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Disabling Disorder (disabling + disorder)
Selected AbstractsDysregulation of the BMP-p38 MAPK Signaling Pathway in Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP),,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2006Jennifer L Fiori Abstract FOP is a disabling disorder in which skeletal muscle is progressively replaced with bone. Lymphocytes, our model system for examining BMP signaling, cannot signal through the canonical Smad pathway unless exogenous Smad1 is supplied, providing a unique cell type in which the BMP,p38 MAPK pathway can be examined. FOP lymphocytes exhibit defects in the BMP,p38 MAPK pathway, suggesting that altered BMP signaling underlies ectopic bone formation in this disease. Introduction: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification of connective tissues. Whereas the primary genetic defect in this condition is unknown, BMP4 mRNA and protein and BMP receptor type IA (BMPRIA) protein are overexpressed in cultured lymphocytes from FOP patients, supporting that altered BMP signaling is involved in this disease. In this study, we examined downstream signaling targets to study the BMP,Smad and BMP,p38 mitogen-activated protein kinase (MAPK) pathways in FOP. Materials and Methods: Protein phosphorylation was assayed by immunoblots, and p38 MAPK activity was measured by kinase assays. To examine BMP target genes, the mRNA expression of ID1, ID3, and MSX2 was determined by quantitative real-time PCR. Statistical analysis was performed using Student's t -test or ANOVA. Results: FOP lymphocytes exhibited increased levels of p38 phosphorylation and p38 MAPK activity in response to BMP4 stimulation. Furthermore, in response to BMP4, FOP cells overexpressed the downstream signaling targets ID1 by 5-fold and ID3 by 3-fold compared with controls. ID1 and ID3 mRNA induction was specifically blocked with a p38 MAPK inhibitor, but not extracellular signal-related kinase (ERK) or c-Jun N-terminal kinase (JNK) inhibitors. MSX2, a known Smad pathway target gene, is not upregulated in control or FOP cells in response to BMP, suggesting that lymphocytes do not use this limb of the BMP pathway. However, introduction of Smad1 into lymphocytes made the cells competent to regulate MSX2 mRNA after BMP4 treatment. Conclusions: Lymphocytes are a cell system that signals primarily through the BMP,p38 MAPK pathway rather than the BMP,Smad pathway in response to BMP4. The p38 MAPK pathway is dysregulated in FOP lymphocytes, which may play a role in the pathogenesis of FOP. [source] Fibrodysplasia Ossificans Progressiva (FOP), a Disorder of Ectopic Osteogenesis, Misregulates Cell Surface Expression and Trafficking of BMPRIA,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Lourdes Serrano de la Peņa Abstract FOP is a disorder in which skeletal muscle is progressively replaced with bone. FOP lymphocytes, a model system for exploring the BMP pathway in these patients, exhibit a defect in BMPRIA internalization and increased activation of downstream signaling, suggesting that altered BMP receptor trafficking underlies ectopic bone formation in this disease. Introduction: Fibrodysplasia ossificans progressiva (FOP) is a severely disabling disorder characterized by progressive heterotopic ossification of connective tissues. Whereas the genetic defect and pathophysiology of this condition remain enigmatic, BMP4 mRNA and protein are overexpressed, and mRNAs for a subset of secreted BMP antagonists are not synthesized at appropriate levels in cultured lymphocytes from FOP patients. These data suggest involvement of altered BMP signaling in the disease. In this study, we investigate whether the abnormality is associated with defective BMP receptor function in lymphocytes. Materials and Methods: Cell surface proteins were quantified by fluorescence-activated cell sorting (FACS). Protein phosphorylation was assayed by immunoprecipitation and immunoblotting. Protein synthesis and degradation were examined by [35S]methionine labeling and pulse-chase assays. mRNA was detected by RT-PCR. Results: FOP lymphocytes expressed 6-fold higher levels of BMP receptor type IA (BMPRIA) on the cell surface compared with control cells and displayed a marked reduction in ligand-stimulated internalization and degradation of BMPRIA. Moreover, in control cells, BMP4 treatment increased BMPRIA phosphorylation, whereas BMPRIA showed ligand-insensitive constitutive phosphorylation in FOP cells. Our data additionally support that the p38 mitogen-activated protein kinase (MAPK) signaling pathway is a major BMP signaling pathway in these cell lines and that expression of inhibitor of DNA binding and differentiation 1 (ID-1), a transcriptional target of BMP signaling, is enhanced in FOP cells. Conclusions: These data extend our previous observations of misregulated BMP4 signaling in FOP lymphocytes and show that cell surface overabundance and constitutive phosphorylation of BMPRIA are associated with a defect in receptor internalization. Altered BMP receptor trafficking may play a significant role in FOP pathogenesis. [source] Guidelines for the Management of Rheumatoid Arthritis 2002 UpdateJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 10 2002APRN-C, Mary Jo Goolsby EdD Rheumatoid arthritis (RA) is a progressive polyarthritis that is responsible for over nine million office visits annually. It is likely that most nurse practitioners will care for one or more patients with RA because approximately 1% of the adult population is affected by this disabling disorder. The guideline reviewed in this month's column describes the recommended care of patients who have been previously diagnosed with RA. [source] Current Understandings on Complex Regional Pain SyndromePAIN PRACTICE, Issue 2 2009Marissa De Mos MD Abstract The mechanisms underlying complex regional pain syndrome (CRPS) have been increasingly studied over the past decade. Classically, this painful and disabling disorder was considered to emerge from pathology of the central nervous system. However, the involvement of additional peripheral disease mechanisms is likely, and recently these mechanisms have also attracted scientific attention. The present article provides an overview of the current understandings regarding pathology of the autonomic and somatic nervous system in CRPS, as well as the roles of neurogenic inflammation, hypoxia, and the contribution of psychological factors. Potential connections between the separate disease mechanisms will be discussed. Additionally, currently known risk factors for CRPS will be addressed. Insight into risk factors is of relevance as it facilitates early diagnosis and tailored treatment. Moreover, it may provide clues for further unraveling of the pathogenesis and etiology of CRPS. [source] The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: Two years' follow-up of the randomized controlled trialANNALS OF NEUROLOGY, Issue 1 2004Marius A. Kemler MD Chronic reflex sympathetic dystrophy is a painful, disabling disorder for which no treatment with proven effect is available. We performed a randomized trial in a 2 to 1 ratio of patients, in which 36 patients were treated with spinal cord stimulation and physical therapy (SCS+PT), and 18 patients received solely PT. Twenty-four SCS+PT patients were given a permanent spinal cord stimulation system after successful test stimulation; the remaining 12 patients received no permanent system. We assessed pain intensity, global perceived effect, functional status, and health-related quality of life. Patients were examined before randomization, before implantation, and also at 1, 3, 6, 12, and 24 months thereafter. At 2 years, three patients were excluded from the analysis. The intention-to-treat analysis showed improvements in the SCS+PT group concerning pain intensity (,2.1 vs 0.0cm; p < 0.001) and global perceived effect (43% vs 6% "much improved"; p = 0.001). There was no clinically important improvement of functional status. Health-related quality of life improved only in the group receiving spinal cord stimulation. After careful selection and successful test stimulation, spinal cord stimulation results in a long-term pain reduction and health-related quality of life improvement in chronic reflex sympathetic dystrophy. [source] Prevalence of narcolepsy with cataplexy in NorwayACTA NEUROLOGICA SCANDINAVICA, Issue 4 2009M. S. Heier Objectives,,, Narcolepsy is a lifelong disabling disorder that may be alleviated by relevant treatment. Patients frequently report 10,15 years from the first symptoms to the time they get the diagnosis and treatment can be started. In order to offer a sufficient diagnostic and therapeutic service to this patient group, a reliable estimation of the prevalence of the disorder is important. A study of the prevalence of narcolepsy with cataplexy in Norway was therefore undertaken. Materials and methods,,, The Ullanlinna Narcolepsy scale (UNS) was sent to 14548 randomly selected Norwegians between 20 and 60 years. Additionally, the study included telephone interviews and clinical evaluation of responders with ,14 points on the UNS, and in those with suspected narcolepsy, polygraphic sleep recordings and human leucocyte antigen (HLA)-typing. Results,,, A total of 8992 responders answered the questionnaire (response rate 61.8%), 267 had ,14 points on the UNS, 156 were interviewed and 15 had sleep recordings. In two HLADQB1*0602-positive patients sleep recordings were compatible with narcolepsy. Conclusions,,, The results indicate a prevalence of 0.022% and approximately 1000 patients with narcolepsy with cataplexy in Norway. [source] | ||||||||||