John W. Finnie

Long-Term Exposure of Eμ-Pim1 Transgenic Mice to 898.4 MHz Microwaves does not Increase Lymphoma Incidence

Abstract Utteridge, T. D., Gebski, V., Finnie, J. W., Vernon-Roberts, B. and Kuchel, T. R. Long-Term Exposure of Eμ-Pim1 Transgenic Mice to 898.4 MHz Microwaves does not Increase Lymphoma Incidence. Radiat. Res. 158, 357–364 (2002). A total of 120 Eμ-Pim1 heterozygous mice and 120 wild-type mice were exposed for 1 h/day 5 days/week at each of the four exposure levels in “Ferris-wheel” exposure systems for up to 104 weeks to GSM-modulated 898.4 MHz radiation at SARs of 0.25, 1.0, 2.0 and 4.0 W/kg. In addition, 120 heterozygous and 120 wild-type mice were sham-exposed; there was also an unrestrained negative control group. Four exposure levels were used to investigate whether a dose–response effect could be detected. Independent verification confirmed that the exposures in the current study were nonthermal. There was no significant difference in the incidence of lymphomas between exposed and sham-exposed groups at any of the exposure levels. A dose–response effect was not detected. The findings showed that long-term exposures of lymphoma-prone mice to 898.4 MHz GSM radiofrequency (RF) radiation at SARs of 0.25, 1.0, 2.0 and 4.0 W/kg had no significant effects when compared to sham-irradiated animals. A previous study (Repacholi et al., Radiat. Res. 147, 631–640, 1997) reported that long-term exposure of lymphoma-prone mice to one exposure level of 900 MHz RF radiation significantly increased the incidence of non-lymphoblastic lymphomas when compared to sham-irradiated animals.

Electrophysiological, Electroanatomical, and Structural Remodeling of the Atria as Consequences of Sustained Obesity

BACKGROUND Obesity and atrial fibrillation (AF) are public health issues with significant consequences. OBJECTIVES This study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity. METHODS Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-β1 expression. RESULTS Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p < 0.001); LA volume (p < 0.001); LA pressure (p < 0.001), and PA pressures (p < 0.001); reduced atrial CV (LA p < 0.001) with increased conduction heterogeneity (p < 0.001); increased fractionated electrograms (p < 0.001); decreased posterior LA voltage (p < 0.001) and increased voltage heterogeneity (p < 0.001); no change in the effective refractory period (ERP) (p > 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-β1 protein (p = 0.002) were increased in the obese group. CONCLUSIONS Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-β1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.

Traumatic Brain Injury

Animal models have played a critical role in elucidating the complex pathogenesis of traumatic brain injury, the major cause of death and disability in young adults in Western countries. This review discusses how different types of animal models are useful for the study of neuropathologic processes in traumatic, blunt, nonmissile head injury.

Effect of long-term mobile communication microwave exposure on vascular permeability in mouse brain

Aims: To study the effect of long‐term exposure to global system for mobile communication (GSM) radiofrequency fields on vascular permeability in murine brains. Methods: Using a purpose‐designed exposure system at 900 MHz, mice were given a 60‐minute far‐field, whole body exposure on each of 5 days per week for 104 weeks at specific absorption rates (SAR) of 0.25, 1.0, 2.0 and 4.0 W/kg. Control mice were sham‐exposed or permitted free movement in a cage to evaluate any stress‐related effects. Albumin immunohistochemistry was used to detect increased vascular permeability and the efficacy of the vascular tracer was confirmed with a positive control group exposed to a clostridial toxin known to increase vascular permeability in the brain. Results: In all exposed and control groups, albumin extravasation was minimal, often leptomeningeal, and was deemed insignificant as a maximum of three capillaries or venules in a given brain showed leakage from the very many blood vessels present in the three coronal brain sections. Conclusions: These results suggest that prolonged exposure to mobile telephone‐type radiation produces negligible disruption to blood‐brain barrier integrity at the light microscope level using endogenous albumin as a vascular tracer.Abbreviations: BBB, blood-brain barrier; GSM, global system for mobile communication; RF, radiofrequency; SAR, specific absorption rate.

Histopathological changes in the brain of mice given Clostridium perfringens type D epsilon toxin

The distribution, severity and frequency of brain lesions produced in mice by the administration of Clostridium perfringens Type D epsilon toxin were examined by light microscopy. The granular layer of the cerebellum was the area most frequently affected in mice given single doses of toxin. Sequential changes in brain morphology were examined from 1 h to 7 days after injection of toxin. Lesions progressed from an initial vasogenic oedema to malacic foci which commonly were focal and bilaterally symmetrical, with a predilection for white matter. The topographical distribution of these malacic areas is discussed.

Ultrastructural changes in the brain of mice given Clostridium perfringens type D epsilon toxin

Mice were given lethal and sublethal doses of Clostridium perfringens Type D epsilon toxin and the early morphological changes in perfusion-fixed intoxicated brains were examined from 30 min to 6 h post-inoculation. The initial ultrastructural finding was swelling of astrocytes, especially the perivascular extensions of these cells. Astrocytes in the cerebellum appeared to be particularly sensitive to this toxin. These changes were quickly followed by evidence of severe endothelial damage, with the endothelial cytoplasm becoming attenuated, vacuolated and very electron-dense. A pathogenetic sequence of events leading to malacia, derived from ultrastructural observations, is proposed.

Effect of global system for mobile communication (GSM)-like radiofrequency fields on vascular permeability in mouse brain

Summary The effect of global system for mobile communication (GSM) radiofrequency fields on vascular permeability in the brain was studied using a purpose‐designed exposure system at 898.4 MHz. Mice ( n = 30) were given a single far field, whole body exposure for 60 minutes at a specific absorption rate of 4 W/kg. Control mice were also sham‐exposed ( n = 10) or permitted free movement in a cage ( n = 10) to exclude any stress‐related effects. Vascular permeability changes were detected using albumin immunohistochemistry and the efficacy of this vascular tracer was confirmed with a positive control group exposed to a clostridial toxin known to increase vascular permeability in the brain. No significant difference in albumin extravasation was detected between any of the groups at the light microscope level using the albumin marker.

Establishment of a Single-Dose Irinotecan Model of Gastrointestinal Mucositis

Background: Irinotecan is a common cytotoxic agent used in advanced colorectal cancers. However, a major clinical problem with this cytotoxic is that it causes gastrointestinal mucositis manifest by severe diarrhoea. To date there is no established single dose of irinotecan in rats to enable determination of changes occurring following administration. Therefore, the primary aim of this study was to determine a single dose of irinotecan that induced reproducible gastrointestinal mucositis in DA rats. The secondary aim was to determine if the presence of tumour altered the development of mucositis. Methods: Eighty-eight rats were divided into two groups, 44 received tumours and 44 remained tumour naïve. These were randomized to receive a single dose of irinotecan at 150, 200, 250 or 300 mg/kg. Two control groups of rats received either no treatment or 2 doses of 150 mg/kg irinotecan, shown previously to induce reproducible gastrointestinal mucositis. Rats were monitored closely for incidence and severity of diarrhoea, and mortality, before being killed 48 and 144 h following treatment. Results: Rats administered 250 and 300 mg/kg of irinotecan all developed diarrhoea, and this was associated with high mortality rates (up to 100%). Necropsies revealed that many of these rats had duodenal perforations and fatty lysis consistent with peritonitis. The lower doses of 150 and 200 mg/kg irinotecan also caused diarrhoea, but were not associated with high mortality rates. Histopathological examination confirmed small and large intestinal damage in all rats that received irinotecan, regardless of dose. Tumour-bearing rats had worse diarrhoea and higher mortality compared to tumour-naïve rats. Conclusions: We find that a single dose of 200 mg/kg irinotecan causes reproducible gastrointestinal mucositis as measured by levels of diarrhoea, and small and large intestinal histology. Importantly this dose has a low mortality. The response to irinotecan is more pronounced in tumour-bearing rats.

Effect of mobile telephony on blood-brain barrier permeability in the fetal mouse brain

Aims: To study the effect of mobile telephone exposure on blood‐brain barrier (BBB) permeability in the immature brain. Methods: Using a purpose‐designed exposure system at 900 MHz, pregnant mice were given a single, far‐field, whole body exposure at a specific absorption rate of 4 W/kg for 60 min/day from day 1 to day 19 of gestation. Pregnant control mice were sham‐exposed or freely mobile in a cage without further restraint and a positive control group with cadmium‐induced BBB damage was also included. Immediately prior to parturition on gestational day 19, fetal heads were collected, fixed in Bouins fixative and paraffin embedded. Disruption of BBB integrity was detected immunohistochemically using endogenous albumin as a vascular tracer in cerebral cortex, thalamus, basal ganglia, hippocampus, cerebellum, midbrain and medulla. Results: No albumin extravasation was found in exposed or control brains. Conclusion: In this animal model, whole of gestation exposure to global system for mobile communication‐like radiofrequency fields did not produce any increase in vascular permeability in the fetal brain regions studied using endogenous albumin as a light microscopic immunohistochemical marker.Abbreviations: BBB, blood‐brain barrier; RF, radiofrequency; SAR, specific absorption rate.

An Ovine Model of Toxic, Nonischemic Cardiomyopathy—Assessment by Cardiac Magnetic Resonance Imaging

BACKGROUND There is a paucity of published experience investigating novel treatment strategies in preclinical and clinical studies of nonischemic cardiomyopathy. We set out to validate an ovine model of doxorubicin-induced cardiomyopathy, using cardiac magnetic resonance (CMR) to assess cardiac function. METHODS AND RESULTS Ten Merino sheep (51 +/- 8 kg) underwent intracoronary infusions of doxorubicin (1 mg/kg dose) every 2 weeks. Cardiac magnetic resonance was performed at baseline and at 6 weeks after final doxorubicin dose, along with transthoracic echocardiography, measurement of right heart pressure, and cardiac output. After final CMR examination, heart specimens were harvested for histologic analysis. The total dose of doxorubicin administered per animal was 3.8 +/- 0.5 mg/kg. Two animals died prematurely during the study protocol, with evidence of myocarditis. In the remaining 8 sheep, left ventricular ejection fraction dropped from 46.2 +/- 4.7% to 31.3 +/- 8.5% (P < .001), accompanied by reductions in fractional shortening (31.6 +/- 1.8% baseline versus 18.2 +/- 3.9% final, P < .01), cardiac output (3.8 +/- 0.6 L/min versus 3.0 +/- 0.4 L/min, P < .05) and right ventricular ejection fraction (39.5 +/- 5.6% versus 28.9 +/- 9.6%, P < .05). However, significant end-diastolic dilatation of the left ventricle was not observed. Delayed gadolinium uptake was detected by CMR in 2 sheep, in a typical nonischemic pattern. Widespread, multifocal histologic abnormalities consisted of cardiomyocyte degeneration, vasculopathy, inflammatory infiltrates, and replacement fibrosis. CONCLUSIONS Moderate-severe cardiac dysfunction was reproducibly achieved through high-dose intracoronary doxorubicin, with acceptable animal mortality. CMR provides a powerful tool for assessing myocardial function, structural remodeling, and viability in such models.