Super-enhancer mediated regulation of adult ß-globin gene expression: the role of eRNA and Integrator.

Super-enhancers (SEs) mediate high transcription levels of target genes. Previous studies have shown that SEs recruit transcription complexes and generate enhancer RNAs (eRNAs). We characterized transcription at the human and murine ß-globin locus control region (LCR) SE. We found that the human LCR is capable of recruiting transcription complexes independently from linked globin genes in transgenic mice. Furthermore, LCR hypersensitive site 2 (HS2) initiates the formation of bidirectional transcripts in transgenic mice and in the endogenous ß-globin gene locus in murine erythroleukemia (MEL) cells. HS2 3'eRNA is relatively unstable and remains in close proximity to the globin gene locus. Reducing the abundance of HS2 3'eRNA leads to a reduction in ß-globin gene transcription and compromises RNA polymerase II (Pol II) recruitment at the promoter. The Integrator complex has been shown to terminate eRNA transcription. We demonstrate that Integrator interacts downstream of LCR HS2. Inducible ablation of Integrator function in MEL or differentiating primary human CD34+ cells causes a decrease in expression of the adult ß-globin gene and accumulation of Pol II and eRNA at the LCR. The data suggest that transcription complexes are assembled at the LCR and transferred to the globin genes by mechanisms that involve Integrator mediated release of Pol II and eRNA from the LCR.

Regulation of RNA Polymerase II Transcription Initiation and Elongation by Transcription Factor TFII-I.

Transcription by RNA polymerase II (Pol II) is regulated by different processes, including alterations in chromatin structure, interactions between distal regulatory elements and promoters, formation of transcription domains enriched for Pol II and co-regulators, and mechanisms involved in the initiation, elongation, and termination steps of transcription. Transcription factor TFII-I, originally identified as an initiator (INR)-binding protein, contains multiple protein-protein interaction domains and plays diverse roles in the regulation of transcription. Genome-wide analysis revealed that TFII-I associates with expressed as well as repressed genes. Consistently, TFII-I interacts with co-regulators that either positively or negatively regulate the transcription. Furthermore, TFII-I has been shown to regulate transcription pausing by interacting with proteins that promote or inhibit the elongation step of transcription. Changes in TFII-I expression in humans are associated with neurological and immunological diseases as well as cancer. Furthermore, TFII-I is essential for the development of mice and represents a barrier for the induction of pluripotency. Here, we review the known functions of TFII-I related to the regulation of Pol II transcription at the stages of initiation and elongation.

Anti-inflammatory effects of sphingosine kinase modulation in inflammatory arthritis.

Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P(1) receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P(1) enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E(2) production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-alpha, IL-6, IL-1beta, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-alpha, IFN-gamma, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.

Intramuscular electrical stimulation for shoulder pain in hemiplegia: does time from stroke onset predict treatment success?

BACKGROUND: A randomized clinical has shown the effectiveness of intramuscular electrical stimulation for the treatment of poststroke shoulder pain. OBJECTIVE: Identify predictors of treatment success and assess the impact of the strongest predictor on outcomes. METHOD: This is a secondary analysis of a multisite randomized clinical trial of intramuscular electrical stimulation for poststroke shoulder pain. The study included 61 chronic stroke survivors with shoulder pain randomized to a 6-week course of intramuscular electrical stimulation (n = 32) versus a hemisling (n = 29). The primary outcome measure was Brief Pain Inventory Question 12. Treatment success was defined as > or = 2-point reduction in this measure at end of treatment and at 3, 6, and 12 months posttreatment. Forward stepwise regression was used to identify factors predictive of treatment success among participants assigned to the electrical stimulation group. The factor most predictive of treatment success was used as an explanatory variable, and the clinical trials data were reanalyzed. RESULTS: Time from stroke onset was most predictive of treatment success. Subjects were divided according to the median value of stroke onset: early (<77 weeks) versus late (> 77 weeks). Electrical stimulation was effective in reducing poststroke shoulder pain for the early group (94% vs 7%, P < .001) but not for the late group (31% vs 33%). Repeated-measure analysis of variance revealed significant treatment (P < .001), time from stroke onset (P = .032), and treatment by time from stroke onset interaction (P < .001) effects. CONCLUSIONS: Stroke survivors who are treated early after stroke onset may experience greater benefit from intramuscular electrical stimulation for poststroke shoulder pain. However, the relative importance of time from stroke onset versus duration of pain is not known.

Seronegative spondyloarthropathy--studies from the Asia Pacific region.

Recent therapeutic advances, in particular the use of anti-tumour necrosis factor (anti-TNF) agents, have revived interest in the seronegative spondyloarthropathies (SpA), a group of arthritides characterised by axial skeletal involvement and the absence of rheumatoid factor. The purpose of this article is to review the studies that have been done in the Asia Pacific region, as a broad understanding of the scope and severity of this group of diseases would enable rheumatologists and physicians in this part of the world to better manage their patients. The majority of genetic studies have focused on the associations of HLA-B27 with ankylosing spondylitis (AS) and SpA, while a few studies examined the associations of the CARD, IL-1, LMP2, TAP and TGF with AS. There are a handful of studies on the immunological responses to bacteria and cytokine levels in AS. The onset and clinical features of SpA have been reported from most countries in the region, but no data on patient outcomes, using current measurement tools such as the Bath Ankylosing Spondylitis Disease Activity index (BASDAI), is available. Validation of these instruments of measurement as well as classification criteria in different ethnic populations is necessary where no prior data exist. Future studies will likely be focused on better clinical characterisation of patient cohorts, particularly with regard to the use of currently used measurement tools for disease activity and spinal function and mobility, and the identification of the need for biologic therapy in each country.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

Elimination of Salmonella enterica serotype enteritidis in intestinal epithelial cells by mechanisms other than nitric oxide.

Production of nitric oxide (NO) by intestinal epithelial cells is induced after infection with Salmonella spp. or some other enteroinvasive bacteria. However, direct evidence of the role of NO in the elimination of intracellular pathogens in intestinal mucosa has not been established. This study investigated whether NO mediates killing of Salmonella enterica serovar Enteritidis in human intestinal epithelial cells by using parent Henle-407 cell line and a transfected cell line not capable of induced NO production (Henle-NO(def)). NO synthesis was studied as combined accumulation of nitrite and nitrate, as inducible nitric oxide synthase (iNOS) protein determined by Western blotting and as iNOS mRNA detected by reverse transcription (RT)-PCR. Although parent and Henle-NO(def) cells differed markedly in their ability to produce NO after infection, they eliminated S. Enteritidis equally, as determined by cfu counts. The presence of aminoguanidine, a selective iNOS inhibitor, during the infection blocked the production of NO but did not affect the elimination of the bacteria. These data suggest that NO does not have a direct role in the elimination of intracellular Salmonellae by human intestinal epithelial cells.

Are physiological changes experienced by healthy subjects during acu-TENS associated with acupuncture point sensations?

BACKGROUND: Transcutaneous electrical nerve stimulation over acupuncture points (acu-TENS) has been reported to improve clinical outcomes. The objectives of the present study were to investigate whether acupuncture point sensations were experienced during acu-TENS, and whether such sensations were associated with any concomitant changes in autonomic nervous system activity. METHODS: This study adopted a single-blinded, randomised, controlled trial methodology. A total of 36 healthy subjects were randomly assigned to an experimental group (acu-TENS on right LI4 and LI11 points); control group (acu-TENS to bilateral kneecaps); or placebo group (sham acu-TENS on right LI4 and LI11 points). Heart rate (HR), mean arterial blood pressure (MAP), SD of the NN interval (SDNN) and low frequency to high frequency ratio (LF/HF) were measured before, during and after intervention. The Hong Kong Chinese version of the Massachusetts General Hospital Acupuncture Sensation Scale (C-MMASS) index was used for quantifying the acupuncture point stimulation sensations. RESULTS: The experimental group showed a significant increase in HR (mean (SD) 73.5 (6.3) to 75.9 (6.7) bpm, p=0.027), MAP (88.5 (4.5) to 91.0 (4.1) mm Hg, p=0.004), SDNN (143.36 (8.58) to 153.69 (7.64) ms, p=0.002) and LF/HF (1.26 (0.19) to 1.31 (0.21), p=0.037) during the intervention. The control group showed a significant increase in SDNN (140.21 (8.72) to 143.39 (9.47) ms, p=0.009) and LF/HF (1.21 (0.09) to 1.23 (0.12), p=0.033). There were no significant physiological changes in the placebo group. Overall C-MMASS indices for the experimental, control and placebo groups were 3.23 (0.3), 2.14 (0.6) and 0.29 (0.32), respectively. The between-group difference was statistically significant (F=139.24, df=2, p<0.05). However, correlation analysis did not support any association between sensation intensity and physiological responses in any groups (γ ranged from -0.36 to 0.25). CONCLUSIONS: This study showed that 'acupuncture point sensations' were experienced during acu-TENS to LI4 and LI11, but such sensations were not associated with physiological responses induced during the stimulation.

Electrical stimulation for treating chronic poststroke shoulder pain using a fully implanted microstimulator with internal battery.

This case report describes the first stroke survivor with chronic poststroke shoulder pain treated with electrical stimulation delivered via a fully implanted microstimulator containing a rechargeable internal battery. In light of existing efficacy data for similar types of treatment, the investigational system described in this report was developed to address the limitations of previously evaluated electrical stimulation devices. A 58-yr-old male stroke survivor with chronic hemiparesis and chronic shoulder pain received up to 6 hrs of stimulation daily over 12 wks. The microstimulator was implanted percutaneously near the axillary nerve at the quadrilateral space, under local anesthesia during an outpatient procedure. The implantation procedure was well tolerated. There were no adverse events related to the implantation procedure or treatment (implanted peripheral nerve stimulation). Outcomes were obtained before treatment, after 12 wks of treatment, and at 3-mo follow-up. Question no. 12 of the Brief Pain Inventory was used as the primary outcome measure to evaluate response to treatment. Shoulder pain decreased from 8/10 before treatment to 4/10 after treatment and decreased further to 3/10 at 3-mo follow-up. Passive range of motion and motor function also improved after treatment. Sensation, shoulder subluxation, activities, and quality-of-life did not change. The feasibility, safety, and efficacy of implanted peripheral nerve stimulation to treat poststroke shoulder pain should be evaluated further in clinical trials already underway.

Identification of interleukin-7 as a candidate disease mediator in spondylarthritis.

OBJECTIVE: Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA. METHODS: Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor beta2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor alpha and IL-1beta. CONCLUSION: In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted.

Poststroke shoulder pain: its relationship to motor impairment, activity limitation, and quality of life.

OBJECTIVE: To assess the relationship between poststroke shoulder pain, upper-limb motor impairment, activity limitation, and pain-related quality of life (QOL). DESIGN: Cross-sectional, secondary analysis of baseline data from a multisite clinical trial. SETTING: Outpatient rehabilitation clinics of 7 academic medical centers. PARTICIPANTS: Volunteer sample of 61 chronic stroke survivors with poststroke shoulder pain and glenohumeral subluxation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured poststroke shoulder pain with the Brief Pain Inventory question 12 (BPI 12), a self-reported 11-point numeric rating scale (NRS) that assesses "worst pain" in the last 7 days. Motor impairment was measured with the Fugl-Meyer Assessment (FMA). Activity limitation was measured with the Arm Motor Ability Test (AMAT) and the FIM instrument. Pain-related QOL was measured with BPI question 23, a self-reported 11-point NRS that assesses pain interference with general activity, mood, walking ability, normal work, interpersonal relationships, sleep, and enjoyment of life. RESULTS: Stepwise regression analyses indicated that poststroke shoulder pain is associated with the BPI 23, but not with the FMA, FIM, or AMAT scores. CONCLUSIONS: Poststroke shoulder pain is associated with reduced QOL, but not with motor impairment or activity limitation.

Intramuscular electrical stimulation for hemiplegic shoulder pain: a 12-month follow-up of a multiple-center, randomized clinical trial.

OBJECTIVE: Assess the effectiveness of intramuscular electrical stimulation in reducing hemiplegic shoulder pain at 12 mos posttreatment. DESIGN: A total of 61 chronic stroke survivors with shoulder pain and subluxation participated in this multiple-center, single-blinded, randomized clinical trial. Treatment subjects received intramuscular electrical stimulation to the supraspinatus, posterior deltoid, middle deltoid, and upper trapezius for 6 hrs/day for 6 wks. Control subjects were treated with a cuff-type sling for 6 wks. Brief Pain Inventory question 12, an 11-point numeric rating scale was administered in a blinded manner at baseline, end of treatment, and at 3, 6, and 12 mos posttreatment. Treatment success was defined as a minimum 2-point reduction in Brief Pain Inventory question 12 at all posttreatment assessments. Secondary measures included pain-related quality of life (Brief Pain Inventory question 23), subluxation, motor impairment, range of motion, spasticity, and activity limitation. RESULTS: The electrical stimulation group exhibited a significantly higher success rate than controls (63% vs. 21%, P = 0.001). Repeated-measure analysis of variance revealed significant treatment effects on posttreatment Brief Pain Inventory question 12 (F = 21.2, P < 0.001) and Brief Pain Inventory question 23 (F = 8.3, P < 0.001). Treatment effects on other secondary measures were not significant. CONCLUSIONS: Intramuscular electrical stimulation reduces hemiplegic shoulder pain, and the effect is maintained for > or =12 mos posttreatment.

Triceps denervation as a predictor of elbow flexion contractures in C5 and C6 tetraplegia.

OBJECTIVE: To determine whether the existence of elbow flexion contractures in persons with C5 or C6 tetraplegia is related to a lack of residual voluntary triceps function and triceps denervation (ie, lower motoneuron damage). DESIGN: A retrospective study of impairment data from 74 arms to identify the incidence of elbow flexion contractures and the contributing factors toward this deformity. SETTING: Five spinal cord injury (SCI) rehabilitation centers in the United States, 1 in England, and 1 in Australia. PARTICIPANTS: Forty-three subjects with motor complete C5 or C6 traumatic SCI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Active and passive elbow extension, triceps voluntary muscle strength, and triceps response to electric stimulation. RESULTS: Subjects with weak voluntary triceps had significantly fewer and less severe elbow flexion contractures than those with paralyzed triceps ( P =.024). Subjects with completely denervated triceps (ie, no response to electric stimulation) had significantly more elbow flexion contractures than subjects with even a weak response to electric stimulation ( P =.003). Overall, 51% of the arms could not be passively extended to zero. Forty-six percent of the arms classified as C5 lacked full passive elbow extension, compared with 63% of the arms classified as C6 ( P =.302). CONCLUSIONS: A relationship has been found between elbow flexion contractures and lack of residual voluntary triceps and triceps denervation in subjects with C5 or C6 tetraplegia. There should be a greater awareness of the elbow flexion contractures that may develop as a result of this relationship. A better understanding of this deformity and its characteristics can lead to more effective clinical treatment and prevention strategies.

Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy.

OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in spondylarthropathy (SpA) synovitis. METHODS: Paired samples of synovial biopsy tissue as well as serum and synovial fluid (SF) from 41 patients with SpA and 20 patients with rheumatoid arthritis (RA) and serum samples from 20 healthy controls were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay for the presence of MMPs 1, 2, 3, and 9 and TIMPs 1 and 2. In addition, sera from 16 patients with ankylosing spondylitis (AS) and peripheral synovitis and 17 patients with AS and exclusively axial involvement were analyzed. An additional cohort of SpA patients was analyzed at baseline and after 12 weeks of infliximab treatment. RESULTS: Staining for MMPs and TIMPs showed a cellular and interstitial pattern in the synovial lining and sublining layers that was similar between the RA and SpA patients. Involvement of MMPs and TIMPs in SpA synovitis was suggested by the correlation with cellular infiltration, vascularization, and cartilage degradation. Higher serum levels of MMPs 3 and 9 were revealed in SpA and RA patients as compared with healthy controls. Production of MMP-3, but not MMP-9, in the serum reflected the presence of peripheral synovitis, as indicated by 1) the correlation between serum levels, SF levels (which were 1,000-fold higher than the serum levels), and synovial expression of MMP-3, 2) the increased levels of MMP-3 in AS patients with peripheral disease and not exclusively axial involvement, and 3) the correlation of serum and SF MMP-3 with parameters of synovial, but not systemic, inflammation. The modulation of the MMP/TIMP system by tumor necrosis factor alpha (TNFalpha) blockade was confirmed by the down-regulation of all MMPs and TIMPs in the synovium and a pronounced and rapid decrease of serum MMP-3. CONCLUSION: MMPs and TIMPs are highly expressed in SpA synovitis and mirror both the inflammatory and tissue-remodeling aspects of the local disease process. Serum MMP-3, originating from the inflamed joint, represents a valuable biomarker for peripheral synovitis. Modulation of the MMP/TIMP system by infliximab could contribute to the antiinflammatory and tissue-remodeling effects of TNFalpha blockade in SpA.

Intramuscular neuromuscular electric stimulation for poststroke shoulder pain: a multicenter randomized clinical trial.

OBJECTIVE: To assess the effectiveness of intramuscular neuromuscular electric stimulation (NMES) in reducing poststroke shoulder pain. DESIGN: Multicenter, single-blinded, randomized clinical trial. SETTING: Ambulatory centers of 7 academic rehabilitation centers in the United States. PARTICIPANTS: Volunteer sample of 61 chronic stroke survivors with shoulder pain and subluxation. INTERVENTION: Treatment subjects received intramuscular NMES to the supraspinatus, posterior deltoid, middle deltoid, and trapezius for 6 hours a day for 6 weeks. Control subjects were treated with a cuff-type sling for 6 weeks. Main outcome measure Brief Pain Inventory question 12 (BPI 12), an 11-point numeric rating scale administered in a blinded manner at the end of treatment, and at 3 and 6 months posttreatment. RESULTS: The NMES group exhibited significantly higher proportions of success based on the 3-point or more reduction in BPI 12 success criterion at the end of treatment (65.6% vs 24.1%, P<.01), at 3 months (59.4% vs 20.7%, P<.01), and at 6 months (59.4% vs 27.6%, P<.05). By using the most stringent "no pain" criterion, the NMES group also exhibited significantly higher proportions of success at the end of treatment (34.4% vs 3.4%, P<.01), at 3 months (34.4% vs 0.0%, P<.001), and at 6 months (34.4% vs 10.3%, P<.05). CONCLUSIONS: Intramuscular NMES reduces poststroke shoulder pain among those with shoulder subluxation and the effect is maintained for at least 6 months posttreatment.

Serum levels of matrix metalloproteinase 3 and macrophage colony-stimulating factor 1 correlate with disease activity in ankylosing spondylitis.

OBJECTIVE: To assess the usefulness of measuring serum matrix metalloproteinase 3 (MMP-3) and macrophage colony-stimulating factor (M-CSF) in patients with ankylosing spondylitis (AS). METHODS: Serum levels of MMP-3 and M-CSF were measured in AS patients who did and did not receive infliximab treatment. These were compared with those of 28 healthy subjects. RESULTS: In the group of AS patients not treated with biologics, both M-CSF and MMP-3 correlated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) values, but not with each other. Logistic regression analysis showed that MMP-3 values were high in those with severely active disease. Infusions of infliximab in AS patients led to a significant decrease in the values of the BASDAI as well as the serum MMP-3, but no change in the serum M-CSF values. CONCLUSION: MMP-3 and M-CSF are potentially useful markers of AS disease activity.

Genetic studies in familial ankylosing spondylitis susceptibility.

OBJECTIVE: To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non-major histocompatibility complex (MHC) genes. METHODS: The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the Allele-Sharing Model (ASM) computer program. RESULTS: Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA-DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P = 6.8 x 10(-20) for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58-174.71 cM) in multipoint analysis, with the smallest P value (4.2 x 10(-3)) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P = 6.2 x 10(-5)). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P = 0.014); this was confirmed by subsequent fine mapping studies. CONCLUSION: Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.