Effect of Tumor Perfusion and Receptor Density on Tumor Control Probability in 177Lu-DOTATATE Therapy: An In Silico Analysis for Standard and Optimized Treatment.

The aim of this work was to determine a minimal tumor perfusion and receptor density for 177Lu-DOTATATE therapy using physiologically based pharmacokinetic (PBPK) modeling considering, first, a desired tumor control probability (TCP) of 99% and, second, a maximal tolerated biologically effective dose (BEDmax) for organs at risk (OARs) in the treatment of neuroendocrine tumors and meningioma. Methods: A recently developed PBPK model was used. Nine virtual patients (i.e., individualized PBPK models) were used to perform simulations of pharmacokinetics for different combinations of perfusion (0.001-0.1 mL/g/min) and receptor density (1-100 nmol/L). The TCP for each combination was determined for 3 different treatment strategies: a standard treatment (4 cycles of 7.4 GBq and 105 nmol), a treatment maximizing the number of cycles based on BEDmax for red marrow and kidneys, and a treatment having 4 cycles with optimized ligand amount and activity. The red marrow and the kidneys (BEDmax of 2 Gy15 and 40 Gy2.5, respectively) were assumed to be OARs. Additionally, the influence of varying glomerular filtration rates, kidney somatostatin receptor densities, tumor volumes, and release rates was investigated. Results: To achieve a TCP of at least 99% in the standard treatment, a minimal tumor perfusion of 0.036 ± 0.023 mL/g/min and receptor density of 34 ± 20 nmol/L were determined for the 9 virtual patients. With optimization of the number of cycles, the minimum values for perfusion and receptor density were considerably lower, at 0.022 ± 0.012 mL/g/min and 21 ± 11 nmol/L, respectively. However, even better results (perfusion, 0.018 ± 0.009 mL/g/min; receptor density, 18 ± 10 nmol/L) were obtained for strategy 3. The release rate of 177Lu (or labeled metabolites) from tumor cells had the strongest effect on the minimal perfusion and receptor density for standard and optimized treatments. Conclusion: PBPK modeling and simulations represent an elegant approach to individually determine the minimal tumor perfusion and minimal receptor density required to achieve an adequate TCP. This computational method can be used in the radiopharmaceutical development process for ligand and target selection for specific types of tumors. In addition, this method could be used to optimize clinical trials.

Effects of Far-Infrared Therapy on Foot Circulation Among Hemodialysis Patients With Diabetes Mellitus.

BACKGROUND: Far-infrared radiation (FIR) therapy improves vessel dilation, circulation, vessel endothelial function, and angiogenesis and reduces atherosclerosis. However, evidence of FIR therapy's effects on foot circulation among diabetic patients undergoing hemodialysis is scarce. AIM: To determine whether FIR therapy improves foot circulation in diabetic patients undergoing hemodialysis. DESIGN: Quasi-experimental. METHODS: In June to November 2017, diabetic patients undergoing hemodialysis (N = 58) at a hemodialysis center in northern Taiwan were divided into two groups: the experimental group (n = 31) received FIR therapy to the bilateral dorsalis pedis artery (40 min/session, 3 times/week for 6 months) and the control group (n = 27) received conventional dialysis care. Paired t test, independent samples t test, two-proportion Z test, and repeated-measures analysis of covariance were performed to compare changes from baseline to the end of the 6-month intervention between the groups. RESULTS: Significant positive effects of FIR therapy on temperature, pulse, and blood flow of the dorsalis pedis artery were observed. Sensitivity to pain, tactility, and pressure also improved significantly in the experimental group. The Edinburgh Claudication Questionnaire revealed that the experimental group had reductions in subjective experiences of soreness, tingling, and coldness in the feet. CONCLUSION: The findings of significant improvements to objective and subjective measures of blood flow and neural function in the experimental group indicate that FIR therapy improves blood circulation to the feet. This therapy thus has great potential to be an effective adjuvant treatment for patients with diabetes mellitus undergoing hemodialysis.

Impact of Single Dose Photons and Carbon Ions on Perfusion and Vascular Permeability: A Dynamic Contrast-Enhanced MRI Pilot Study in the Anaplastic Rat Prostate Tumor R3327-AT1.

We collected initial quantitative information on the effects of high-dose carbon (12C) ions compared to photons on vascular damage in anaplastic rat prostate tumors, with the goal of elucidating differences in response to high-LET radiation, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-AT1 rat prostate tumors received a single dose of either 16 or 37 Gy 12C ions or 37 or 85 Gy 6 MV photons (iso-absorbed and iso-effective doses, respectively). The animals underwent DCE-MRI prior to, and on days 3, 7, 14 and 21 postirradiation. The extended Tofts model was used for pharmacokinetic analysis. At day 21, tumors were dissected and histologically examined. The results of this work showed the following: 1. 12C ions led to stronger vascular changes compared to photons, independent of dose; 2. Tumor growth was comparable for all radiation doses and modalities until day 21; 3. Nonirradiated, rapidly growing control tumors showed a decrease in all pharmacokinetic parameters (area under the curve, Ktrans, ve, vp) over time; 4. 12C-ion-irradiated tumors showed an earlier increase in area under the curve and Ktrans than photon-irradiated tumors; 5. 12C-ion irradiation resulted in more homogeneous parameter maps and histology compared to photons; and 6. 12C-ion irradiation led to an increased microvascular density and decreased proliferation activity in a largely dose-independent manner compared to photons. Postirradiation changes related to 12C ions and photons were detected using DCE-MRI, and correlated with histological parameters in an anaplastic experimental prostate tumor. In summary, this pilot study demonstrated that exposure to 12C ions increased the perfusion and/or permeability faster and led to larger changes in DCE-MRI parameters resulting in increased vessel density and presumably less hypoxia at the end of the observation period when compared to photons. Within this study no differences were found between curative and sub-curative doses in either modality.

Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization.

Previously, we demonstrated that nitric oxide (NO) synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor sepiapterin (SP) inhibits tumor progression. Endothelial dysfunction characterizes the poorly functional vasculature of solid tumors, and since NO is critical for regulation of endothelial function we asked whether SP, by recoupling NOS, improves tumor vasculature structure and function-enhancing chemotherapeutic delivery and response to radiotherapy. MMTV-neu mice with spontaneous breast tumors were treated with SP by oral gavage and evaluated by multispectral optoacoustic tomographic analysis of tumor HbO2 and by tissue staining for markers of hypoxia, blood perfusion, and markers of endothelial and smooth muscle proteins. Recoupling tumor NOS activity results in vascular normalization observed as reduced tumor hypoxia, improved tumor percentage of HbO2 and perfusion, as well as increased pericyte coverage of tumor blood vessels. The normalized vasculature and improved tumor oxygenation led to a greater than 2-fold increase in radiation-induced apoptosis compared with radiation or SP alone. High-performance liquid chromatography analysis of tumor doxorubicin levels showed a greater than 50% increase in doxorubicin uptake and a synergistic effect on tumor cell apoptosis. This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy.

Fundamental Aspects of Electromagnetic Hyperthermia in Medicine.

This article considers the fundamental advantages of electromagnetic hyperthermia over different techniques for heating the human being's body. It also presents basic parameters that characterize hyperthermia and electromagnetic techniques for heating biological tissues. Apart from that, engineering solutions directed at providing effective hyperthermia are outlined.

Radiation and circulatory disease.

Exposure to therapeutic doses of ionizing radiation is associated with damage to the heart and coronary arteries. However, only recently have studies with high-quality individual dosimetry data allowed this risk to be quantified while also adjusting for concomitant chemotherapy, and medical and lifestyle risk factors. At lower levels of exposure the evidence is less clear. In this article I review radiation-associated risks of circulatory disease in groups treated with radiotherapy for malignant and non-malignant disease, and in occupationally- or environmentally-exposed groups receiving rather lower levels of radiation dose, also for medical diagnostic purposes. Results of a meta-analysis suggest that excess relative risks per unit dose for various types of heart disease do not exhibit statistically significant (p>0.2) heterogeneity between studies. Although there are no marked discrepancies between risks derived from the high-dose therapeutic and medical diagnostic studies and from the moderate/low dose occupational and environmental studies, at least for ischemic heart disease and stroke there are indications of larger risks per unit dose for lower dose rate and fractionated exposures. Risks for stroke and other types of circulatory disease are significantly more variable (p<0.0001), possibly resulting from confounding and effect-modification by well known (but unobserved) risk factors. Adjustment for any of mean dose, dose fractionation or age at exposure results in the residual heterogeneity for cerebrovascular disease becoming non-significant. The review provides strong evidence in support of a causal association between both low and high dose radiation exposure and most types of circulatory disease.

Effects of pulsed electromagnetic fields on peripheral blood circulation in people with diabetes: A randomized controlled trial.

Cutaneous blood flow provides nourishment that plays an essential role in maintaining skin health. We examined the effects of pulsed electromagnetic fields (PEMFs) on cutaneous circulation of dorsal feet. Twenty-two patients with diabetes mellitus (DM) and 21 healthy control subjects were randomly allocated to receive either PEMFs or sham PEMFs (0.5 mT, 12 Hz, 30 min). Blood flow velocity and diameter of the small vein were examined by using ultrasound biomicroscopy; also, microcirculation at skin over the base of the 1st metatarsal bone (Flux1) and distal 1st phalange (Flux2) was measured by laser Doppler flowmetry before and after intervention. Results indicated that PEMFs produced significantly greater changes in blood flow velocity of the smallest observable vein than did sham PEMFs (both P < 0.05) in both types of subjects. However, no significant difference was found in changes of vein diameter, nor in Flux1 and Flux2, between PEMFs and sham PEMFs groups in subjects with or without DM. We hypothesized that PEMFs would increase blood flow velocity of the smallest observable vein in people with or without DM. Bioelectromagnetics. 37:290-297, 2016. © 2016 Wiley Periodicals, Inc.

Millimeter waves as a source of selective heating of skin.

This study demonstrates that 20-100 GHz range can be used for spatially-accurate focusing of heating inside the skin achieved by varying frequency and exposure beam size, as well as by enforcing air convection. The latter is also used to reduce overheating of skin surface. Heating at different skin depths depending on these parameters is investigated in detail using the hybrid bio-heat equation. In particular, it is shown that decreasing frequency and/or increasing exposure beam size at forced airflow result in elevation of heating of deeper layers of tissue and decrease of skin surface temperature. Changes of water content within 15%, which exceed those due to aging and presence of tumors, only slightly affect heating. Exposure intensity necessary to reach a target temperature significantly increases in different areas of body with elevated blood flow. Dependence on exposure intensity and hyperthermia treatment duration is also investigated and discussed. Results of this study suggest that the lower part of the millimeter-wave range is an attractive alternative for non-invasive thermal treatment of skin cancer with a high spatial resolution.

MRI-Tracked Tumor Vascular Changes in the Hours after Single-Fraction Irradiation.

The purpose of this study was to characterize changes in tumor vascular parameters hours after a single radiation exposure in an orthotopic brain tumor model. U-251 human brain tumors were established intracerebrally in rat brains, and tumor blood flow, forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) were measured using magnetic resonance imaging (MRI). Tumors were exposure to a single stereotactic radiation treatment of 20 Gy. Vascular parameters were assessed one additional time between 2 and 24 h after irradiation. After the second MRI session, brain tissue histology was examined for gross changes and apoptosis. In separate studies, cerebral blood flow was measured in nonimplanted controls before radiation exposure and 2 and 24 h after 20 Gy irradiation, and in implanted rats before radiation exposure and at 2 and 24 h after 6 Gy irradiation. Significant changes were observed in tumor-bearing rat brains in the hours after 20 Gy irradiation. Two hours after 20 Gy irradiation, tumor blood flow decreased nearly 80% and ve decreased by 30%. At 4 h, the K(trans) increased by 30% over preirradiation values. Extensive vacuolization and an increase in apoptosis were evident histologically in rats imaged 2 h after irradiation. Between 8 and 12 h after irradiation, all vascular parameters including blood flow returned to near preirradiation values. One day after irradiation, tumor blood flow was elevated 40% over preirradiation values, and other vascular parameters, including K(trans) and ve, were 20-40% below preirradiation values. In contrast, changes in vascular parameters observed in the normal brain 2 or 24 h after 20 Gy irradiation were not significantly different from preirradiation values. Also, tumor blood flow appeared to be unchanged at 2 h after 6 Gy irradiation, with a small increase observed at 24 h, unlike the tumor blood flow changes after 20 Gy irradiation. Large and significant changes in vascular parameters were observed hours after 20 Gy irradiation using noninvasive MRI techniques. It is hypothesized that cellular swelling hours after a high dose of radiation, coinciding with vacuolization, led to a decrease in tumor blood flow and v(e). Four hours after radiation exposure, K(trans) increased in concert with an increase in tumor blood flow. Vascular permeability normalized, 24 h after 20 Gy irradiation, as characterized by a decrease in K(trans). Vascular parameters did not change significantly in the normal brain after 20 Gy irradiation or in the tumor-bearing brain after 6 Gy irradiation.

The impact of including spatially longitudinal heterogeneities of vessel oxygen content and vascular fraction in 3D tumor oxygenation models on predicted radiation sensitivity.

PURPOSE: Oxygen distribution models have been used to analyze the influences of oxygen tensions on tissue response after radiotherapy. These distributions are often generated assuming constant oxygen tension in the blood vessels. However, as red blood cells progress through the vessels, oxygen is continuously released into the plasma and the surrounding tissue, resulting in longitudinally varying oxygen levels in the blood vessels. In the present study, the authors investigated whether a tumor oxygenation model that incorporated longitudinally varying oxygen levels would provide different predictions of necrotic fractions and radiosensitivity compared to commonly used models with a constant oxygen pressure. METHODS: Our models simulated oxygen diffusion based on a Green's function approach and oxygen consumption according to the Michaelis-Menten equation. The authors constructed tumor models with different vascular fractions (VFs), from which they generated depth oxygenation curves and a look-up table of oxygen pressure gradients. The authors evaluated models of spherical tumors of various sizes, from 1 to 10(4) mg. The authors compared the results from a model with constant vessel oxygen (CVO) pressure to those from models with longitudinal variations in oxygen saturation and either a constant VF (CVF) or variable VF (VVF) within the tumor tissue. The authors monitored the necrotic fractions, defined as tumor regions with an oxygen pressure below 1 mmHg. Tumor radiation sensitivity was expressed as D99, the homogeneous radiation dose required for a tumor control probability of 0.99. RESULTS: In the CVO saturation model, no necrosis was observed, and decreasing the VF could only decrease the D99 by up to 10%. Furthermore, the D99 vs VF dependence was similar for different tumor masses. Compared to the CVO model, the extended CVF and VVF models provided clearly different results, including pronounced effects of VF and tumor size on the necrotic fraction and D99, necrotic fractions ranging from 0% to 97%, and a maximal D99 increment of 57%. Only minor differences were observed between different vessel architectures, i.e., CVF vs VVF. In the smallest tumor with a low necrotic fraction, the D99 strictly decreased with increasing blood velocity. Increasing blood velocity also decreased the necrotic fraction in all tumor sizes. VF had the most profound influence on both the necrotic fraction and on D99. CONCLUSIONS: Our present analysis of necrotic formation and the impact of tumor oxygenation on D99 demonstrated the importance of including longitudinal variations in vessel oxygen content in tumor models. For small tumors, radiosensitivity was particularly dependent on VF and slightly dependent on the blood velocity and vessel arrangement. These dependences decreased with increasing tumor size, because the necrotic fraction also increased, thereby decreasing the number of viable tumor cells that required sterilization. The authors anticipate that the present model will be useful for estimating tumor oxygenation and radiation response in future detailed studies.

Antiangiogenic effect of methotrexate and PUVA on psoriasis.

Vascular endothelial growth factor (VEGF) is important factor for angiogenesis in psoriasis. Methotrexate and psoralen and ultraviolet light A (PUVA) mainly target the T cell-mediated immunopathology of psoriasis. Our work aimed at estimating VEGF mRNA in psoriatic patients and investigating whether the standard therapeutic modalities (methotrexate and PUVA) exert their antiangiogenic activity through altering VEGF levels. Twenty-four chronic plaque psoriasis patients were enrolled. Patients were divided into two groups (12 patients each); group A received intramuscular methotrexate and group B was treated by PUVA three times/week in a PUVA 1000 cabin for 10 weeks each. Twelve healthy volunteers served as controls. A skin biopsy was taken from lesional skin before and after treatment for RT-PCR detection of VEGF mRNA. Capillary perfusion scanning using LASER Doppler perfusion imaging was performed on the same psoriatic plaque before and after treatment and was also done for the controls. Following both methotrexate and PUVA, a significant reduction in the amount of VEGF mRNA (P < 0.001 and P = 0.002, respectively) and capillary perfusion (P = 0.002) occurred. These reductions were significantly higher in the methotrexate group (P < 0.001 and  P = 0.001, respectively) than in the PUVA group. The percentage of clinical improvement in the examined psoriatic plaque was significantly positively correlated with the percentage of reduction in the amount of VEGF mRNA (r = 0.850, P < 0.001) and the percentage of reduction in the capillary perfusion (r = 0.684, P < 0.001). Both modalities may exert an antiangiogenic effect. Methotrexate appears to have possibly a more potent antiangiogenic effect than PUVA.

Effects of GSM 900 MHz on middle cerebral artery blood flow assessed by transcranial Doppler sonography.

Mobile phone use has increased worldwide but its possible effects on the brain remain unclear. The aim of the present study was to investigate the effect of acute exposure to a radio frequency electromagnetic field (RF EMF) generated by a mobile phone operating in the Global System for Mobile Communication (GSM) 900 MHz on cerebral blood flow. Twenty-nine volunteers attended two experimental sessions: a sham exposure session and a real exposure session in a cross-over double-blind study in which a mobile phone was positioned on the left side of the head. In one session, the mobile phone was operated without RF radiation (sham phone) and in the other study it was operated with RF radiation (real phone) for 20 min. Thus, each subject served as its own control. Middle cerebral artery blood flow was monitored noninvasively by transcranial Doppler sonography to measure middle cerebral artery blood flow velocity. Pulsatility index and resistance index were also evaluated. A voluntary breath holding physiological test was carried out as a positive control for testing cerebral vasoreactivity. Hemodynamic variables were recorded and analyzed before, during and after mobile phone exposure. No significant changes were detected in studied variables in middle cerebral arteries during sham or real exposure. In the exposed side the cerebral blood flow velocity, the pulsatility index and the resistance index during sham and real exposure were respectively: [61.9 ± 1.3, 61.7 ± 1.3 cm/s (P = 0.89)]; [0.93 ± 0.03, 0.90 ± 0.02 (P = 0.84)] and [0.58 ± 0.01, 0.58 ± 0.01 (P = 0.96)] at baseline; and [60.6 ± 1.3, 62 ± 1.6 cm/s (P = 0.40)]; [0.91 ± 0.03, 0.87 ± 0.03 (P = 0.97)]; [0.57 ± 0.01, 0.56 ± 0.01 (P = 0.82)] after 20 min of exposure. Twenty minutes of RF exposure to a mobile phone does not seem to affect the cerebral circulation.

Assessment of intermittent UMTS electromagnetic field effects on blood circulation in the human auditory region using a near-infrared system.

The aim of the present study was to assess the potential effects of intermittent Universal Mobile Telecommunications System electromagnetic fields (UMTS-EMF) on blood circulation in the human head (auditory region) using near-infrared spectroscopy (NIRS) on two different timescales: short-term (effects occurring within 80 s) and medium-term (effects occurring within 80 s to 30 min). For the first time, we measured potential immediate effects of UMTS-EMF in real-time without any interference during exposure. Three different exposures (sham, 0.18 W/kg, and 1.8 W/kg) were applied in a controlled, randomized, crossover, and double-blind paradigm on 16 healthy volunteers. In addition to oxy-, deoxy-, and total haemoglobin concentrations ([O(2) Hb], [HHb], and [tHb], respectively), the heart rate (HR), subjective well-being, tiredness, and counting speed were recorded. During exposure to 0.18 W/kg, we found a significant short-term increase in Δ[O(2) Hb] and Δ[tHb], which is small (≈17%) compared to a functional brain activation. A significant decrease in the medium-term response of Δ[HHb] at 0.18 and 1.8 W/kg exposures was detected, which is in the range of physiological fluctuations. The medium-term ΔHR was significantly higher (+1.84 bpm) at 1.8 W/kg than for sham exposure. The other parameters showed no significant effects. Our results suggest that intermittent exposure to UMTS-EMF has small short- and medium-term effects on cerebral blood circulation and HR.

Hypoxia and perfusion labeling during photodynamic therapy.

The development of tumor hypoxia during illumination for photodynamic therapy (PDT) can negatively affect treatment outcome. Furthermore, the spatial distribution of this hypoxia may impact the balance between tumor cell damage and vascular damage as mechanisms of photodynamic effect. The hypoxia markers EF3 [(2-(2-nitroimidazol-1 [H]-yl)-N-(3,3,3-trifluoropropyl)acetamide)] or EF5 [(2-(2-nitroimidazol-1 [H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide)] can provide a quantitative description of the intratumor distribution of hypoxia during PDT. In vivo perfusion labeling coupled with immunohistochemical staining for vascular structure can provide accompanying information on the status of tumor blood flow at treatment conclusion. Taken together these data can be used to access the relative spatial distributions of hypoxia and perfusion during PDT.

Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms.

Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.

KTP/532 YAG laser treatment for allergic rhinitis.

BACKGROUND: The purpose of this study was to investigate the efficacy of the KTP/532 YAG laser to reduce nasal congestion and discharge in patients with allergic rhinitis. METHODS: Forty-eight patients with symptoms of allergic rhinitis were treated with the KTP/532 laser. All had positive skin tests for common allergens. Treatments were provided on an ambulatory basis in one to three sessions under local anesthesia with lidocaine nose spray. Outcome was determined by daily symptom reports and regular endoscopy examination and interviews for 12 months. RESULTS: Treatment was very well tolerated. There were no major side effects. At examination after 1 year, nasal obstruction was improved in 69% and nasal discharge in 40% of cases. CONCLUSION: The KTP/532 YAG laser is effective for the treatment of nasal obstruction and discharge. Comparison with other techniques showed it to be the most effective in reducing nasal discharge. It can be done as an office procedure and does not damage the nasal mucous membrane. The KTP/532 YAG laser is effective as an additional treatment for patients refractory to medication.

Delayed loss of cone and remaining rod photoreceptor cells due to impairment of choroidal circulation after acute light exposure in rats.

PURPOSE: To examine the long-term effects of acute photooxidative stress in the retina, retinal pigment epithelium (RPE), and choroid. METHODS: Albino rats injected with either the protective antioxidant phenyl-N-tert-butylnitrone (PBN) or saline 30 minutes before exposure to 5 klx white fluorescent light for 6 hours were kept for up to 3 months in 5 lux cyclic light. Electroretinograms were recorded, and the outer nuclear layer (ONL) and the choroidal thickness and area were measured after hematoxylin-eosin (H&E) staining. The expression of rod, cone, and RPE cell markers was detected by Western blotting, and apoptosis was analyzed by TUNEL staining. Oxidative stress was analyzed by immunohistochemistry against 4-hydroxynonenal (4-HNE)-modified proteins. Retinal and choroidal ultrastructures were observed by transmission electron microscopy (TEM). Choroidal circulation was analyzed by in vivo staining of the choroidal layer by trypan blue. RESULTS: In the saline-injected animals, TUNEL- and 4-HNE-labeling in the ONL, RPE, and choroid were higher 24 hours and 7 days after light exposure, and ERG amplitude, ONL and choroidal thickness and area, and rhodopsin and RPE65 expression were lower 7 or more days after light exposure than in phenyl-N-tert-butylnitrone (PBN)-injected animals. In the saline-injected animals, the expression of mid-wavelength opsin and the presence of cone cells in the ONL and the choroidal circulation were preserved for 7 days after light exposure but started to decrease by 1 month and continued to decrease for 3 months after light exposure. An increase in TUNEL-positive cells was observed in the ONL at the inferior peripheral retina, just behind the iris, by 3 months after light exposure. Delayed loss of cone cells, remaining rod cells, and choroidal circulation were counteracted by PBN treatment. CONCLUSIONS: Although cone cells are resistant to cell damage induced by acute photooxidative stress, progressive loss of cone cells continued for up to 3 months after light exposure. Impaired choroidal circulation is likely to be involved in the mechanism of delayed photoreceptor cell death after light exposure. Preserving choroidal circulation may provide a novel target for preserving the cone and the remaining rod cells in patients with retinal degeneration such as retinitis pigmentosa.

[Low-energy wideband electromagnetic radiation and manual therapy in the treatment of neurological manifestations of spinal osteochondrosis].

It is shown that the advanced technique of low-energy wideband electromagnetic radiation improves vascular tonicity and peripheral circulation while a modified technique of manual therapy facilitates movements in the affected part of the spine and reduces tonicity of the muscles involved in the pathological process.

Effect of the alternative magnetic stimulation on peripheral circulation for regenerative medicine.

Regenerative medicine for patients with peripheral atherosclerosis attracts considerable attention around the world. However, ethical problems persist in gene therapy. This study evaluates the effect of alterative magnetic stimulation on peripheral circulation. The effect of magnetic stimulation as a medical treatment was examined using a thermograph for 11 healthy volunteers. The thermograph was used to measure the rise in skin temperature. The experimental results suggested an improvement in the peripheral circulation. The results of our study suggest the effectiveness of alternative magnetic stimulation on atherosclerosis. We intend to extend our study in order to establish a methodology for regenerative medical treatment for patients with peripheral atherosclerosis. Further, we wish to advance the current research in the field of angiogenesis.

[Study of the systemic-organ blood circulation in acute period of the multiple trauma based on water-electrolytic metabolism and its correction with EHF-therapy].

In the present paper the new approach to study of relationships of system blood circulation and its correction with the help of effect of EHF-therapy on the organism of person is offered. The method is based on the study of dynamic indexes of water-electrolytic metabolism, cell structure of a blood, ECG, REG, computer-aided tomography of the brain. The correlation between cell structure of blood, ionic structure and dynamic indexes of water-electrolytic metabolism is found out. Some parameters, factor of solubility of oxygen, parameters of a common water of organism were designed.