Background-Hyperglycemia on admission is associated with increased mortality rates in patients with ST-elevation myocardial infarction (STEMI). However, data regarding the relationship between hyperglycemia and myocardial damage in STEMI are scarce. The aim of this study was to determine the relationship of diabetes mellitus status and hyperglycemia on myocardial damage assessed by cardiovascular magnetic resonance imaging and to evaluate the longterm prognostic significance of hyperglycemia in a high-risk STEMI population. Methods and Results-Glucose levels were determined on admission in 411 consecutive STEMI patients reperfused by primary angioplasty. Patients were categorized on the basis of diabetes mellitus status and admission glucose level. Magnetic resonance imaging was performed for assessment of infarct size and microvascular obstruction. The primary clinical end point was the occurrence of major adverse cardiovascular events at long-term follow-up. STEMI patients with pre-existing diabetes mellitus were at greater risk for major adverse cardiovascular events (32% versus 11%; P<0.001) despite having similar infarct sizes and extent of reperfusion injury than nondiabetic patients. Glycemic status on admission was associated with greater myocardial damage and an increased risk for major adverse cardiovascular events (P<0.001). In nondiabetic patients, the risk of severe myocardial injury started to rise once admission glucose exceeded 7.8 mmol/L, whereas the threshold was higher among patients with diabetes mellitus (≥11.1 mmol/L). Conclusions-The higher mortality rate in diabetic versus nondiabetic STEMI patients is not explained by more pronounced myocardial damage. Hyperglycemia on admission is associated with greater myocardial injury and an increased risk of major adverse cardiovascular events at long-term follow-up. However, hyperglycemia has a stronger relationship to myocardial injury in nondiabetic compared with diabetic patients. Eitel et al Hyperglycemia and Prognosis in STEMI 709unselected, high-risk STEMI population treated by primary percutaneous coronary intervention (PCI), and (3) to compare the hyperglycemia-associated risk at long-term follow-up in patients without antecedent DM versus those with DM. Methods Study PopulationThis study was conducted at a single tertiary care center between February 2006 and August 2008. The study protocol was approved by the local ethics committee, and all patients gave written informed consent. Patients with STEMI undergoing primary PCI were eligible if the onset of symptoms was <12 hours before PCI and if they had ST-segment elevation of at least 0.1 mV in ≥2 extremity leads or at least 0.2 mV in ≥2 precordial leads. Exclusion criteria were previous fibrinolysis, emergency coronary artery bypass surgery, and contraindications to CMRI at study entry, such as implanted pacemakers, defibrillators, claustrophobia, or metallic intracranial implants. Primary PCI and Subsequent TreatmentPrimary PCI was performed according to standard clinical practice. The ...

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Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to “typical” segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with “classical” progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder.

Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and the nervous system. Replacement therapy with the currently approved enzyme relies on M6P-mediated endocytosis. However, therapeutic outcomes still leave room for improvement, especially with regard to skeletal muscles. We tested the uptake, activity, and effect on glucose metabolism of a non-phosphorylated recombinant human GAA produced in moss (moss-GAA). Three variants of moss-GAA differing in glycosylation pattern have been analyzed: two with terminal mannose residues in a paucimannosidic (Man3) or high-mannose (Man 5) configuration and one with terminal N-acetylglucosamine residues (GnGn). Compared to alglucosidase alfa the moss-GAA GnGn variant showed increased uptake in differentiated myotubes. Moreover, incubation of immortalized muscle cells of Gaa−/− mice with moss-GAA GnGn led to similarly efficient clearance of accumulated glycogen as with alglucosidase alfa. These initial data suggest that M6P-residues might not always be necessary for the cellular uptake in enzyme replacement therapy (ERT) and indicate the potential of moss-GAA GnGn as novel alternative drug for targeting skeletal muscle in Pompe patients.

Expression of phospholipid biosynthetic genes in yeast requires activator protein Ino2 which can bind to the UAS element inositol/choline-responsive element (ICRE) and trigger activation of target genes, using two separate transcriptional activation domains, TAD1 and TAD2. However, it is still unknown which cofactors mediate activation by TADs of Ino2. Here, we show that multiple subunits of basal transcription factor TFIID (TBP-associated factors Taf1, Taf4, Taf6, Taf10 and Taf12) are able to interact in vitro with activation domains of Ino2. Interaction was no longer observed with activation-defective variants of TAD1. We were able to identify two nonoverlapping regions in the N-terminus of Taf1 (aa 1-100 and aa 182-250) each of which could interact with TAD1 of Ino2 as well as with TAD4 of activator Adr1. Specific missense mutations within Taf1 domain aa 182-250 affecting basic and hydrophobic residues prevented interaction with wild-type TAD1 and caused reduced expression of INO1. Using chromatin immunoprecipitation we demonstrated Ino2-dependent recruitment of Taf1 and Taf6 to ICRE-containing promoters INO1 and CHO2. Transcriptional derepression of INO1 was no longer possible with temperature-sensitive taf1 and taf6 mutants cultivated under nonpermissive conditions. This result supports the hypothesis of Taf-dependent expression of structural genes activated by Ino2.