Impact of impaired fractional flow reserve after coronary interventions on outcomes: a systematic review and meta-analysis

BACKGROUND: FFR is routinely used to guide percutaneous coronary interventions (PCI). Visual assessment of the angiographic result after PCI has limited efficacy. Even when the angiographic result seems satisfactory FFR after a PCI might be useful for identifying patients with a suboptimal interventional result and higher risk for poor clinical outcome who might benefit from additional procedures. The aim of this meta-analysis was to investigate available data of studies that examined clinical outcomes of patients with impaired vs. satisfactory fractional flow reserve (FFR) after percutaneous coronary interventions (PCI). METHODS: This meta-analysis was carried out according to the Cochrane Handbook for Systematic Reviews. The Mantel-Haenszel method using the fixed-effect meta-analysis model was used for combining the results. Studies were identified by searching the literature through mid-January, 2016, using the following search terms: fractional flow reserve, coronary circulation, after, percutaneous coronary intervention, balloon angioplasty, stent implantation, and stenting. Primary endpoint was the rate of major adverse cardiac events (MACE). Secondary endpoints included rates of death, myocardial infarction (MI), repeated revascularisation. RESULTS: Eight relevant studies were found including a total of 1337 patients. Of those, 492 (36.8 %) had an impaired FFR after PCI, and 853 (63.2 %) had a satisfactory FFR after PCI. Odds ratios indicated that a low FFR following PCI was associated with an impaired outcome: major adverse cardiac events (MACE, OR: 4.95, 95 % confidence interval [CI]: 3.39–7.22, p <0.001); death (OR: 3.23, 95 % CI: 1.19–8.76, p = 0.022); myocardial infarction (OR: 13.83, 95 % CI: 4.75–40.24, p <0.0001) and repeated revascularisation (OR: 4.42, 95 % CI: 2.73–7.15, p <0.0001). CONCLUSIONS: Compared to a satisfactory FFR, a persistently low FFR following PCI is associated with a worse clinical outcome. Prospective studies are needed to identify underlying causes, determine an optimal threshold for post-PCI FFR, and clarify whether simple additional procedures can influence the post-PCI FFR and clinical outcome. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12872-016-0355-7) contains supplementary material, which is available to authorized users

Toll-Like Receptor 2 Induced Angiogenesis and Invasion Is Mediated through the Tie2 Signalling Pathway in Rheumatoid Arthritis

BACKGROUND: Angiogenesis is a critical early event in inflammatory arthritis, facilitating leukocyte migration into the synovium resulting in invasion and destruction of articular cartilage and bone. This study investigates the effect of TLR2 on angiogenesis, EC adhesion and invasion using microvascular endothelial cells and RA whole tissue synovial explants ex-vivo. METHODS: Microvascular endothelial cells (HMVEC) and RA synovial explants ex vivo were cultured with the TLR2 ligand, Pam3CSK4 (1 µg/ml). Angiopoietin 2 (Ang2), Tie2 and TLR2 expression in RA synovial tissue was assessed by immunohistology. HMVEC tube formation was assessed using Matrigel matrix assays. Ang2 was measured by ELISA. ICAM-1 cell surface expression was assessed by flow cytometry. Cell migration was assessed by wound repair scratch assays. ECM invasion, MMP-2 and -9 expression were assessed using transwell invasion chambers and zymography. To examine if the angiopoietin/Tie2 signalling pathway mediates TLR2 induced EC tube formation, invasion and migration assays were performed in the presence of a specific neutralising anti-Tie2mAb (10 ug/ml) and matched IgG isotype control Ab (10 ug/ml). RESULTS: Ang2 and Tie2 were localised to RA synovial blood vessels, and TLR2 was localised to RA synovial blood vessels, sub-lining infiltrates and the lining layer. Pam3CSK4 significantly increased angiogenic tube formation (p<0.05), and upregulated Ang2 production in HMVEC (p<0.05) and RA synovial explants (p<0.05). Pam3CSK4 induced cell surface expression of ICAM-1, from basal level of 149±54 (MFI) to 617±103 (p<0.01). TLR-2 activation induced an 8.8±2.8 fold increase in cell invasion compared to control (p<0.05). Pam3CSK4 also induced HMVEC cell migration and induced MMP-2 and -9 from RA synovial explants. Neutralisation of the Ang2 receptor, Tie2 significantly inhibited Pam3CSK4-induced EC tube formation and invasion (p<0.05). CONCLUSION: TLR2 activation promotes angiogenesis, cell adhesion and invasion, effects that are in part mediated through the Tie2 signalling pathway, key mechanisms involved in the pathogenesis of RA

Psycho-education programme for temporomandibular disorders: a pilot study

BACKGROUND: Temporomandibular disorders (TMDs) are by far the most predominant condition affecting the temporomandibular joint (TMJ), however many patients have mild self-limiting symptoms and should not be referred for specialist care. The aim of this pilot study was to develop a simple, cost-effective management programme for TMDs using CD-ROM. 41 patients (age 18–70) participated in this study, patients were divided into three groups: the 1st group were involved in an attention placebo CD-ROM (contain anatomical information about the temporomandibular system), the 2nd group received information on CD-ROM designed to increase their control and self efficacy, while the 3rd group received the same programme of the 2nd group added to it an introduction to self-relaxing techniques followed by audio tape of progressive muscle relaxation exercises. Each of the groups was asked to complete a number of questionnaires on the day of initial consultation and six weeks afterwards. RESULTS: The two experimental groups (2nd & 3rd) were equally effective in reducing pain, disability and distress, and both were more effective than the attention placebo group (1st), however the experimental groups appeared to have improved at follow-up relative to the placebo-group in terms of disability, pain and depressed mood. CONCLUSION: This pilot study demonstrates the feasibility and acceptability of the design. A full, randomized, controlled trial is required to confirm the efficacy of the interventions developed here

Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy

Intravesical bacillus Calmette-Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS- and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer

VEGF, FGF1, FGF2 and EGF gene polymorphisms and psoriatic arthritis

BACKGROUND: Angiogenesis appears to be a first-order event in psoriatic arthritis (PsA). Among angiogenic factors, the cytokines vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factors 1 and 2 (FGF1 and FGF2) play a central role in the initiation of angiogenesis. Most of these cytokines have been shown to be upregulated in or associated with psoriasis, rheumatoid arthritis (RA) or ankylosing spondylitis (AS). As these diseases share common susceptibility associations with PsA, investigation of these angiogenic factors is warranted. METHODS: Two hundred and fifty-eight patients with PsA and 154 ethnically matched controls were genotyped using a Sequenom chip-based MALDI-TOF mass spectrometry platform. Four SNPs in the VEGF gene, three SNPs in the EGF gene and one SNP each in FGF1 and FGF2 genes were evaluated. Statistical analysis was performed using Fisher's exact test, and the Cochrane-Armitage trend test. Associations with haplotypes were estimated by using weighted logistic models, where the individual haplotype estimates were obtained using Phase v2.1. RESULTS: We have observed an increased frequency in the T allele of VEGF +936 (rs3025039) in control subjects when compared to our PsA patients [Fisher's exact p-value = 0.042; OR 0.653 (95% CI: 0.434, 0.982)]. Haplotyping of markers revealed no significant associations. CONCLUSION: The T allele of VEGF in +936 may act as a protective allele in the development of PsA. Further studies regarding the role of pro-angiogenic markers in PsA are warranted

Disease-associated pathophysiologic structures in pediatric rheumatic diseases show characteristics of scale-free networks seen in physiologic systems: implications for pathogenesis and treatment

<p>Abstract</p> <p>Background</p> <p>While standard reductionist approaches have provided some insights into specific gene polymorphisms and molecular pathways involved in disease pathogenesis, our understanding of complex traits such as atherosclerosis or type 2 diabetes remains incomplete. Gene expression profiling provides an unprecedented opportunity to understand complex human diseases by providing a global view of the multiple interactions across the genome that are likely to contribute to disease pathogenesis. Thus, the goal of gene expression profiling is not to generate lists of differentially expressed genes, but to identify the physiologic or pathogenic processes and structures represented in the expression profile.</p> <p>Methods</p> <p>RNA was separately extracted from peripheral blood neutrophils and mononuclear leukocytes, labeled, and hybridized to genome level microarrays to generate expression profiles of children with polyarticular juvenile idiopathic arthritis, juvenile dermatomyositis relative to childhood controls. Statistically significantly differentially expressed genes were identified from samples of each disease relative to controls. Functional network analysis identified interactions between products of these differentially expressed genes.</p> <p>Results</p> <p><it>In silico </it>models of both diseases demonstrated similar features with properties of scale-free networks previously described in physiologic systems. These networks were observable in both cells of the innate immune system (neutrophils) and cells of the adaptive immune system (peripheral blood mononuclear cells).</p> <p>Conclusion</p> <p>Genome-level transcriptional profiling from childhood onset rheumatic diseases suggested complex interactions in two arms of the immune system in both diseases. The disease associated networks showed scale-free network patterns similar to those reported in normal physiology. We postulate that these features have important implications for therapy as such networks are relatively resistant to perturbation.</p

Molecular detection (k-ras) of exfoliated tumour cells in the pelvis is a prognostic factor after resection of rectal cancer?

<p>Abstract</p> <p>Background</p> <p>After total mesorectal excision (TME) for rectal cancer around 10% of patients develops local recurrences within the pelvis. One reason for recurrence might be spillage of cancer cells during surgery. This pilot study was conducted to investigate the incidence of remnant cancer cells in pelvic lavage after resection of rectal cancer. DNA from cells obtained by lavage, were analysed by denaturing capillary electrophoresis with respect to mutations in hotspots of the <it>k-ras </it>gene, which are frequently mutated in colorectal cancer.</p> <p>Results</p> <p>Of the 237 rectal cancer patients analyzed, 19 had positive lavage fluid. There was a significant survival difference (p = 0.006) between patients with <it>k-ras </it>positive and negative lavage fluid.</p> <p>Conclusion</p> <p>Patients with <it>k-ras </it>mutated cells in the lavage immediately after surgery have a reduced life expectation. Detection of exfoliated cells in the abdominal cavity may be a useful diagnostic tool to improve the staging and eventually characterize patients who may benefit from aggressive multimodal treatment of rectal cancer.</p

Echium oil is not protective against weight loss in head and neck cancer patients undergoing curative radio(chemo)therapy: a randomised-controlled trial

Background: Therapy-induced mucositis and dysphagia puts head and neck (H&N) cancer patients at increased risk for developing cachexia. Omega-3 fatty acids (n-3 FA) have been suggested to protect against cachexia. We aimed to examine if echium oil, a plant source of n-3 FA, could reduce weight loss in H&N cancer patients undergoing radio(chemo)therapy with curative intent. Methods: In a double-blind trial, patients were randomly assigned to echium oil (intervention (I) group; 7.5 ml bis in die (b.i.d.), 235 mg/ml α-linolenic acid (ALA) + 95 mg/ml stearidonic acid (SDA) + 79 mg/ml γ-linolenic acid (GLA)) or n-3 FA deficient sunflower oil high oleic (control (C) group; 7.5 ml b.i.d.) additional to standard nutritional support during treatment. Differences in percentage weight loss between both groups were analysed according to the intention-to-treat principle. Erythrocyte FA profile, body composition, nutritional status and quality of life were collected. Results: Ninety-one eligible patients were randomised, of whom 83 were evaluable. Dietary supplement adherence was comparable in both groups (median, I: 87%, C: 81%). At week 4, the I group showed significantly increased values of erythrocyte n-3 eicosapentanoic acid (EPA, 14% vs −5%) and n-6 GLA (42% vs −20%) compared to the C group, without a significant change in n-6 arachidonic acid (AA, 2% vs −1%). Intention-to-treat analysis could not reveal a significant reduction in weight loss related to echium oil consumption (median weight loss, I: 8.9%, C: 7.6%). Also, no significant improvement was observed in the other evaluated anthropometric parameters. Conclusions: Echium oil effectively increased erythrocyte EPA and GLA FAs in H&N cancer patients. It failed however to protect against weight loss, or improve nutritional parameters. Trial registration: ClinicalTrials.gov Identifier NCT01596933