Targeting extracellular DNA to deliver IGF-1 to the injured heart.

There is a great need for the development of therapeutic strategies that can target biomolecules to damaged myocardium. Necrosis of myocardium during a myocardial infarction (MI) is characterized by extracellular release of DNA, which can serve as a potential target for ischemic tissue. Hoechst, a histological stain that binds to double-stranded DNA can be conjugated to a variety of molecules. Insulin-like growth factor-1 (IGF-1), a small protein/polypeptide with a short circulating-half life is cardioprotective following MI but its clinical use is limited by poor delivery, as intra-myocardial injections have poor retention and chronic systemic presence has adverse side effects. Here, we present a novel delivery vehicle for IGF-1, via its conjugation to Hoechst for targeting infarcted tissue. Using a mouse model of ischemia-reperfusion, we demonstrate that intravenous delivery of Hoechst-IGF-1 results in activation of Akt, a downstream target of IGF-1 and protects from cardiac fibrosis and dysfunction following MI

Clinical outcome of paediatric patients with traumatic brain injury (TBI) receiving 3% hypertonic saline (HTS) in the emergency room of a tertiary care hospital

Objective: To determine the clinical outcome and mean length of hospital stay of paediatric patients with severe blunt traumatic head injury (THI) receiving 3% hypertonic saline (HTS) in the Emergency Department (ED).Methodology: This case series study was conducted at the Department of Emergency Medicine, Aga Khan University Hospital, Karachi, from 2014 to 2015 via chart review of 105 patients. Detailed history and clinical examination of all paediatric patients aged 2-16 years was recorded which included moderate to severe head injury as classified by the Glasgow Coma Scale (GCS) by the Brain Trauma Foundation. As per routine care after admission of such a patient, for resuscitation 3% HTS was administered. GCS was recorded at 6 hours and at the time of discharge.Results: Of the 105 patients, 76 (72.4%) were male and 29 (27.6%) were female, and the mean age was 61.6+45.9 months. Traumatic brain injury (TBI) was found moderate in 60 (57.1%) cases and severe in 45 (42.9%) of our patients as per the GCS. Six hours after resuscitation with 3% hypertonic saline, 45 (43%) patients normalised as per GCS, 39 (37%) patients had moderate TBI and 21 (20%) had severe TBI. Forty five patients had a hospital stay of 2-3 days. The GCS improved after resuscitation with 3% hypertonic saline in emergency department, with a mean length of stay of 4.6+3.9 and 12.6+10.7 days in moderate and severe head injury respectively with a P value of \u3c0.001, and was normal in 94 (89.5%) patients at the time of discharge.Conclusions: Paediatric patients with TBI receiving 3% hypertonic saline results in improved GCS and a decrease in the length of hospital stay

Cardiomyocyte Aldose Reductase Causes Heart Failure and Impairs Recovery from Ischemia

<div><p>Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α–myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.</p> </div