Browsing by Subject "WEAKNESS"

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  • Marttila, Minttu; Mubashir, Hanif; Lemola, Elina; Nowak, Kristen J.; Laitila, Jenni; Gronholm, Mikaela; Wallgren-Pettersson, Carina; Pelin, Katarina (2014)
    Background: Nemaline myopathy (NM) is a rare genetic muscle disorder, but one of the most common among the congenital myopathies. NM is caused by mutations in at least nine genes: Nebulin (NEB), alpha-actin (ACTA1), alpha-tropomyosin (TPM3), beta-tropomyosin (TPM2), troponin T (TNNT1), cofilin-2 (CFL2), Kelch repeat and BTB (POZ) domain-containing 13 (KBTBD13), and Kelch-like family members 40 and 41 (KLHL40 and KLHL41). Nebulin is a giant (600 to 900 kDa) filamentous protein constituting part of the skeletal muscle thin filament. Around 90% of the primary structure of nebulin is composed of approximately 35-residue alpha-helical domains, which form super repeats that bind actin with high affinity. Each super repeat has been proposed to harbor one tropomyosin-binding site. Methods: We produced four wild-type (WT) nebulin super repeats (S9, S14, S18, and S22), 283 to 347 amino acids long, and five corresponding repeats with a patient mutation included: three missense mutations (p.Glu2431Lys, p.Ser6366Ile, and p.Thr7382Pro) and two in-frame deletions (p.Arg2478_Asp2512del and p.Val3924_Asn3929del). We performed F-actin and tropomyosin-binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays. We also used the GST pull-down assay to test the affinity of WT nebulin super repeats for WT alpha- and beta-tropomyosin, and for beta-tropomyosin with six patient mutations: p.Lys7del, p. Glu41Lys, p.Lys49del, p.Glu117Lys, p.Glu139del and p.Gln147Pro. Results: WT nebulin was shown to interact with actin and tropomyosin. Both the nebulin super repeats containing the p.Glu2431Lys mutation and nebulin super repeats lacking exon 55 (p.Arg2478_Asp2512del) showed weak affinity for F-actin compared with WT fragments. Super repeats containing the p.Ser6366Ile mutation showed strong affinity for actin. When tested for tropomyosin affinity, super repeats containing the p.Glu2431Lys mutation showed stronger binding than WT proteins to tropomyosin, and the super repeat containing the p.Thr7382Pro mutation showed weaker binding than WT proteins to tropomyosin. Super repeats containing the deletion p. Val3924_Asn3929del showed similar affinity for actin and tropomyosin as that seen with WT super repeats. Of the tropomyosin mutations, only p.Glu41Lys showed weaker affinity for nebulin (super repeat 18). Conclusions: We demonstrate for the first time the existence of direct tropomyosin-nebulin interactions in vitro, and show that nebulin interactions with actin and tropomyosin are altered by disease-causing mutations in nebulin and tropomyosin.
  • Kemp, Kirsi; Mertanen, Reija; Lääperi, Mitja; Niemi-Murola, Leila; Lehtonen, Lasse; Castren, Maaret (2020)
    Background Nonspecific complaint (NSC) is a common presenting complaint in the emergency setting, especially in the elderly population. Individual studies have shown that it is associated with significant morbidity and mortality. This prognostic systematic review draws a synthesis of reported outcomes for patients presenting with NSC and compares them with outcomes for patients presenting with a specific complaint. Methods We conducted a literature search for publications, abstracts and conference presentations from Ovid, Scopus and Web of Science for the past 20 years. Studies were included which treated adult patients presenting to the Emergency Medical Services or Emergency Department with NSC. 2599 studies were screened for eligibility and quality was assessed using the SIGN assessment for bias tool. We excluded any low-quality studies, resulting in nine studies for quantitative analysis. We analysed the included studies for in-hospital mortality, triage category, emergency department length of stay, admission rate, hospital length of stay, intensive care admissions and re-visitation rate and compared outcomes to patients presenting with specific complaints (SC), where data were available. We grouped discharge diagnoses by ICD-10 category. Results We found that patients presenting with NSC were mostly older adults. Mortality for patients with NSC was significantly increased compared to patients presenting with SC [OR 2.50 (95% CI 1.40-4.47)]. They were triaged as urgent less often than SC patients [OR 2.12 (95% CI 1.08-4.16)]. Emergency department length of stay was increased in two out of three studies. Hospital length of stay was increased by 1-3 days. Admission rates were high in most studies, 55 to 84%, and increased in comparison to patients with SC [OR 3.86 (95% CI 1.76-8.47)]. These patients seemed to require more resources than patients with SC. The number for intensive care admissions did not seem to be increased. Data were insufficient to make conclusions regarding re-visitation rates. Discharge diagnoses were spread throughout the ICD-10 main chapters, infections being the most prevalent. Conclusions Patients with NSC have a high risk of mortality and their care in the Emergency Department requires more time and resources than for patients with SC. We suggest that NSC should be considered a major emergency presentation.
  • Piirilä, Päivi; Similä, Minna E.; Palmio, Johanna; Wuorimaa, Tomi; Ylikallio, Emil; Sandell, Satu; Haapalahti , Petri; Uotila, Lasse; Tyynismaa, Henna; Udd, Bjarne; Auranen, Mari (2016)
    Introduction: Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders. Methods: Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia. Results: A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease. Discussion: Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.