RESUMO
BACKGROUND: The shoulder is the most frequently dislocated joint in the body. Multiple causes and pathologies account for the various types of shoulder instability. Multi-directional instability (MDI) and multi-directional laxity with antero-inferior instability (MDL-AII) are similar in pathology, less common and more difficult to treat. These instabilities are caused by ligamentous capsular redundancy. When non-operative management fails for these patients, quality of life is significantly impaired and surgical treatment is required to tighten the ligaments and joint capsule. The current reference (gold) standard treatment for MDI/MDL-AII is an open inferior capsular shift (ICS) surgical procedure. An alternative treatment involves arthroscopic thermal shrinkage of redundant capsular tissue to tighten the joint. However, there is a lack of scientific evidence to support the use of this technique called, electrothermal arthroscopic capsulorrhaphy (ETAC). This trial will compare the effectiveness of ETAC to open ICS in patients with MDI and MDL-AII, using patient-based quality of life outcome assessments. METHODS: This study is a multi-centre randomized clinical trial with a calculated sample size of 58 patients (p = 0.05, 80% power). Eligible patients are clinically diagnosed with MDI or MDL-AII and have failed standardized non-operative management. A diagnostic shoulder arthroscopy is performed to confirm eligibility, followed by intra-operative randomization to the ETAC or ICS surgical procedure. The primary outcome is the disease-specific quality of life questionnaire (Western Ontario Shoulder Instability Index), measured at baseline, 3, 6, 12 and 24 months. Secondary outcomes include shoulder-specific measures (American Shoulder and Elbow Surgeons Score and Constant Score). Other outcomes include recurrent instability, complications and operative time. The outcome measurements will be compared on an intention-to-treat basis, using two-sample independent t-tests to assess statistical significance. A Generalized Estimated Equations (GEE) analysis will determine whether there is an effect over time. DISCUSSION: This ongoing trial has encountered unexpected operational and practical issues, including slow patient enrollment due to high intra-operative exclusion rates. However, the authors have a greater understanding of multi-directional laxity in the shoulder and anticipate the results of this trial will provide the medical community with the best scientific clinical evidence on the efficacy of ETAC compared to open ICS.
RESUMO
Signal transducers and activators of transcription (STATs) are critical intracellular signaling molecules for many cytokines. We compared the ability of T84 epithelial cells to activate STATs in response to cytokines [interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-10, and tumor necrosis factor-alpha (10 ng/ml)] and conditioned medium from superantigen [Staphylococcus aureus enterotoxin B (SEB)]-activated peripheral blood mononuclear cells (PBMC) using electrophoretic mobility shift assays (EMSA). Of the cytokines tested, only IFN-gamma caused a STAT-1 response. Exposure to SEB-PBMC-conditioned medium resulted in STAT-1 or STAT-1/3 activation, and inclusion of anti-IFN-gamma antibodies in the conditioned medium abolished the STAT-1 signal. Cells treated with transcription factor decoys, DNA oligonucleotides bearing the STAT-1 recognition motif, and then SEB-PBMC-conditioned medium displayed a reduced STAT-1 signal on EMSA, yet this treatment did not prevent the drop in transepithelial resistance (measured in Ussing chambers) caused by SEB-PBMC-conditioned medium. In contrast, the phosphatidylinositol 3'-kinase (PI 3-K) inhibitor LY-294002 significantly reduced the drop in transepithelial resistance caused by SEB-PBMC-conditioned medium. Thus data are presented showing STAT-1 (+/-STAT-3) and PI 3-K activation in epithelial cells in response to immune mediators released by superantigen immune activation. Although the involvement of STAT-1/-3 in the control of barrier function remains a possibility, PI-3K has been identified as a regulator of T84 paracellular permeability.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Mucosa Intestinal/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Superantígenos/farmacologia , Transativadores/metabolismo , Antineoplásicos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Células Cultivadas , Cromonas/farmacologia , Colo/citologia , Impedância Elétrica , Enterotoxinas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Genisteína/farmacologia , Humanos , Imidazóis/farmacologia , Interferon gama/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/farmacologia , Fator de Transcrição STAT1 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Interleukins 4 and 13 can affect their target cells by activation of signal transducer and activator of transcription 6 (STAT 6) or phosphatidylinositol 3-kinase (PI3K). We examined the signal transduction events involved in IL-4 and IL-13 regulation of epithelial paracellular permeability using T84 cells, a model human colonic epithelium. T84 cells treated with IL-4 or IL-13 displayed virtually identical dose- and time-dependent STAT 6 activation as assessed by electrophoretic mobility shift assay (EMSA) and decreases in transepithelial resistance (TER). STAT 6 DNA binding activity was maximal in nuclear extracts 30 min after exposure to IL-4 or IL-13, and TER was maximally reduced by 24 h post-treatment. Pretreatment of epithelia with transcription factor decoys (phosphorothioated DNA oligonucleotides containing the STAT 6 binding site) dramatically reduced STAT 6 activation as detected by EMSA, but did not attenuate the TER reduction by IL-4 or IL-13. In contrast, although the PI3K inhibitors wortmannin and LY294002 did not affect IL-4 or IL-13 STAT 6 activation, they significantly inhibited the ability of either cytokine to lower TER. Thus, we provide evidence for PI3K as the major proximal signaling event in IL-4 and IL-13 regulation of TER and speculate that pharmacological targeting of enterocytic PI3K activity may represent a means to manipulate epithelial permeability.