The cardiac response to increased work includes a reactivation of fetal genes. The response to a decrease in cardiac work is not known. Such information is of clinical interest, because mechanical unloading can improve the functional capacity of the failing heart. We compared here the patterns of gene expression in unloaded rat heart with those in hypertrophied rat heart. Both conditions induced a re-expression of growth factors and proto-oncogenes, and a downregulation of the 'adult' isoforms, but not of the 'fetal' isoforms, of proteins regulating myocardial energetics. Therefore, opposite changes in cardiac workload in vivo induce similar patterns of gene response. Reactivation of fetal genes may underlie the functional improvement of an unloaded failing heart.

The cardiac conduction system is an anatomically discrete segment of specialized myocardium that initiates and propagates electrical impulses to coordinate myocardial contraction. To define the molecular composition of the mouse ventricular conduction system we used microdissection and transcriptional profiling by serial analysis of gene expression (SAGE). Conduction-system-specific expression for Id2, a member of the Id gene family of transcriptional repressors, was identified. Analyses of Id2-deficient mice demonstrated structural and functional conduction system abnormalities, including left bundle branch block. A 1.2 kb fragment of the Id2 promoter proved sufficient for cooperative regulation by Nkx2-5 and Tbx5 in vitro and for conduction-system-specific gene expression in vivo. Furthermore, compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system. We conclude that a molecular pathway including Tbx5, Nkx2-5, and Id2 coordinates specification of ventricular myocytes into the ventricular conduction system lineage.

MA-dependent individuals are more impulsive than controls, and this may be causally related to memory deficits but was unrelated to any other measure of psychiatric or cognitive impairment or any drug use history variable.

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Transcriptional regulation of nuclear encoded mitochondrial proteins is dependent on nuclear transcription factors that act on genes encoding key components of mitochondrial transcription, replication, and heme biosynthetic machinery. Cellular factors that target expression of proteins to the heart have been well characterized with respect to excitation-contraction coupling. No information currently exists that examines whether parallel transcriptional mechanisms regulate nuclear encoded expression of heart-specific mitochondrial isoforms. The muscle CPT-I␤ isoform in heart is a TATAless gene that uses Sp-1 proteins to support basal expression. The rat cardiac fatty acid response element (؊301/؊289), previously characterized in the human gene, is responsive to oleic acid following serum deprivation. Deletion and mutational analysis of the 5-flanking sequence of the carnitine palmitoyltransferase I␤ (CPT-I␤) gene defines regulatory regions in the ؊391/ ؉80 promoter luciferase construct. When deleted or mutated constructs were individually transfected into cardiac myocytes, CPT-I/luciferase reporter gene expression was significantly depressed at sites involving a putative MEF2 sequence downstream from the fatty acid response element and a cluster of heart-specific regulatory regions flanked by two Sp1 elements. Each site demonstrated binding to cardiac nuclear proteins and competition specificity (or supershifts) with oligonucleotides and antibodies. Individual expression vectors for Nkx2.5, serum response factor (SRF), and GATA4 enhanced CPT-I reporter gene expression 4 -36-fold in CV-1 cells. Although cotransfection of Nkx and SRF produced additive luciferase expression, the combination of SRF and GATA-4 cotransfection resulted in synergistic activation of CPT-I␤. The results demonstrate that SRF and the tissue-restricted isoform, GATA-4, drive robust gene transcription of a mitochondrial protein highly expressed in heart. Expression of nuclear and mitochondrial encoded expression of respiratory chain subunits occurs despite physical separation of transcriptional events within separate genomes. Stimulation and coordination of mitochondrial gene expression from these two sites is accomplished by the nuclear respiratory factors, NRF-1 and NRF-2 (1, 2). Using electrical stimulation to produce hypertrophic growth of neonatal cardiac myocytes, the transcriptional activation of cytochrome c is preceded by induction of NRF-1 mRNA (3). This observation is consistent with NRF-1 induction as a prerequisite for synthesis of respiratory chain components. These basic insights into cellular factors that link nuclear events to mitochondrial gene activation are critical for adaptation to environmental stresses and the necessity for enhanced energy production.In contrast to subcellular coordination of mitochondrial biogenesis and respiratory chain synthesis, less is known concerning tissue-specific transcriptional regulation of nuclear encoded genes involved in energy metabolism. These genes are particularly important in cardiac...

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We report a premature infant with disseminated fungal infection identified as Bipolaris spicifera. The infant was born at 23 4/7 weeks' gestation, weighing 780 g. At day of life (DOL) 7 erythematous areas on the back were noticed that progressed to black, necrotic skin lesions. A shave biopsy showed invasive fungal organisms that were identified by culture as B. spicifera. The lesions progressed despite aggressive surgical debridement and antifungal therapy. On autopsy, fungal organisms found throughout the internal organs confirmed disseminated disease with B. spicifera. This organism is now more often recognized as a human pathogen; however, this is the first reported case in a neonate.