ABSTRACT
Expanded non-coding RNA repeats of CCUG are the underlying genetic causes for myotonic dystrophy type 2 (DM2). There is an urgent need for effective medications and potential drug targets that may alleviate the progression of the disease. In this study, 3140 small-molecule drugs from FDA-approved libraries were screened through lethality and locomotion phenotypes using a DM2 Drosophila model expressing 720 CCTG repeats in the muscle. We identified ten effective drugs that improved survival and locomotor activity of DM2 flies, including four that share the same predicted targets in the TGF-ß pathway. The pathway comprises two major branches, the Activin and BMP pathways, which play critical and complex roles in skeletal development, maintenance of homeostasis, and regeneration. The Drosophila model recapitulates pathological features of muscle degeneration in DM2, displaying shortened lifespan, a decline in climbing ability, and progressive muscle degeneration. Increased levels of p-smad3 in response to activin signaling were observed in DM2 flies. Decreased levels of activin signaling using additional specific inhibitors or genetic method ameliorated climbing defects, crushed thoraxes, structure, and organization of muscle fibers. Our results demonstrate that a decrease in activin signaling is sufficient to rescue muscle degeneration and is, therefore, a potential therapeutic target for DM2.
ABSTRACT
Objective: To explore the incidence and risk factors of vascular cognitive impairment (VCI) for in-hospital atrial fibrillation (AF) patients. Methods: A total of 303 in-hospital AF patients were studied. Based on MMSE score evaluation, the patients were divided into 2 groups: Non-VCI group, n=216 and VCI group, n=87. The incidence of VCI was assessed and different cognitive functions were studied by uni- and multivariate regression analysis. Results: Compared with Non-VCI group, the patients in VCI group had the elder age, higher proportion of CHA2DS2-VASC score ≥ 2, more with persistent/permanent AF, more combining diabetes and heart failure (HF), more had increased systolic blood pressure, mean arterial pressure, pulse pressure, left atrial (LA) diameter and serum creatinine; less male and decreased left ventricular end-diastolic diameter, P<0.05 and P<0.001. The occurrence rate of VCI for in-hospital patients was 40.3％, with age and CHA2DS2-VASC score increasing, the incidence of VCI was elevating and the occurrence rates in female was higher than male, the patients with persistent/permanent AF was higher than paroxysmal AF, P<0.05 and P<0.001. Multiple linear regression analysis showed that age (OR=-0.1135, 95％ CI -0.1708 to -0.0562, P=0.0001), female (OR=-1.2528, 95％ CI -2.2056 to -0.3000, P=0.0105), education [primary school level (OR=3.2193, 95％ CI 1.844-4.5940, P<0.0001),middle school and above level (OR=5.9104, 95％ CI 4.6055-7.2154, P<0.0001)], HF (OR=-1.9357, 95％ CI -3.5522 to-0.3192, P=0.0196), stroke (OR=-1.6349, 95％ CI -2.7517 to -0.5181, P=0.0044) and LA diameter (OR=-0.1252, 95％ CI-0.1962 to -0.0541, P=0.0006) were related to VCI occurrence in hospitalized AF patients. Conclusion: The incidence of VCI was high in hospitalized AF patients; elder age, female, lower education, HF, stroke and enlarged LA diameter were the risk factors for VCI occurrence in AF patients.
ABSTRACT
Objective: To explore the incidence and risk factors of vascular cognitive impairment (VCI) for in-hospital atrial fibrillation (AF) patients. Methods: A total of 303 in-hospital AF patients were studied. Based on MMSE score evaluation, the patients were divided into 2 groups: Non-VCI group, n=216 and VCI group, n=87. The incidence of VCI was assessed and different cognitive functions were studied by uni- and multivariate regression analysis. Results: Compared with Non-VCI group, the patients in VCI group had the elder age, higher proportion of CHA2DS2-VASC score ≥ 2, more with persistent/permanent AF, more combining diabetes and heart failure (HF), more had increased systolic blood pressure, mean arterial pressure, pulse pressure, left atrial (LA) diameter and serum creatinine; less male and decreased left ventricular end-diastolic diameter, P<0.05 and P<0.001. The occurrence rate of VCI for in-hospital patients was 40.3％, with age and CHA2DS2-VASC score increasing, the incidence of VCI was elevating and the occurrence rates in female was higher than male, the patients with persistent/permanent AF was higher than paroxysmal AF, P<0.05 and P<0.001. Multiple linear regression analysis showed that age (OR=-0.1135, 95％ CI -0.1708 to -0.0562, P=0.0001), female (OR=-1.2528, 95％ CI -2.2056 to -0.3000, P=0.0105), education [primary school level (OR=3.2193, 95％ CI 1.844-4.5940, P<0.0001),middle school and above level (OR=5.9104, 95％ CI 4.6055-7.2154, P<0.0001)], HF (OR=-1.9357, 95％ CI -3.5522 to-0.3192, P=0.0196), stroke (OR=-1.6349, 95％ CI -2.7517 to -0.5181, P=0.0044) and LA diameter (OR=-0.1252, 95％ CI-0.1962 to -0.0541, P=0.0006) were related to VCI occurrence in hospitalized AF patients. Conclusion: The incidence of VCI was high in hospitalized AF patients; elder age, female, lower education, HF, stroke and enlarged LA diameter were the risk factors for VCI occurrence in AF patients.
ABSTRACT
OBJECTIVE: To evaluate the clinical effects of double-bundle reconstruction of anterior cruciate ligament (ACL) using hamstring tendon auto graft under arthroscopy. METHODS: From April 2009 to March 2010, 25 patients (13 males and 12 females) with ACL deficiency were treated with arthroscopy, ranging in age from 17 to 43 years, with an average of 25.8 years. There were 17 patients caused by sports injuries, 6 patients caused by accidental falling, and 2 patients caused by traffic injury. The average duration of the disease was 3 months. The main symptom was knee instability in 8 patients, and knee pain and swelling in other patients. Pivot shift test was positive in 15 cases, and Lachman test was positive in 25 cases, the ADT (anterior drawer test) was positive in 25 cases. The anterior transition of the tibia measured by KT2000 instrument was (7.1 +/- 2.4) mm more than the contralateral knee. The average Lysholm score was 40.0 +/- 5.4. The Tegner activity scores averaged 3.2 +/- 0.7. The double tibial tunnels and double femoral tunnels were drilled on the footprint of the ACL to reconstruct the anteromedial and posterolateral bundles under arthroscopy. Tendons were fixed with Endo-buttons at the femoral side and with biodegradable interference screw at the tibial side. Postoperative symptoms and signs were observed during follow-up period. The anterior transition of the tibia was measured by KT2000, and the Lysholm score and Tegner scores were used for evaluating knee function. Statistically analyzed was performed with SPSS 15.0. RESULTS: All the patients were followed up, and the duration ranged from 24 to 35 months (averaged, 27 months). At the latest follow-up, there was no positive pivot shift, while the Lachman test and ADT were negative or positive of grade I. The average Lysholm score of the 25 cases was 40.0 +/- 5.4 before operation, and 85.0 +/- 4.5 at the latest follow-up, 3.2 +/- 0.7 before operation and 7.5 +/- 0.2 at the latest follow-up for Tegner activity score. Statistically, the difference between preoperative score and the postoperative score was significant. CONCLUSION: Double-bundle reconstruction of ACL with hamstring tauto graft under arthroscopy is effective and reliable to restore the stability of the knee, and the clinical effect is good to excellent.
