Genetic factors influencing alpha-particle-induced chromosomal instability.

Alpha-particle-induced chromosomal instability in haemopoietic cells obtained from the CBA/H, DBA/2 and C57BL/6 inbred strains of mouse has been demonstrated at frequencies dependent on genotype. The CBA/H and DBA/2 strains may be regarded as 'sensitive' and the C57BL/6 strain as 'resistant'; resistance was dominant in cells from F1 hybrids. Previously, in cultures where we demonstrated radiation-induced chromosomal instability we also demonstrated an enhanced and persisting oxyradical activity. Quantitative differences in superoxide generation have now been correlated with genetically determined differences in the expression of chromosomal instability. Our findings demonstrate an important influence of genetic factors in alpha-particle-induced chromosomal instability.

Radiation-induced genomic instability and persisting oxidative stress in primary bone marrow cultures.

There is accumulating evidence that cells exposed to low and often environmentally relevant doses of ionizing radiation survive the initial insult, but transmit genomic instability to their progeny. The underlying mechanism of radiation-induced genomic instability is unknown. We present bio-chemical evidence consistent with the hypothesis that enhanced and persistent oxy-radical activity may be responsible.

Differentiation and delayed cell death in embryonal stem cells exposed to low doses of ionising radiation.

Embryonal stem cells have been used to study the effects of environmentally relevant doses of radiation on cell death and differentation. The ES cells were found to have a greater than 60% chance of surviving the traversal of a single alpha-particle, the lowest possible dose of high linear energy transfer radiation a cell may receive. The ES cells appeared to possess the cell cycle checkpoints believed to prevent the transmission of the radiation damage. However, delayed effects were observed in the progeny. An increased incidence of apoptosis and haempoietic differentiation capacity was found to persist in the ES cell population over many cell divisions. Since both cell death and differentiation are known to play a key role in tissue kinetics, an ES cell model will provide a valuable and versatile cell system for studying the role of cell death and differentiation in the pathology of radiogenic diseases.

Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting.

In this prospective, randomized, double-blind, placebo-controlled study, the clinical, biochemical, and hemodynamic effects of xanthine oxidase inhibition in patients undergoing coronary artery bypass grafting were assessed. Allopurinol pretreatment significantly reduced the use of inotropic support after the operation (5 of 25 patients versus 13 of 25 patients, p < 0.01) and increased the rate of peripheral warming (11.4 +/- 0.85 hours versus 14.4 +/- 1 hours, p < 0.02). Twenty patients (9 in the allopurinol group and 11 in the placebo group) underwent invasive hemodynamic monitoring and intraoperative coronary sinus cannulation. The cardiac indexes of both groups were similar before the operation and for the first postoperative hour; thereafter, the cardiac index increased significantly in only the active treatment group (F = 3.33 and df = 5.90, p < 0.004). Products of lipid peroxidation (thiobarbituric acid reactive substances) increased significantly in only the placebo group, with increases being evident both in the systemic circulation (9.5 +/- 3.2 nmol/gm albumin, p < 0.007, and 24 +/- 5 nmol/gm albumin, p < 0.001, at 30 seconds and 2 minutes of reperfusion, respectively) and the coronary sinus (19.4 +/- 5.8 nmol/gm albumin, p < 0.004, and 28 +/- 4 nmol/gm albumin, p < 0.001, at 2 and 5 minutes of reperfusion, respectively. No significant difference was evident between the groups with respect to cardiac enzyme or vitamin E release. It is proposed that xanthine oxidase inhibition exerts its beneficial effects by reducing the level of free radical activity associated with reperfusion during coronary artery bypass grafting.

Lipid peroxidation and changes in vitamin E levels during coronary artery bypass grafting.

The effects of ischemia and reperfusion on arterial and coronary sinus vitamin E and thiobarbituric acid reactive substance levels were investigated in 10 patients undergoing routine coronary artery bypass grafting. Serial sampling was performed during bypass operations, before the initial period of crossclamping and at 30 seconds and 2, 5, and 10 minutes after final crossclamp removal. A net myocardial loss of vitamin E occurred in the first 5 minutes of myocardial reperfusion (0.84 +/- 0.21 mumol/mmol cholesterol; p < 0.01). Myocardial vitamin E loss correlated positively with the total crossclamp time (rho = -0.695; p < 0.05) but was independent of cardiac enzyme release and duration of cardiopulmonary bypass. The concentration of thiobarbituric acid reactive substance rose significantly in the systemic circulation (+14 nmol/gm albumin; F > 17; p < 0.002) at 2 and 5 minutes after crossclamp removal. A significant increase of thiobarbituric acid reactive substance levels was also found in the coronary sinus blood 10 minutes after crossclamp removal (+8 nmol/gm albumin; F > 14; p < 0.004). However, there was no net arterial-coronary sinus difference in thiobarbituric acid reactive substance levels. The change in arterial thiobarbituric acid reactive substance levels in each patient was inversely correlated with their control vitamin E level (F = 9.53; p < 0.01). Our findings suggest that systemic lipid peroxidation occurs during bypass and that vitamin E may play a protective role during routine bypass grafting by attenuating the degree of peroxidative damage.