Background and Aims : The aim of this study was to generate an experimental rabbit common carotid artery model of intermediate stage atherosclerosis and the subsequent, investigating the effect of Extremely Low Frequency (ELF) magnetic field exposure on the foam cells- rich plaque structure in this model.Methods: Atherosclerotic plaque was induced via perivascular cold injury, using liquid nitrogen at the carotid artery of New Zealand white rabbits, before being fed a 1.5% cholesterol-rich diet for four weeks. Results from histopathology showed the progressive changes, from the foam cells and extracellular lipid droplets proliferation, up to vessel wall thickening and lumen narrowing, resulting in the formation of intermediate stage atherosclerosis with moderate stenosis (< 30%) in all of the rabbits' arteries. Then, treatment group underwent high- intensity ELF magnetic field (500 μT, 50 Hz, 30 min/day) exposure, using Helmholtz coils, for four weeks.Results: Histopathology results showed the formation of atherosclerotic plaque with lipid- laden cells, atheroma, intraplaque neovessels and severe stenosis (>70%) in all of the rabbits' arteries in the treatment group. Results from color Doppler ultrasonography at the stenotic region showed a significant increase in the mean value for blood mean velocity, wall mean thickness, percentage of luminal cross sectional area of stenosis and significant reduction in the mean value for blood volume flow in the treatment group compared with the other groups (P<0.05)Conclusions: Oxidative stress and angiogenesis effect of high intensity ELF magnetic field irradiation, can cause to increase the intraplaque neovessels and immune cells density, resulting in plaque remodeling and vulnerable plaque formation. Background and Aims : The aim of this study was to generate an experimental rabbit common carotid artery model of intermediate stage atherosclerosis and the subsequent, investigating the effect of Extremely Low Frequency (ELF) magnetic field exposure on the foam cells- rich plaque structure in this model. Methods: Atherosclerotic plaque was induced via perivascular cold injury, using liquid nitrogen at the carotid artery of New Zealand white rabbits, before being fed a 1.5% cholesterol-rich diet for four weeks. Results from histopathology showed the progressive changes, from the foam cells and extracellular lipid droplets proliferation, up to vessel wall thickening and lumen narrowing, resulting in the formation of intermediate stage atherosclerosis with moderate stenosis (< 30%) in all of the rabbits' arteries. Then, treatment group underwent high- intensity ELF magnetic field (500 μT, 50 Hz, 30 min/day) exposure, using Helmholtz coils, for four weeks. Results: Histopathology results showed the formation of atherosclerotic plaque with lipid- laden cells, atheroma, intraplaque neovessels and severe stenosis (>70%) in all of the rabbits' arteries in the treatment group. Results from color Doppler ultrasonography at the stenotic region showed a significant increase in the mean value for blood mean velocity, wall mean thickness, percentage of luminal cross sectional area of stenosis and significant reduction in the mean value for blood volume flow in the treatment group compared with the other groups (P<0.05) Conclusions: Oxidative stress and angiogenesis effect of high intensity ELF magnetic field irradiation, can cause to increase the intraplaque neovessels and immune cells density, resulting in plaque remodeling and vulnerable plaque formation.

Background and Aims : Mechanical changes include thickening of arterial wall, alteration of arterial elasticity, contraction of smooth muscle, increase in sensitivity to pharmacological stimulation and increase in arterial viscoelasticity, i.e., arteriosclerosis. There is therefore interest in the application of non-invasive clinical tools to assess arterial biomechanical parameters. In this study, we aimed to investigate the effect of high- intensity exercise on biomechanical parameters of healthy human subjects'arteries.Methods: In this study we used a new computerized analysis method for measurement of instantaneous changes in far and near arterial walls in sequential ultrasound images. In this method, two algorithms, i.e., maximum gradient and dynamic programming, were composed and implemented. Approximately 70 sequential ultrasound images spanning three cardiac cycles were analyzed from each examination to detect instantaneous changes in the far and near walls and lumen maximum, minimum, and mean diameters.Results: from new ultrasound image processing software- based automatic method showed a significant reduction in the mean value for shear elastic modulus and a significant increase in the mean value for radial strain, compliance and distensibility index in the treatment (high intensity exercise) group compared with the other groups (P<0.05).Conclusions: Nitric Oxide (NO) is considered the most important endothelial-derived vasodilation factor. It is concluded that the administration of high- intensity exercise, can cause to enhance the endothelial NO synthase, resulting in an increase in the arterial diameter and an improvement in the arterial biomechanical parameters. Furthermore, we concluded that our new computerized automatic method is reliable to accurate and repeated evaluation of arterial biomechanical parameters. Background and Aims : Mechanical changes include thickening of arterial wall, alteration of arterial elasticity, contraction of smooth muscle, increase in sensitivity to pharmacological stimulation and increase in arterial viscoelasticity, i.e., arteriosclerosis. There is therefore interest in the application of non-invasive clinical tools to assess arterial biomechanical parameters. In this study, we aimed to investigate the effect of high- intensity exercise on biomechanical parameters of healthy human subjects'arteries. Methods: In this study we used a new computerized analysis method for measurement of instantaneous changes in far and near arterial walls in sequential ultrasound images. In this method, two algorithms, i.e., maximum gradient and dynamic programming, were composed and implemented. Approximately 70 sequential ultrasound images spanning three cardiac cycles were analyzed from each examination to detect instantaneous changes in the far and near walls and lumen maximum, minimum, and mean diameters. Results: from new ultrasound image processing software- based automatic method showed a significant reduction in the mean value for shear elastic modulus and a significant increase in the mean value for radial strain, compliance and distensibility index in the treatment (high intensity exercise) group compared with the other groups (P<0.05). Conclusions: Nitric Oxide (NO) is considered the most important endothelial-derived vasodilation factor. It is concluded that the administration of high- intensity exercise, can cause to enhance the endothelial NO synthase, resulting in an increase in the arterial diameter and an improvement in the arterial biomechanical parameters. Furthermore, we concluded that our new computerized automatic method is reliable to accurate and repeated evaluation of arterial biomechanical parameters.

Background and Aims : Atherosclerosis is the leading cause of infarction. Atherosclerotic lesions are considered to be advanced when the accumulation of lipid is associated with the disorganization and deformity of the arterial wall. In this study, we investigated focused ultrasound effectiveness on destruction of neovessles in advanced atherosclerotic plaque.Methods: Briefly, New Zealand white rabbits underwent primary perivascular severe cold injury at the right common carotid artery followed by a 1.5 % cholesterol- rich diet injury for 8 weeks. Histopathology and ultrasonography results showed the formation of advanced atherosclerosis with neovessel- rich plaque and severe stenosis (> 70%) in all of the rabbits’ arteries. The animals treated by PESDA (Perfluorocarbon- Exposed Sonicated Dextrose Albumin) microbubbles (100 ml/kg, 2- 5 × 105 bubbles/ml)- mediated pulsed- focused ultrasound (I= 60 W/cm2, F= 750 KHz, PD= 50 ms) therapy.Results: from histopathology, B-mode and color Doppler ultrasonography showed a significant reduction in the mean value for blood mean velocity, intraplaque neovessels density, wall mean thickness and percentage of luminal cross- sectional area of stenosis and significant increase in the mean value for blood volume flow at the stenotic region in the treatment group compared with the other groups (p < 0.05).Conclusions: Enhanced inertial cavitation effect of high- intensity pulsed focused ultrasound, induced by collapsed PESDA microbubbles within the intraplaque neovessels, can cause to destroy the neovessels and significantly dilate the luminal cross- sectional area of stenosis. This protocol may be a potential treatment to advanced atherosclerosis with neovascularization in comparison with conventional bypass surgery and stenting. Background and Aims : Atherosclerosis is the leading cause of infarction. Atherosclerotic lesions are considered to be advanced when the accumulation of lipid is associated with the disorganization and deformity of the arterial wall. In this study, we investigated focused ultrasound effectiveness on destruction of neovessles in advanced atherosclerotic plaque. Methods: Briefly, New Zealand white rabbits underwent primary perivascular severe cold injury at the right common carotid artery followed by a 1.5 % cholesterol- rich diet injury for 8 weeks. Histopathology and ultrasonography results showed the formation of advanced atherosclerosis with neovessel- rich plaque and severe stenosis (> 70%) in all of the rabbits’ arteries. The animals treated by PESDA (Perfluorocarbon- Exposed Sonicated Dextrose Albumin) microbubbles (100 ml/kg, 2- 5 × 105 bubbles/ml)- mediated pulsed- focused ultrasound (I= 60 W/cm2, F= 750 KHz, PD= 50 ms) therapy. Results: from histopathology, B-mode and color Doppler ultrasonography showed a significant reduction in the mean value for blood mean velocity, intraplaque neovessels density, wall mean thickness and percentage of luminal cross- sectional area of stenosis and significant increase in the mean value for blood volume flow at the stenotic region in the treatment group compared with the other groups (p < 0.05). Conclusions: Enhanced inertial cavitation effect of high- intensity pulsed focused ultrasound, induced by collapsed PESDA microbubbles within the intraplaque neovessels, can cause to destroy the neovessels and significantly dilate the luminal cross- sectional area of stenosis. This protocol may be a potential treatment to advanced atherosclerosis with neovascularization in comparison with conventional bypass surgery and stenting.

Background and Aims : The rupture of vulnerable atherosclerosis and the subsequent formation of thrombi are the main factors responsible for myocardial infarctions. Macrophages are responsible for the prevalence of inflammation in atherosclerotic lesions. In the present study, we developed a shock wave sonoporation therapy system and investigated its effect on advanced atherosclerosis regression using Positron Emission Tomography (PET) imaging.Methods: Atheromatous plaque with foam cell- rich content and thin- fibrous cap was induced via perivascular cold injury, using liquid nitrogen at the right common carotid artery of New Zealand white rabbits, before being fed a 2% cholesterol-rich diet for six weeks. Then, the lesion region treated using extracorporeal focused shock waves (V= 22 Kv, F=0.3 Hz, Impulses= 100) accompanied by intravenous combined High-density lipoprotein (HDL) (80 mg/Kg) and pentostatin (5 mg/Kg) - loaded PESDA (Perfluorocarbon- Exposed Sonicated Dextrose Albumin) microbubbles (100ml/kg, 2-5 ×105 bubbles/ml) administration. The accumulation of 18F-FDG in plaques was evaluated.Results: from PET imaging study and histopathology showed a significant reduction in the mean value for immune cells, lipid content and 18F- FDG accumulation in the treatment group compared with the other groups (P< 0.05).Conclusions: Enhanced sonoporation effect of shock waves, induced by collapsed microbubbles and Reverse Cholesterol Transport (RCT) and anti- inflammatory effect of HDL, accompanied by cytotoxic and anti- inflammatory effect of pentostatin and anti- inflammatory effect of shock wave, can cause to reduce the inflammatin and lipid content within the plaque. Furthermore we conclude PET imaging is reliable to accurate and repeated evaluation of inflammation in this model. Background and Aims : The rupture of vulnerable atherosclerosis and the subsequent formation of thrombi are the main factors responsible for myocardial infarctions. Macrophages are responsible for the prevalence of inflammation in atherosclerotic lesions. In the present study, we developed a shock wave sonoporation therapy system and investigated its effect on advanced atherosclerosis regression using Positron Emission Tomography (PET) imaging. Methods: Atheromatous plaque with foam cell- rich content and thin- fibrous cap was induced via perivascular cold injury, using liquid nitrogen at the right common carotid artery of New Zealand white rabbits, before being fed a 2% cholesterol-rich diet for six weeks. Then, the lesion region treated using extracorporeal focused shock waves (V= 22 Kv, F=0.3 Hz, Impulses= 100) accompanied by intravenous combined High-density lipoprotein (HDL) (80 mg/Kg) and pentostatin (5 mg/Kg) - loaded PESDA (Perfluorocarbon- Exposed Sonicated Dextrose Albumin) microbubbles (100ml/kg, 2-5 ×105 bubbles/ml) administration. The accumulation of 18F-FDG in plaques was evaluated. Results: from PET imaging study and histopathology showed a significant reduction in the mean value for immune cells, lipid content and 18F- FDG accumulation in the treatment group compared with the other groups (P< 0.05). Conclusions: Enhanced sonoporation effect of shock waves, induced by collapsed microbubbles and Reverse Cholesterol Transport (RCT) and anti- inflammatory effect of HDL, accompanied by cytotoxic and anti- inflammatory effect of pentostatin and anti- inflammatory effect of shock wave, can cause to reduce the inflammatin and lipid content within the plaque. Furthermore we conclude PET imaging is reliable to accurate and repeated evaluation of inflammation in this model.

Background and Aims: It is known that high-fat diet, induce hypercholesterolemia, deterioration of arterial wall, both morphologically and mechanically. Mechanical changes include thickening of arterial wall, alteration of arterial elasticity, contraction of smooth muscle, increase in sensitivity to pharmacological stimulation and increase in arterial viscoelasticity, i.e., arteriosclerosis. The present study aimed to investigate the effect of high-density lipoprotein (HDL)- loaded microbubbles- mediated shock wave sonoporation therapy on mechanical parameters of abdominal aorta with advanced atherosclerotic plaque.

Background and Aims: Cardiac shock wave therapy is a potential and effective remedy to promote revascularization in the ischemic myocardium of patients with refractory coronary heart disease (CHD). In this study, we developed an experimental confocal dual- pulse shock wave therapy system and investigated its effectiveness on myocardial angiogenesis in the hypercholesterolemic rabbit accompanied by angiopoietin-1 (Ang-1)- loaded microbubbles administration.

Background and Aims: Thromboembolism, characterized by formation a thrombus in a blood vessel that breaks loose and is carried by the blood stream to plug another vessel. The clot may plug a vessel in the lungs (pulmonary embolism), brain (stroke), gastrointestinal tract, kidneys, or leg. The aim of this study was to generate an animal carotid artery model of thromboembolic occlusion and the subsequent investigating the feasibility of tissue plasminogen activator (tPA) - mediated dual frequency ultrasound thrombolytic therapy in this model.

Background and Aims: In this study, we developed an experimental focused low- level confocal dual pulse electrohydraulic shock wave thrombolytic therapy system, and investigated its effectiveness on common carotid artery recanalization, accompanied by intravenous streptokinase and Optison microbubbles administration, wherein diagnostic ultrasound imaging system is combined with the therapy system, with a goal of increased safety.

Background and Aims: Atherosclerotic lesions are considered to be advanced when the accumulation of lipid, cells and matrix is associated with the disorganization, repair, thickening and deformity of the arterial wall. In this study, we investigated shock wave therapy effectiveness on advanced atherosclerosis with neovessels- rich plaque.

Anxiety and depression impact dramatically on public health, underlying the importance of alternative cost-effective treatments. Previous studies have shown that biophysical treatment can significantly reduce anxiety symptoms and recently, salivary alpha-amylase (SAA) has been identified as an objective correlate of the sympathetic-parasympathetic imbalance related to increased stress burden, defined as allostatic load. The aim of this study was to evaluate the effect of biophysical therapy on SAA levels, in addition to the Depression Anxiety Stress Scale (DASS)-21 questionnaire. Twenty-four workers (sales representatives) presenting with mild anxiety/stress symptoms (Generalized Anxiety Disorder 7-item scale of > 5) were randomized to biophysical treatment (N = 12) or placebo control (N = 12). The biophysical group underwent electromagnetic information transfer through an aqueous system procedure, with daily self-administration for one month. SAA collection and the DASS-21 questionnaire were undertaken at baseline and after one month in all patients. Clinical characteristics and baseline DASS-21 subscale scores were similar between placebo and biophysical group at baseline. After one month, patients receiving biophysical therapy had significantly reduced SAA levels compared to the placebo group (27.8 ± 39.4 vs. 116.8 ± 114.9 U/mL, p = 0.019). All three DASS-21 subscales, depression (9.3 ± 5.1 vs. 5.7 ± 5.5, p = 0.1), anxiety (6.7 ± 25 vs. 3.7 ± 2.2, p = 0.0049) and stress (10.8 ± 4.2 vs. 7.3 ± 3.7, p = 0.041) were also decreased after biophysical treatment compared to placebo after one month. Our findings suggest that biophysical therapy can benefit workers with mild (subclinical) anxiety/stress. These results were also validated by the concomitant reduction of SAA levels and an improvement in DASS-21 subscales. The underlying molecular mechanisms of this therapy remain to be characterized.

From the past, we know how much “serendipity” has played a pivotal role in scientific discoveries. The definition of serendipity implies the finding of one thing while looking for something else. The most known example of this is the discovery of penicillin. Fleming was studying “Staphylococcus influenzae” when one of his culture plates became contaminated and developed a mold that created a bacteria-free circle. Then he found within the mold, a substance that proved to be very active against the vast majority of bacteria infecting human beings. Serendipity had a key role in the discovery of a wide panel of psychotropic drugs as well, including aniline purple, lysergic acid diethylamide, meprobamate, chlorpromazine, and imipramine. Actually, many recent studies support a step back in current strategies that could lead to new discoveries in science. This change should seriously consider the idea that to further focus research project milestones that are already too focused could be a mistake. How can you observe something that others did not realize before you? Probably, one pivotal requirement is that you pay a high level of attention on what is occurring all around you. But this is not entirely enough, since, specifically talking about scientific discoveries, you should have your mind sufficiently unbiased from mainstream infrastructures, which normally make you extremely focused on a particular endpoint without paying attention to potential “unexpected discoveries”. Research in medicine should probably come back to the age of innocence and avoid the age of mainstream reports that do not contribute to real advances in the curing of human diseases. Max Planck said “Science progresses not because scientists change their minds, but rather because scientists attached to erroneous views die, and are replaced”, and Otto Warburg used the same words when he realized the lack of acceptance of his ideas. This editorial proposes a series of examples showing, in a practical way, how unfocused research may contribute to very important discoveries in science.

Background and Aims: In this study, we developed an experimental radiofrequency thermal balloon angioplasty that allows controlling both pressure of inflation and local heating, and investigated its effectiveness on neointimal hyperplasia reduction accompanied by photodynamic therapy.

Chronic Kidney Disease (CKD) and its clinical evolution are an emerging issue, due to an increasingly aging population. Consequently, the evaluation of integrative strategies to manage the decline in renal function is warranted. The previous evidence indicates that a biophysical integrated approach can significantly improve renal function. Nevertheless, controlled trials assessing the clinical efficacy of this strategy are still needed. A 12-month controlled study was designed to assess the clinical outcome of a group of elderly patients affected by stage II/IIIa CKD randomly assigned to either control or biophysical treatment. In addition to the standard treatment with renin–angiotensin–aldosterone system inhibitors, the biophysical group underwent electromagnetic information transfer through aqueous system procedure every 3 months. Estimated glomerular filtration rate (eGFR), according to CKD–epidemiology collaboration formula, was calculated at baseline and every 3 months. A total of 238 patients were included in the study, 118 (73.9 ± 3.8 years) in the biophysical therapy group and 120 (74.6 ± 4.2 years) in the control group. At baseline, mean eGFR was 69 ± 11.8 ml/min in the biophysical group and 70.7 ± 11.5 ml/min in the control group. After 1 year, eGFR was 74.1 ± 12.3 ml/min in the biophysical group, compared to 66.3 ± 11.9 ml/min in the control group, with a statistically significant difference between groups (p < 0.0001). The observed improvement in eGFR in the biophysical group was independent of age, gender, and antihypertensive treatment. This study shows a potential contribution of a biophysical integrated strategy to support renal function against its natural decline in the elderly, warranting further clinical evaluation.

Aim: As is well recognized, the majority of atherosclerosis start with an inflammatory process, resulting in endothelial dysfunction. We developed an experimental extracorporeal photobiomodulation therapy procedure, and investigated its effectiveness on endothelial function in the rat injured abdominal aorta.

Aim: Intermediate stage atherosclerosis is highlighted by infiltration of oxidized low-density lipoprotein and foam cell formation, resulting in the thickening of arterial walls and decreased arterial lumen space. In this study, we developed an experimental shock wave therapy system, and investigated its effectiveness on intermediate stage atherosclerosis reduction, wherein diagnostic B- mode ultrasound is combined with shock wave therapy system, with a goal of increased safety.

Articular pain is one of the most frequent complaints practitioners face in their daily work. With an aging population, many patients have multiple comorbidities that are associated with the presence of chronic diseases, while others experience allergies, side effects or do not respond to standard medications or procedures. Therefore, there is an urgent need for new effective and safe strategies to manage articular pain, especially in its chronic manifestations. This randomized controlled trial was designed to assess the efficacy of a single therapy session using a biophysical procedure matched with a common non-steroidal anti-inflammatory drug (ibuprofen) and placebo. Biophysical therapy was performed using a Med Select 729 device. One hundred fifty patients (mean age 56±15.6 years) diagnosed with acute or chronic articular pain at different locations were randomized into 3 groups and the Numeric Pain Rating Score (NPRS) was used to measure pain at baseline, after one week, one month, and three months. While no difference in NPRS was observed at baseline among the 3 groups, a statistically significant difference was observed at all subsequent time points, respectively, after one week (p less than 0.05), one month (p less than 0.001), and three months (p less than 0.01), for both ibuprofen and biophysical groups vs placebo. Biophysical treatment of articular pain was shown to be as effective as a conventional non-steroidal anti-inflammatory treatment over a period of 3 months compared to placebo and could, therefore, represent an integrative, safe and long-lasting therapy to be considered for the management of acute and particularly chronic articular pain in current medical practice.