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D A McRae

Publications and source records attributed to D A McRae.

13 recordsLinked to original sources
PubMed1999

Changes in the noninvasive, in vivo electrical impedance of three xenografts during the necrotic cell-response sequence.

PURPOSE: To investigate the noninvasive, in vivo use of electrical impedance spectroscopy (EIS) as a method for observing the real-time, cellular-level responses of a volume of tissue to therapies. Here, we studied the EIS response during the development and progression of hyperthermia-induced coagulative necrosis in three diverse human xenografts. METHODS AND MATERIALS: A necrotic cell response sequence was selectively induced in three types of subcutaneously-grown human tumor xenografts by applying hyperthermia at 44.5 degrees C. The electrical impedance of the tumors was measured from 100 Hz to 10 MHZ, noninvasively, in vivo during the treatments. From the full spectrum EIS, ratios between resistivities at selected frequencies (p-ratios) were used as indicators of the changes in the electrical impedance spectra of each tumor's cell population. RESULTS: The rho-ratios consistently demonstrated characteristic, early, rapid increases which coincided with cell and organelle swelling typical of early necrosis. These increases subsequently slowed, but no decrease began before the end of treatment, unlike previous, similarly treated, thermo-sensitive EMT6 mouse tumors. This was consistent with the xenograft histology, which revealed ubiquitous, early-stage coagulative necrosis, with no gross plasma membrane damage at the end of treatment. The extent of both the necrosis and p-ratio changes were similar to those seen early in the EMT6 tumor treatment. Within several days after treatment, the xenograft volumes regressed nearly completely, suggesting completion of the cell populations' necrotic response (lysing) during this period. Consistent with this, extended EIS measurements over a 24-h posttreatment period allowed tracking of the necrotic response sequence through this lysing phase for one type of xenograft. CONCLUSION: The change in the electrical impedance of a volume of tumor tissue which occurs during and/or after a hyperthermia treatment can be correlated with the extent of necrosis observed histologically in the cell population.

Adenocarcinoma↗
PubMed1996

Deconvolved electrical impedance spectra track distinct cell morphology changes.

A two-component Cole-Cole model was used to obtain statistically significant fits to 100-Hz-10-MHz impedance data for EMT-6 mouse tumors during the progressive histological changes induced by hyperthermia. The resulting fitting parameters were used to deconvolute and reconstruct the two dispersions which confer the predominant impedance features to this tissue. The time-dependent changes of these two dispersions were correlated with the concurrent, heat-induced morphological changes of the tumors' cells. The higher frequency dispersion (fc approximately 1 MHz) was identified with a Maxwell-Wagner relaxation process linked to the overall volume response of the cells. The lower frequency dispersion (fc approximately 10 kHz) represented an alpha-relaxation associated with the surface morphology and integrity of the plasma membranes. Thus, two aspects of the characteristic cellular damage sequence in these tumors were found to be separately discernable and trackable in real-time using the impedance data.

Animals↗
PubMed1995

Dynamic scaling in the dielectric response of excised EMT-6 tumours undergoing hyperthermia.

A constant-phase-angle response (CPA) has been identified in the dielectric spectrum of EMT-6 tissues undergoing hyperthermia. A dynamic scaling relationship between the static permittivity and conductivity using the CPA frequency exponent n has been shown to occur during the destructive phase of hyperthermia. This behaviour has been attributed to the self-similar structure of the internal membrane compartments of the cells and described by means of a hierarchical circuit model. In this way the CPA exponent has been related to the convolution of internal membrane surfaces lying in between the mitochondria and the outer cell wall. The dynamic scaling is assigned to the progressive destruction of cell membranes in sequence from the outside inwards.

Animals↗
PubMed1995

Radioresistant DNA synthesis in SV40-immortalized ataxia telangiectasia fibroblasts.

Ataxia telangiectasia (AT) is an autosomal recessive disease, characterized by both neurological disorders and a high incidence of early-onset cancers. On a cellular level, cellular radiosensitivity and radioresistant DNA synthesis are the hallmarks of AT. While expression of cellular radiosensitivity varies somewhat among affected individuals, radioresistant DNA synthesis is seen consistently and, in fact, is the only end point used for assigning individuals to genetic complementation groups. For this reason, complementation-group-specific correction of radioresistant DNA synthesis in AT cells has long been thought to be an absolute requirement for confirmation of a bona fide clone of an AT gene. Since primary AT cells grow poorly in culture, SV40-immortalized AT fibroblasts are the usual recipients of transfected DNA in these studies. In experiments reported here, we demonstrate that SV40-immortalized AT fibroblasts have significantly reduced radioresistant DNA synthesis compared to primary AT fibroblasts, and their response to radiation is more like normal cells, in that both the radiosensitive and radioresistant components appear to be present. This suggests that there may be an interaction between SV40 proteins and the AT gene product or its downstream elements. This partial "complementation" of radioresistant DNA synthesis in SV40-immortalized AT cells complicates complementation cloning strategies, and should be considered when terminally screening putative AT gene clones by analysis of radioresistant DNA synthesis.

Ataxia Telangiectasia↗
PubMed1994

The effect of hyperthermia-induced tissue conductivity changes on electrical impedance temperature mapping.

Changes in tissue electrical conductivity in the low radiofrequency range due to tissue temperature coefficients (TCS), approximately 2% degrees C-1, have been investigated by others as a non-invasive means of determining tissue temperature changes during the application of therapeutic hyperthermia. However, the occurrence of additional changes in conductivity due to non-TC effects, for example, from heat-induced oedema, or changes in cellular volume or membrane characteristics, can result in incorrect temperature determination based solely on the TC. This paper (i) presents estimates of the errors that will occur in temperature mapping using electrical impedance measurements if non-TC effects are ignored, using examples of excised and in vivo EMT6 tumours, (ii) presents a method of differentiating the onset of non-TC effects from TC effects using conductance measurements, thereby allowing for use of the TC method until the onset of non-TC effects, and (iii) suggests a means of using conductance measurements to monitor the course of hyperthermia treatments, without the use of temperature information, based on hyperthermia-induced cellular changes.

Animals↗
PubMed1992

The dielectric parameters of excised EMT-6 tumours and their change during hyperthermia.

The electrical impedance from 100 Hz to 40 MHz of freshly excised EMT-6 tumours was measured periodically while the tumours were exposed to typical hyperthermia heating regimens. During hyperthermia, the EMT-6 tumour displays a characteristic response sequence which includes cellular swelling, progressive membrane damage, cellular shrinking and subsequent progressive histolysis. It was found that the changes in the tumour tissue dielectric properties reflected these hyperthermia-induced histological changes. In particular the parameters delta epsilon, sigma s and fc progressed to, reached, and retreated from extrema as the cells swelled to a maximum and then contracted. These parameters continued retreating beyond their original values as the beta-dispersion progressively collapsed during the period of progressive histolysis. The Cole-Cole parameter alpha increased during most of these histological changes, indicating a broadening of the dispersion, which suggests differential cell response during this period. Differences in the time-course between dielectric components may reflect the combined effects of cellular swelling and concurrent progressive membrane changes. Changes in rate and shape of the dielectric response with hyperthermia temperature are discussed in terms of possible cellular responses during hyperthermia.

Animals↗
PubMed1989

Musical hallucinations in a deaf elderly woman.

Musical hallucinations had caused an 86-year-old deaf woman to become anxious and depressed. She was admitted, and tranquilizing and hypnotic drugs afforded some slight improvement. The use of her hearing aid to increase ambient noise levels reduced the intensity of the hallucinations, and the patient improved.

Aged↗
PubMed1981

Middle temporal veins - a potential hazard in the Gillies' Operation.

In an undergraduate practical anatomy class, large middle temporal veins were observed in one cadaver following reflection of the temporal fascia. A survey of their form, size and arrangement was undertaken. The veins of this region were examined in 20 cadavers. Middle temporal veins, which varied markedly in size, were present in 11 cadavers. Each had two to four tributaries, parallel to the muscle fisciculi draining downwards into the main stem which lay obliquely across temporalis muscle from the upper lateral rim of the orbit to the root of the zygomatic process. In the Gillies' operation for the elevation of a fractured zygoma, an elevator is passed blindly down upon temporalis muscle, deep to the temporal fascia and the depressed bone. The procedure may result in damage to these veins.

Humans↗
PubMed1980

Mitotic division of oligodendrocytes which have begun myelination.

Examination of spinal cords of 5 days old mice showed a number of examples of oligodendrocytes, in various phases of mitosis, which remained in contact with the axons which they were myelinating. Cells in prophases had thick processes between the perikaryon and the myelinating axons but as mitosis proceeded the oligodendrocyte processes became thin and spider-like, probably due to the extrusion of cytoplasm from the processes into the perikaryon. Mitotic astrocytes were also present.

Animals↗
PubMedDate not supplied

Changes in electrical impedance of skeletal muscle measured during hyperthermia.

The electrical impedance of rat skeletal muscle was measured from 100 Hz to 40 MHz during the application of typical hyperthermia heating regimens. Trials were performed employing freshly excised tissue heated to target temperatures from 39.5 to 50 degrees C. Abrupt and rapid decreases in the low-frequency beta-dispersion occurred very shortly after reaching hyperthermia temperatures. These rapid decreases continued at a rate and to an extent dependent upon the target temperature, and then, as heating continued, abruptly changed to a much slower rate which continued indefinitely. The initial rapid changes were associated with microscopically observed muscle fibre rounding and radial shrinkage, with accompanying increasing interstitial oedema. The subsequent slow changes were associated with a slow histolysis. The time- and temperature-dependence of the rapid resistivity changes evidenced similarities to typical hyperthermia endpoint responses. An Arrhenius analysis of the rate of the resistivity changes yielded a break at 43 degrees C, with activation energies of 36.1 and 58.3 kcal/mol above and below this break. Preliminary in vivo impedance data displayed qualitative similarities to the excised tissue findings.

Animals↗
PubMedDate not supplied

Non-invasive, in-vivo electrical impedance of EMT-6 tumours during hyperthermia: correlation with morphology and tumour-growth-delay.

The electrical impedance at frequencies from 100 Hz to 40 MHz of EMT-6 tumours was measured non-invasively, in vivo, during hyperthermia using an apparatus constructed for this purpose. Histology and morphometry were performed on tumours harvested periodically during the heating. A ratio of conductivities at two frequencies (sigma (10MHz)/sigma (10kHz)), which minimizes the tissues temperature-coefficient effects, was used to correlate impedance changes with the histopathological changes. The bulk of the cell population followed a necrotic cell death sequence during heating. Initial increase of the sigma-ratio correlated with cell swelling, and a reversal of the rate of this increase correlated with the appearance of small membrane breaks and evidence of mitochondrial damage. A continued, slowing sigma-ratio increase to a maximum correlated with continued cell swelling accompanied by increasing membrane disruption. The subsequent decrease in sigma-ratio correlated with continued general cell lysing. Between the appearance of the first membrane breaks (sigma-ratio peak) and the evidence of general lysing (sigma-ratio peak), the tumour-growth-delay increased non-linearly. Because the sigma-ratio consistently discerned these events, these measurements were able to predict the fate of this cell population when subjected to hyperthermia. Knowledge of temperature or time of heating was not required.

Animals↗
PubMedDate not supplied

Hyperthermia and verapamil inhibit the growth of human colon cancer xenografts in vivo through apoptosis.

BACKGROUND: The long-term goal of this work is to develop a new therapeutic regimen for the treatment of colon cancer in humans which will include hyperthermic intraperitoneal perfusion of verapamil as an alternative to administration of chemotherapy. METHODS AND RESULTS: Hyperthermia and verapamil caused a significant inhibition of the growth of human colon cancer (HT-29) xenografts. Both apoptosis detection assays, TUNEL and H and E staining, have shown that approximately 50% of human colon cancer cells underwent apoptosis after hyperthermia and verapamil administration. The TUNEL assay has demonstrated that DNA strand breaks appeared fairly rapidly and maximum breakage occurred at 2 hours after the treatment. Histopathological assay has showed maximum apoptotic morphological changes at 12 hours after treatment. CONCLUSION: Thus, the results of our in vivo experiments confirmed our previously obtained in vitro data concerning the significant ability of the combination of hyperthermia and verapamil to inhibit human colon cancer cell growth through programmed cell death.

Animals↗