Contractions Induced in Human Pulmonary Arteries by a H2S Donor, GYY 4137, Are Inhibited by Low-Frequency (20 kHz) Ultrasound.

The present study aimed to investigate the effect of a H2S donor, GYY 4137, on human pulmonary arteries and whether low-frequency ultrasound (20 kHz, 4 W/cm2) inhibits GYY 4137 contractions. Functional studies were conducted on human and rat pulmonary arteries mounted on microvascular myographs. We placed an ultrasonic gadget in the tissue organ bath to insonate the arteries with low-frequency ultrasound. To measure the effect of the low-frequency ultrasound on the entrance of extracellular Ca2+, the preparations were placed in a Ca2+-free solution, and the thromboxane agonist, U46619, and extracellular calcium were added in the presence of insonation. In isolated human pulmonary arteries, GYY 4137 induced contractions, which were most pronounced in the arteries contracted with the thromboxane analogue, U46619. The transient GYY4137 contractions were reversed by low-frequency ultrasound, a blocker of KV7 channels, XE-991 (10 µM), and glibenclamide (1 µM), a blocker of ATP-sensitive channels. Low-frequency ultrasound also inhibited the contractions induced by the smooth muscle entrance of increasing extracellular calcium concentrations. The present findings show that GYY 4137 can cause a transient contraction of pulmonary arteries in human arteries. GYY 4137 alone does not cause significant vascular contraction in rat lung arteries, but it contracts rat lung arteries precontracted with U46619. The transient contractions induced by GYY 4137 can be inhibited by low-frequency ultrasound, probably by counteracting the influx of external Ca2+. The effect of low-frequency ultrasound counteracts contraction in pulmonary arteries; therefore, a possibility could be to develop a larger device allowing treatment of patients with pulmonary hypertension.

Low-frequency ultrasound for pulmonary hypertension therapy.

BACKGROUND: Currently, there are no reliable clinical tools that allow non-invasive therapeutic support for patients with pulmonary arterial hypertension. This study aims to propose a low-frequency ultrasound device for pulmonary hypertension therapy and to demonstrate its potential. METHODS: A novel low-frequency ultrasound transducer has been developed. Due to its structural properties, it is excited by higher vibrational modes, which generate a signal capable of deeply penetrating biological tissues. A methodology for the artificial induction of pulmonary hypertension in sheep and for the assessment of lung physiological parameters such as blood oxygen concentration, pulse rate, and pulmonary blood pressure has been proposed. RESULTS: The results showed that exposure of the lungs to low-frequency ultrasound changed physiological parameters such as blood oxygen concentration, pulse rate and blood pressure. These parameters are most closely related to indicators of pulmonary hypertension (PH). The ultrasound exposure increased blood oxygen concentration over a 7-min period, while pulse rate and pulmonary blood pressure decreased over the same period. In anaesthetised sheep exposed to low-frequency ultrasound, a 10% increase in SpO2, a 10% decrease in pulse rate and an approximate 13% decrease in blood pressure were observed within 7 min. CONCLUSIONS: The research findings demonstrate the therapeutic efficiency of low-frequency ultrasound on hypertensive lungs, while also revealing insights into the physiological aspects of gas exchange within the pulmonary system.

Development of a Low-Frequency Piezoelectric Ultrasonic Transducer for Biological Tissue Sonication.

The safety of ultrasound exposure is very important for a patient's well-being. High-frequency (1-10 MHz) ultrasound waves are highly absorbed by biological tissue and have limited therapeutic effects on internal organs. This article presents the results of the development and application of a low-frequency (20-100 kHz) ultrasonic transducer for sonication of biological tissues. Using the methodology of digital twins, consisting of virtual and physical twins, an ultrasonic transducer has been developed that emits a focused ultrasound signal that penetrates into deeper biological tissues. For this purpose, the ring-shaped end surface of this transducer is excited not only by the main longitudinal vibrational mode, which is typical of the flat end surface transducers used to date, but also by higher mode radial vibrations. The virtual twin simulation shows that the acoustic signal emitted by the ring-shaped transducer, which is excited by a higher vibrational mode, is concentrated into a narrower and more precise acoustic wave that penetrates deeper into the biological tissue and affects only the part of the body to be treated, but not the whole body.

Stock price reaction to the drug development setbacks in the pharmaceutical industry.

BACKGROUND: Investments in pharmaceutical companies remain challenging due to the inherent uncertainties of risk assessment. OBJECTIVES: Our paper aims to assess the impact of the drug development setbacks (DDS) on the stock price of pharmaceutical companies while taking into account the company's financial situation, pipeline size and trend of the stock price before the DDS. METHODS: The model-based clustering based on finite Gaussian mixture modeling was employed to identify the clusters of pharmaceutical companies with homogenous parameters. An artificial neural network was constructed to aid the prediction of the positive mean rate of return 120 days after the DDS. RESULTS: Our results reveal that a higher pipeline size and a lower rate of return before the DDS, as well as a lower ratio of the market value of the equity and the book value of the total liabilities, are associated with a positive mean rate of return 120 days after the DDS. CONCLUSION: In general, the DDS have a negative impact on the company's stock price, but this risk can be minimized by investors choosing the companies that satisfy certain criteria. Graphical abstract The higher pipeline size(spip) and lower rate of return before (srr) the drug development setback (DDS) and the Market Value of Equity/Book Value of Total Liabilities ratio (sx4) are associated with a positive mean rate of return 120 days after the DDS.

Local Vibrational Therapy for Essential Tremor Reduction: A Clinical Study.

Background and objectives: tremor is an unintentional and rhythmic movement of any part of the body that is a typical symptom of Essential Tremor (ET). ET impairs the quality of life of patients and is treated with pharmacotherapy. We investigated the tremor reduction efficacy of an innovative vibrational medical device (IMD) in ET patients. Materials and Methods: we conducted a prospective, single-center, single-arm, pragmatic study in ET patients with an extended safety study to evaluate the efficacy and safety of the Vilim Ball-a local hand-arm vibration device that produces vibrations in the frequency range of 8-18 Hz and amplitude from 0 to 2 mm. The primary endpoint was the decrease in the power spectrum after device use. The secondary endpoints were safety outcomes. Results: In total, 17 patients with ET were included in the main study, and no patients withdrew from the main study. The tremor power spectrum (m2/s3 Hz) was lower after the device use, represented as the mean (standard deviation): 0.106 (0.221); median (Md) 0.009 with the interquartile range; IQR, 0.087 vs. 0.042 (0.078); Md = 0.009 with the IQR 0.012; Wilcoxon signed-rank test V = 123; and p = 0.027. Seven patients reported that vibrational therapy was not effective. Two patients reported an increase in tremor after using the device. In the extended safety study, we included 51 patients: 31 patients with ET and 20 with Parkinsonian tremor, where 48 patients reported an improvement in tremor symptoms and 49 in function. No serious adverse events were reported, while two patients in the Parkinsonian tremor group reported a lack of efficacy of the proposed medical device. Conclusions: the device reduces essential tremor in some patients and is safe to use in ET.

Low-Frequency (20 kHz) Ultrasonic Modulation of Drug Action.

We tested the effect of low-frequency ultrasound (LUS, 20 kHz, 4 W/cm2) on the function of rat mesentery and human pulmonary arteries with wire myography. The vessels were induced to contract with either noradrenaline or physiologic saline solution (PSS) with a high potassium concentration (KPSS) and then incubated with capsaicin (2.1 × 10-7 M, TRPV1 [transient receptor potential vanilloid 1] activator), dopamine (1 × 10-4 M, dopamine and α2-receptor activator), or fenoldopam (dopamineA1 receptor agonist, 1 × 10-4 M) with and without glibenclamide (1 µM, KATP [adenosine triphosphate {sensitive potassium channel (ATP)}-sensitive potassium channel] inhibitor and α2-receptor modulator), and insonated. Vessels were incubated in Ca2+-free PSS and induced to contract with added extracellular Ca2+ and noradrenaline. Pulmonary arteries were induced to contract with KPSS and dopamine. Then the vessels were insonated. LUS inhibited the influx of external Ca2+, inhibited the dopamine-induced vasoconstriction in the KPSS (glibenclamide reversible), reduced the capsaicin-induced vasorelaxation, increased the gentamicin-induced vasorelaxation and increased the dopamine-induced contraction in the KPSS in human pulmonary arteries.

Experimental investigation of the determination for the safe operating regime of ultrasound tube-shaped waveguide wire for internal blood vessel debulking.

BACKGROUND: Majority of limb amputations are caused by circulatory disturbances such as vascular occlusions and strictures. Discovery of modern and more advanced ultrasonic interventional vascular debulking methodology would likely save limbs of CVD patients and their lives in an economical way. However, there is a lack of researches regarding the ultrasound's effect on physiological functions of human blood cells. The tube-shaped ultrasound waveguide wire with orifices at its operational end was offered as the alternative to some currently patented interventional thrombosis treatment solutions. OBJECTIVE: To establish the safe operating regime of the proposed device. METHODS: The temperature rise induced by the cavitation process and friction between the waveguide and surrounding fluids was measured and microscopic pictures of human blood were made. RESULTS: Blood insonation lasting 15 seconds, leads to blood clot formation. If insonation continues for 30 seconds some cells are totally destroyed. In addition, the safe operating regime was established. To avoid heating of the environment to the temperature harmful for the medium (blood) and surrounding tissues, is achieved when the system should be on for 40%, and of for 60% of the period of 1 second. CONCLUSIONS: The safe operating regime of the proposed device was established.

Adaptation of cardiovascular system stent implants.

Time-consuming design and manufacturing processes are a serious disadvantage when adapting human cardiovascular implants as they cause unacceptable delays after the decision to intervene surgically has been made. An ideal cardiovascular implant should have a broad range of characteristics such as strength, viscoelasticity and blood compatibility. The present research proposes the sequence of the geometrical adaptation procedures and presents their results. The adaptation starts from the identification of a person's current health status while performing abdominal aortic aneurysm (AAA) imaging, which is a point of departure for the mathematical model of a cardiovascular implant. The computerized tomography scan shows the patient-specific geometry parameters of AAA and helps to create a model using COMSOL Multiphysics software. The initial parameters for flow simulation are taken from the results of a patient survey. The simulation results allow choosing the available shape of an implant which ensures a non-turbulent flow. These parameters are essential for the design and manufacturing of an implant prototype which should be tested experimentally for the assurance that the mathematical model is adequate to a physical one. The article gives a focused description of competences and means that are necessary to achieve the shortest possible preparation of the adapted cardiovascular implant for the surgery.

Influence of low-frequency vibrations on blood flow improvement in human's limbs.

The fundamental cause of diabetic limbs' problem is insufficient blood supply. The aim of the current work was to experimentally and numerically investigate the blood flow velocity and pressure changes in the channel during vibrational excitation. The micro-scale Particle Image Velocimetry (µPIV) technique as well as corresponding numerical channel model in COMSOL Multiphysics software were used to investigate the influence of external vibrations. Momentum upstream flow were noted on the fluid that was influenced by vibrations. Furthermore, momentum flow velocity increased by more than 3 times in both experimentally and theoretically. These results show that suggested novel low-frequency vibrational excitation method should be investigated in clinical studies in case of improvement of blood circulation in human limbs.