Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

Background Medium-dose (25 gray) x-ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x-ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium-dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3-month or 6-month follow-up, the animals underwent an open-chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium-dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

The Effect of Resveratrol on Radioiodine Therapy-Associated Lacrimal Gland Damage.

PURPOSE: We have evaluated the potential radioprotective, antioxidant and anti-apoptotic effects of resveratrol (RSV) against high-dose radioactive iodine (RAI) therapy associated damage of the lacrimal glands by biochemical, histopathological and immunohistochemical methods. MATERIALS AND METHODS: Thirty Wistar-albino rats were randomly divided into three groups; the control group received no treatment or medication, the RAI group received RAI but no medication and the RSV group received oral RAI and intraperitoneal RSV. RSV was started at day one, before RAI administration, and continued for 8 days. Bilateral intraorbital (IG), extraorbital (EG), and Harderian (HG) lacrimal glands were evaluated in all rats for histopathological, immunohistochemical, tissue cytokine and oxidant and antioxidant level assessment. RESULTS: RSV group restored inflammation, fibrosis, vacuolization, change in nucleus characteristics, lipofuscin-like accumulation and cellular morphologic patterns were statistically significant in all lacrimal gland types, compared to the RAI group (p < .05 for all variables). Similarly, elevated Caspase-3 and TUNEL levels in the RAI group were significantly alleviated in the RSV group in all lacrimal gland types (p < .05 for all variables). RAI administration significantly elevated TNF-α, IL-6, NF-кb levels, and decreased IL-10 levels (p < .05 for all parameters) whereas TOS levels significantly increased and TAS levels were significantly decreased. However, RSV significantly diminished TNF-α, IL-6, IL-4, and NF-кb levels. Furthermore, RSV significantly decreased TOS and increased TAS levels (p < .05 for all variables). CONCLUSIONS: We conclude that with its anti-cancer effect as well as its antioxidant effect RSV has protected the histopathological pattern of the lacrimal glands from the damage, decreased inflammation in histopathologic assessments, and decreased tissue cytokine levels, apoptosis and DNA fragmentation on the lacrimal glands after RAI.

Proteomic Evaluation of the Natural History of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Non-human Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing Includes Dysregulation of the Retinoid Pathway.

Exposure to ionizing radiation results in injuries of the hematopoietic, gastrointestinal, and respiratory systems, which are the leading causes responsible for morbidity and mortality. Gastrointestinal injury occurs as an acute radiation syndrome. To help inform on the natural history of the radiation-induced injury of the partial body irradiation model, we quantitatively profiled the proteome of jejunum from non-human primates following 12 Gy partial body irradiation with 2.5% bone marrow sparing over a time period of 3 wk. Jejunum was analyzed by liquid chromatography-tandem mass spectrometry, and pathway and gene ontology analysis were performed. A total of 3,245 unique proteins were quantified out of more than 3,700 proteins identified in this study. Also a total of 289 proteins of the quantified proteins showed significant and consistent responses across at least three time points post-irradiation, of which 263 proteins showed strong upregulations while 26 proteins showed downregulations. Bioinformatic analysis suggests significant pathway and upstream regulator perturbations post-high dose irradiation and shed light on underlying mechanisms of radiation damage. Canonical pathways altered by radiation included GP6 signaling pathway, acute phase response signaling, LXR/RXR activation, and intrinsic prothrombin activation pathway. Additionally, we observed dysregulation of proteins of the retinoid pathway and retinoic acid, an active metabolite of vitamin A, as quantified by liquid chromatography-tandem mass spectrometry. Correlation of changes in protein abundance with a well-characterized histological endpoint, corrected crypt number, was used to evaluate biomarker potential. These data further define the natural history of the gastrointestinal acute radiation syndrome in a non-human primate model of partial body irradiation with minimal bone marrow sparing.

Experimental investigation and histopathological identification of acute thermal damage in skeletal porcine muscle in relation to whole-body SAR, maximum temperature, and CEM43 °C due to RF irradiation in an MR body coil of birdcage type at 123 MHz.

PURPOSE: This study is an investigation of the relationship between several characteristic parameters and acute thermal damage in porcine skeletal muscle. MATERIAL AND METHODS: Fourteen pigs under injection anaesthesia were placed into a magnetic resonance body coil and exposed for different time durations to different specific energy absorption rate (SAR) levels at 123 MHz. Local temperatures were measured using four temperature sensors. Sensors 1-3 were placed in skeletal muscle and one sensor was placed in the rectum. Sensors 1 and 2 were placed in hot-spot areas and sensor 3 was placed at the periphery of the animals. The pigs were exposed to whole-body SAR (SAR-wb) between 2.5 W/kg and 5.2 W/kg for 30 or 60 min. Three animals received no SAR. After each experiment, muscle samples adjacent to the positions of sensors 1-3 were taken for frozen section analysis. Three characteristic parameters were chosen for investigation: SAR-wb, maximum sensor temperature (T-max), and cumulative equivalent minutes at 43 °C (CEM43 °C). RESULTS: Histopathological criteria were established to detect acute thermal tissue damage in frozen sections such as widening of intercellular space between the muscle fibres and loss of glycogen. Clear tissue damage thresholds were found for T-max and CEM43 °C, though not for SAR-wb. For all animals with high thermal exposure, damage was also found for muscle samples adjacent to the peripheral sensor 3. CONCLUSIONS: Both T-max and CEM43, are able to predict thermal damage in porcine muscle. However, CEM43 is the less ambiguous parameter. The reasons for the occurrence of the aforementioned damage at low local temperatures at the animals' periphery remain unclear and further investigations are needed.

Tissue permittivity: a monitor for progressive tissue fibrosis as observed in bystander tissues following experimental high dose rate irradiation.

Fibrosis is a pathological condition resulting from radiation injury which often limits the prescription of higher (or boost) doses of radiation, risking inadequate tumor control in patients. Recent studies have documented reduction in fibrotic lesions after administration of pentoxyfilline and tocopherol combinations to breast cancer patients receiving adjuvant radiation therapy. Despite the promise of these findings, no techniques or markers are available which can be used to identify the onset or progression of fibrosis in such patients at stages early enough to allow maximum benefit from these types of pharmacological agents. Relative permittivity of skeletal muscle has been investigated in an animal model utilizing high dose rate radiation both at the treatment site as well as on the contralateral site, and was found to be directly related to the formation and progression of fibrotic lesions. A cubic increase in the quantified fibrotic fraction of the tissue (2.7%-13.9% over 11 w post irradiation) was reflected in a linear increase in the tissue's relative permittivity (epsilon(r) = 6.3-8.8 over 11 w post irradiation). These findings mandate further investigation of the relationship between tissue's relative permittivity and subcellular injury leading to fibrosis using electrical impedance spectroscopy (EIS).

Evaluation of the effects of high dose irradiation on canine thigh muscle by follow-up magnetic resonance imaging and phosphorus-31 magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: The authors investigate alterations of proton T1 and T2 relaxation times and phosphorus metabolites of canine thigh muscle tissue after high dose x-ray irradiation by follow-up magnetic resonance imaging (MRI) and phosphorus-31 (31P) magnetic resonance spectroscopy (MRS). METHODS: A group of 20 dogs was used for MRI and in vivo 31P MRS. Single doses of 5,000 and 10,000 cGy were delivered to the right thigh muscle of groups of 10 dogs each. All MRI and 31P MRS examinations were performed before irradiation and 1, 7, 14, 28, 42, and 56 days after irradiation. For measurement of T1, repetition time (TR) was measured at 300, 500, 1000, 1500, 2000 msec and echo time (TE) was fixed at 12 msec. Also, for measurement of T2, TE was measured at 20, 40, 60, and 80 msec and TR was fixed at 2000 msec. Image selected in vivo spectroscopy (ISIS) pulse sequence was used to obtain 31P MR spectra. Peak areas for each phosphorus metabolite were measured using a Marquart algorithm. RESULTS: Magnetic resonance imaging signal began to change at 28 days after a single dose of 10,000 cGy, whereas there was no significant MRI signal change until 56 days after a single dose of 5,000 cGy. Also, extensive MRI signal changes were observed at 42 days after a single dose of 10,000 cGy. Significant correlation was established between T2 and a lapse of time although there was no correlation between T1 and a lapse of time. T2 value increased substantially corresponding to the time period after x-ray irradiation. Although MR spectral change was not observed until 42 days after a single dose of 5,000 cGy, it began at 14 days after a single dose of 10,000 cGy. And, significant MR spectral changes were observed at 28 and 42 days. Inorganic phosphate and phosphodiesters signal intensities increased while phosphocreatine signal intensity decreased. The pH value was 7.22 +/- 0.05 at control, and 6.98 +/- 0.04 at 42 days after a single dose of 10,000 cGy. CONCLUSIONS: The postirradiation follow-up MRI and 31P MRS studies demonstrated that morphologic and metabolic changes were dependent upon the x-ray dose and a lapse of time.

Preliminary study on antiradiation effect of kuei-pi-tang.

In order to evaluate the potential action of Kuei-Pi-Tang as an antiradiation agent, colony forming units of bone marrow cells in the spleen (CFUs) were used. Different sequences of X-ray irradiation with or without Kuei-Pi-Tang administration in the groups of ICR strain mice were intraperitoneally injected 10mg/20g or 20mg/20g, once a day, for consecutive seven days before or after 4Gy X-ray irradiation. After the different treatments, whole blood was collected from the tail endings to observe the fluctuation of leukocytes, erythrocytes and thrombocytes. The administration of 20mg/20g was more effective than that of 10mg/20g. Lower radiosensitivity was observed with the treatment of 20mg/20g of Kui-Pi-Tang than that of 10mg/20g. The injection of Kuei-Pi-Tang accelerated the recovery of blood cell counts of leukocytes, erythrocytes and thrombocytes in mice irradiated with 4Gy, especially for leukocytes under the treatments with 20mg/20g of Kuei-Pi-Tang administered after irradiation.

Brain nuclear magnetic resonance imaging enhanced by a paramagnetic nitroxide contrast agent: preliminary report.

Contrast-enhancing agents for demonstrating abnormalities of the blood-brain barrier may extend the diagnostic utility of proton nuclear magnetic resonance (NMR) imaging. "TES," a nitroxide stable free radical derivative, was tested as a central nervous system contrast enhancer in dogs with experimentally induced unilateral cerebritis or radiation cerebral damage. After intravenous injection of TES, the normal brain showed no change in NMR appearance, but areas of disease demonstrated a dramatic increase (up to 45%) in spin-echo intensity and a decrease in T1 relaxation times. The areas of disease defined by TES enhancement were either not evident on the nonenhanced NMR images or were better defined after contrast administration. In-depth tests of toxicity, stability, and metabolism of this promising NMR contrast agent are now in progress.

EEG monitoring of focal lesions of the blood-brain barrier.

This paper presents a modified method for the EEG detection and monitoring of small focal blood-brain barrier (BBB) lesions. The method uses high dose IV penicillin (1.2 X 10(6) mu/kg) to produce a spike focus at BBB lesions, penicillin encephalopathy. The EEG is recorded and the epileptic spikes are counted by an automatic computer program. The computer produces an objective quantitative results. The method is verified empirically on traumatic and radiation BBB lesions.