Cervical manipulation accelerates recovery and further correction of cervical alignment in mechanical neck pain (MNP) patients with neck exercise: A randomized controlled trialWu, Deng, Zhao
et alComplement Ther Clin Pract (2025) 59, 101969
Abstract: Mechanical neck pain (MNP) is often associated with changes in cervical sagittal alignment, causing pain and functional limitations.This study evaluated the additional effects of cervical manipulation in patients with MNP undergoing neck retraction exercise.Patients with MNP were randomly assigned to either the cervical manipulation plus neck retraction exercise group (CM + NRE) or the neck retraction exercise group (NRE). Both groups completed their respective regimens over an 8-week period. Primary outcomes include visual analogue scale (VAS) and cervical range of motion (CROM). Secondary outcomes include neck disability index (NDI), neck muscle strength, and cervical sagittal alignment (relative rotation angles [RRA]; absolute rotation angles [C2-7ARA]; cervical sagittal vertical axis [c2-7SVA]). The statistical analysis applied intention-to-treat (ITT) and per-protocol (PP) analyses.In the ITT analysis, the CM + NRE group demonstrated more pronounced changes in VAS and CROM after the first treatment (VAS: d = 1.83, P = 0.001; CROM: d = 1.92, P = 0.001), at 4 weeks (VAS: d = 0.98, P = 0.001; CROM: d = 1.05, P = 0.001), 8 weeks (VAS: d = 1.05, P = 0.001; CROM: d = 0.93, P = 0.001), and at a 4-week follow-up (VAS: d = 1.16, P = 0.001; CROM: d = 0.91, P = 0.001). In the assessments of NDI, RRA, and C2-7ARA, the CM + NRE group showed significantly greater changes compared to the NRE group (p < 0.05). These results were consistent with the PP analysis.Cervical manipulation enhances the effectiveness of neck retraction exercise, which promotes rapid recovery from neck pain and stiffness and further facilitates the correction of cervical sagittal alignment in patients with MNP.Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
CpG oligodeoxynucleotides and pan-serotype inhibitors control neurotropic Dengue infection in novel immune competent neonatal mouse modelMendoza, Ireland, Lee
et alEmerg Microbes Infect (2025)
Abstract: Dengue virus (DENV) is a growing global public health threat. The lack of symptomatic immune competent animal models for Dengue has hindered the screening and development of effective therapeutics that can be used to control dengue virus replication and thereby control the progression to severe dengue disease. To address this, we established an infection model in neonatal C57BL/6 mice and showed that a systemic Dengue challenge leads to ataxia, seizures, paralysis, and death within 15 days. The virus was found predominantly in the eye and brain where DENV infects neurons but not astrocytes and causes extensive infiltration of macrophages and microglia activation. The response to infection included upregulation of multiple genes linked to interferons (Ifna, Ifnb, Ifng, Irf7, Irf8, Mx1, Stat1 and Bst2), inflammation (Il6,Tnfa), complement (Cfb,C1ra,C2, C3), cytolysis (Gzma, Gzmb, Prf1) consistent with antiviral responses and inflammation together with neuroprotective regulatory signals (Il27, Il10, and stat2). The increased proinflammatory signature was associated downregulation neurodevelopmental genes (Calb2, Pvalb, Olig1 and Olig2). We tested the utility of this mouse model by assessing the protection conferred by direct antivirals JNJ-A07 and ST-148 and host-directed antiviral immunomodulatory CpG oligodeoxynucleotide (ODN), alone or in combination against lethal dengue viral infection. The data showed that immunomodulatory CpG ODN and antiviral JNJ-A07 improved survival of neonatal mice, and protection from lethal neurotropic infection was optimal when treatments were combined. This study suggests that combination of an effective dengue antiviral along with a host directed therapeutic may be a useful strategy to protect against Dengue virus infections.
Drug-resistant epilepsy associated with peripheral complement decreases and sex-specific cytokine imbalances: a pilot studyPinzon-Hoyos, Li, McGee
et alSci Rep (2025) 15 (1), 5096
Abstract: Drug-resistant epilepsy (DRE) presents significant challenges in treatment and management. While seizure-related alterations in peripheral immune players are increasingly recognized, the involvement of the immune complement system remains insufficiently explored in DRE. We studied complement components and their relationship to cytokine profiles in serum samples from 46 DRE patients and 45 matched healthy controls. We examined relationships between these molecules and clinical outcomes, including epilepsy duration, intelligence scores, and age. We identified DRE-associated complement decreases, including reduced levels of C1q, Factor H, C4, C4b, C3, and C3b/iC3b, as well as elevated bFGF. DRE females showed dysregulation of the classical complement pathway and lower TNFα and interleukin-8 compared to healthy females. DRE males exhibited dysregulation of the classical, lectin, and terminal complement pathways, with trends of increased CCL2 and CCL5 compared to healthy males. Specific complement and inflammatory markers (C2, IL-8, and IL-9) correlated with full-scale IQ scores in DRE patients. Our study reveals significantly lower levels of circulating complement components in DRE and sex-specific complement dysregulation and cytokine imbalances. These findings suggest an underlying peripheral immune system vulnerability that may be sex-dependent and warrants further investigation in DRE.© 2025. The Author(s).
Granzyme K activates the entire complement cascadeDonado, Theisen, Zhang
et alNature (2025)
Abstract: Granzymes are a family of serine proteases that are mainly expressed by CD8+ T cells, natural killer cells and innate-like lymphocytes1. Although their primary function is thought to be the induction of cell death in virally infected cells and tumours, accumulating evidence indicates that some granzymes can elicit inflammation by acting on extracellular substrates1. We previously found that most tissue CD8+ T cells in rheumatoid arthritis synovium, and in inflamed organs for some other diseases, express granzyme K (GZMK)2, a tryptase-like protease with poorly defined function. Here, we show that GZMK can activate the complement cascade by cleaving the C2 and C4 proteins. The nascent C4b and C2b fragments form a C3 convertase that cleaves C3, enabling the assembly of a C5 convertase that cleaves C5. The resulting convertases generate all the effector molecules of the complement cascade: the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. In rheumatoid arthritis synovium, GZMK is enriched in regions with abundant complement activation, and fibroblasts are the main producers of complement proteins that serve as substrates for GZMK-mediated complement activation. Furthermore, Gzmk-deficient mice are significantly protected from inflammatory disease, exhibiting reduced arthritis and dermatitis, with concomitant decreases in complement activation. Our findings describe the discovery of a previously unidentified mechanism of complement activation that is driven entirely by lymphocyte-derived GZMK. Given the widespread abundance of GZMK-expressing T cells in tissues in chronic inflammatory diseases, GZMK-mediated complement activation is likely to be an important contributor to tissue inflammation in multiple disease contexts.© 2025. The Author(s), under exclusive licence to Springer Nature Limited.
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