Blood-brain barrier permeability in rats exposed to electromagnetic fields used in wireless communication

iological effects of radio frequency electromagnetic fields (EMF) on the blood-brain barrier (BBB) have been studied in Fischer 344 rats of both sexes. The rats were not anaesthetised during the exposure. All animals were sacrificed by perfusion–fixation of the brains under chloralhydrate anaesthesia after the exposure. The brains were perfused with saline for 3–4 minutes, and thereafter perfusion fixed with 4% formaldehyde for 5–6 minutes. Whole coronal sections of the brains were dehydrated and embedded in paraffin and sectioned at 5 m. Albumin and fibrinogen were demonstrated immunohistochemically and classified as normal versus pathological leakage. In the present investigation we exposed male and female Fischer 344 rats in a Transverse Electromagnetic Transmission line chamber to microwaves of 915 MHz as continuous wave (CW) and pulse-modulated with different pulse power and at various time intervals. The CW-pulse power varied from 0.001 W to 10 W and the exposure time from 2 min to 960 min. In each experiment we exposed 4–6 rats with 2–4 controls randomly placed in excited and non-excited TEM-cells respectively. We have in total investigated 630 exposed rats at various modulation frequencies and 372 controls. The frequency of pathological rats is significantly increased (p < 0:0001) from 62=372 (ratio: 0:170:02) for control rats to 244=630 (ratio: 0:390:03) in all exposed rats. Grouping the exposed animals according to the level of specific absorbed energy (J/kg) give significant difference in all levels above 1.5 J/kg. The exposure was 915 MHz microwaves either pulse modulated (PW) at 217 Hz with 0.57 ms pulse width, at 50 Hz with 6.6 ms pulse width or continuous wave (CW). The frequency of pathological rats (0:17) among controls in the various groups is not significantly different. The frequency of pathological rats was 170=481 (0:350:03) among rats exposed to pulse modulated (PW) and 74=149 (0:500:07) among rats exposed to continuous wave exposure (CW). These results are both highly significantly different to their corresponding controls (p < 0:0001) and the frequency of pathological rats after exposure to pulsed radiation (PW) is significantly less (p < 0:002) than after exposure to continuous radiation (CW)

Efficient internalization into low-passage glioma cell lines using adenoviruses other than type 5: an approach for improvement of gene delivery to brain tumours

There is a need for improvement of the commonly used adenovirus vectors based on serotype 5. This study was performed on three adenovirus serotypes with a CAR-binding motif (Ad4p, Ad5p and Ad17p) and three non-CAR-binding serotypes (Ad11p, Ad16p and Ad21p). The capacity of these alternative adenovirus vector candidates to deliver DNA into low-passage glioma cell lines from seven different donors was evaluated. The non-CAR-binding serotype Ad16p was the most efficient serotype with regard to import of its DNA, as well as initiation of hexon protein expression. Ad16p established hexon expression in 60–80 % of the cell population in gliomas from all donors tested. The other non-CAR-binding serotypes, Ad11p and Ad21p, showed hexon expression in 25–60 and 40–80 % of cells, respectively. The corresponding figure for the best CAR-binding serotype, Ad5p, was only 25–65 %, indicating greater variability between cells from different donors than serotype Ad16p had. The other CAR-binding serotypes, Ad4p and Ad17p, were refractory to some of the gliomas, giving a maximum of only 45 and 40 % hexon expression, respectively, in the most permissive cells. Interestingly, the transduction capacity of the CAR-binding serotypes was not correlated to the level of CAR expression on the cells

Nerve cell damage in mammalian brain after exposure to microwaves from GSM mobile phones.

The possible risks of radio-frequency electromagnetic fields for the human body is a growing concern for our society. We have previously shown that weak pulsed microwaves give rise to a significant leakage of albumin through the blood-brain barrier. In this study we investigated whether a pathologic leakage across the blood-brain barrier might be combined with damage to the neurons. Three groups each of eight rats were exposed for 2 hr to Global System for Mobile Communications (GSM) mobile phone electromagnetic fields of different strengths. We found highly significant (p< 0.002) evidence for neuronal damage in the cortex, hippocampus, and basal ganglia in the brains of exposed rats

Fiber Mediated Receptor Masking in Non-Infected Bystander Cells Restricts Adenovirus Cell Killing Effect but Promotes Adenovirus Host Co-Existence

The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses

Glial Progenitor-Like Phenotype in Low-Grade Glioma and Enhanced CD133-Expression and Neuronal Lineage Differentiation Potential in High-Grade Glioma

Background: While neurosphere-as well as xenograft tumor-initiating cells have been identified in gliomas, the resemblance between glioma cells and neural stem/progenitor cells as well as the prognostic value of stem/progenitor cell marker expression in glioma are poorly clarified. Methodology/Principal Findings: Viable glioma cells were characterized for surface marker expression along the glial genesis hierarchy. Six low-grade and 17 high-grade glioma specimens were flow-cytometrically analyzed for markers characteristics of stem cells (CD133); glial progenitors (PDGFR alpha, A2B5, O4, and CD44); and late oligodendrocyte progenitors (O1). In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens. Irrespective of the grade and morphological diagnosis of gliomas, glioma cells concomitantly expressed PDGFRa, A2B5, O4, CD44 and GFAP. In contrast, O1 was weakly expressed in all low-grade and the majority of high-grade glioma specimens analyzed. Co-expression of neuronal markers was observed in all high-grade, but not low-grade, glioma specimens analyzed. The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31. In contrast, distinct CD133 expression profiles in up to 90% of CD45-negative glioma cells were observed in 12 of the 17 high-grade glioma specimens and the majority of these CD133 expressing cells were CD31 negative. The CD133 expression correlates inversely with length of patient survival. Surprisingly, cytogenetic analysis showed that gliomas contained normal and abnormal cell karyotypes with hitherto indistinguishable phenotype. Conclusions/Significance: This study constitutes an important step towards clarification of lineage commitment and differentiation blockage of glioma cells. Our data suggest that glioma cells may resemble expansion of glial lineage progenitor cells with compromised differentiation capacity downstream of A2B5 and O4 expression. The concurrent expression of neuronal markers demonstrates that high-grade glioma cells are endowed with multi-lineage differentiation potential in vivo. Importantly, enhanced CD133 expression marks a poor prognosis in gliomas

Effect of high voltage electrical pulses on subcutaneous glioma tumours on rats

The antitumour effect of applied high voltage exponential pulses was investigated on rats with subcutaneously implanted N32 brain tumours. Superficial tumours on the thigh were produced by the injection of 100 000 N32 glioma cells on Fischer-344 rats. Four weeks after inoculation, a solid tumour has grown to a size of about 1 cm located directly under the skin. Short electric high voltage pulses were given transdermally through stainless steel plate electrodes. Sixteen exponential pulses with initial field strength of 1300-1400 V/cm and a time constant of 1 ms were delivered with a BTX600 device at approximately one pulse per second. The treatment was repeated during 4 consecutive days. Tumour response was studied by measuring the length, width and thickness of the tumour with a slide-calliper and estimating the tumour volume as an ellipsoid. Animals (treated and controls) were sacrificed when the size of the tumour had reached a predetermined value (5 cm3). In the first experiment this occurred after 50±4 days for the treated animals, excluding cured, compared to 40±1.3 for their controls and in the second experiment after 64±24 days excluding cured animals compared to 37.6±3 for the controls. All treated animals showed an initial partial or complete tumour remission within a few days after the end of the 4-day treatment. Two out of ten treated animals were cured with no sign of recurrence after 100 days. Copyright (C) 1998 Elsevier Science S.A

ITPP treatment of RG2 glioblastoma in a rat model

Background: Inositol trispyrophosphate (ITPP) has been shown to reduce tumour growth in different animal cancer models, as well as of human U87 glioma cells grafted onto chick chorioallantoic membrane (CAM). The aim of this study was to establish whether ITPP crosses the blood-brain barrier and whether it halts the growth of RG2 glioblastoma tumour. Materials and Methods: A model comprising of Fischer 344 rats was chosen and RG2 cells were implanted either intracranially, or subcutaneously on the left hind leg, and the animals were treated with ITPP either intraperitoneally, intravenously or both routes combined. Overall survival was then calculated. Results: No prolonged survival was seen in animals treated with ITPP. The route of ITPP administration did not affect outcome. Conclusion: ITPP had no favourable effect upon survival in our animal model with RG2 glioblastoma tumours in Fischer 344 rats

Experimental studies of brain tumour development during exposure to continuous and pulsed 915 MHz radiofrequency radiation

It has been suggested that electromagnetic fields (EMFs) act as a promoter late in the carcinogenesis process. To date, however, noconvincing laboratory evidence has been obtained indicating that EMFs cause tumour promotion at non-thermal exposure levels. The effects of EMF exposure in a rat brain glioma model were investigated. The exposure consisted of 915 MHz microwaves, both as continuous waves (1 W), and modulated with 4, 8, 16 and 200 Hz in 0.5 ms pulses and 50 Hz in 6 ms pulses (2 W per pulse). Fischer 344 rats of both sexes, weighing 150-250 g, were used in the experiments. 5000 RG2 cells in 5 μ1 nutrient solution were injected by the stereotaxic technique into the head of the right caudate nucleus in 37 experimental rats and 37 matched controls. The exposed animals were kept unanaesthetized in well ventilated transverse electromagnetic (TEM) cells producing 915 MHz continuous or modulated microwaves. Exposure was started on day five after inoculation. The animals were exposed for 7 hd d-1 for 5 d per week during two to three weeks. The controls were kept in an identical TEM cell without EMF exposure. All brains were examined histopathologically and the tumour size was determined. Our study does not show a significant difference in tumour size between animals exposed to 915 MHz microwaves, and those not exposed. Our preliminary results do not support that even an extensive daily exposure to EMF promotes tumour growth when given from the fifth day after the start of tumour growth in the rat brain until the death of the animal which by then has a large brain tumour. Further studies with higher specific absorption rate levels are in progress