Background: Duchenne muscular dystrophy (DMD) is caused by the loss of dystrophin. Severe and ultimately lethal, DMD progresses relatively slowly in that patients become wheelchair bound only around age twelve with a survival expectancy reaching the third decade of life. Methods: The mildly-affected mdx mouse model of DMD, and transgenic DysDMTB-mdx and Fiona-mdx mice expressing dystrophin or utrophin, respectively, were exposed to either mild (scruffing) or severe (subordination stress) stress paradigms and profiled for their behavioral and physiological responses. A subgroup of mdx mice exposed to subordination stress were pretreated with the beta-blocker metoprolol. Findings: Subordination stress caused lethality in »30% of mdx mice within 24 h and »70% lethality within 48 h, which was not rescued by metoprolol. Lethality was associated with heart damage, waddling gait and hypo-locomotion, as well as marked up-regulation of the hypothalamus-pituitary-adrenocortical axis. A novel cardiovascular phenotype emerged in mdx mice, in that scruffing caused a transient drop in arterial pressure, while subordination stress caused severe and sustained hypotension with concurrent tachycardia. Transgenic expression of dystrophin or utrophin in skeletal muscle protected mdx mice from scruffing and social stress-induced responses including mortality. Interpretation: We have identified a robust new stress phenotype in the otherwise mildly affected mdx mouse that suggests relatively benign handling may impact the outcome of behavioural experiments, but which should also expedite the knowledge-based therapy development for DMD.

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO(2) in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 +/- 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO(2) measured within 10-15 min after heating for 30 min at 42.5 degrees C was about three-fold greater than that in the control tumours. About 62% of pO(2) values measured in control tumours were <5 mm Hg. After heating at 42.5 degrees C for 30 min, 37% of pO(2) values were <5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.

No abstract

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO2 in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 +/- 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO(2) measured within 10-15 min after heating for 30 min at 42.5 degrees C was about three-fold greater than that in the control tumours. About 62% of PO(2) values measured in control tumours were < 5 mm Hg. After heating at 42.5 degrees C for 30 min, 37% of PO(2) values were < 5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.

No abstract