CD4+CD25-Foxp3+ T cells as a marker of disease activity and organ damage in systemic lupus erythematosus patients.

INTRODUCTION: T regulatory cells (Treg) play an important role in the maintenance of immune cell homeostasis, as it has been reported that CD4+CD25+ T cells suppress the auto-reactive responses in autoimmune diseases such as systemic lupus erythematosus (SLE). The clinical significance of the recently identified population of CD4+CD25-Foxp3+ T cells and whether they are associated with particular organ involvement is still not clear. So, the aim of our study was to evaluate the presence of CD4+CD25-Foxp3+ cells in SLE patients in comparison to healthy controls and to determine whether their frequency is associated with disease activity and particular clinical manifestations in these SLE patients. MATERIAL AND METHODS: The frequency of CD4+CD25-Foxp3+ T cells was analyzed in 56 female SLE patients and 30 healthy female control subjects, using flow cytometry (FACS). CD4+CD25-Foxp3+ T cells were correlated with clinical and laboratory data and the SLE Disease Activity Index (SLEDAI). RESULTS: The level of CD4+CD25-Foxp3+ T cells was significantly increased in SLE patients (15.57 ±4.32%) as compared with the control group (2.46 ±0.65%). A significant correlation was observed for the percentage of CD4+CD25-Foxp3+ T cells with clinical disease activity scores and disease duration (r = 0.6, p < 0.001; r = 0.3, p = 0.02 respectively). It was also positively correlated with renal impairment and hematological involvement. CONCLUSIONS: Systemic lupus erythematosus patients exhibited an altered level of their CD4+Foxp3+ T cells with increased levels of CD4+CD25-Foxp3+ cells.

Biomechanical analysis using FEA and experiments of a standard plate method versus three cable methods for fixing acetabular fractures with simultaneous THA.

Acetabular fractures potentially account for up to half of all pelvic fractures, while pelvic fractures potentially account for over one-tenth of all human bone fractures. This is the first biomechanical study to assess acetabular fracture fixation using plates versus cables in the presence of a total hip arthroplasty, as done for the elderly. In Phase 1, finite element (FE) models compared a standard plate method versus 3 cable methods for repairing an acetabular fracture (type: anterior column plus posterior hemi-transverse) subjected to a physiological-type compressive load of 2207N representing 3 x body weight for a 75kg person during walking. FE stress maps were compared to choose the most mechanically stable cable method, i.e. lowest peak bone stress. In Phase 2, mechanical tests were then done in artificial hemipelvises to compare the standard plate method versus the optimal cable method selected from Phase 1. FE analysis results showed peak bone stresses of 255MPa (Plate method), 205MPa (Mears cable method), 250MPa (Kang cable method), and 181MPa (Mouhsine cable method). Mechanical tests then showed that the Plate method versus the Mouhsine cable method selected from Phase 1 had higher stiffness (662versus 385N/mm, p=0.001), strength (3210versus 2060N, p=0.009), and failure energy (8.8versus 6.2J, p=0.002), whilst they were statistically equivalent for interfragmentary sliding (p≥0.179) and interfragmentary gapping (p≥0.08). The Plate method had superior mechanical properties, but the Mouhsine cable method may be a reasonable alternative if osteoporosis prevents good screw thread interdigitation during plating.

Vitamin D receptor Fok1 & Bsm 1 Gene Polymorphisms in Systemic Lupus Erythematosus and Osteoarthritis: Autoimmune Inflammatory versus Degenerative Model.

Vitamin D deficiency has been described in SLE and OA. Low vitamin D level is prevalent in Egyptian SLE patients while controversial studies are present regarding its level in OA patients in Egypt. We investigated whether vitamin D receptor (VDR) genes Bsm1 and Fok1 polymorphisms could be used as genetic markers for the susceptibility to SLE and /or OA in a sample of Egyptian population. The study was carried out on 100 SLE patients, 100 osteoarthritic patients and 100 normal controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Our results showed a statistically significant difference in Fok1 genotype distribution between SLE and OA patients (p=0.001). In SLE group, the "f" allele was significantly over-represented where 30% had "f" allele compared to 0% in OA (P = 0.03). Fok1 ff genotypes showed a significant association with disease activity in SLE patients. In addition, the fb haplotype frequency was significantly higher in SLE patients than controls (P=0.01). In conclusion Fok1 genotype and f allelic frequencies may be susceptible risk factors for SLE rather than OA in Egyptian patients.

Obesity-related adipokines predict patient-reported shoulder pain.

BACKGROUND/AIMS: Increasingly, an inflammatory modulating effect of adipokines within synovial joints is being recognized. To date, there has been no work examining a potential association between the presence of adipokines in the shoulder and patient-reported outcomes. This study undertakes an investigation assessing these potential links. METHODS: 50 osteoarthritis patients scheduled for shoulder surgery completed a pre-surgery questionnaire capturing demographic information including validated, patient-reported function (Disabilities of the Arm, Shoulder, and Hand questionnaire) and pain (Short Form McGill Pain Questionnaire) measures. Synovial fluid (SF) samples were analyzed for leptin, adiponectin, and resistin levels using Milliplex MAP assays. Linear regression modeling was used to assess the association between adipokine levels and patient-reported outcomes, adjusted for age, sex, BMI, and disease severity. RESULTS: 54% of the cohort was female (n = 27). The mean age (SD) of the sample was 62.9 (9.9) years and the mean BMI (SD) was 28.1 (5.4) kg/m(2). From regression analyses, greater SF leptin and adiponectin levels, but not regarding resistin, were found to be associated with greater pain (p < 0.05). Adipokine levels were not associated with functional outcome scores. CONCLUSIONS: The identified association between shoulder-derived SF leptin and adiponectin and shoulder pain is likely explained by the pro-inflammatory characteristics of the adipokines and represents potentially important therapeutic targets.

Inflammatory predictors of ongoing pain 2 years following knee replacement surgery.

INTRODUCTION: The prevalence of unrelieved pain following total knee arthroplasty (TKA) is substantial. OBJECTIVE: We asked if cytokine markers of inflammation in preoperative serum or knee synovial fluid (SF) would predict pain 2 years following TKA. METHODS: Demographic data and functional outcomes were recorded at baseline and 2 years with the WOMAC index. Serum and SF tissue samples were collected at the time of surgery. Linear regression modeling was used to determine the relationship between SF/serum inflammatory markers and a lesser improvement in self reported pain at two years follow-up. RESULTS: Of our 28 patient cohort, significant correlations between serum and SF levels were found for IL-1ß (p<0.002), MIP-1ß (p<0.001), adiponectin (p<0.001) and leptin (p<0.001). Adjusted analysis showed that greater SF concentrations of TNF-α, MMP-13 and IL-6 were independent predictors of less pain improvement at two years follow-up (p<0.05). CONCLUSIONS: Those patients, having ongoing pain despite no clinical or radiological cause, may have an inflammatory profile characterizing a predisposition to ongoing pain after TKA. LEVEL OF EVIDENCE: Prognosis study, Level 2.

Chronic hepatitis C viral infection reduces NK cell frequency and suppresses cytokine secretion: Reversion by anti-viral treatment.

Impaired activity of NK (natural killer) cells has been proposed as a mechanism contributing to viral persistence and chronic infection in hepatitis C (HCV) infection. We aimed to assess the impact of HCV infection on NK cells regarding frequency, subset distribution, and cytotoxic and cytokine secretion functions, as well as IFN-alpha and ribavirin therapeutic effects on NK cells. Significant reduction of total NK frequency and the CD56(dim)16(+) subset was observed in chronic HCV patients. IFN-gamma expression upon stimulation with K562 was severely suppressed but cytotoxicity measured by CD107a expression was maintained. These adverse effects were reversed after treatment with pegylated IFN-alpha and ribavirin; however, these skewed functions were not recovered in treatment-resistant patients. Thus, HCV chronic infection severely affects NK functions, except for cytotoxicity. Altered NK cell frequency and cytokine secretion by HCV infection may contribute to impaired cellular immune response and virus persistence.

Mechanotransduction of extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase activity in smooth muscle is dependent on the extracellular matrix and regulated by matrix metalloproteinases.

Excessive wall stretch of distensible hollow organs in cardiovascular and urinary systems can activate matrix metalloproteinases (MMPs), thereby releasing matrix neoepitopes and growth factor ligands, leading to ERK1/2 activation. However, the role of MMPs in mechanotransduction of ERK1/2 signaling in the bladder is unknown. We examined bladders undergoing sustained distension over time, which provides a novel platform for smooth muscle mechanotransduction studies. Bladder distension ex vivo caused increased proliferation and MMP activity. Conditioned medium from distended compared with undistended bladders induced proliferation in bladder smooth muscle cells (BSMCs). When conditioned medium from distended bladders was used to proteolyze collagen type I matrices, matrices augmented BSMC proliferation, which was inhibited if bladders were distended in presence of broad-spectrum MMP inhibitors. Distension of ex vivo bladders also induced ERK1/2 phosphorylation in situ, which was dependent on MMP activity in the intact bladder. Similarly, stretching BSMCs in vitro induced increases in ERK1/2 activation and ERK1/2-dependent proliferation under discrete mechanical conditions, and distension conditioned medium itself induced MMP-dependent ERK1/2 activation in BSMCs. Overall, stretch-induced proliferation and ERK1/2 signaling in bladder tissue and BSMCs likely depend on secreted MMP activity. Identification of intermediaries between MMPs and ERK1/2 may elaborate novel mechanisms underlying mechanotransduction in bladder smooth muscle.