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Established Disease (established + disease)
Selected AbstractsExamination of intravenous and intra-CSF protein delivery for treatment of neurological diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2009Kim M. Hemsley Abstract Mucopolysaccharidosis type IIIA is a neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Absent or greatly reduced activity of sulphamidase, a lysosomal protein, results in intracellular accumulation of heparan sulphate. Subsequent neuroinflammation and neurodegeneration typify this and many other lysosomal storage disorders. We propose that intra-cerebrospinal fluid protein delivery represents a potential therapeutic avenue for treatment of this and other neurodegenerative conditions; however, technical restraints restrict examination of its use prior to adulthood in mice. We have used a naturally-occurring Mucopolysaccharidosis type IIIA mouse model to determine the effectiveness of combining intravenous protein replacement (1 mg/kg) from birth to 6 weeks of age with intra-cerebrospinal fluid sulphamidase delivery (100 ,g, fortnightly from 6 weeks) on behaviour, the level of heparan sulphate-oligosaccharide storage and other neuropathology. Mice receiving combination treatment exhibited similar clinical improvement and reduction in heparan sulphate storage to those only receiving intra-cerebrospinal fluid enzyme. Reductions in micro- and astrogliosis and delayed development of ubiquitin-positive lesions were seen in both groups. A third group of intravenous-only treated mice did not exhibit clinical or neuropathological improvements. Intra-cerebrospinal fluid injection of sulphamidase effectively, but dose-dependently, treats neurological pathology in Mucopolysaccharidosis type IIIA, even when treatment begins in mice with established disease. [source] Conventional MRI in Multiple SclerosisJOURNAL OF NEUROIMAGING, Issue 2007Massimo Filippi MD ABSTRACT During the past 10 years, conventional magnetic resonance imaging (cMRI) has become an established tool for the assessment of patients with multiple sclerosis (MS) and to monitor treatment trials. This is mainly due to the sensitivity and reproducibility of cMRI in the detection of MS-related damage. A large effort has also been devoted to develop imaging strategies capable of providing accurate estimates of the extent of disease-related damage not only in the brain, but also in the spinal cord and optic nerve. Guidelines have been defined to integrate MR findings in the diagnostic evaluation of patients at presentation with clinically isolated syndromes suggestive of MS, and specific acquisition protocols have been offered for monitoring longitudinal changes in patients with established disease. Despite the fact that the role of cMRI in MS has been profoundly obviated by the advent of modern and quantitative MR techniques, several issues are still unresolved. Technical development in acquisition and postprocessing, as well as the introduction of high-field magnets in the clinical arena, are likely to increase our understanding of disease pathobiology, mainly through an increased ability to quantify the extent of gray matter damage. [source] Inflammatory cytokines in glomerulonephritisNEPHROLOGY, Issue 2002RC ATKINS SUMMARY: The importance of various inflammatory cytokines in mediating renal disease is now recognized, and the potential for the use of cytokine blockade as a therapeutic intervention is under active investigation. Studies in rat anti-glomerular basement membrane (GBM) disease model showed that antagonism of the proinflammatory cytokine IL-1 inhibited induction of glomerulonephritis, and prevented progression of established disease. A second cytokine Tumour Necrosis Factor-alpha (TNF-,) had similar proinflammatory effects to IL-1 in this model. Blocking the actions of both cytokines together, however, had no added benefit. Another cytokine Macrophage Migration Inhibitory Factor (MIF) has been shown to override the anti-inflammatory effects of corticosteriods. Renal MIF is markedly up-regulated in rat anti-GBM disease and blocking studies have demonstrated MIF plays a pathological role in mediating renal injury in this model. the importance of MIF in glomerulonephritis has been demonstrated by the fact that MIF is produced locally within the kidney, that it reflects the severity of the cellular immune response, and can be measured in the urine. Macrophage Migration Inhibitory Factor is up-regulated in human glomerular disease and correlates with loss of renal function and is thus a potential target for therapy for human glomerulonephritis. Thus, the inflammatory cytokines, IL 1, TNF-, and MIF each play a role in the immune/inflammatory process in glomerulonephritis. Blocking their action reduces disease and cytokine blocking agents have therapeutic potential. [source] Role of Th17 cells in human autoimmune arthritisARTHRITIS & RHEUMATISM, Issue 10 2010Jan Leipe Objective To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides. Methods Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage,specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell,inducing conditions were analyzed in vitro. Results The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients. Conclusion Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease. [source] Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone miceARTHRITIS & RHEUMATISM, Issue 7 2010Guo-Min Deng Objective Spleen tyrosine kinase (Syk) is involved in membrane-mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB × NZW)F1 lupus-prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus-prone mice and whether they result in improvement in skin disease and modification of established disease. Methods Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow. Results We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks. Conclusion Syk inhibition suppresses the development of lupus skin and kidney disease in lupus-prone mice, suppresses established disease in lupus-prone mice, and may represent a valuable treatment for patients with SLE. [source] Gene expression profiling in autoantibody-positive patients with arthralgia predicts development of arthritis,ARTHRITIS & RHEUMATISM, Issue 3 2010Lisa G. M. van Baarsen Objective To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers. Methods The study group comprised 109 anti,citrullinated protein antibody (ACPA), and/or rheumatoid factor,positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction. Results In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at-risk patients, based on differential expression of immune-related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN),mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8,156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN-mediated immunity and/or cytokine/chemokine-activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21,0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease. Conclusion The results of this study indicate that IFN-mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine. [source] Amphoteric liposomes enable systemic antigen-presenting cell,directed delivery of CD40 antisense and are therapeutically effective in experimental arthritisARTHRITIS & RHEUMATISM, Issue 4 2009Evangelos Andreakos Objective Mediation of RNA interference by oligonucleotides constitutes a powerful approach for the silencing of genes involved in the pathogenesis of inflammatory disease, but in vivo application of this technique requires effective delivery to immune cells and/or sites of inflammation. The aim of the present study was to develop a new carrier system to mediate systemic administration of oligonucleotides to rheumatoid arthritis (RA) joints, and to develop an antisense oligonucleotide (ASO),based approach to interfere with CD40,CD154 interactions in an experimental model of RA. Methods A novel liposomal carrier with amphoteric properties, termed Nov038, was developed and assessed for its ability to systemically deliver an ASO directed against CD40 (CD40-ASO). Male DBA/1 mice with collagen-induced arthritis were treated with Nov038-encapsulated CD40-ASO, and the effects of treatment on various parameters of disease activity, including clinical score, paw swelling, lymph node responses, and inflammatory cytokine production in the joints, were assessed. Results Nov038 was well tolerated, devoid of immune-stimulatory effects, and efficacious in mediating systemic oligonucleotide delivery to sites of inflammation. In mice with collagen-induced arthritis, Nov038 enabled the therapeutic administration of CD40-ASO and improved established disease, while unassisted CD40-ASO was ineffective, and anti,tumor necrosis factor , (anti-TNF,) treatment was less effective in this model. Nov038/CD40-ASO efficacy was attributed to its tropism for monocyte/macrophages and myeloid dendritic cells (DCs), resulting in rapid down-regulation of CD40, inhibition of DC antigen presentation, and reduction in collagen-specific T cell responses, as well as decreased levels of TNF,, interleukin-6 (IL-6), and IL-17 in arthritic joints. Conclusion Amphoteric liposomes represent a novel carrier concept for systemic and antigen-presenting cell,targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038/CD40-ASO constitutes a potent alternative to monoclonal antibody,based approaches for interfering with CD40,CD40L interactions. [source] Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritisARTHRITIS & RHEUMATISM, Issue 6 2007Milena Pitashny Objective Pathogenic monoclonal anti,double-stranded DNA (anti-dsDNA) antibodies up-regulate the expression of lipocalin-2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal anti-dsDNA antibodies promote the local secretion of lipocalin-2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin-2 represents a marker of kidney involvement in SLE. Methods Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross-sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin-2 were assessed. Results Among SLE patients, urinary lipocalin-2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3,45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1,20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0,11.1; n = 14), urinary levels of lipocalin-2 in SLE patients were significantly higher (non-normalized median 19.3 ng/ml, IQR 8,34.2) (P = 0.004). The presence of lipocalin-2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity. Conclusion The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin-2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE. [source] Mycobacterial Hsp65-IgG,expressing tolerogenic B cells confer protection against adjuvant-induced arthritis in Lewis ratsARTHRITIS & RHEUMATISM, Issue 5 2007Shailesh R. Satpute Objective Tolerization of T cells directed against a target autoantigen is a desired goal of experimental approaches for the treatment of autoimmune diseases, and novel and improved methods of tolerance induction are continuously being sought. Because most traditional methods of tolerance induction using soluble antigen are effective in the prevention of autoimmunity but fail to control established disease, this study was carried out to explore an innovative tolerogenic approach for the treatment of ongoing disease, using the rat adjuvant-induced arthritis (AIA) model of human rheumatoid arthritis. Methods Lewis (RT.1l) rats were injected subcutaneously with heat-killed Mycobacterium tuberculosis H37Ra to induce AIA. Before or after AIA induction, Lewis rats were treated intraperitoneally (IP) with tolerogenic B cells expressing a fusion construct of mycobacterial 65-kd heat-shock protein (Hsp65) and IgG heavy-chain. For comparison, control rats were treated IP with ovalbumin (OVA),IgG,expressing B cells or soluble mycobacterial Hsp65, and the effects on AIA were observed. We also tested the immune response to mycobacterial Hsp65 in B cell,tolerized rats. Results Administration of tolerogenic mycobacterial Hsp65,expressing B cells as well as soluble mycobacterial Hsp65, but not OVA-expressing B cells, resulted in a significant decrease in the severity of subsequent AIA. However, in rats with established disease, only the B cell regimen of mycobacterial Hsp65, but not the soluble antigen, suppressed ongoing AIA. Conclusion Mycobacterial Hsp65-IgG,expressing B cells can successfully attenuate the progression of AIA. This study introduces a promising approach for the treatment of arthritis that should be further explored. [source] REVIEW ARTICLE: Reducing fracture risk with calcium and vitamin DCLINICAL ENDOCRINOLOGY, Issue 3 2010Paul Lips Summary Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to adequate compliance. This study tries to define the types of patients, both at risk of osteoporosis and with established disease, who may benefit from calcium and vitamin D supplementation. The importance of adequate compliance in these individuals is also discussed. Calcium and vitamin D therapy has been recommended for older persons, either frail and institutionalized or independent, with key risk factors including decreased bone mineral density (BMD), osteoporotic fractures, increased bone remodelling as a result of secondary hyperparathyroidism and increased propensity to falls. In addition, treatment of osteoporosis with a bisphosphonate was less effective in patients with vitamin D deficiency. Calcium and vitamin D supplementation is a key component of prevention and treatment of osteoporosis unless calcium intake and vitamin D status are optimal. For primary disease prevention, supplementation should be targeted to those with dietary insufficiencies. Several serum 25-hydroxyvitamin D (25(OH)D) cut-offs have been proposed to define vitamin D insufficiency (as opposed to adequate vitamin D status), ranging from 30 to 100 nmol/l. Based on the relationship between serum 25(OH)D, BMD, bone turnover, lower extremity function and falls, we suggest that 50 nmol/l is the appropriate serum 25(OH)D threshold to define vitamin D insufficiency. Supplementation should therefore generally aim to increase 25(OH)D levels within the 50,75 nmol/l range. This level can be achieved with a dose of 800 IU/day vitamin D, the dose that was used in succesfull fracture prevention studies to date; a randomized clinical trial assessing whether higher vitamin D doses achieve a greater reduction of fracture incidence would be of considerable interest. As calcium balance is not only affected by vitamin D status but also by calcium intake, recommendations for adequate calcium intake should also be met. The findings of community-based clinical trials with vitamin D and calcium supplementation in which compliance was moderate or less have often been negative, whereas studies in institutionalized patients in whom medication administration was supervised ensuring adequate compliance demonstrated significant benefits. [source] | ||||||||||