Sporadic Inclusion Body Myositis (sIBM) is an inflammatory myopathy (IIM) without a specific diagnostic biomarker until autoantibodies to the cytosolic 5'-nucleotidase 1A (
/Mup44) were reported. The ...objectives of our study were to determine the sensitivity and specificity of anti-NT5c1A for sIBM, demonstrate demographic, clinical and serological predictors for anti-NT5c1A positivity and determine if anti-nuclear antibody (ANA) indirect immunofluorescence (IIF) staining on HEp-2 cells is a reliable screening method for anti-NT5c1A.
Sera from sIBM patients and controls were stored at -80°C until required for analysis. IgG antibodies to NT5c1A were detected by an addressable laser bead immunoassay (ALBIA) using a full-length human recombinant protein. Autoantibodies to other autoimmune myopathy antigens (Jo-1, OJ, TIF1y, PL-12, SAE, EJ, MDA5, PL7, SRP, NXP2, MI-2) were detected by line immunoassay (LIA), chemiluminescence immunoassay (CIA) or enzyme linked immunosorbent assay (ELISA) and ANA detected by IIF on HEp-2 substrate. Demographic, clinical and serological data were obtained by chart review.
Forty-three patients with sIBM, 537 disease control patients with other autoimmune, degenerative and neuromuscular diseases, and 78 healthy controls were included. 48.8% (21/43) of sIBM patients were positive for anti-NT5c1A. The overall sensitivity, specificity, positive predictive value, and negative predictive value of anti-NT5c1A for sIBM were 0.49, 0.92, 0.29, and 0.96, respectively. Compared to sIBM, the frequency of anti-NT5c1A was lower in both the disease control group (8.8%, OR 0.10 95%CI: 0.05-0.20,
< 0.0001) and in the apparently healthy control group (5.1%, OR 0.06 95%CI: 0.02-0.18,
< 0.0001). In the univariable analysis, sIBM patients with more severe muscle weakness were more likely to be anti-NT5c1A positive (OR 4.10 95% CI: 1.17, 14.33,
= 0.027), although this was not statistically significant (adjusted OR 4.30 95% CI: 0.89, 20.76,
= 0.069) in the multivariable analysis. The ANA of sIBM sera did not demonstrate a consistent IIF pattern associated with anti-NT5c1A.
Anti-NT5c1A has moderate sensitivity and high specificity for sIBM using ALBIA. The presence of anti-NT5c1A antibodies may be associated with muscle weakness. Anti-NT5c1A antibodies were not associated with a specific IIF staining pattern, hence screening using HEp-2 substrate is unlikely to be a useful predictor for presence of these autoantibodies.
The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an ...insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKα2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background: Exercise is a modifiable factor that is inversely related to risk for breast cancer. To determine if physical activity has a preventative effect on development of premalignant breast ...lesions, we examined the association between exercise and the incidence of proliferative benign breast disease. Methods: In 1997, the Nurses' Health Study II cohort reported levels of physical activity during adolescence and adulthood using a validated recall instrument. We followed 40,318 participants free from benign breast disease (BBD) or cancer prospectively for four years and confirmed 232 proliferative benign breast lesions by centralized pathology review. Cox proportional hazards models estimated the age-adjusted and multivariable-adjusted relative risks for physical activity and proliferative benign breast disease. Results: We observed a significant inverse association for walking and incidence of BBD, risk was reduced by 9% per hour of walking (95% CI 0% to 17%), (p trend = 0.05). Despite a small number of cases, risk of columnar cell lesions also suggested an inverse association with strenuous activity (RR for 4 or more hours of strenuous activity per week = 0.62; 0.31-1.22 compared to < 1 h per week). Conclusions: This study suggests that exercise may be inversely associated with the risk of developing proliferative benign breast disease, one of the earliest steps in the development of breast cancer.
The most likely diagnosis is rheumatoid arthritis. A thorough history and physical examination are important in distinguishing rheumatoid arthritis from other causes of polyarthritis, such as ...systemic lupus erythematosus and other connective tissue diseases, spondyloarthritis with peripheral joint involvement, joint infections, crystalline arthritis and osteoarthritis. Rheumatoid arthritis should be suspected on the basis of clinical findings: bilateral and symmetric peripheral joint pain and swelling, particularly in small joints, and morning stiffness for more than 30 minutes.1 The classification criteria for rheumatoid arthritis were revised in 2010 to increase the chances of early detection (Box 1).1 In a study involving 2258 patients with early rheumatoid arthritis, the new criteria had a sensitivity of 71%-84% and a specificity of 60%- 74% for detection.2 This implies that there are risks of false-negative and false-positive diagnoses, particularly when the probablity of having the disease is low in a primary care setting. Therefore, the criteria may serve as a guide but should not be used in isolation. Consensus statements recommend measuring the erythrocyte sedimentation rate or the C-reactive protein level or both in cases of suspected rheumatoid arthritis; however, these tests are nonspecific. 1,4 Detecting the presence of the antibodies associated with rheumatoid arthritis, such as rheumatoid factor (RF) and anticitrullinated peptide antibody (commonly measured as anticyclic citrullinated peptide antibody anti-CCP2) is also recoimnended to aid in diagnosis.1 Systematic reviews of the diagnostic value of antibodies in undifferentiated inflammatory arthritis showed that antibodies associated with rheumatoid arthritis are predictive of the disease ( positive likelihood ratio 1.1-13.5 for rheumatoid factor and 12.7 for anti-CCP2).5,6 However, rheumatoid factor can be found in other conditions, such as bacterial endocarditis, hepatitis C virus infection and primary biliary cirrhosis, whereas anti-CCP2 has a higher specificity for rheumatoid arthritis (96% v. 86%).6 Testing for anti-CCP2 and rheumatoid factor is not helpful for ruling out disease, because up to 50% of patients with rheumatoid arthritis are antibody-negative.6 It should be performed only if persistent synovitis is present, and antibody status should not be used in isolation to rule in or rule out the disease.7
Objective
To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology ...(ACR).
Methods
This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta‐regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi‐criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects.
Results
The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE‐specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.
Conclusion
These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To review the pharmacology, pharmacokinetics, efficacy, and safety of romiplostim, the first drug approved for use in patients with immune thrombocytopenic purpura (ITP).
Articles were identified ...through searches of MEDLINE (1966-January 2009) and International Pharmaceutical Abstracts (1970-January 2009) using the key words romiplostim and AMG 531. Searches were limited to articles published in English. The manufacturer was contacted for additional data.
Clinical trials and pharmacokinetic data were selected for review.
Romiplostim is a second-generation thrombopoietic receptor agonist that exerts its therapeutic effect by stimulating megakaryopoiesis. Subcutaneous therapy results in a dose-dependent increase in platelets; however, interindividual variability exists. Time to peak concentration is approximately 14 hours, and the elimination half-life is approximately 3.5 days (range 1-34). Romiplostim undergoes endothelial recirculation and is eliminated by the reticuloendothelial system. The results of 2 Phase 3, randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of romiplostim for increasing platelet counts in patients with ITP refractory to other therapies, including splenectomy. Effects on platelets were transient and decreased within 2 weeks of discontinuing the drug. Interim results of an open-label extension study revealed that romiplostim has sustained efficacy and tolerability for up to 156 weeks at a dosage range of 1-17 microg/kg/wk (mean 5.9 +/- 3.9). The most common adverse effects include headache, fatigue, epistaxis, and contusion. Romiplostim is also under investigation for treatment of thrombocytopenia associated with myelodysplastic syndrome. The drug must be ordered directly from the manufacturer through a limited access program, and weekly subcutaneous injections are given in the clinic setting.
Romiplostim is effective for the management of ITP in adults refractory to other therapies, including splenectomy.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).
This ...international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects.
The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.
These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.
The authors' aim was to understand how persons with Down syndrome (DS) perform different tasks and to assess if there were any differences in performance based on the type of instructions. This is ...important because of neurological differences in persons with DS and neurological demands for performing different types of tasks. Twenty right-handed participants with DS, 20 chronological age-matched (CA), and 20 mental age-matched (MA) performed unimanual, bimanual, discrete, and continuous drumming following visual, auditory, and verbal instructions. Overall, discrete drumming was performed with shorter movement times than continuous drumming and unimanual drumming was performed with shorter movement amplitude than bimanual drumming. With respect to instructions, persons with DS performed with smaller amplitudes, thus more efficient movements, following the visual instructions than auditory and verbal instructions for all types of tasks, whereas CA performed similarly with all instructions and MA performed with smaller amplitudes with visual instructions than auditory instructions. These results suggest that visual instruction provides the best information for people with DS to aid in performance of many different types of movements.
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BFBNIB, DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infections are common complications of necrotising vasculitis. We aimed to determine the rate of infections in patients with severe necrotising vasculitis treated with cyclophosphamide (CYC) combined ...with high dose glucocorticoids (GC).
Searches of MEDLINE, Embase and Cochrane Library databases (1990 to May 2016) were performed. Inclusion criteria were randomised controlled trials of intravenous (IV) or oral (PO) CYC induction therapy for granulomatosis and polyangiitis (GPA), microscopic poyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and systemic polyarteritis nodosa (PAN). Pooled rates of infectious complications were determined by random effects meta-analyses. Meta-regression was performed to identify variables associated with severe infection.
Search results yielded 2636 references; 14 studies with a total of 888 subjects met inclusion criteria. The mean age of participants ranged from 39 to 75 years. Mean cumulative doses of CYC were 2.7 to 50.4 g and of GC were 6 to 13 g. The pooled rate per year per gram of CYC of severe infection was 2.2% (95% CI: 0.9, 5.3%, I2 = 58.7%), any infection was 5.6% (95% CI: 1.8, 16.7%, I2 = 79.1%) and infection-related deaths was 1.7% (95% CI: 0.8, 3.9%, I2 = 0%). By meta-regression, age, creatinine and cumulative GC dose were not significantly associated with the rate of severe infections.
The rate of severe infections and infection related mortality in patients with severe necrotising vasculitis treated with CYC + GC induction therapy is high.
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