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Bloch W Fleischmann BK Lorke DE Andressen C Hops B Hescheler J Addicks K 《Cardiovascular research》1999,43(3):675-684
OBJECTIVE: The aim of the present study was the investigation of the expression of NOS during cardiomyogenesis and its functional role. DESIGN: The qualitative and quantitative expression of NOS isoforms during different stages of cardiac development was evaluated using immunocytochemistry and dot blots, respectively. The functional relevance of NOS expression during cardiomyogenesis was investigated using the in vitro ES cell-differentiation model and selective pharmacological agents. RESULTS: On day 7.5 of embryonic development (E7.5) none of the NOS isoforms were expressed in the embryo, whereas the inducible (iNOS), as well as the endothelial (eNOS) isoforms were detected in the extraembryonic parts. In contrast, starting from E9.5 rat and murine embryos displayed prominent iNOS and eNOS expression. This was correlated with high expression of soluble guanylylcyclase (sGC) as well as high cyclic GMP (cGMP) content. During further development after E14.5 both, iNOS as well as eNOS, started to be downregulated and shortly prior to birth reduced staining for eNOS was found, whereas iNOS was hardly detectable. We further investigated whether NO plays a role for cardiomyogenesis, using in vitro ES cell-derived cardiomyocytes differentiating within embryoid bodies (EBs). The NOS expression pattern in these cells paralleled the one detected in vivo. We demonstrate that continuous incubation of EBs with the NOS inhibitors L-NMMA (2-10 mM) or L-NA (2-10 mM) for 4 to 9 days after plating resulted in a pronounced differentiation arrest of cardiomyocytes, whereas this effect could be reversed by coapplication of the NO-donor spermine-NONOate (10 microM). CONCLUSIONS: Both, iNOS and eNOS isoforms are prominently expressed during early stages of cardiomyogenesis. Around E14.5 NOS expression starts to decline. Moreover, the NO-generation is required for cardiomyogenesis since NOS inhibitors prevent the maturation of terminally differentiated cardiomyocytes using the ES cell system. 相似文献
34.
Fleischmann RM Baumgartner SW Tindall EA Weaver AL Moreland LW Schiff MH Martin RW Spencer-Green GT 《The Journal of rheumatology》2003,30(4):691-696
OBJECTIVE: Approximately 3% of the US population over the age of 65 years has rheumatoid arthritis (RA). We compared the safety and efficacy of etanercept (Enbrel) in patients with RA who were > or = 65 years to those < 65 years in open-label and double-blind, randomized clinical trials. METHODS: Patients from 4 double-blind, randomized controlled trials and 5 open-label trials were included in this retrospective analysis. Patients were grouped by age (< 65 or > or = 65 yrs) at time of study entry. All patients received etanercept subcutaneously twice weekly. Improvement in signs and symptoms was assessed by the proportion of patients who achieved the American College of Rheumatology definition of improvement (ACR 20). The ACR 50 and ACR 70 responses were calculated in an analogous fashion. Safety was assessed at regularly scheduled visits. RESULTS: Of 1128 patients enrolled in etanercept trials, 197 (17%) were > or = 65 years of age. Clinical response was rapid and sustained and did not differ between age groups. At one year, 69% of patients < 65 years and 66% of patients > or = 65 years met the ACR 20. Forty percent of the patients > or = 65 years met the ACR 50 and 17% met the ACR 70. Etanercept was well tolerated. Although injection site reactions, headache, and rhinitis occurred somewhat more frequently in younger patients, the overall rates and types of other adverse events were comparable in both groups. CONCLUSION: Etanercept is a new treatment option for older patients with RA and has substantial benefit and comparable safety regardless of patient age. 相似文献
35.
Anne S. Chin Martin J. Willemink Aya Kino Virginia Hinostroza Anna M. Sailer Michael P. Fischbein R. Scott Mitchell Gerald J. Berry D. Craig Miller Dominik Fleischmann 《Journal of the American College of Cardiology》2018,71(24):2773-2785
Background
Limited intimal tears (LITs) of the aorta (Class 3 dissection variant) are the least common form of aortic pathology in patients presenting with acute aortic syndrome (AAS). LITs are difficult to detect on imaging and may be underappreciated.Objectives
This study sought to describe the frequency, pathology, treatment, and outcome of LITs compared with other AAS, and to demonstrate that LITs can be detected pre-operatively by contemporary imaging.Methods
The authors retrospectively reviewed 497 patients admitted for 513 AAS events at a single academic aortic center between 2003 and 2012. AAS were classified into classic dissection (AD), intramural hematoma, LIT, penetrating atherosclerotic ulcer, and rupturing thoracic aortic aneurysm. The prevalence, pertinent risk factors, and detailed imaging findings with surgical and pathological correlation of LITs are described. Management, early outcomes, and late mortality are reported.Results
Among 497 patients with AAS, the authors identified 24 LITs (4.8% of AAS) in 16 men and 8 women (17 type A, 7 type B). Patients with LITs were older than those with AD, and type A LITs had similarly dilated ascending aortas as type A AD. Three patients presented with rupture. Eleven patients underwent urgent surgical aortic replacement, and 2 patients underwent endovascular repair. Medial degeneration was present in all surgical specimens. In-hospital mortality was 4% (1 of 24), and in total, 5 patients with LIT died subsequently at 1.5 years (interquartile range [IQR]: 0.3 to 2.5 years). Computed tomography imaging detected all but 1 LIT, best visualized on volume-rendered images.Conclusions
LITs are rare acute aortic lesions within the dissection spectrum, with similar presentation, complications, and outcomes compared with AD and intramural hematoma. Awareness of this lesion allows pre-operative diagnosis using high-quality computed tomography angiography. 相似文献36.
Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes 总被引:27,自引:0,他引:27
Genovese MC Bathon JM Martin RW Fleischmann RM Tesser JR Schiff MH Keystone EC Wasko MC Moreland LW Weaver AL Markenson J Cannon GW Spencer-Green G Finck BK 《Arthritis and rheumatism》2002,46(6):1443-1450
OBJECTIVE: To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis (RA) who received monotherapy with either etanercept or methotrexate (MTX) for 2 years and to assess the safety of this therapy. METHODS: In the Enbrel ERA (early rheumatoid arthritis) trial, 632 patients with early, active RA were randomized to receive either twice-weekly subcutaneous etanercept (10 mg or 25 mg) or weekly oral MTX (mean dosage 19 mg per week) for at least 1 year in a double-blind manner. Following the blinded phase of the trial, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. Radiograph readers remained blinded to treatment group assignment and the chronologic order of images. RESULTS: At 24 months, more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20% improvement criteria (72% and 59%, respectively; P = 0.005), and more had no increase in total score and erosion scores on the Sharp scale (P = 0.017 and P = 0.012, respectively). The mean changes in total Sharp score and erosion score in the 25-mg etanercept group (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P = 0.001). Significantly more patients in the 25-mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the Health Assessment Questionnaire disability index (P < 0.001). Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events. CONCLUSION: Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity, arresting structural damage, and decreasing disability over 2 years in patients with early, aggressive RA. 相似文献
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38.
Furst DE Saag K Fleischmann MR Sherrer Y Block JA Schnitzer T Rutstein J Baldassare A Kaine J Calabrese L Dietz F Sack M Senter RG Wiesenhutter C Schiff M Stein CM Satoi Y Matsumoto A Caldwell J Harris RE Moreland LW Hurd E Yocum D Stamler DA 《Arthritis and rheumatism》2002,46(8):2020-2028
OBJECTIVE: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). METHODS: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. RESULTS: ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. CONCLUSION: Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily. 相似文献
39.
Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor,SigH 总被引:1,自引:0,他引:1
40.
Evidence that a 90-kDa phosphoprotein, an associated kinase, and a specific phosphatase are involved in the regulation of Cloudman melanoma cell proliferation by insulin.
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R D Fleischmann J M Pawelek 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(4):1007-1011
Proliferation of wild-type Cloudman S91 melanoma cells is inhibited when insulin is included in the culture medium. Using growth inhibition as a selective marker, we isolated variant cell lines that are either resistant to insulin or dependent upon insulin for growth. We have studied the effects of insulin on proliferation by using combined genetic and biochemical approaches. Through a series of genetic hybridization analyses, we have identified three complementation groups and determined that, in general, insulin-sensitivity is dominant to insulin-resistance. Through analyses of in vitro protein phosphorylation reactions, we have identified a protein of approximately 90 kDa (pp90) whose phosphorylation is a function of at least one of the complementation groups. Although pp90 is not phosphorylated in extracts of insulin-resistant variants, it is phosphorylated in extracts of insulin-sensitive hybrids formed between complementing resistant variants. Insulin itself exhibits little or no regulation over the phosphorylation of pp90; rather, the ability to phosphorylate pp90 correlates with the ability of cells to respond to insulin. Migration in NaDodSO4/polyacrylamide gels, solubility characteristics, and divalent cation requirements indicate that pp90 is distinct from the 95-kDa beta-subunit of the insulin receptor. Both pp90 and its associated phosphoprotein kinase are found in 30,000 X g pellets of sonicated cell lysates, whereas a specific pp90 phosphoprotein phosphatase activity is found in 30,000 X g supernatant fractions. Phosphorylation of pp90 occurs at tyrosine and serine residues. Our evidence indicates that the state of phosphorylation of pp90 is an important determinant in the regulation of cellular proliferation by insulin. 相似文献