient way. We analyze the feasibility of our reduced models for Microgate's prototype of the adaptive mirror of the Giant Magellan Telescope., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Objectives: We describe the development of Your Multiple Sclerosis Questionnaire and present the real-world usability testing results of Your Multiple Sclerosis Questionnaire., Methods: The Your Multiple Sclerosis Questionnaire tool was developed in four stages to collect feedback from people living with MS (plwMS), patient organizations, and clinicians on content, format, and applicability. To assess its usability, 13 clinicians across 7 countries completed an online survey after using the tool with plwMS in a total of 261 consultations from September, 2020 to July, 2021., Results: The initial Your Multiple Sclerosis Questionnaire version was based on findings from previous research developing MSProDiscuss™, a clinician-completed tool. Subsequently, insights from plwMS obtained during cognitive debriefing, patient councils and advisory boards led to changes including the addition of mood and sexual problems and the definition of relapse. All 13 clinicians completed the individual survey, whereas 10 clinicians completed the final survey. Clinicians "strongly agreed" or "agreed" that Your Multiple Sclerosis Questionnaire was easy to use and understand (98.5%; 257/261 patient consultations). The clinicians were willing to use the tool again with the same patient (98.1%; 256/261 patient consultations). All clinicians who completed the final survey (100%; 10/10) reported the tool to have a positive influence on their clinical practice, helped patients engage with their MS, facilitated discussion with patients, and complemented neurological assessment., Conclusion: Your Multiple Sclerosis Questionnaire benefits both plwMS and clinicians by facilitating a structured discussion and engaging the plwMS to self-monitor and self-manage. Your Multiple Sclerosis Questionnaire is compatible with telemedicine practice and integration of the tool into electronic health records would enable tracking of the disease evolution and individual monitoring of MS symptoms over time., Competing Interests: The author(s)declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article:M.K. and B.S. are employees of Novartis. J.V. was an employee of Novartis Pharma AG during the development of the tool and the usability testing until the final version of the manuscript development. G.G. received consulting fees from AbbVie, Actelion, Atara Bio, Biogen, Celgene, Sanofi-Genzyme, Genentech, GlaxoSmithKline, Merck-Serono, Novartis, Roche and Teva, for research from Biogen, Roche, Merck, Merck-Serono, Novartis, Sanofi-Genzyme, and Takeda. E.A. received compensation for consulting from Actelion/Janssen, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Genzyme, Novartis, Sanofi, and TG Therapeutics, and for research from Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center. O.H. received consulting fees from Biogen, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; funding for research from Biogen, Novartis, and Sanofi; and as a speaker from Merck, Novartis, Roche, and Sanofi. C.O.G. received consulting fees from Novartis, Alexion, and Roche; compensation for research from Alexion; and as a speaker from Novartis and Roche. P.V. has received compensation for consulting and/or research and registration, travel, and accommodation for meetings from Biogen, Roche, Novartis, Sanofi, Teva, Merck, AB Science, Imcyse and Celgene. T.Z. has received compensation for consulting and lecturing from Alexion, Biogen, Celgene, Novartis, Roche, Sanofi, and Teva and for research from Biogen, Novartis, Roche, Teva, and Sanofi. Y.X. has nothing to disclose. R.R.C. has received compensation for consulting services and speaking fees from Biogen, Roche, Novartis, Bayer, Merck, Sanofi, Genzyme, Teva Pharmaceutical Industries Ltd, and Almirall. M.T. has received compensation for consulting from Novartis, Biogen, Merck, Roche, and Sanofi, and her institution received support for research from Biogen, Merck, Novartis, and Roche. R.G. has received compensation for serving as a consultant or speaker from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. He, or the institution he works for, has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. He has also received honoraria as a Journal Editor from SAGE and Thieme Verlag. E.T. has received compensation for consulting from Novartis, Biogen, and Sanofi/Genzyme Europe B.V., (© The Author(s) 2023.)

Herein we present the first double deprotonation of acetonitrile (CH 3 CN) using two equivalents of a bimetallic iron-aluminium complex. The products of this reaction contain an exceeding simple yet rare [CHCN] 2- dianion moiety that bridges two metal fragments. DFT calculations suggest that the bonding to the metal centres occurs through heavily polarised covalent interactions. Mechanistic studies reveal the intermediacy of a monomeric [CH 2 CN] - complex, which has been characterised in situ. Our findings provide an important example in which a bimetallic metal complex achieves a new type of reactivity not previously encountered with monometallic counterparts. [1, 2] The isolation of a [CHCN] 2- dianion through simple deprotonation of CH 3 CN also offers the possibility of establishing a broader chemistry of this motif., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.)

Ti(IV) and Ti(III) complexes using the tBu PCP ligand have been synthesized ( tBu PCP = C 6 H 3 -2,6-(CH 2 P t Bu 2 ) 2 ). The [ tBu PCP]Li synthon can be reacted with TiCl 4 (THF) 2 to form ( tBu PCP)TiCl 3 ( 1 ) in limited yields due to significant reduction of the titanium synthon. The Ti(III) complex ( tBu PCP)TiCl 2 ( 2 ) has been further characterized. This can have half an equivalent of halide abstracted to form [{( tBu PCP)TiCl} 2 {μ-Cl}][B(C 6 F 5 ) 4 ] ( 3 ) and can also be methylated, forming ( tBu PCP)TiMe 2 ( 4 ). All the Ti(III) complexes have been characterized using EPR and X-ray crystallography, giving insight into their electronic structures, which are further supported by DFT calculations., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Objective: In binaurally deaf subjects, speech processing particularly benefits from a cochlear implant (CI) in the right ear, which is contralateral to the commonly left speech-dominant hemisphere. However, it is unclear whether such effects of implantation side also occur in speech processing in patients with single-sided deafness (SSD)., Methods: Lateralization of N1 responses was analyzed with a high-density electroencephalogram (EEG) in fourteen adults with postlingually acquired left or right SSD who received a CI in adulthood. During recording, patients performed a speech and a pure-tone discrimination task. Lateralization of N1 responses was assessed by side-specific global field power (GFP) and compared (a) between normal hearing and CI-implanted ears within subjects and (b) between implantation sides across subjects., Results: N1 responses were stronger in the contralateral than in the ipsilateral hemisphere during stimulation of the normal hearing ear (except for left speech stimulation), and was bilateral symmetric with CI stimulation on either side. A significant correlation between speech discrimination performance and left lateralization was found across subjects for the left CI ear., Conclusions: CI stimulation altered auditory processing across hemispheres. Speech discrimination in left CI-implanted SSD patients improved with left lateralization of the N1 response., Significance: Side-specific rehabilitation in SSD patients might improve speech processing across hemispheres., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. B.S. received travel expenses from Cochlear Deutschland GmbH & Co. KG outside of the submitted work., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression., Objective: The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting., Methods: In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs' overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made., Results: In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice., Conclusions: MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice., (©Tjalf Ziemssen, Gavin Giovannoni, Enrique Alvarez, Virender Bhan, Carrie Hersh, Olaf Hoffmann, Celia Oreja-Guevara, Rene R Robles-Cedeño, Maria Trojano, Patrick Vermersch, Pamela Dobay, Mudeer Khwaja, Bianca Stadler, Benedict Rauser, Thomas Hach, Daniela Piani-Meier, Jason Burton. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.10.2021.)

The unmet demand for selective and remote detection of biological entities has urged nanobiotechnology to prioritize the innovation of biolabels that can be remotely detected. Magnetic nanowires (MNWs) have been deemed promising for remote detection as the magnetic fields can deeply and safely penetrate into tissue. However, the overlapping nature of the magnetic signatures has been a long-standing challenge for selective detection, which we resolve here. To do so, 13 types of MNWs with unique irreversible switching field (ISF) signatures were synthesized for labeling canine osteosarcoma (OSCA-8) cancer cells (one set) and polycarbonate biopolymers (12 sets). After characterizing the ISF signature of each MNW type, the MNW-labeled cancer cells were transferred onto MNW-labeled biopolymers to determine the most distinguishable ISF signatures and to discern the principles for reliable selective detection of biological entities. We show that tailoring the ISF of MNWs by tuning their coercivity is a highly effective approach for generating distinct magnetic biolabels for selective detection of cells. These findings smooth the path for the progression of nanobiotechnology by enabling the remote and selective detection of biological entities using MNWs.

During the emission phase of ejaculation, the sperm is driven from the cauda epididymidis, where it is stored, through the vas deferens by strong contractions. These contractions are thought of as being mainly induced by the sympathetic nervous system and the neurotransmitter noradrenaline. In the present study, we investigated the effect of oxytocin (suggested to exert effects during ejaculation as well) on defined segments of the rat and human epididymis using live imaging. Our results indicate that it is the very last part of the epididymis, segment 19 (S19) in rat and likewise segment 9 in human, which responds in a uniquely strong and rapid manner to oxytocin (similar to noradrenaline). Because of the complex nature of this contractile response, we developed an imaging analysis method, which allowed us to quantify multidirectional contractions and to display them using heat maps. The reaction of S19 to oxytocin was concentration-dependent and could be inhibited by pretreatment with oxytocin antagonists (atosiban and cligosiban), but not with an arginine vasopressin 1 A antagonist (SR49059). In both rat and human tissue, pretreatment with the alpha-1 adrenoreceptor antagonist tamsulosin inhibited the response to noradrenaline, whereas the effect of oxytocin was unimpaired. Our data (from men and rodents) strongly suggest that the hormone oxytocin is involved in the ejaculatory process. Thus, oxytocin-based medications might be a promising non-adrenergic treatment option for ejaculatory disorders. Additionally, we propose that S19 could be an advantageous model (detecting very low concentrations of oxytocin) to test the bioactivity of new oxytocin agonists and oxytocin antagonists., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

The main bottleneck for implementing magnetic nanowires (MNWs) in cell-biology research for multimodal therapeutics is the inapplicability of the current state of the art for selective detection and stimulation of MNWs. Here, we introduce a methodology for selective detection of MNWs in platforms that have multiple magnetic signals, such as future multimodal therapeutics. After characterizing the signatures of MNWs, MNWs were surface-functionalized and internalized into canine osteosarcoma (OSCA-8) cancer cells for cell labeling, manipulation, and separation. We also prepared and characterized magnetic biopolymers as multimodal platforms for future use in controlling the movement, growth, and division of cancer cells. First, it is important to have methods for distinguishing the magnetic signature of the biopolymer from the magnetically labeled cells. For this purpose, we use the projection method to selectively detect and demultiplex the magnetic signatures of MNWs inside cells from those inside magnetic biopolymers. We show that tailoring the irreversible switching field of MNWs by tuning their coercivity is a highly effective approach for generating distinct magnetic biolabels for selective detection of cancer cells. These findings open up new possibilities for selective stimulation of MNWs in multimodal therapeutic platforms for drug delivery, hyperthermia cancer therapy, and mitigating cancer cell movement and proliferation.

In this review, the role of oxytocin and oxytocin-like agents (acting via the oxytocin receptor and belonging to the oxytocin-family) in the male reproductive tract is considered. Previous research (dating back over 60 years) is revised and connected with recently found aspects of the role oxytocin plays in male reproductive health. The local expression of oxytocin and its receptor in the male reproductive tract of different species is summarized. Colocalization and possible crosstalk to other agents and receptors and their resulting effects are discussed. The role of the newly reported oxytocin focused signaling pathways in the male reproductive tract, other than mediating contractility, is critically examined. The structure and effect of the most promising oxytocin-agonists and -antagonists are reviewed for their potential in treating male disorders with origins in the male reproductive tract such as prostate diseases and ejaculatory disorders., (Copyright © 2020 Stadler, Whittaker, Exintaris and Middendorff.)

Contractions of the adult epididymal duct are well known in the context of sperm transport. Some reports also describe contractions of the epididymal duct during development, but data about their character, regulation and function are sparse. In the foetal human epididymis we found luminal cells and could identify them as exfoliated epithelial cells originating from the epididymis and not from testis by using antibodies against neutral endopeptidase as an epithelial epididymal duct marker. Exfoliated cells were also found in the epididymal duct after birth. Time-lapse imaging revealed directional transport of luminal cells in the neonatal rat epididymis interrupted by pendular movement. Spontaneous contractions were discovered in the neonatal epididymis and an association between these contractions and the transport of the luminal cells could be observed. Both, transport and spontaneous contractions, were affected significantly by substances known to contract (noradrenaline) or relax (the phosphodiesterase 5 inhibitor sildenafil) smooth muscle cells. Immunohistochemistry showed staining for the proliferation marker proliferating-cell-nuclear-antigen (PCNA) in cells of the ductal lumen of the neonatal rat epididymis indicating the extrusion of cells also during proliferation. Our data showed spontaneous contractions of the immature epididymal duct associated with the transport of exfoliated luminal cells before the first occurrence of sperm cells. Results suggest an important role including both (i) a mechanical place holder function of exfoliated luminal cells (ii) together with a novel idea of organized waste disposal of these cells during development.

Background: The safety profile of biologic drugs might present substantial regional differences. Since 2009, the Brazilian Society of Rheumatology has maintained BIOBADABRASIL (Brazilian Registry for Biologic Drugs), a registry for monitoring of biologic therapies in rheumatic diseases., Objectives: The aim of this study was to verify the incidence rate (IR) of serious infections in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients on biologic drugs., Methods: BIOBADABRASIL prospectively included patients with rheumatic diseases who started the first biologic drug or a synthetic disease-modifying antirheumatic drug as a parallel control group. This study focuses on serious infectious adverse events (SIAEs) in RA and SpA patients on biologic drugs compared with controls, from January 2009 to June 2015. Time of exposure was set from initiation of the drug to the date of last administration or censorship. Serious infectious adverse events IR was calculated per 1000 patient/years with 95% confidence interval (CI)., Results: A total of 1698 patients (RA, 1121; SpA, 577) were included, 7119 patient/years. Serious infectious adverse events were more common among patients on tumor necrosis factor inhibitors (TNFi's) than controls (adjusted IR ratio, 2.96 [95% CI, 2.01-4.36]; p < 0.001). Subsequent TNFi was associated with a higher SIAEs incidence when compared with first TNFI (adjusted IR ratio, 1.55 [95% CI, 1.15-2.08]; p = 0.004). Serious infectious adverse events were associated with age and corticosteroids intake. Serious infectious adverse events were more frequent in the respiratory tract in all subgroups., Conclusions: In BIOBADABRASIL, biologic drugs, especially the subsequent TNFi, were associated with a higher risk of serious infections compared with synthetic DMARDs. Corticosteroid intake and age represented risk factors for SIAEs. Constant monitoring is required to follow the safety profile of drugs in the clinical setting of rheumatic conditions in Brazil.

Background: Photodynamic therapy (PDT) is a palliative treatment for malignant biliary obstruction., Objective: The objective of this article is to assess the feasibility and safety of this technique., Methods: In this nationwide, retrospective study of prospectively collected clinical data, all patients treated with PDT using polyhematoporphyrin in Austria from March 2004 to May 2013 were included. Feasibility, adverse events, stent patency and mortality rates were investigated., Results: Eighty-eight patients (54 male, 34 female, median age 69 years) underwent 150 PDT procedures at seven Austrian referral centers for biliary endoscopy. The predominant underlying disease was Klatskin tumor (79/88). All PDT procedures were feasible without technical issues. Cholangitis was the most frequent adverse event (21/88). Stent patency was 246 days (95% CI 203-289) median and was significantly longer for metal than for plastic stents (269 vs. 62 days, p  < 0.01). The median survival was 12.4 months (95% CI 9.7-14.9 m) calculated from first PDT and 15.6 months (95% CI 12.3-18.7 m) calculated from initial diagnosis. In patients suffering from biliary tract cancer, Cox regression revealed the number of PDT treatment sessions as the only independent predictor of survival at a multivariate analysis ( p  = 0.048)., Conclusion: PDT using polyhematoporphyrin was feasible and safe in this nationwide analysis. Survival data suggest a benefit of PDT in this unselected real-life patient population. Prospective trials comparing PDT to other palliative treatments will help to define its role in the management of malignant biliary obstruction. The study is registered at ClinicalTrials.gov number: NCT02504957.

Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60 mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 ± 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 ± 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3 × 6 log10 IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n = 77), DCV+SMV (n = 18), and DCV+SMV+SOF (n = 2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels <43 IU/mL. CTP and MELD scores significantly improved between DCV-based treatment initiation and last contact. Three virological breakthroughs and 2 relapses occurred in patients treated with DCV+SMV with or without RBV. None of the 8 patient deaths (6 during and 2 after therapy) were attributed to therapy. In conclusion, DCV-based all-oral antiviral therapy was well tolerated and resulted in a high sustained virological response in LT recipients with severe recurrent HCV infection. Most treated patients experienced stabilization or improvement in their clinical status., (© 2016 American Association for the Study of Liver Diseases.)

In this special topic of Biomicrofluidics, the importance of microfluidics in the field of drug delivery is highlighted. Different aspects from cell-drug carrier interactions, delivery vehicle assembly to novel drug delivery devices are considered. The contributing reviews and original articles illustrate the synergistic outcomes between these two areas of research with the aim to have a positive impact on biomedical applications.

Introduction: The coincidence of echinococcosis and hepatocellular carcinoma (HCC) is quite rare. We report the case of a 45-year-old man who was admitted to our hospital because of abdominal pain in the right upper quadrant and jaundice. Clinical features and diagnostics: There was no history of weight loss or fever. No abdominal mass was palpable. The laboratory reports showed increased transaminase levels. Ultrasonography revealed an inhomogenous, cystic lesion measuring 6 cm in diameter in the segments VI and VII. Serology for echinococcosis was negative, alpha-fetoprotein (AFP) was considerably increased. CT scan showed a solid mass of 3,7 cm in diameter adjacent to the cystic lesion., Therapy and Course: Anthelminthic therapy with albendazole caused a massive increase of cholestasis parameters and treatment had to be stopped. The simultaneous occurrence of serologically negative cystic echinococcosis and HCC was suspected and partial liver resection was performed. Histological examination confirmed both diagnoses and tumor resection in healthy tissue. 5 months after resection CT scan showed multicentric HCC affecting the whole liver. Palliative therapy with sorafenib was established., Discussion: The coincidence of HCC and cystic echinococcosis in the non-cirrhotic liver of a young man is a rare event. Despite resection in healthy tissue multicentric HCC was diagnosed 5 months later. Only few cases of simultaneous occurrence of HCC and echinococcosis have been published so far. Some authors considered echinococcosis as a trigger for HCC. A causal link between both entities has not been demonstrated until now., (© Georg Thieme Verlag KG Stuttgart · New York.)

Degeneration of intervertebral discs (IVDs) is associated with back pain and elevated levels of inflammatory cells. It has been hypothesised that discogenic pain is a direct result of vascular and neural ingrowth along annulus fissures, which may expose the avascular nucleus pulposus (NP) to the systemic circulation and induce an autoimmune reaction. In this study, we confirmed our previous observation of antibodies in human degenerated and post-traumatic IVDs cultured in vitro. We hypothesised that the presence of antibodies was due to an autoimmune reaction against specific proteins of the disc. Furthermore we identified antigens which possibly trigger an autoimmune response in degenerative disc diseases. We demonstrated that degenerated and post-traumatic IVDs contain IgG antibodies against typical extracellular proteins of the disc, particularly proteins of the NP. We identified IgGs against collagen type II and aggrecan, confirming an autoimmune reaction against the normally immune privileged NP. We also found specific IgGs against collagens types I and V, but not against collagen type III. In conclusion, this study confirmed the association between disc degeneration and autoimmunity, and may open the avenue for future studies on developing prognostic, diagnostic and therapy-monitoring markers for degenerative disc diseases.

Nodular sclerosis is a rare form of presentation related to both systemic and localized forms of scleroderma. We describe the case of a patient with nodular sclerosis in order to alert the medical community to recognize this entity.

Background: It has been observed that patients with systemic lupus erythematosus and discoid lesions have a milder systemic disease., Objective: To compare the clinical, demographic and autoantibody profile of systemic lupus erythematosus patients with and without discoid lesions., Methods: We carried out a retrospective study involving 288 systemic lupus erythematosus patients who met at least four classification criteria of the American College of Rheumatology for systemic lupus erythematosus, comparing the clinical, serological and demographic factors between patients with and without discoid manifestations., Results: Of the 288 patients, 13.8% had discoid lesions. Univariate analysis found no differences in the prevalence of malar rash, photosensitivity, arthritis, serositis, leukopenia, lymphopenia and hemolytic anemia or anemia of the central nervous system (p = ns). Renal lesions were more common in those without discoid lesions (p =0.016), and hemolysis (p<0.0001) was more common in those with discoid lesions. Regarding the profile of autoantibodies, only the anti-RNP antibody was more common in those with discoid events (p =0.04). In a logistic regression study, only the renal lesions and anti-RNP maintained their associations with discoid manifestations., Conclusion: Patients with lesions of systemic lupus erythematosus and discoid lesions have lower prevalence of renal involvement and a greater presence of anti RNP.

Objective: Previously an experimental computer system was developed to automatically produce first drafts of genetic counseling patient letters containing biomedical evidence-based arguments. However, letters written by genetic counselors also employ strategies to help clients cope. The objectives of this research were to discover methods for addition of coping-related strategies to the drafts and to explore their efficacy., Methods: Using an argumentation-based approach, the system design was modified to add coping-related strategies used by actual genetic counselors. An evaluation of computer-produced drafts was performed comparing those containing only biomedical arguments to those with coping strategies added to biomedical arguments., Results: The evaluation mainly found no significant impact of adding coping strategies., Conclusion: The main contribution of this work was to show how coping-related strategies can be produced by an artificial intelligence approach within an argumentation-based theoretical framework. A possible future application would be to improve computer-drafted genetic counseling patient letters., Practice Implications: Computer-assisted drafting of letters has potential to aid in the practice of genetic counseling. Further research is needed to demonstrate the efficacy of adding coping strategies to computer-produced drafts., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Objective: Using an in silico allergen clustering method, we have recently shown that allergen extracts are highly cross-reactive. Here we used serological data from a multi-array IgE test based on recombinant or highly purified natural allergens to evaluate whether co-reactions are true cross-reactions or co-sensitizations by allergens with the same motifs., Methods: The serum database consisted of 3142 samples, each tested against 103 highly purified natural or recombinant allergens. Cross-reactivity was predicted by an iterative motif-finding algorithm through sequence motifs identified in 2708 known allergens., Results: Allergen proteins containing the same motifs cross-reacted as predicted. However, proteins with identical motifs revealed a hierarchy in the degree of cross-reaction: The more frequent an allergen was positive in the allergic population, the less frequently it was cross-reacting and vice versa. Co-sensitization was analyzed by splitting the dataset into patient groups that were most likely sensitized through geographical occurrence of allergens. Interestingly, most co-reactions are cross-reactions but not co-sensitizations., Conclusions: The observed hierarchy of cross-reactivity may play an important role for the future management of allergic diseases., (© 2011 John Wiley & Sons A/S.)

Motion analysis of optically trapped objects is demonstrated using a simple 2D Fourier transform technique. The displacements of trapped objects are determined directly from the phase shift between the Fourier transform of subsequent images. Using end- and side-view imaging, the stiffness of the trap is determined in three dimensions. The Fourier transform method is simple to implement and applicable in cases where the trapped object changes shape or where the lighting conditions change. This is illustrated by tracking a fluorescent particle and a myoblast cell, with subsequent determination of diffusion coefficients and the trapping forces.

Background: Dieulafoy lesions consist of aberrant submucosal arteries, which can cause severe GI bleeding. The predominant location of Dieulafoy lesions is the upper GI tract., Objective: To our best knowledge, this is the first systematic study on the frequency of bleeding from Dieulafoy lesions in the small bowel and the efficacy of enteroscopic therapy regarding primary hemostasis and long-term follow-up., Design: Multicenter, retrospective, observational study., Setting: Nine Austrian centers doing double-balloon enteroscopy or single-balloon enteroscopy., Patients: This study involved 284 consecutive patients who were referred for double-balloon enteroscopy or single-balloon enteroscopy because of suspicion of mid-GI bleeding., Intervention: A total of 317 double-balloon enteroscopy and 78 single-balloon enteroscopy procedures were performed in 284 patients with suspected mid-GI bleeding., Main Outcome Measurements: Demographic, clinical, procedural, and outcome data were collected., Results: A Dieulafoy lesion in the small bowel was identified as the source of mid-GI bleeding in 3.5% of patients, with a mean of 1.5 enteroscopy sessions required per diagnosis. In 9 cases the Dieulafoy lesion was found by enteroscopy from an oral approach, and in 1 patient the lesion was found by an anal approach. In all patients primary endoscopic hemostasis was successful. Eight of 10 patients were free from rebleeding episodes (median follow-up 14.5 months, interquartile range 10.0-17.5 months). In 2 of 10 patients, rebleeding occurred, and a surgical intervention was necessary., Limitations: Retrospective study., Conclusion: Bleeding from Dieulafoy lesions of the small bowel seems to occur more frequently than previously estimated. Most of these lesions are located in the proximal jejunum and can be managed successfully by enteroscopy. After successful endoscopic hemostasis, rebleeding episodes occur in only 20% of patients., (Copyright © 2011 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background: Intravenous immunoglobulin (IVIG) preparations are increasingly used for the treatment of autoimmune and chronic inflammatory diseases. Naturally occurring autoantibodies against Siglec-9 and Fas are thought to contribute to the anti-inflammatory effects of IVIG via cell death regulation of leukocytes and tissue cells. Dimeric IVIG fractions are suspected to contain idiotypic (Id)-anti-idiotypic complexes of antibodies, which might also include anti-Siglec-9 and anti-Fas autoantibodies., Methods: Dimeric IVIG fractions were separated from monomeric IVIG by size-exclusion chromatography and remonomerized by low pH treatment. Binding studies of total, monomeric, and dimeric IVIG were performed using surface plasmon resonance and flow cytometry on primary human neutrophils., Results: Anti-Siglec-9 and anti-Fas autoantibodies were contained in both monomeric and dimeric IVIG fractions, but anti-Siglec-9 antibodies were highly enriched in dimeric IVIG. The propensity to engage in dimer formation was paratope dependent. IVIG binding to Siglec-9 was specific and sialylation independent. Interestingly, we detected anti-idiotypic antibodies (anti-Ids) against anti-Siglec-9 autoantibodies in dimeric, but not in monomeric fractions of IVIG., Conclusions: Our study supports the concept that idiotype-anti-idiotype (Id-anti-Id) interactions contribute to the dimer formation in IVIG preparations. To our knowledge, this is the first description of Id-anti-Id dimers of death receptor-specific antibodies in IVIG. Such Id-anti-Id interactions might determine the activity of immunomodulatory antibodies present both in IVIG and the patient., (© 2011 John Wiley & Sons A/S.)

Polyvalent Ig preparations, derived from the pooled plasma of thousands of healthy donors, contain a complex mix of both 'acquired' and natural antibodies directed against pathogens as well as foreign and self/auto antigens (Ag). Depending on their formulation, donor pool size, etc., liquid Ig preparations contain monomeric and dimeric IgG. The dimeric IgG fraction is thought to represent mainly idiotype-antiidiotype Ab pairs. Treatment of all IgG fractions at pH 4 effectively monomerizes the IgG dimers resulting in separated idiotype-antiidiotype Ab pairs and thus in a comparable F(ab')(2) binding site availability of the different IgG fractions. Previously, we identified an increased anti-self-reactivity within the monomerized dimer fraction. This study addressed if, among the different IgG fractions, an analogous preferential reactivity was evident in the response against different pathogen-derived protein and carbohydrate antigens. Therefore, we assessed the activity of total unseparated IgG, the monomeric and dimeric IgG fractions against antigenic structures of bacterial and viral antigens/virulence factors. All fractions showed similar reactivity to protein antigens except for exotoxin A of Pseudomonas aeruginosa, where the dimeric fraction, especially when monomerized, showed a marked increase in reactivity. This suggests that the production of antiidiotypic IgG antibodies contributes to controlling the immune response to certain categories of pathogens. In contrast, the monomeric IgG fractions showed increased reactivity towards pathogen-associated polysaccharides, classically regarded as T-independent antigens. Taken together, the differential reactivity of the IgG fractions seems to indicate a preferential segregation of antibody reactivities according to the nature of the antigen., (© 2011 CSL Behring AG. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.)

Background: Aggregation of the high-affinity IgE receptor (FcεRI) with the low-affinity IgG receptor (FcγRIIb) on basophils or mast cells has been shown to inhibit allergen-induced cell degranulation. Molecules cross-linking these two receptors might therefore be of interest for the treatment of allergic disorders. Here, we demonstrate the generation of a novel bispecific fusion protein efficiently aggregating FcεRI-bound IgE with FcγRIIb on the surface of basophils to prevent pro-inflammatory mediator release., Methods: Alternative binding molecules recognizing receptor-bound human IgE were selected from DARPin (designed ankyrin repeat protein) libraries. One of the selected DARPins was linked to the Fc-part of a human IgG(1) antibody for binding to FcγRIIb., Results: The resulting anti-IgE DARPin-Fc fusion protein was not anaphylactogenic and inhibited allergen-induced basophil activation in whole blood assays. Both binding moieties of the fusion protein, namely the anti-IgE DARPin as well as the IgG(1) Fc-part, were required to achieve this inhibitory effect. Most importantly, inhibition was faster and more efficient than with Omalizumab, a humanized anti-IgE antibody currently used for the treatment of severe asthma., Conclusion: This novel anti-IgE DARPin-Fc fusion protein might represent a potential drug candidate for preventive or immediate treatment of allergic reactions., (© 2011 John Wiley & Sons A/S.)

Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions., (©2011 AACR.)

Background: Cross reactions are an often observed phenomenon in patients with allergy. Sensitization against some allergens may cause reactions against other seemingly unrelated allergens. Today, cross reactions are being investigated on a per-case basis, analyzing blood serum specific IgE (sIgE) levels and clinical features of patients suffering from cross reactions. In this study, we evaluated the level of sIgE compared to patients' total IgE assuming epitope specificity is a consequence of sequence similarity., Methods: Our objective was to evaluate our recently published model of molecular sequence similarities underlying cross reactivity using serum-derived data from IgE determinations of standard laboratory tests. We calculated the probabilities of protein cross reactivity based on conserved sequence motifs and compared these in silico predictions to a database consisting of 5362 sera with sIgE determinations., Results: Cumulating sIgE values of a patient resulted in a median of 25-30% total IgE. Comparing motif cross reactivity predictions to sIgE levels showed that on average three times fewer motifs than extracts were recognized in a given serum (correlation coefficient: 0.967). Extracts belonging to the same motif group co-reacted in a high percentage of sera (up to 80% for some motifs)., Conclusions: Cumulated sIgE levels are exaggerated because of a high level of observed cross reactions. Thus, not only bioinformatic prediction of allergenic motifs, but also serological routine testing of allergic patients implies that the immune system may recognize only a small number of allergenic structures., (© 2010 John Wiley & Sons A/S.)

Introduction: The pull-PEG (percutaneous endoscopic gastrostomy) is the most commonly used procedure for PEG placement. Alternative methods may be used in patients with an obstructed oesophagus. We here present the case of an unusual complication during PEG placement with the new introducer technique and gastropexy., Case Report: A 74-year-old men with progressive thymus cell carcinoma was referred for a PEG procedure. Since the tumour stenosis in the oesophagus was only passable with a slim-sight endoscope (5,9 mm), we decided in favour of the direct PEG method with gastropexy. The procedure was performed without any complications. 35 days later we changed the balloon catheter and were able to easily inflate the balloon. Surprisingly, the X-ray performed thereafter, revealed a misplacement of the catheter in the colon without any notable contrast medium in the stomach. Although the patient expressed no complaints, he underwent surgery on the same day proving the colocutaneous fistula. There were no signs of peritonitis. The patient's postoperative recovery was uneventful., Discussion: Pull-PEG requires an intact oesophageal passage. The spread of bacteria and tumour cells is a possible risk factor. Direct punction PEG might be better in these cases. This method is not a standard procedure, but the recent implementation of an additional gastropexy represents a significant improvement. We experienced a rare complication, which was first described in 1987. However, this case is the first documented complication in association with gastropexy. This case shows that even gastropexy does not prevent colon interposition. Therefore, an endoscopic or radiological control of the tube placement after changing seems to be necessary.