Gene therapy is a promising approach to the treatment of many forms of disease, including cancer. Of critical concern in its implementation is the ability to control the location, duration, and level of expression of the therapeutic gene. Here, we propose the use of local heat in combination with a heat-sensitive promoter to help accomplish this. Certain members of the family of heat shock protein (hsp) promoters display a regulation that depends strongly on temperature. We present a study of natural hsp70 induction in rat leg by MRI-guided focused ultrasound to investigate the hsp70 promoter as a possible candidate for use in control of gene expression with local heat. A temperature increase of 5-8 degrees C in the focal region for 45 minutes led to a differential expression of the hsp70 mRNA between the focal region and the surrounding tissue ranging from a factor of 3 to 67.
The principles of a fast T2*-sensitized MR imaging method (Moonen et al., Magn. Reson. Med. 26, 184 (1992)) are extended to further increase T2* sensitivity. It is shown that the period of T2*-weighting can be lengthened by n TR-periods by appropriate gradient schemes without RF refocusing resulting in progressively delayed gradient-recalled echoes. This extension of the echo-shifting concept thus introduces large flexibility in the choice of T2*-weighting without changing total imaging time. The coherence pathway formalism is used to evaluate and describe the selection of the desired echo and the attenuation of unwanted coherences. The new techniques are demonstrated for tracking a bolus of susceptibility contrast agent in cat brain. Relative blood-volume maps are derived with expected contrast between white and gray matter.
Previous studies in animals suggested that neonatal lesions of the ventral hippocampus disrupt development of prefrontal cortex and its regulation of dopaminergic activity. In the present study, we assayed an in vivo chemical marker of neuronal integrity (proton magnetic resonance spectroscopy signal of N-acetylaspartate, NAA) in prefrontal cortex and striatum of rats with neonatal excitotoxic lesions of the ventral hippocampus. We also measured in post-mortem tissue expression of EAAC1 mRNA, a molecular marker of intrinsic neurons. In the cohort studied at juvenile age and again at young adulthood [postnatal day (PD) 37 and 71], we found selective reductions of NAA in the prefrontal cortex only at PD 71. Emergence of neuronal pathology was temporally associated with emergence of amphetamine-induced hyperlocomotion. Reduced prefrontal NAA was confirmed in the second cohort studied at an older age (PD 120). Expression of EAAC1 mRNA was significantly reduced in prefrontal cortex of the lesioned rats. No changes in NAA were found in the striatum in either cohort and cortical area size was not changed. These results suggest that early ventral hippocampal lesions produce developmental neuronal pathology in prefrontal cortex that is temporally associated with dysregulation of dopamine behaviors and is reminiscent of the temporal profile of the onset of schizophrenia.
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