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Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies. [ABSTRACT FROM AUTHOR]

Non-releaser experiments (phase 2, I n i = 13/24): When using non-releaser basophils without IL-3 priming, nine out of 13 aiCSU patients' sera were not able to stimulate unprimed basophils (Fig. Group A represents CSU sera not active on non-releaser basophils, in contrast to group B whose sera activate non-releaser basophils without the addition of IL-3 primer. It seems that the serum of some aiCSU patients contains a factor ("second signal") that may act as a basophil primer, enhancing signalling through Fc RI and inducing CD63 up-regulation. [Extracted from the article]

Inflammatory reaction following a spinal cord injury (SCI) contributes substantially to secondary effects, with both beneficial and devastating effects. This review summarizes the current knowledge concerning the structural features (vascular, cellular, and biochemical events) of SCI and gives an overview of the regulation of post-traumatic inflammation.Spinal Cord (2003) 41, 369-378. doi:10.1038/sj.sc.3101483 [ABSTRACT FROM AUTHOR]

Abstract Background As proinflammatory cytokines seem to play a role in discogenic back pain, substances exhibiting anti-inflammatory effects on intervertebral disc cells may be used as minimal-invasive therapeutics for intradiscal/epidural injection. The purpose of this study was to investigate the anti-inflammatory and anti-catabolic potential of curcuma, which has been used in the Indian Ayurvedic medicine to treat multiple ailments for a long time. Methods Human disc cells were treated with IL-1β to induce an inflammatory/catabolic cascade. Different extracts of curcuma as well as curcumin (= a component selected based on results with curcuma extracts and HPLC/MS analysis) were tested for their ability to reduce mRNA expression of proinflammatory cytokines and matrix degrading enzymes after 6 hours (real-time RT-PCR), followed by analysis of typical inflammatory signaling mechanisms such as NF-κB (Western Blot, Transcription Factor Assay), MAP kinases (Western Blot) and Toll-like receptors (real-time RT-PCR). Quantitative data was statistically analyzed using a Mann Whitney U test with a significance level of p Results Results indicate that the curcuma DMSO extract significantly reduced levels of IL-6, MMP1, MMP3 and MMP13. The DMSO-soluble component curcumin, whose occurrence within the DMSO extract was verified by HPLC/MS, reduced levels of IL-1β, IL-6, IL-8, MMP1, MMP3 and MMP13 and both caused an up-regulation of TNF-α. Pathway analysis indicated that curcumin did not show involvement of NF-κB, but down-regulated TLR2 expression and inhibited the MAP kinase JNK while activating p38 and ERK. Conclusions Based on its anti-inflammatory and anti-catabolic effects, intradiscal injection of curcumin may be an attractive treatment alternative. However, whether the anti-inflammatory properties in vitro lead to analgesia in vivo will need to be confirmed in an appropriate animal model.

Summary: Background. Patients with autoimmune forms of chronic spontaneous ur-ticaria (aiCSU) exhibit autoantibodies against the high-affinity IgE recep-tor (FcεRI) and IgE. As the presence of these autoantibodies does not cor-relate with disease activity, the functional affinity/avidity may be relevant in aiCSU. This exploratory study aimed to characterize the quantity and avidity of autoantibodies against IgE and FcεRI over 6 months. Methods. The serum of 49 patients with CSU and 30 healthy control subjects was obtained at baseline and 6 months. Serum was analyzed by ELISA, to determine the quantity and avidity of anti-IgE and anti-FcεRI autoan-tibodies, and by basophil activation test (CU-BAT). Results. An increase in the quantity of anti-FcεRI and anti-IgE antibodies and a simultaneous decrease in avidity was found in all patients with CSU after 6 months: median anti-IgE increased from 6.7 ng/mL (IQR 5.1-12.5) to 23.8 ng/mL (IQR 12.3-121.5), p < 0.001, median anti-FcεRI from 52.4 ng/mL (IQR 26.3-111.4) to 129.5 ng/mL (IQR 73.7-253.7), p < 0.001. Me-dian anti-IgE avidity decreased from 75.8% (IQR 55.3-90.8) to 56.4% (IQR 30.6-76.2), p = 0.019 and median anti-FcεRI avidity from 75.1% (IQR 49.8-90.0) to 52.2 (IQR 38.2-60.1), p < 0.001. In contrast, the frequency of activated basophils did not change significantly over time. Surprisingly, autoantibody avidity did not correlate with basophil acti-vation. Conclusions. Both the quantity and avidity of anti-FcεRI and anti-IgE antibodies change over time, demonstrating that the CU-BAT is more suitable to diagnose aiCSU. In addition, the avidity of anti-FcεRI and anti-IgE antibodies do not correlate with CU-BAT and disease activ-ity, suggesting that further factors independent of anti-FcεRI and anti-IgE autoantibodies contribute to aiCSU.

Background: Chronic subdural hematoma (cSDH) is a disease affecting mainly elderly individuals. The reported incidence ranges from 2.0/100,000 to 58 per 100,000 person-years when only considering patients who are over 70 years old, with an overall incidence of 8.2-14.0 per 100,000 persons. Due to an estimated doubling of the population above 65 years old between 2000 and 2030, cSDH will become an even more significant concern. To gain an overview of cSDH hospital admission rates, treatment, and outcome, we performed this multicenter national cohort study of patients requiring surgical treatment of cSDH., Methods: A multicenter cohort study included patients treated in 2013 in a Swiss center accredited for residency. Demographics, medical history, symptoms, and medication were recorded. Imaging at admission was evaluated, and therapy was divided into burr hole craniostomy (BHC), twist drill craniostomy (TDC), and craniotomy. Patients' outcomes were dichotomized into good (mRS, 0-3) and poor (mRS, 4-6) outcomes. A two-sided t -test for unpaired variables was performed, while a chi-square test was performed for categorical variables, and a p -value of <0.05 was considered to be statistically significant., Results: A total of 663 patients were included. The median age was 76 years, and the overall incidence rate was 8.2/100,000. With age, the incidence rate increased to 64.2/100,000 in patients aged 80-89 years. The most prevalent symptoms were gait disturbance in 362 (58.6%) of patients, headache in 286 (46.4%), and focal neurological deficits in 252 (40.7%). CSDH distribution was unilateral in 478 (72.1%) patients, while 185 presented a bilateral hematoma with no difference in the outcome. BHC was the most performed procedure for 758 (97.3%) evacuations. CSDH recurrence was noted in 104 patients (20.1%). A good outcome was seen in almost 81% of patients. Factors associated with poor outcomes were age, GCS and mRS on admission, and the occurrence of multiple deficits present at the diagnosis of the cSDH., Conclusion: As the first multicenter national cohort-based study analyzing the disease burden of cSDH, our study reveals that the hospital admission rate of cSDH was 8.2/100,000, while with age, it rose to 64.2/100,000. A good outcome was seen in 81% of patients, who maintained the same quality of life as before the surgery. However, the mortality rate was 4%., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 El Rahal, Beck, Ahlborn, Bernasconi, Marbacher, Wanderer, Burkhardt, Daniel, Ferrari, Hausmann, Kamenova, Kothbauer, Lutz, Mariani, Alfieri, Schöni, Schucht, Raabe, Regli, Kuhlen, Seule, Soleman, Starnoni, Zaldivar, Zweifel, Schaller and Fung.)

Study Design: Multicenter prospective observational study., Objective: Diffusion tensor imaging in flexion extension improves the diagnosis of degenerative cervical myelopathy (DCM). We aimed to provide an imaging biomarker for the detection of DCM., Summary of Background Data: DCM is the most common form of spinal cord dysfunction in adults; however, imaging surveillance for myelopathy remains poorly characterized., Patients and Methods: Symptomatic DCM patients were examined in maximum neck flexion-extension and neutral positions in a 3T-magnetic resonance imaging scanner and allocated to 2 groups: (1) Patients with visible intramedullary hyperintensity (IHIS) on T2-weighted imaging (IHIS+, n = 10); and (2) Patients without IHIS (IHIS-, n = 11). Range of motion, space available for the spinal cord, apparent diffusion coefficient (ADC), axial diffusivity (AD), radial diffusivity, and fractional anisotropy were measured and compared between the neck positions and between the groups as well as between control (C2/3) and pathologic segments., Results: Significant differences between the control level (C2/3) and pathologic segments were appreciated for the IHIS+ group at neutral neck position in AD; at flexion in ADC and AD; and at neck extension in ADC, AD, and fractional anisotropy values. For the IHIS- group, significant differences between the control level (C2/3) and pathologic segments were found only for ADC values in neck extension. When comparing diffusion parameters between groups, radial diffusivity was significantly different in all 3 neck positions., Conclusion: Significant increases in ADC values between the control and pathologic segments were found for both groups in neck extension only. This may serve as a diagnostic tool to identify early changes in the spinal cord related to myelopathy to indicate potentially reversible spinal cord injury and support the indication for surgery in select circumstances., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Schouwenburg, Unger, Payne, Kaiser, Pico-Knijnenburg, Pfeiffer, Hausmann, Friedmann, Erbel, Seidl, van Zessen, Stubbs, van der Burg and Warnatz.)

The SARS-CoV-2 pandemic has claimed many lives and disrupted the quality of life of most individuals. Diagnostic tests not only serve to confirm past exposure but can provide information crucial for guiding healthcare options for patients. Current diagnostic tests for the presence of the SARS-CoV-2 virus or anti-spike protein antibodies do not address the question whether longer lasting cellular immunity is mounted in most individuals. Using an activation marker flow cytometric immunoassay (SARS-CoV-2 lymphocytes analysis), we showed that both CD4+/CD8+ T cell and B cell activation differ between naïve and infected individuals up to 11 months after infection. On the basis of the specificity of this diagnostic tool for detecting both SARS-CoV-2-experienced T and B cells, we propose that this assay could benefit immunocompromised individuals who are unable to mount sustained antibody responses, by determining cellular immunity as possible partial protection, and for studying immune correlates of protection - thereby increasing knowledge of COVID-19 in a wider range of patient groups.

Background: Chlorhexidine (CHX) is a widely utilized disinfectant that can cause IgE-mediated urticaria/anaphylaxis. The cross-reactivity of patients with IgE-mediated CHX allergy with other disinfectants, which share structural similarities with CHX like polyhexanide (polyhexamethylene biguanide; PHMB), alexidine (ALX), or octenidine (OCT), is unknown., Methods: Forty-four patients with anaphylaxis or urticaria upon CHX exposure and positive skin prick test (SPT) and/or positive CHX ImmunoCAP test (Phadia TFS, Uppsala, Sweden) were recruited. IgE to the biguanide and/or hexamethylene structure was investigated with PHMB ImmunoCAP (n = 32) and by basophil activation tests (BAT) with CHX and ALX (n = 37). Inhibition tests of CHX and PHMB ImmunoCAPs by CHX, ALX, PHMB, and OCT were performed., Results: IgE reactivity to PHMB as surrogate marker for biguanide/hexamethylene reactivity was detected in 5/32 sera. Seven of 37 patients showed a positive BAT with ALX, but only under optimized conditions. Binding to CHX ImmunoCAP was inhibited by ALX in 1/32 sera, and binding to PHMB was blocked by ALX (1/5) and by OCT in another (1/5). In SPT, 9/10 patients were positive for CHX and 3 of them with ALX (only at highest concentration at 5 mg/mL). A further patient reacted primarily with OCT and showed IgE cross-reactivity with CHX, ALX, and PHMB., Conclusion: The IgE response to CHX seems polyclonal. The chloroguanide ending of CHX is the main epitope for the IgE and is suitable as screening assay to detect CHX reactivity. IgE-reactivities with the biguanide or hexamethylene components of other disinfectants (ALX, PHMB) can be detected by SPT, PHMB ImmunoCAP, and ALX-BAT in 15%-33% of CHX-allergic patients., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Sensitization to Hymenoptera venom in patients without a history of systemic allergic reactions to Hymenoptera stings is frequently found and can be due to the presence of specific IgE to cross-reactive carbohydrate determinants (CCD). This study investigates 105 pollen allergic subjects for the presence of specific IgE to honeybee or wasp venom, pollen, the MUXF3 carbohydrate epitope from bromelain and recombinant Hymenoptera venom components. In addition, in a subgroup of patients (n = 10) a basophil activation test (BAT) using bee and wasp venom was performed. Specific IgE to Hymenoptera venom was detected in 45.7% of the pollen allergic subjects and in 26.7% of the non-atopic controls, both without a history of systemic allergic reactions to Hymenoptera stings. The high sensitization rate in atopic patients could partially be explained by cross-sensitization between pollen and Hymenoptera venom due to specific IgE to CCDs. In our study population, only 20% showed a sensitization to CCDs. Primary sensitization due to sting exposure, high total IgE values or unspecific binding and detection of low affinity antibodies in the test procedure could be reasons. Thus, determination of specific IgE to Hymenoptera venom in patients without a history of systemic allergic reactions as screening test is not recommended., Competing Interests: Oliver Hausmann is an employee of ADR-AC GmbH, a specialized laboratory offering basophil activation tests for routine diagnostics in Switzerland. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare no conflict of interest.

Recently, the role of infection of the intervertebral disc (IVD) with Cutibacterium acnes ( C. acnes ) as a contributor to disc-related low back pain (LBP) has been discussed. The aim of this study was to investigate whether and how C. acnes contributes to the inflammatory processes during IVD disease. The prevalence of C. acnes infection in human IVD tissue was determined by aerobic and anaerobic culture. Thereafter, primary human IVD cells were infected with a reference and a clinical C. acnes strain and analyzed for pro-inflammatory markers (gene/protein level). In a subsequent experiment, the involvement of the Toll-like receptor (TLR) pathway was investigated by co-treatment with sparstolonin B, a TLR2/4 inhibitor. We detected C. acnes in 10% of IVD biopsies (with either herniation or degeneration). Stimulating IVD cells with both C. acnes strains strongly and significantly upregulated expression of Interleukin (IL)-1β, IL-6, IL-8, and inducible nitric oxide synthase (iNOS). IL-6, cyclooxygenase (COX)-2, and iNOS expression was reduced upon TLR2/4 inhibition in 3 out of 5 donors, whereby responders and non-responders could not be differentiated by their basal TLR2 or TLR4 expression levels. We demonstrate that exposure of IVD cells to C. acnes induces an inflammatory response that may contribute to the development of discogenic LBP by involving TLR2/4 activation, yet only in a subgroup of patients. Whether the same response will be observed in vivo and where lower inoculums are present remains to be proven in future studies.

Objective: To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU)., Methods: Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment., Results: Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption., Conclusions: Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs., Methods: Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5 days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed., Results: Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3 days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity., Conclusions: Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies. These slides can be retrieved under Electronic Supplementary Material.

Background: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology., Objectives: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients., Methods: We quantified T H 1/T H 2/T H 17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation., Results: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3 + CCR6 - T H 1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet) + B cells in lymph nodes, and an accumulation of T-bet + CD21 low B cells in peripheral blood of affected patients., Conclusion: Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21 low B cells might serve as a marker of this IFN-γ-associated dysregulation., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to different drugs. The initial symptoms are mostly severe exanthems or drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting drugs can be identified by positive skin or in vitro tests. The drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30-40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated drugs with clinically diverse symptoms., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Drug hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed. Here, we show that the mode of action of drugs leading to immune/inflammatory cell stimulation is a further decisive factor in understanding and managing DHR. Three mechanisms can be delineated: (a) some drugs have or gain the ability to bind covalently to proteins, form new antigens, and thus elicit immune reactions to hapten-carrier complexes (allergic/immune reaction); (b) a substantial part of immune-mediated DHR is due to a typical off-target activity of drugs on immune receptors like HLA and TCR (pharmacological interaction with immune receptors, p-i reactions); such p-i reactions are linked to severe DHR; and (c) symptoms of DHR can also appear if the drug stimulates or inhibits receptors or enzymes of inflammatory cells (pseudo-allergy). These three distinct ways of stimulations of immune or inflammatory cells differ substantially in clinical manifestations, time of appearance, dose dependence, predictability, and cross-reactivity, and thus need to be differentiated., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Intervertebral disc (IVD) disease, which is characterised by age-related changes in the adult disc, is the most common cause of disc failure and low back pain. The purpose of this study was to analyse the potential of the biologically active polyphenol epigallocatechin 3-gallate (EGCG) for the treatment of painful IVD disease by identifying and explaining its anti-inflammatory and anti-catabolic activity. Human IVD cells were isolated from patients undergoing surgery due to degenerative disc disease (n = 34) and cultured in 2D or 3D. An inflammatory response was activated by IL-1β, EGCG was added, and the expression/activity of inflammatory mediators and pathways was measured by qRT-PCR, western blotting, ELISA, immunofluorescence and transcription factor assay. The small molecule inhibitor SB203580 was used to investigate the involvement of the p38 pathway in the observed effects. The analgesic properties of EGCG were analysed by the von Frey filament test in Sprague-Dawley rats (n = 60). EGCG significantly inhibited the expression of pro-inflammatory mediators and matrix metalloproteinases in vitro, as well as radiculopathic pain in vivo, most probably by modulation of the activity of IRAK-1 and its downstream effectors p38, JNK and NF-κB.

Purpose: The Swiss Federal Office of Public Health demanded a nationwide HTA registry for lumbar total disc arthroplasty (TDA), to decide about its reimbursement. The goal of the SWISS spine registry is to generate evidence about the safety and efficiency of lumbar TDA., Methods: Two hundred forty-eight cases treated between 3-2005 and 6-2006, who were eligible for the 5-year follow-up were included in the study. Follow-up rates for 3-6 months, 1, 2 and 5 years were 85.9, 77.0, 44.0 and 51.2 %, respectively. Outcome measures were back and leg pain, medication consumption, quality of life, intraoperative and postoperative complication and revision rates. Additionally, segmental mobility, ossification, adjacent and distant segment degeneration were analysed at the 5-year follow-up., Results: There was a significant, clinically relevant and lasting reduction of back (preop/postop 73/29 VAS points) and leg pain (preop/postop VAS 55/22) and a consequently decreased analgesics consumption and quality of life improvement (preop/postop 0.30/0.76 EQ-5D score points) until 5 years after surgery. The rates for intraoperative and early postoperative complications were 4.4 and 3.2 %, respectively. The overall complication rate during five postoperative years was 23.4 %, and the adjacent segment degeneration rate was 10.7 %. In 4.4 % of patients, a revision surgery was performed. Cumulative survivorship probability for a revision/re-intervention-free 5-year postoperative course was 90.4 %. At the 5-year follow-up, the average range of motion of the mobile segments (86.8 %) was 9.7°. In 43.9 % of patients, osteophytes at least potentially affecting the range of motion were seen., Conclusions: Lumbar TDA appeared as efficient in long-term pain alleviation, consequent reduction of pain medication consumption and improvement of quality of life. The procedure also appeared sufficiently safe, but surgeons have to be aware of a list of potential adverse events. The outcome is stable over the 5-year postoperative period. The vast majority of treated segments remained mobile after 5 years, although almost half of patients showed osteophytes.

Purpose: Although inflammatory processes play an essential role in painful intervertebral disc (IVD) degeneration, the underlying regulatory mechanisms are not well understood. This study was designed to investigate the expression, regulation and importance of specific toll-like receptors (TLRs)--which have been shown to play an essential role e.g. in osteoarthritis--during degenerative disc disease., Methods: The expression of TLRs in human IVDs was measured in isolated cells as well as in normal or degenerated IVD tissue. The role of IL-1β or TNF-α in regulating TLRs (expression/activation) as well as in regulating activity of down-stream pathways (NF-κB) and expression of inflammation-related genes (IL-6, IL-8, HSP60, HSP70, HMGB1) was analyzed., Results: Expression of TLR1/2/3/4/5/6/9/10 was detected in isolated human IVD cells, with TLR1/2/4/6 being dependent on the degree of IVD degeneration. Stimulation with IL-1β or TNF-α moderately increased TLR1/TLR4 mRNA expression (TNF-α only), and strongly increased TLR2 mRNA expression (IL-1β/TNF-α), with the latter being confirmed on the protein level. Stimulation with IL-1β, TNF-α or Pam3CSK4 (a TLR2-ligand) stimulated IL-6 and IL-8, which was inhibited by a TLR2 neutralizing antibody for Pam3CSK4; IL-1β and TNF-α caused NF-κB activation. HSP60, HSP70 and HMGB1 did not increase IL-6 or IL-8 and were not regulated by IL-1β/TNF-α., Conclusion: We provide evidence that several TLRs are expressed in human IVD cells, with TLR2 possibly playing the most crucial role. As TLRs mediate catabolic and inflammatory processes, increased levels of TLRs may lead to aggravated disc degeneration, chronic inflammation and pain development. Especially with the identification of more endogenous TLR ligands, targeting these receptors may hold therapeutic promise.

Knowing the clinical warning signs of immunodeficiency (ID) in adulthood is crucial for early detection of the over 200 forms of primary ID known to date. Many of these congenital diseases with a genetic background already manifest in childhood. Antibody deficiency diseases represent an important exception, with common variable immunodeficiency (CVID) being the most common form of ID. The median age of onset of CVID is 24 years. Unfortunately, the delay in diagnosis is still in excess of 4 years. General practitioners as well as allergists play a particularly important role in early detection. ID patients who present primarily with signs of immune dysregulation pose an even greater diagnostic challenge. Thus, autoimmune cytopenia, inflammatory bowel diseases, or sarcoid-like granulomatous inflammation can be the first manifestation in up to 20 % of ID patients. Secondary forms of ID [e. g., due to long-term corticosteroid treatment, HIV-infection, leukemia, lymphoma, nephrotic syndrome, malabsorption syndrome] need to be differentiated from primary antibody deficiency. Considering the overlap with allergic symptoms [ID accompanied by a susceptibility to eczema, elevated total IgE, blood eosinophilia], the present article discusses, the clinical warning signs of ID, the first diagnostic steps required and the option of further diagnostic work up at specialist centers for complex cases, as well as the treatment options for such cases.

Background: The Swiss Federal Office of Public Health demanded a nationwide HTA-registry for cervical total disc arthroplasty (TDA), to decide about its reimbursement. The goal of the SWISSspine registry is to generate evidence about the safety and efficiency of cervical TDA., Materials and Methods: Three hundred thirty-two cases treated between 3.2005 and 6.2006 who were eligible for 5 years follow-ups were included in the study. Follow-up rates for 3-6 months, 1, 2 and 5 years were 84.6, 74.4, 50.6 and 64.8 %, respectively. Outcome measures were neck and arm pain, medication, quality of life, intraoperative and postoperative complication and revision rates. In addition, segmental mobility, ossification, adjacent and distant segment degeneration were analyzed at the 5-year follow-up., Results: There was significant, clinically relevant and lasting reduction of neck (preop/postop 60/21 VAS points) and arm pain (preop/postop VAS 67/17) and a consequently decreased analgesics consumption and quality of life improvement (preop/postop 0.39/0.82 EQ-5D points) until the 5-year follow-up. The rates for intraoperative and early postoperative complications were 0.6 and 7.2 %, respectively. In 0.6 % an early and in 3.9 % a late revision surgery was performed. At the 5-year follow-up, the average range of motion of the mobile segments (88.2 %) was 10.2°. In 40.7 % of the patients osteophytes at least potentially affecting range of motion were seen., Conclusions: Cervical TDA appeared as safe and efficient in long-term pain alleviation, consequent reduction of pain killer consumption and in improvement of quality of life. The improvement is stable over the 5 years postoperative period. The vast majority of treated segments remained mobile after 5 years, although 40.7 % of patients showed osteophytes.