Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-alpha2-deficient congenital muscular dystrophy (MDC1A)

BACKGROUND: Laminin-alpha2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-beta and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. METHODS: L-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. RESULTS: We found that TGF-beta signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. CONCLUSION: These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A

Intersection Cohomology of Rank One Local Systems for Arrangement Schubert Varieties

In this thesis we study the intersection cohomology of arrangement Schubert varieties with coefficients in a rank one local system on a hyperplane arrangement complement. We prove that the intersection cohomology can be computed recursively in terms of certain polynomials, if a local system has only $\pm 1$ monodromies. In the case where the hyperplane arrangement is generic central or equivalently the associated matroid is uniform and the local system has only $\pm 1$ monodromies, we prove that the intersection cohomology is a combinatorial invariant. In particular when the hyperplane arrangement is associated to the uniform matroid of rank $n-1$ over $n$ elements, and the local system has $\pm 1$ monodromies, we can give a closed formula for the intersection cohomology

Copolymerization of Ethylene and 4-Penten-1-ol Using an Aryl Sulfonate Phosphine Palladium Catalyst

Our goal was to investigate the copolymerization of ethylene with 4-penten-1-ol using an aryl sulfonate phosphine catalyst. In addition to several polymerizations of ethylene, used as control runs, more than a dozen copolymerizations were conducted at reasonable yields. As a main variable in these runs, we changed the comonomer concentration (ca. 0.10 to 2.82 mol/L). However, also the influence of polymerization time (1 h versus 21 hours runs), temperature (80 versus 95 oC), and catalyst concentration (160 μmol/L versus 820 μmol/L) was determined. Activities for all the runs were determined. For the first time, the 13C NMR spectra of the copolymers were analyzed and all peak assignments made. In addition, 1H NMR spectra were completely analyzed. Based on these spectra, the comonomer contents in the copolymers could be determined. The reactivity ratios for ethylene and 4-penten-1-ol were determined using the methods of Fineman-Ross and Kelen-Tüdŏs. Molecular weight properties measured by GPC are reported, as well as DSC-based melting temperatures. Some TGA measurements were conducted to determine the heat stability and purities of the copolymers. Finally the nature of the mechanism of the polymerization, coordinative as expected or radical, has been also discussed

Multi-morbidities are Not a Driving Factor for an Increase of COPD-Related 30-Day Readmission Risk

Background and Objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. COPD is expensive to treat, whereas the quality of care is difficult to evaluate due to the high prevalence of multi-morbidity among COPD patients. In the US, the Hospital Readmissions Reduction Program (HRRP) was initiated by the Centers for Medicare and Medicaid Services to penalize hospitals for excessive 30-day readmission rates for six diseases, including COPD. This study examines the difference in 30-day readmission risk between COPD patients with and without comorbidities.Methods: In this retrospective cohort study, we used Cox regression to estimate the hazard ratio of 30-day readmission rates for COPD patients who had no comorbidity and those who had one, two or three, or four or more comorbidities. We controlled for individual, hospital and geographic factors. Data came from three sources: Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID), Area Health Resources Files (AHRF) and the American Hospital Association’s (AHA’s) annual survey database for the year of 2013.Results: COPD patients with comorbidities were less likely to be readmitted within 30 days relative to patients without comorbidities (aHR from 0.84 to 0.87, p \u3c 0.05). In a stratified analysis, female patients with one comorbidity had a lower risk of 30-day readmission compared to female patients without comorbidity (aHR = 0.80, p \u3c 0.05). Patients with public insurance who had comorbidities were less likely to be readmitted within 30 days in comparison with those who had no comorbidity (aHR from 0.79 to 0.84, p \u3c 0.05).Conclusion: COPD patients with comorbidities had a lower risk of 30-day readmission compared with patients without comorbidity. Future research could use a different study design to identify the effectiveness of the HRRP

Organizational, Technological, and Environmental Determinants of Electronic Commerce Adoption in Small and Medium Enterprises in Taiwan

In the Internet age, the development of electronic commerce (EC) was considered a major indicator of the overall competitiveness of organizations. Moreover, the EC marketing channel can bring customers more benefits, such as greater shopping convenience and potentially lower prices. In Taiwan, small and medium enterprises (SMEs) represent 98% of the total number of business. Today, most SMEs were forced to adopt EC by their major suppliers and value chain partners in order to carry out business processes more efficiently. Hence, the purpose of this study is to seek the determinants of the extent of EC adoption by SMEs in Taiwan. This study presents a framework based on Tornatzky and Fleischer\u27s (1990) OTE model that includes organizational context, technological context, and environmental context, which have been widely used to examine the factors that influence organizational technology adoption. According to the OTE model, the research model of this study identified nine determinants, including (1) organizational size, (2) CEOs\u27 attitudes toward EC adoption, (3) CEOs\u27 innovativeness, (4) CEOs\u27 technology knowledge, (5) CEOs\u27 perceptions of EC on relative advantages, (6) CEOs\u27 perceptions of EC on compatibility, (7) CEOs\u27 perceptions of EC on complexity, (8) information intensity, and (9) competition intensity. A quantitative, correlational, non-experimental and explanatory research design based on a questionnaire survey was used to collect data, test hypotheses, and answer research questions in this study. 1,500 CEOs of Taiwanese SMEs were randomly selected from the database of E-Volunteer and invited to participate via email on a hyper-link provided to the survey web site. A total of 219 usable questionnaires were obtained for data analysis. The results of this study indicated that all three contexts were important in the decision of EC adoption by Taiwanese SMEs. The findings also supported significance of five determinants that had a positive relationship with the extent of EC adoption. These determinants were organizational size and CEOs\u27 attitudes toward EC adoption, CEOs\u27 perceptions of EC on relative advantage and compatibility, and information intensity. No statistically significant relationship with the extent of EC adoption was established for CEOs\u27 technology knowledge, CEOs\u27 perception of EC on complexity, and competition intensity. This study may not only expand the current body of EC knowledge, but also contribute to the knowledge of CEOs concerning SMEs, EC consultants, suppliers or value chain partners, and government agencies