The role of miR-155-5p in inflammation and mechanical loading during intervertebral disc degeneration.

BACKGROUND: Intervertebral disc (IVD) degeneration is a multifactorial pathological process resulting in the dysregulation of IVD cell activity. The catabolic shift observed in IVD cells during degeneration leads to increased inflammation, extracellular matrix (ECM) degradation, aberrant intracellular signaling and cell loss. Importantly, these pathological processes are known to be interconnected and to collectively contribute to the progression of the disease. MicroRNAs (miRNAs) are known as strong post-transcriptional regulators, targeting multiple genes simultaneously and regulating numerous intracellular pathways. Specifically, miR-155-5p has been of particular interest since it is known as a pro-inflammatory mediator and contributing factor to diseases like cancer and osteoarthritis. This study investigated the role of miR-155-5p in IVD degeneration with a specific focus on inflammation and mechanosensing. METHODS: Gain- and loss-of-function studies were performed through transfection of human Nucleus pulposus (NP) and Annulus fibrosus (AF) cells isolated from degenerated IVDs with miR-155-5p mimics, inhibitors or their corresponding non-targeting control. Transfected cells were then subjected to an inflammatory environment or mechanical loading. Conditioned media and cell lysates were collected for phosphorylation and cytokine secretion arrays as well as gene expression analysis. RESULTS: Increased expression of miR-155-5p in AF cells resulted in significant upregulation of interleukin (IL)-8 cytokine secretion during cyclic stretching and a similar trend in IL-6 secretion during inflammation. Furthermore, miR-155-5p mimics increased the expression of the brain-derived neurotrophic factor (BDNF) in AF cells undergoing cyclic stretching. In NP cells, miR-155-5p gain-of-function resulted in the activation of the mitogen-activated protein kinase (MAPK) signaling pathway through increased phosphorylation of p38 and p53. Lastly, miR-155-5p inhibition caused a significant increase in the anti-inflammatory cytokine IL-10 in AF cells and the tissue inhibitor of metalloproteinases (TIMP)-4 in NP cells respectively. CONCLUSION: Overall, these results show that miR-155-5p contributes to IVD degeneration by enhancing inflammation through pro-inflammatory cytokines and MAPK signaling, as well as by promoting the catabolic shift of AF cells during mechanical loading. The inhibition of miR-155-5p may constitute a potential therapeutic approach for IVD degeneration and low back pain.

IgE-mediated chlorhexidine allergy-Cross-reactivity with other biguanide disinfectants.

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.

Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy.

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.

Sexual and urinary function following anterior lumbar surgery in females.

AIMS: Anterior lumbar interbody fusion procedures (ALIF) and total disc replacement (TDR) with anterior exposure of the lumbar spine entail a risk of a vascular injury and dysfunction of the sympathetic and parasympathetic nerves due to disturbance of the inferior and superior hypogastric plexus. While retrograde ejaculation is a known complication of the anterior spinal approach in males, post-operative sexual as well as urinary function in females has not yet been thoroughly investigated and was hence the aim of this study. METHODS: Fifteen female patients documented their sexual and urinary function preoperatively, 3 months and 6 months postoperatively, using the validated questionnaires FSFI (Female Sexual Function Index) and ICIQ (International Consultation of Incontinence Questionnaire). Randomization tests were used to statistically analyze expectation values over time (two-sided, P < 0.05). RESULTS: While no statistically significant change in the total FSFI score occurred over time, a significant increase in FSFI desire score was noted between preoperative (2.95 ± 0.8) and 6 months follow-up (3.51 ± 0.6, P = 0.02). Urinary continence remained unchanged over time. CONCLUSION: In summary, ALIF and lumbar TDR do not seem to negatively influence sexual and urinary function in females. In contrast, increased sexual desire was noted, likely secondary to post-surgical pain relief.

The TH1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21low common variable immunodeficiency.

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 TH1/TH2/TH17 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- TH1 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+CD21low 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. CD21low B cells might serve as a marker of this IFN-γ-associated dysregulation.

Expression and Activity of TRPA1 and TRPV1 in the Intervertebral Disc: Association with Inflammation and Matrix Remodeling.

Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1ß) or tumor necrosis factor alpha (TNF-α) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 µM), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 µM AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.

Laborabklärung der Medikamentenallergie: Grenzen und Möglichkeiten.

The diagnosis of drug allergy is essentially based on a detailed anamnesis, involving the doctors who first treated the patient, and skin testing (prick, intradermal and epicutaneous / patch tests). In the allergological practice / clinic, provocation tests with the presumed trigger are only carried out if the indication is very clear (see articles in this issue on drug allergy children, allergies to betalactam and other antibiotics as well as analgesic intolerance). The provocation with a probably tolerable alternative is in the foreground. Unfortunately, the skin tests of certain drug groups have a low sensitivity even under optimal conditions, but very good specificity. Accordingly, positive skin tests are mostly relevant, but negative skin tests cannot rule out an allergy. In recent years, it has therefore proved successful to carry out supplementary laboratory tests in the clarification of drug allergies. The serological tests (IgE) are of little help. In contrast, the test forms based on the analysis of leukocytes (basophil activation test, BAT, and lymphocyte transformation test, LTT) have gained in importance and complement the diagnostic repertoire. In the combination of all test methods (skin test, LTT, BAT, sometimes provocation test) the trigger of a drug allergy can be defined in a good 70 % of cases and in most cases a safe therapeutic alternative can be found. In the following, we will discuss the importance of laboratory diagnostics in drug allergy.

Inflammaging in cervical and lumbar degenerated intervertebral discs: analysis of proinflammatory cytokine and TRP channel expression.

PURPOSE: To investigate and compare the occurrence of inflammatory processes in the sites of disc degeneration in the lumbar and cervical spine by a gene array and subsequent qPCR and to investigate the mechanistic involvement of transient receptor potential channels TRPC6 and TRPV4. METHODS: The gene expression of inflammatory cytokines and TRP channels was measured in human disc samples obtained from patients undergoing discectomy at the cervical (n = 24) or lumbar (n = 27) spine for degenerative disc disease (DDD) and disc herniation (DH) and analyzed for differences with regard to spinal level, IVD degeneration grade, Modic grade, age, sex, disc region and surgical extent. RESULTS: Aside from genes with known implication in DDD and DH, four previously unreported genes from the interferon and TRP families (IFNA1, IFNA8, IFNB1, TRPC6) could be detected. A correlation between gene expression and age (IL-15) and IVD degeneration grade (IFNA1, IL-6, IL-15, TRPC6), but not Modic grade, was identified. Significant differences were detected between cervical and lumbar discs (IL-15), nucleus and annulus (IL-6, TNF-α, TRPC6), single-level and multi-level surgery (IL-6, IL-8) as well as DDD and DH (IL-8), while sex had no effect. Multiple gene-gene pair correlations, either between different cytokines or between cytokines and TRP channels, exist in the disc. CONCLUSION: This study supports the relevance of IL-6 and IL-8 in disc diseases, but furthermore points toward a possible pathological role of IL-15 and type I interferons, as well as a mechanistic role of TRPC6. With limited differences in the inflammatory profile of cervical and lumbar discs, novel anti-inflammatory or TRP-modulatory strategies for the treatment of disc pathologies may be applicable independent of the spinal region.

TRPC6 in simulated microgravity of intervertebral disc cells.

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.

Multiple Drug Hypersensitivity.

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.

Classification of Drug Hypersensitivity into Allergic, p-i, and Pseudo-Allergic Forms.

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.

Five-year results of lumbar disc prostheses in the SWISSspine registry.

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.

Expression and regulation of toll-like receptors (TLRs) in human intervertebral disc cells.

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-1ß 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-1ß or TNF-α moderately increased TLR1/TLR4 mRNA expression (TNF-α only), and strongly increased TLR2 mRNA expression (IL-1ß/TNF-α), with the latter being confirmed on the protein level. Stimulation with IL-1ß, TNF-α or Pam3CSK4 (a TLR2-ligand) stimulated IL-6 and IL-8, which was inhibited by a TLR2 neutralizing antibody for Pam3CSK4; IL-1ß 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-1ß/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.

Exploring the Impact of TLR-2 Signaling on miRNA Dysregulation in Intervertebral Disc Degeneration.

Toll-like receptors (TLRs) are key mediators of inflammation in intervertebral disc (IVD) degeneration. TLR-2 activation contributes to the degenerative process by increasing the expression of extracellular matrix-degrading enzymes, pro-inflammatory cytokines, and neurotrophins. As potent post-transcriptional regulators, microRNAs can modulate intracellular mechanisms, and their dysregulation is known to contribute to numerous pathologies. This study aims to investigate the impact of TLR-2 signaling on miRNA dysregulation in the context of IVD degeneration. Small-RNA sequencing of degenerated IVD cells shows the dysregulation of ten miRNAs following TLR-2 activation by PAM2CSK4. The miR-155-5p is most significantly upregulated in degenerated and non-degenerated annulus fibrosus and nucleus pulposus cells. Sequence-based target and pathway prediction shows the involvement of miR-155-5p in inflammation- and cell fate-related pathways and TLR-2-induced miR-155-5p expression leads to the downregulation of its target c-FOS. Furthermore, changes specific to the activation of TLR-2 through fragmented fibronectin are seen in miR-484 and miR-487. Lastly, miR-100-3p, miR-320b, and miR-181a-3p expression exhibit degeneration-dependent changes. These results show that TLR-2 signaling leads to the dysregulation of miRNAs in IVD cells as well as their possible downstream effects on inflammation and degeneration. The identified miRNAs provide important opportunities as potential therapeutic targets for IVD degeneration and low back pain.

Five-year results of cervical disc prostheses in the SWISSspine registry.

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.

Lumbar total disc replacement: correlation of clinical outcome and radiological parameters.

BACKGROUND: The objective of this study was to correlate various radiological parameters with clinical outcome in patients who had undergone lumbar total disc replacement (TDR). Lumbar TDR is one possible treatment option in patients with low back pain (LBP), offering an alternative to lumbar fusion. Favourable clinical outcome hinges on a number of radiological parameters, such as mobility, sintering, and-most importantly-accurate positioning of the implant. METHODS: A total of 46 patients received a prosthetic disc because of degenerative lumbar disc disorders. Follow-up evaluation included analysis of radiographs and subjective rating of the clinical status by the patient using the North American Spine Society (NASS) patient questionnaire, visual analogue scale (VAS) for pain and state of health, and the EuroQol EQ-5D. Radiological follow-up took place after 2 years. Coronal and sagittal positions of the prosthesis, intervertebral disc height, facet joint pressure, mobility, sintering, and calcification were evaluated. Optimal positioning of the prosthesis was defined as a central coronal position and a most dorsal position in the sagittal plane. Based on the radiologically determined placement of the prosthesis, the patient population was divided into three groups, i.e., prosthesis ideally placed (<2 mm), discretely shifted (2-3 mm), or suboptimally placed (>3 mm). RESULTS: Overall, 81 % of patients stated that they would undergo the operation again. Health status was stable at a VAS score of 7.04 points 2 years after TDR, compared to 3.97 points before TDR. Mean working capacity had increased from 53 % preoperatively to 88 % 2 years after TDR. Overall, 39 % of the prostheses were rated as ideally positioned, while 13 % were discretely shifted and 48 % were suboptimally placed with respect to one of the radiological criteria. In 80.4 % of patients, follow-up assessment after ≥2 years indicated good mobility at the operated segment, while calcification was noted in 4 % and sintering was detected in 15 % of the implants. CONCLUSIONS: Our data indicate poor correlation between clinical outcome and position of the prosthesis. Although 48 % of the implants were suboptimally placed in either the coronal or sagittal plane, most of the patients reached a very good clinical outcome. However, suboptimally placed devices appeared to cause significantly more neurological symptoms in long-term follow-up.

A Diagnostic Biomarker for Cervical Myelopathy Based on Dynamic Magnetic Resonance Imaging.

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.

Incidence, therapy, and outcome in the management of chronic subdural hematoma in Switzerland: a population-based multicenter cohort study.

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%.

Individual IL-3 priming is crucial for consistent in vitro activation of donor basophils in patients with chronic urticaria.

BACKGROUND: The in vivo autologous serum skin test (ASST) is the diagnostic gold standard to detect autoantibodies against FcεRI or IgE itself, as well as other autoreactive serum components, in patients with chronic spontaneous urticaria (CU). Coincubation of patient sera with donor basophils and measuring their degranulation in vitro could be a safe alternative but has shown inconsistent results. OBJECTIVE: Optimization of the basophil activation test to detect autoreactive serum components in patients with CU. METHODS: The ability of patient sera to induce CD63 and CD203c in donor basophils (n = 15) was measured by means of flow cytometry. Sera of 20 patients with CU (10 with positive ASST results), 15 patients with cold urticaria, and 27 healthy control subjects were included to optimize test conditions with donor basophils and a basophil cell line (RBL703/21) followed by testing of 110 consecutive patients from clinical routine. RESULTS: We demonstrate that individual IL-3 priming normalized the initially inconsistent basophil reactivity and led to reproducible and comparable test results irrespective of the basophil donors used. CD203c as an activation marker and the use of a basophil cell line were less suitable for this purpose. CONCLUSION: The basophil activation test with individualized IL-3 priming for each basophil donor is a reproducible and reliable alternative to the ASST. There are several advantages over the ASST: no risk of accidental infection, no influence of antihistamines on the test result, quantifiable results, and a potential in providing treatment monitoring. The exact nature of the degranulating factor or factors in patient sera remains an open question.