Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1(-/-)) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H

Introduction to co-simulation of software and hardware in embedded processor systems

From the dawn of the first use of microprocessors and microcontrollers in embedded systems, the software has been blamed for products being late to market, This is due to software being developed after hardware is fabricated. During the past few years, the use of Hardware Description (or Design) Languages (HDLs) and digital simulation have advanced to a point where the concurrent development of software and hardware can be contemplated using simulation environments. This offers the potential of 50% or greater reductions in time-to-market for embedded systems. This paper is a tutorial on the technical issues that underlie software-hardware (swhw) co-simulation, and the current state of the art. We review the traditional sequential hardware-software design paradigm, and suggest a paradigm for concurrent design, which is supported by co-simulation of software and hardware. This is followed by sections on HDLs modeling and simulation;hardware assisted approaches to simulation; microprocessor modeling methods; brief descriptions of four commercial products for sw-hw co-simulation and a description of our own experiments to develop a co-simulation environment