Abstract 48: Reduction of Histological Damage with Mild Therapeutic Hypothermia after Prolonged Cardiac Arrest

Purpose: The aim of our study was to assess the effect of hypothermia on histological damage in 19 brain regions after prolonged cardiac arrest in pigs. Methods: Pigs were anaesthetized and mechanically ventilated. After stabilisation of pulmonary artery temperature (Tpa) at 38.5±0.2 °C, ventricular fibrillation (VF) was induced and 10 min of untreated VF were followed by 8 min of cardiopulmonary resuscitation (mechanical chest compressions, two doses of vasopressin 0.4 IE/kg). At 8 min of CPR, up to 3 countershocks were delivered. Pigs that had return of spontaneous circulation (ROSC) were randomized to one of 2 groups (control, hypothermia). Pigs in the hypothermia group were cooled to Tpa 33.0±1.0 °C with a surface cooling device (LRS Thermosuit™) circulating ice water over most of the skin surface. Pigs in the control group were kept at 38.5±1.0 °C throughout the experiment. After 14 hours of hypothermia, pigs were rewarmed, weaned and brought to the stable. At day 9 of the experiment, final neurologic examination was performed. After that the animals were sacrificed and perfused with 4 liters of saline, followed by 1 liter of paraformaldehyde (3%, pH 7.4). The brain was removed and 19 different regions of the brain were examined by means of lightmicroscopy using a histopathologic damage score that was used in previous studies. Following damage qualities were considered: edema, eosinophilic necrosis (oncosis), vacuolar degeneration and malacia. The total numeric histological damage score (HDS) was the sum of all area scores. Data are presented as median and interquartile range, group comparison was done with a Mann-Whitney-U test. Results: 16 (29 –35 kg) pigs were randomized. The time to reach target temperature in the hypothermia group (n = 8) was 9.0 (5.3; 11.9) min. Total HDS in the hypothermia group was 71 (61; 84), in the control group 132 (124; 174; p&lt;0.001). Significant (p&lt;0.05) improvements in damage were found in hippocampus, temporal, parietal, frontal and occipital cortex. Conclusions: Histological damage after prolonged cardiac arrest was improved significantly in cooled animals compared to control animals. Not all brain regions could benefit to the same extent.</jats:p

Debio 0507 primarily forms diaminocyclohexane-Pt-d(GpG) and -d(ApG) DNA adducts in HCT116 cells

PURPOSE: To characterize the cellular action mechanism of Debio 0507, we compared the major DNA adducts formed by Debio 0507- and oxaliplatin-treated HCT116 human colon carcinoma cells by a combination of inductively coupled plasma mass spectrometry (ICP-MS) and ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS). METHODS: HCT116 cells were treated with IC(50) doses of Debio 0507 or oxaliplatin for 3 days. Total cellular Pt–DNA adducts were determined by ICP-MS. The DNA was digested, and the major Pt–DNA adducts formed by both drugs were characterized by UPLC/MS/MS essentially as described previously for cisplatin (Baskerville-Abraham et al. in Chem Res Toxicol 22:905–912, 2009). RESULTS: The Pt level/deoxynucleotide was 7.4/10(4) for DNA from Debio 0507-treated cells and 5.5/10(4) for oxaliplatin-treated cells following a 3-day treatment at the IC(50) for each drug. UPLC-MS/MS in the positive ion mode confirmed the major Pt–DNA adducts formed by both drugs were dach-Pt-d(GpG) (904.2 m/z → 610 m/z and 904.2 m/z → 459 m/z) and dach-Pt-d(ApG) (888.2 m/z → 594 m/z and 888.2 m/z → 459 m/z). CONCLUSIONS: These data show that the major DNA adducts formed by Debio 0507 are the dach-Pt-d(GpG) and dach-Pt-d(ApG) adducts and at equitoxic doses Debio 0507 and oxaliplatin form similar levels of dach-Pt-d(GpG) and dach-Pt-d(ApG) adducts. This suggests that the action mechanisms of Debio 0507 and oxaliplatin are similar at a cellular level

Genetic markers on chromosome 7.

Chromosome 7 is frequently associated with chromosome aberrations, rearrangements, and deletions. It also contains many important genes, gene families, and disease loci. This brief review attempts to summarise these and other interesting aspects of chromosome 7. With the rapid accumulation of cloned genes and polymorphic DNA fragments, this chromosome has become an excellent substrate for molecular genetic studies