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  • 1
    Keywords: EXPRESSION ; IN-VIVO ; MOUSE MODEL ; DUCHENNE MUSCULAR-DYSTROPHY ; SYSTEMIC DELIVERY ; ALPHA-SARCOGLYCAN ; GLYCOPROTEIN COMPLEX ; LINKED DILATED CARDIOMYOPATHY ; DEFICIENT CARDIOMYOPATHY ; SKELETAL-MUSCLES
    Abstract: Dystrophin plays an important role in muscle contraction, linking the intracellular cytoskeleton to the extracellular matrix. Mutations of the dystrophin gene leading to a complete loss of the protein cause Duchenne muscular dystrophy (DMD), frequently associated with severe cardiomyopathy. Early clinical trials in DMD using gene transfer to skeletal muscle are underway, but gene transfer to dystrophic cardiac muscle has not yet been tested in humans. The aim of this study was to develop an optimized protocol for cardiac gene therapy in the mouse model of dystrophin deficiency (mdx), using a cardiac promoter for expression of a microdystrophin (mu Dys) transgene packaged into an adeno-associated virus serotype 9 vector (AAV9). In this study adult mdx mice were intravenously injected with 1 x 10(12) genomic particles of AAV9 vectors carrying a cDNA encoding mu Dys under the control of either a ubiquitously active cytomegalovirus (CMV) promoter or a cardiac-specific CMV-enhanced myosin light chain (MLC0.26) promoter. After 10 months, both AAV9 vectors led to sustained mu Dys expression in cardiac muscle, but the MLC promoter conferred about 4-fold higher protein levels. AAV9-CMV-MLC0.26-mu Dys resulted in significant protection of cardiac morphology and function as assessed by histopathology, echocardiography, and left ventricular catheterization. In conclusion, we established an AAV9-mediated gene transfer approach for efficient and specific long-term mu Dys expression in the hearts of mdx mice, resulting in a sustained therapeutic effect. Thus, this approach might be a basis for further translation into a treatment strategy for DMD-associated cardiomyopathy.
    Type of Publication: Journal article published
    PubMed ID: 22248393
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  • 2
    Abstract: The water channel aquaporin-1 (AQP1) mediates about 50% ultrafiltration during a 2-hour hypertonic dwell in global AQP1 knockout (AQP1-/-) mice. Although AQP1 is widely expressed in various cell types including mesothelial cells, the ultrafiltration has been assumed to be mediated via endothelial AQP1 of the peritoneum. The partial embryonic lethality and reduced body weight in AQP1-/- mice may reflect potential confounding phenotypic effects evoked by ubiquitous AQP1 deletion, which may interfere with functional analysis of endothelial AQP1. Using a Cre/loxP approach, we generated and characterised endothelial cell- and time-specific AQP1 knockout (AQP1fl/fl; Cdh5-Cre+) mice. Compared to controls, AQP1fl/fl; Cdh5-Cre+ mice showed no difference in an initial clinical and biological analysis at baseline, including body weight and survival. During a 1-hour 3.86% mini-peritoneal equilibration test (mini-PET), AQP1fl/fl; Cdh5-Cre+ mice exhibited strongly decreased indices for AQP1-related transcellular water transport (43.0% in net ultrafiltration, 93.0% in sodium sieving and 57.9% in free water transport) compared to controls. The transport rates for small solutes of urea and glucose were not significantly altered. Our data provide the first direct experimental evidence for the functional relevance of endothelial AQP1 to the fluid transport in peritoneal dialysis and thereby further validate essential predictions of the three-pore model of peritoneal transport.
    Type of Publication: Journal article published
    PubMed ID: 26760974
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    Electronic Resource
    Electronic Resource
    Springer
    Zeitschrift für Kardiologie 86 (1997), S. 785-787 
    ISSN: 1435-1285
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Einleitung Seit 1951 sind Messungen von kardialen Enzymen fester Bestandteil der Diagnostik von Patienten mit Infarktverdacht und dienen zusammen mit dem EKG der Klassifikation von Patienten mit Thoraxschmerz. Trotz erheblicher Fortschritte in der analytischen Methodik sind der Präzision der Infarktdiagnostik durch Enzyme enge Grenzen gesetzt, die sich aus der fehlenden Organspezifität und der individuellen Variabilität der Blutspiegel der kardialen Enzyme ergeben. Deshalb versagen die Enzymkriterien, wenn es gilt, Mikroinfarkte nachzuweisen oder wenn Herzmuskelnekrosen von skelettmuskulären Schädigungen zu differenzieren sind.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1435-1285
    Keywords: Schlüsselwörter Instabile Angina – Myokardinfarkt – Prädiktoren – Quantitative Koronarangiographie – Restenose ; Key words Myocardial infarction – predictors – quantitative coronary¶angiography – restenosis –¶unstable angina
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Angioplasty in acute coronary syndromes is complicated by a high rate of early vessel reocclusion and restenosis. Therefore, it is recommended to achieve a „stent-like” result by percutaneous transluminal coronary angioplasty (PTCA) or otherwise use coronary stenting (provisional stenting).¶   This study sought to determine angiographic and patient-related factors that are associated with early target vessel reocclusion or luminal renarrowing after coronary intervention in acute coronary syndromes (ACS).¶   In an observational prospective study we investigated 161 patients with ACS (acute myocardial infarction and unstable angina) submitted to PTCA. In 140 patients a follow-up angiography after 10 days was obtained. All angiograms were quantitatively evaluated by computerized measurements.¶   Target vessel reocclusion and early luminal renarrowing was observed in 10 patients (7.1%) and 19 patients (13.6%), respectively. Using univariate analysis, significant risk factors (P 〈0.05) for early reocclusion and renarrowing were diabetes mellitus (relative risk [RR] 6.1 and 5.0), arterial hypertension (RR 7.7 and 3.3), postprocedural lesion length ≥2.5mm (RR 6.8 and 7.1), postprocedural minimal lumen diameter ≤2.5 mm (RR9.0 and 5.8), residual stenosis ≥25% (RR 4.8 and 3.5) and absence of stents (RR 4.1 and 3.2). Moreover, in multivariate analysis hypertension and postprocedural lesion length could be identified as independent risk factors for reocclusion and renarrowing. Diabetes mellitus was found to be an independent risk factor for renarrowing.¶   Conclusions: In a consecutive series of patients with ACS undergoing PTCA with provisional stenting the occurrence of early target vessel reocclusion and luminal renarrowing is lower than previously reported for this subset of patients treated by PTCA alone. Adverse outcome is related to absence of stents, angiographic factors (residual stenosis, lesion length, minimal lumen diameter after procedure) and patient-related factors such as diabetes and hypertension.
    Notes: Zusammenfassung Die Angioplastie beim akuten Koronarsyndrom wird durch eine hohe Rate früher Gefäß-Reokklusionen und Restenosen kompliziert. Daher wird bei der perkutanen transluminalen Koronarangioplastie (PTCA) im klinischen Alltag oft ein „stent-gleiches“ Ergebnis angestrebt und andernfalls eine intrakoronare Stentimplantation durchgeführt (provisional stenting).¶   Diese Studie sollte angiographische und patientenbezogene Risikofaktoren aufzeigen, die für Frühverschluss oder Lumeneinengung des Zielgefäßes nach Koronarintervention bei akutem Koronarsyndrom (AKS) prädisponieren.¶   In einer prospektiven Verlaufsbeobachtung untersuchten wir 161 Patienten mit AKS (akuter Myokardinfarkt und instabile Angina pectoris), die mittels PTCA behandelt wurden. Bei 140 Patienten konnte eine Verlaufsangiographie nach 10 Tagen durchgeführt werden. Alle Angiogramme wurden quantitativ durch computerunterstützte Auswertung analysiert.¶   Reokklusion und Lumeneinengung des Zielgefäßes traten bei 10 Patienten (7,1%) bzw. 19 Patienten auf (13,6%). Als signifikante Risikofaktoren (p 〈0,05) für Frühverschluss und Lumeneinengung zeigten sich in der univariaten Analyse Diabetes mellitus (relatives Risiko [RR] 6,1 und 5,0), arterieller Hypertonus (RR 7,7 und 3,3), postinterventionelle Läsionslänge ≥2,5 mm (RR 6,8 und 7,1), postinterventioneller minimaler Lumendiameter ≤2,5 mm (RR 9,0 und 5,8), Reststenose ≥25% (RR 4,8 und 3,5) und das Fehlen eines Stents (RR 4,1 und 3,2). Außerdem konnten in der multivariaten Analyse Hypertonus und postinterventionelle Läsionslänge als unabhängige Risikofaktoren für Reokklusion und Lumeneinengung identifiziert werden. Zusätzlich fand sich Diabetes mellitus als unabhängiger Risikofaktor für eine Lumeneinengung.¶   Schlussfolgerungen: In einer Verlaufsserie von Patienten mit AKS, die mittels PTCA und provisional stenting behandelt wurden, ist die Inzidenz für Frühverschluss und Lumeneinengung des Zielgefäßes niedriger als bisher für dieses Patientenkollektiv bei alleiniger PTCA beschrieben. Die genannten Komplikationen sind verknüpft mit dem Fehlen eines Stents, angiographischen Faktoren (Reststenose, postinterventionelle Läsionslänge und minimaler Lumendiameter) und patientenbezogenen Faktoren wie Diabetes oder Hypertonus.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0022-2828
    Keywords: C-protein ; Cardiac function ; Development ; Phosphorylation ; Troponin I
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1440
    Keywords: Balloon valvuloplasty ; Aortic stenosis ; Pulsed Doppler
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Percutaneous transluminal valvuloplasty (PTV) was performed in 24 patients (aged 67–86 years, mean: 76±5.7 years) with calcific aortic stenosis and high operative risk. The gradient between maximal left ventricular and aortic pressures (peak-to-peak gradient, PPPG) could be reduced by 52% from 73±21 to 34±12 mmHg (p〈0.001). Peak pressure gradient (PPG), as assessed by continuous wave Doppler, could be reduced from 80±28 to 58±21 mmHg (p〈0.001). Aortic valve area (AVA) as determined by Doppler and two dimensional echocardiography increased significantly from 0.39±0.14 to 0.61±0.3 cm2 (p〈0.05). Clinical symptoms were found to be improved in 5 of 8 patients with impaired ejection fraction and in 11 of 16 patients with normal ejection fraction during the first week after PTV. Complications due to the procedure were surgical revision of femoral artery puncture site in one patient and hemodynamic relevant pericardial effusion in another patient. Transmitral early (E) and late (L) diastolic filling integrals were measured by pulsed Doppler: the ratio E/L decreased significantly after PTV from 0.9±0.5 to 0.63±0.31 (p〈0.03) indicating further reduction of left ventricular early diastolic filling. Ejection fraction, stroke volume and cardiac output did not significantly change immediately after PTV. The results indicate, that PTV can successfully reduce aortic pressure gradients and improve symptoms in patients with calcific aortic stenosis and high operative risk. Doppler echocardiography provides an adequate method to noninvasively evaluate the initial outcome of PTV and seems valuable for the assessment of long term results.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1440
    Keywords: Acute myocardial infarction ; Myosin light chains ; CK-MB-isoenzyme ; Left ventricular function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Infarct size can be estimated noninvasively by analysis of circulating CK-MB and/or cardiac myosin light chains. To investigate whether myosin light chains release is correlated with the impairment of left ventricular function in acute myocardial infarction, this marker protein was determined by liquid phase radioimmunoassay in serial blood samples of 25 patients. Likewise CK-MB was measured in the same blood samples. From the serum concentration changes the cumulative appearance was calculated as an estimate of infarct size. Left ventricular enddiastolic pressure, global and regional ejection fraction were measured immediately and 3 weeks after admission. Particularily during the chronic phase of myocardial infarction a close correlation was found between serological estimates of infarct size and impairment of left ventricular function. The cumulative appearance of myosin light chains was superior to CKMB in assessing the hemodynamic impact of myocardial infarction in the acute and chronic stage. Therefore, myosin light chains are an appropriate serological indicator for the hemodynamic significance of myocardial infarction during the acute and chronic stage and might allow an assessment of the patients' risk.
    Type of Medium: Electronic Resource
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