Background
Ketorolac is an effective non‐steroidal anti‐inflammatory drug, commonly used with local anaesthetics as part of local infiltration analgesia protocols following orthopaedic surgery. ...However, systemic uptake and drug action may be the major mechanism after local infiltration. The aims of this project were to study the effects of a small, systemically ineffective dose of ketorolac given intra‐articularly for post‐operative pain and also to study synovial inflammatory biomarkers. We investigated whether ketorolac affects pro‐inflammatory biomarkers in an in vitro model, as well.
Methods
In this placebo‐controlled, blind, randomized study, we analysed intra‐articular ketorolac (5 mg) in ambulatory minor knee surgery patients with moderate or severe pain (n = 44). We assessed post‐operative pain intensity (n = 44) and analysed microdialysis samples taken from knee synovial tissue every 20 min (n = 34). We also tested cyclooxygenase‐independent effects of ketorolac in synovial cells stimulated by prostaglandin E2 and chondroitin sulphate in vitro.
Results
Intra‐articular ketorolac (5 mg) administration did not reduce pain or synovial pro‐inflammatory cytokines CXCL1, IL‐8, and MCP‐1, 0–120 min after knee arthroscopy. Female gender was a risk factor for moderate or severe pain (relative risk 1.45, 95% confidence interval 1.04–2.01). Paradoxically, ketorolac increased the release of CXCL1 and IL‐8 in prostaglandin E2 and chondroitin sulphate‐stimulated synovial cells in vitro.
Conclusion
Ketorolac prescribed at a low dose intra‐articularly does not produce any detectable analgesic effect after minor knee surgery.
Introduction:
Secondary stroke prevention depends on proper identification of the underlying etiology and initiation of optimal treatment after the index event. The aim of the NOR-FIB study was to ...detect and quantify underlying atrial fibrillation (AF) in patients with cryptogenic stroke (CS) or transient ischaemic attack (TIA) using insertable cardiac monitor (ICM), to optimise secondary prevention, and to test the feasibility of ICM usage for stroke physicians.
Patients and methods:
Prospective observational international multicenter real-life study of CS and TIA patients monitored for 12 months with ICM (Reveal LINQ) for AF detection.
Results:
ICM insertion was performed in 91.5% by stroke physicians, within median 9 days after index event. Paroxysmal AF was diagnosed in 74 out of 259 patients (28.6%), detected early after ICM insertion (mean 48 ± 52 days) in 86.5% of patients. AF patients were older (72.6 vs 62.2; p < 0.001), had higher pre-stroke CHA₂DS₂-VASc score (median 3 vs 2; p < 0.001) and admission NIHSS (median 2 vs 1; p = 0.001); and more often hypertension (p = 0.045) and dyslipidaemia (p = 0.005) than non-AF patients. The arrhythmia was recurrent in 91.9% and asymptomatic in 93.2%. At 12-month follow-up anticoagulants usage was 97.3%.
Discussion and conclusions:
ICM was an effective tool for diagnosing underlying AF, capturing AF in 29% of the CS and TIA patients. AF was asymptomatic in most cases and would mainly have gone undiagnosed without ICM. The insertion and use of ICM was feasible for stroke physicians in stroke units.
Graphical abstract
Objective. Based on the function of fractalkine (CX3CL1), the unique member of the CX3C chemokine subfamily, in endothelial-related inflammation, we hypothesized a role for CX3CL1 and its receptor ...(CX3CR) in Wegener's granulomatosis (WG). In the present study, this hypothesis was tested by different experimental approaches. Methods. We examined plasma levels of CX3CL1 (enzyme immunoassay) and CX3CR1 expression in peripheral blood mononuclear cells (PBMCs) (real-time quantitative RT-PCR and flow cytometry) in 18 WG patients and 15 healthy controls. In eight of these individuals, we also examined CX3CR1-mediated chemotaxis and adhesion in T cells and monocytes as well as the effects of CX3CL1 on monocyte chemoattractant protein (MCP) 1 levels in PBMC supernatants. Results. Our main findings were: (i) WG patients had markedly increased plasma levels of CX3CL1, with particularly high levels in those with active disease, (ii) These increased CX3CL1 levels were accompanied by enhanced expression of its corresponding receptor, CX3XR1, in PBMC, primarily reflecting an increased proportion of CX3CR1+CD3+CD4+ T cells and (iii) The up-regulation of CX3CR1 in PBMC from WG patients affected their functional potential as shown by CX3CL1-induced enhancement of chemotaxis, adhesion, responses as well as MCP-1 stimulation. Conclusion. Based on the ability of CX3CL1 to promote leucocyte infiltration into the vessel wall of inflammatory levels, it is tempting to hypothesize that increased CX3CL1/CX3CR1 interaction could be involved in the pathogenesis of the granulomatous vasculitis characterizing WG.
SUMMARY
To gain further insight into the possible role of interleukin (IL)‐18 in HIV‐1 infection we examined serum levels of IL‐18 in various clinical and immunological stages of HIV‐1 infection ...during cross‐sectional (n = 41) and longitudinal testing (n = 20) and during HAART (n = 21, 24 months follow‐up). Our main findings were that HIV‐1‐infected patients had significantly raised IL‐18 levels comparing healthy controls, particularly in those with advanced disease, that while HAART induced a marked decline in IL‐18, virological treatment failure was associated with persistently raised IL‐18 levels during such therapy and that our in vitro experiments showed an IL‐18‐mediated up‐regulation of the HIV‐1 coreceptor CXCR4 and the pro‐apoptotic mediator TRAIL in PBMC from HIV‐1‐infected patients receiving HAART. HIV‐1 infection appears to be characterized by persistently raised IL‐18 levels and during HAART, such a pattern was associated with virological treatment failure, possibly contributing to immunodeficiency and HIV‐1 replication in these patients.
Background: Enhanced activity of matrix metalloproteinases (MMPs) has been reported to have a pathogenic role in several diseases such as cancer and cardiovascular disorders, and seems also to play a ...part in certain autoimmune diseases. Objective: To examine whether enhanced MMP activity may also have a role in the pathogenesis of Wegener’s granulomatosis (WG). Methods: In a study group of 15 patients with WG and 15 controls, plasma levels and gene expression were measured in freshly isolated peripheral blood mononuclear cells (PBMCs) of several MMPs and their endogenous inhibitors (that is, tissue inhibitors of metalloproteinases (TIMPs)) by enzyme immunoassays and RNase protection assay, respectively. Results: Whereas patients with WG in remission had enhanced gene expression of several MMPs and TIMPs in PBMCs, those with active disease had a selective up regulation of MMP-2 and MMP-8 compared with healthy controls, and a down regulation of TIMP-1 and TIMP-3 compared with other patients with WG. Moreover, plasma levels of TIMP-1 and MMP-8 correlated significantly with C reactive protein levels, further supporting an association between activation of the MMP/TIMP system and disease activity in WG. Finally, these changes in MMP/TIMP expression in WG were accompanied by increased total MMP activity in PBMC supernatants, particularly in those with active disease, suggesting a matrix degrading net effect. Conclusion: These findings suggest that disturbed MMP and TIMP activity has a role in the pathogenesis of WG.
Summary
Chemokines, a group of cytokines that attracts and activates leucocyte subpopulations in inflamed tissue, have been associated with the pathogenesis of a number of inflammatory diseases, and ...some recent reports have suggested their involvement in Wegener's granulomatosis (WG). To elucidate further the possible role of chemokines in WG we examined serum levels of several CC‐ and CXC‐chemokines in WG patients and assessed the ability of corticosteroids to modulate the expression of these mediators in vitro. Our main findings were: (i) WG patients (n = 14) had elevated serum levels of several inflammatory chemokines i.e. regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)‐1 and interleukin (IL)‐8 compared to healthy controls (n = 9), as assessed by enzyme immunoassays (EIAs); (ii) by using EIAs and real‐time reverse transcription‐polymerase chain reaction (RT‐PCR), we demonstrated the ability of methylprednisolone (MP) to down‐regulate both the spontaneous and the staphylococcal enterotoxin B (SEB)‐induced release of chemokines from peripheral blood mononuclear cells (PBMC) in vitro in both WG patients and controls, possibly involving both transcriptional and post‐transcriptional mechanisms; and (iii) the ability of MP to attenuate chemokine secretion was less pronounced in WG patients than in controls, particularly with regard to inhibition of spontaneous release. Our findings suggest a role for chemokines in the pathogenesis of WG. The diminished MP‐mediated suppression of chemokines in PBMC from WG patients suggests that more specific modulators of chemokine levels should be investigated in this disorder.
SUMMARY
Common variable immunodeficiency (CVID) represents a heterogeneous group of antibody deficiency syndromes, characterized by defective antibody production in which T cell deficiency may play a ...pathogenic role. A subgroup of CVID patients has impaired in vitro T cell proliferation. Using microarray analyses of T cells from these patients, we found a gene expression pattern different from healthy controls and patients with X‐linked agammaglobulinaemia. The profile of the differentially expressed genes suggests enhanced cytotoxic effector functions, antigen experienced or chronically activated T cells and a predominance of CCR7– T cells. Further experiments using flow cytometry revealed a striking predominance of CCR7– T cells in a subgroup of CVID patients, and an association with impaired T cell proliferation. Our observations indicate that a predominance of CCR7– T cells with effector‐memory cell features and with reduced proliferative capacity may characterize a subgroup of CVID.
Background Studies in different animal models and plasma analyses in humans suggest that members of the interleukin‐6 (IL‐6) cytokine family may be involved in the pathogenesis of congestive heart ...failure (CHF). Accordingly, we have examined IL‐6‐related cytokines in chronic CHF in humans by analysing gene and protein expression in myocardium derived from patients with end‐stage heart failure and donor hearts.
Methods Gene expression of cytokines/receptors of the IL‐6 family was documented in myocardial samples using cDNA array hybridization and RNase protection assays. Immunohistochemistry was used to detect leukaemia inhibitory factor (LIF), IL‐6 and glycoprotein 130 (gp130) in myocardial tissues.
Results Myocardial gene activity was documented for the majority of IL‐6 family cytokines and their receptors. Immunohistochemical analysis localized IL‐6, LIF and their common receptor subunit gp130 to myocytes and vascular smooth muscle cells. LIF mRNA levels were enhanced in the left ventricles of CHF patients relative to the left ventricles of donor hearts (patients 4·6 ± 4·7 vs. donors 0·3 ± 0·3, P < 0·005). Myocardial IL‐6 and gp130 mRNA levels were not statistically different between patients and donors, but in contrast to LIF mRNA expression in heart explants, gp130 mRNA levels were significantly higher in left atrium compared with left ventricle in both patients and donors.
Conclusions Both mRNA and proteins of gp130 and its ligands IL‐6 and LIF are expressed in both nonfailing and failing human myocardium. The elevated LIF mRNA levels in left ventricles from patients with end‐stage heart failure suggest a role for LIF in the pathogenesis of CHF.
Summary
We examined the effect of interferon (IFN)‐α on the expression of 375 genes relevant to inflammatory and immunological reactions in peripheral blood mononuclear cells (PBMC) from HIV‐infected ...patients by cDNA expression array and real‐time quantitative RT‐PCR. Our main findings were: (i) IFN‐α induced up‐regulation of several genes in the tumour necrosis factor (TNF) superfamily including the ligands APRIL, FasL, TNF‐α and TRAIL, with particularly enhancing effects on the latter in HIV‐infected patients. (ii) While IFN‐α markedly up‐regulated the expression of anti‐angionetic ELR– CXC‐chemokines (e.g. MIG and IP‐10), it suppressed the expression of angiogenic ELR+ CXC‐chemokines (e.g. GRO‐α, IL‐8 and ENA‐78), with similar patterns in both patients and controls. (iii) IFN‐α induced a marked increase in gene expression of the HIV co‐receptor CCR5 in both patients and controls. We suggest that these effects may contribute to both the therapeutic and toxic effects of IFN‐α. Moreover, our findings underscore that the biological effects of IFN‐α in HIV infection are complex and that the clinical net effects of IFN‐α treatment may be difficult to predict. However, the potent enhancing effect of IFN‐α on several pro‐apoptotic genes in the TNF superfamily and the enhancing effect on CCR5 expression suggest a possible pathogenic role of IFN‐α in the progression of HIV‐related immunodeficiency and suggests caution in the therapeutic use of IFN‐α in HIV‐infected individuals.
Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct ...etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management.
Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis.
After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA
DS
-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091).
Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal.
ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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