Abstract Microwaves (pulsed, 2,450 MHz) at an average power density of 3 W/cm 2 were applied directly to the head for 5, 10, or 20 min, producing a peak specific absorption rate of 240 W/kg in the brain, which, after a 10‐min exposure, resulted in brain temperatures in excess of 43°C. A bolus of 86 Rb in isotonic saline was injected intravenously and an arterial sample was collected for 20 s to determine cardiac output. Compared with unexposed controls, uptake of 86 Rb increased most in those regions directly in the path of the irradiation, namely, the occipital and parietal cortex, as well as the dorsal hippocampus, midbrain, and basal ganglia. In a separate group of animals, regional brain‐vascular spaces were found to increase with brain temperature. These results support previous observations indicating that reliably demonstrable increases of blood‐brain barrier permeability are associated with intense, microwave‐induced hyperthermia, and that the observed changes are not due to field‐specific interaction.
Very small amounts of pituitary hormones and their peptide fragments can profoundly affect learning, memory and other behaviors in both rodents and humans. In addition, several potent pituitary hormone analogs have been developed (e.g. ORG-2766) which retain the behavioral but not the endocrine properties of the parent hormone. The abilities of these peptides to influence nervous system functions suggested that they also may be capable of modifying seizure activity. This possibility is supported by the fact that treatment with adrenocorticotropic hormone (ACTH) represents a major effective therapy for at least one clinical convulsive disorder, infantile spasm. This contention also is reinforced by our findings that ORG-2766 markedly reduces both the behavioral severity and the spread of seizure potentials in an animal model of epilepsy, the kindled rat. By contrast, arginine vasopressin and its non-endocrine desglycyl fragment (DGAVP) facilitates the seizure process in this animal model. Our research also suggests that the behavioral and physiological effects of certain anterior and posterior pituitary hormone fragments depend, in part, on their abilities to modulate permeability mechanisms in brain vasculature. In addition, and especially significant from the standpoint of etiology, is the observation that the kindling process itself appears to alter cerebrovascular permeability. In the kindled rat, "permanent" decreases in permeability (60-75%) are found selectively in the hypothalamic and hippocampal regions, weeks after the last seizure. Several lines of evidence indicate that disruption of normal cerebrovascular function occurs following epileptiform seizures. We propose that an immediate increase in cerebral blood flow and cerebrovascular permeability occurs following a single, acute seizure, and that repeated chronic seizures lead to damage to the cerebrovascular system. Sustained damage would be expected to contribute to the development and maintenance of a chronic seizure focus. Such observations suggest a link between important cerebrovascular disturbances associated with seizures and the existing known and proposed electrophysiological, metabolic and neuropathological substrates of epilepsy. They also point to new strategies for the treatment of seizure disorders by focusing on ways to reduce or prevent cerebrovascular damage.
✓ The authors used indicator fractionation techniques to determine blood flow in normal and bluntly traumatized spinal cords of Macaca rhesus monkeys. Normal flow rates were determined for several levels of spinal cord as well as differential values for white and gray matter from representative areas. Flow rates in traumatized tissue, obtained at several different time intervals up to 4 hours after injury, demonstrated marked differences in regional perfusion of the white matter and gray matter after trauma. Gray matter perfusion was nearly obliterated while white matter blood flow persisted and in fact was higher than uninjured controls. The findings do not support the concept of ischemia as a factor in white matter failure. If toxic pathobiochemical alterations are induced by trauma, it may be possible to reverse these changes by exploiting the preserved white matter blood flow for chemotherapeutic intervention.
Purpose This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma. Patients and Methods One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival. Results Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%;P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%;P = 0.043; OS: 55% vs. 27%;P = 0.012). Conclusions Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.
Although duration of unconsciousness is commonly used as a prognostic index following traumatic brain injury (TBI), few controlled studies have statistically evaluated the relationship between unconsciousness and histologic pathology, particularly after moderate head injury. Using a pendulum-striker concussive device, a reproducible model of TBI in rats was developed. This model is uncomplicated by skull fractures, contusions, or experimenter-induced craniotomies. In the present study, the severity of the histopathology observed in this model of moderate closed-head injury at 48 h posttrauma is linearly related to the duration of unconsciousness (p < 0.0001). The pathology, assessed with a silver stain for neurodegeneration, is particularly striking if unconsciousness persists for 4 minutes or more. These data suggest that the initial period of unconsciousness may be a useful predictor of clinical brain histopathology associated with moderate closed-head injury, predicting either the degree of pathology and/or the rate it progresses if left untreated.
