Acid-sensing ion channel blocker diminazene facilitates proton-induced excitation of afferent nerves in a similar manner that Na+/H+ exchanger blockers do.

Tissue acidification causes sustained activation of primary nociceptors, which causes pain. In mammals, acid-sensing ion channels (ASICs) are the primary acid sensors; however, Na+/H+ exchangers (NHEs) and TRPV1 receptors also contribute to tissue acidification sensing. ASICs, NHEs, and TRPV1 receptors are found to be expressed in nociceptive nerve fibers. ASIC inhibitors reduce peripheral acid-induced hyperalgesia and suppress inflammatory pain. Also, it was shown that pharmacological inhibition of NHE1 promotes nociceptive behavior in acute pain models, whereas inhibition of TRPV1 receptors gives relief. The murine skin-nerve preparation was used in this study to assess the activation of native polymodal nociceptors by mild acidification (pH 6.1). We have found that diminazene, a well-known antagonist of ASICs did not suppress pH-induced activation of CMH-fibers at concentrations as high as 25 µM. Moreover, at 100 µM, it induces the potentiation of the fibers' response to acidic pH. At the same time, this concentration virtually completely inhibited ASIC currents in mouse dorsal root ganglia (DRG) neurons (IC50 = 17.0 ± 4.5 µM). Non-selective ASICs and NHEs inhibitor EIPA (5-(N-ethyl-N-isopropyl)amiloride) at 10 µM, as well as selective NHE1 inhibitor zoniporide at 0.5 µM induced qualitatively the same effects as 100 µM of diminazene. Our results indicate that excitation of afferent nerve terminals induced by mild acidification occurs mainly due to the NHE1, rather than acid-sensing ion channels. At high concentrations, diminazene acts as a weak blocker of the NHE. It lacks chemical similarity with amiloride, EIPA, and zoniporide, so it may represent a novel structural motif for the development of NHE antagonists. However, the effect of diminazene on the acid-induced excitation of primary nociceptors remains enigmatic and requires additional investigations.

Artificial Intelligence in the Intensive Care Unit: Present and Future in the COVID-19 Era.

The development of artificial intelligence (AI) allows for the construction of technologies capable of implementing functions that represent the human mind, senses, and problem-solving skills, leading to automation, rapid data analysis, and acceleration of tasks. These solutions has been initially implemented in medical fields relying on image analysis; however, technological development and interdisciplinary collaboration allows for the introduction of AI-based enhancements to further medical specialties. During the COVID-19 pandemic, novel technologies established on big data analysis experienced a rapid expansion. Yet, despite the possibilities of advancements with these AI technologies, there are number of shortcomings that need to be resolved to assert the highest and the safest level of performance, especially in the setting of the intensive care unit (ICU). Within the ICU, numerous factors and data affect clinical decision making and work management that could be managed by AI-based technologies. Early detection of a patient's deterioration, identification of unknown prognostic parameters, or even improvement of work organization are a few of many areas where patients and medical personnel can benefit from solutions developed with AI.

Temperature increase significantly enhances nociceptive responses of C-fibers to ATP, high K+, and acidic pH in mice.

It is well established that temperature affects the functioning of almost all biomolecules and, consequently, all cellular functions. Here, we show how temperature variations within a physiological range affect primary afferents' spontaneous activity in response to chemical nociceptive stimulation. An ex vivo mouse hind limb skin-saphenous nerve preparation was used to study the temperature dependence of single C-mechanoheat (C-MH) fibers' spontaneous activity. Nociceptive fibers showed a basal spike frequency of 0.097 ± 0.013 Hz in control conditions (30°C). Non-surprisingly, this activity decreased at 20°C and increased at 40°C, showing moderate temperature dependence with Q10∼2.01. The fibers' conduction velocity was also temperature-dependent, with an apparent Q10 of 1.38. Both Q10 for spike frequency and conduction velocity were found to be in good correspondence with an apparent Q10 for ion channels gating. Then we examined the temperature dependence of nociceptor responses to high K+, ATP, and H+. Receptive fields of nociceptors were superfused with solutions containing 10.8 mM K+, 200 µM ATP, and H+ (pH 6.7) at three different temperatures: 20, 30, and 40°C. We found that at 30 and 20°C, all the examined fibers were sensitive to K+, but not to ATP or H+. At 20°C, only 53% of fibers were responsible for ATP; increasing the temperature to 40°C resulted in 100% of sensitive fibers. Moreover, at 20°C, all observed fibers were silent to pH, but at 40°C, this number was gradually increased to 87.9%. We have found that the temperature increase from 20 to 30°C significantly facilitated responses to ATP (Q10∼3.11) and H+ (Q10∼3.25), leaving high K+ virtually untouched (Q10∼1.88 vs. 2.01 in control conditions). These data suggest a possible role of P2X receptors in coding the intensity of non-noxious thermal stimuli.

Coupling of Blood Pressure and Subarachnoid Space Oscillations at Cardiac Frequency Evoked by Handgrip and Cold Tests: A Bispectral Analysis.

The aim of the study was to assess blood pressure-subarachnoid space (BP-SAS) width coupling properties using time-frequency bispectral analysis based on wavelet transforms during handgrip and cold tests. The experiments were performed on a group of 16 healthy subjects (F/M; 7/9) of the mean age 27.2 ± 6.8 years and body mass index of 23.8 ± 4.1 kg/m2. The sequence of challenges was first handgrip and then cold test. The handgrip challenge consisted of a 2-min strain, indicated by oral communication from the investigator, at 30% of maximum strength. The cold test consisted of 2 min of hand immersion to approximately wrist level in cold water of 4 °C, verified by a digital thermometer. Each test was preceded by 10 min at baseline and was followed by 10-min recovery recordings. BP and SAS were recorded simultaneously. Three 2-min stages of the procedure, baseline, test, and recovery, were analyzed. We found that BP-SAS coupling was present only at cardiac frequency, while at respiratory frequency both oscillators were uncoupled. Handgrip and cold test failed to affect BP-SAS cardiac-respiratory coupling. We showed similar handgrip and cold test cardiac bispectral coupling for individual subjects. Further studies are required to establish whether the observed intersubject variability concerning the BP-SAS coupling at cardiac frequency has any potential clinical predictive value.

Novel liquid chromatography method based on linear weighted regression for the fast determination of isoprostane isomers in plasma samples using sensitive tandem mass spectrometry detection.

A simple, fast, sensitive and accurate methodology based on a LLE followed by liquid chromatography-tandem mass spectrometry for simultaneous determination of four regioisomers (8-iso prostaglandin F2α, 8-iso-15(R)-prostaglandin F2α, 11ß-prostaglandin F2α, 15(R)-prostaglandin F2α) in routine analysis of human plasma samples was developed. Isoprostanes are stable products of arachidonic acid peroxidation and are regarded as the most reliable markers of oxidative stress in vivo. Validation of method was performed by evaluation of the key analytical parameters such as: matrix effect, analytical curve, trueness, precision, limits of detection and limits of quantification. As a homoscedasticity was not met for analytical data, weighted linear regression was applied in order to improve the accuracy at the lower end points of calibration curve. The detection limits (LODs) ranged from 1.0 to 2.1pg/mL. For plasma samples spiked with the isoprostanes at the level of 50pg/mL, intra-and interday repeatability ranged from 2.1 to 3.5% and 0.1 to 5.1%, respectively. The applicability of the proposed approach has been verified by monitoring of isoprostane isomers level in plasma samples collected from young patients (n=8) subjected to hyperbaric hyperoxia (100% oxygen at 280kPa(a) for 30min) in a multiplace hyperbaric chamber.

Sympathetic Activation Does Not Affect the Cardiac and Respiratory Contribution to the Relationship between Blood Pressure and Pial Artery Pulsation Oscillations in Healthy Subjects.

INTRODUCTION: Using a novel method called near-infrared transillumination backscattering sounding (NIR-T/BSS) that allows for the non-invasive measurement of pial artery pulsation (cc-TQ) and subarachnoid width (sas-TQ) in humans, we assessed the influence of sympathetic activation on the cardiac and respiratory contribution to blood pressure (BP) cc-TQ oscillations in healthy subjects. METHODS: The pial artery and subarachnoid width response to handgrip (HGT) and cold test (CT) were studied in 20 healthy subjects. The cc-TQ and sas-TQ were measured using NIR-T/BSS; cerebral blood flow velocity (CBFV) was measured using Doppler ultrasound of the left internal carotid artery; heart rate (HR) and beat-to-beat mean BP were recorded using a continuous finger-pulse photoplethysmography; respiratory rate (RR), minute ventilation (MV), end-tidal CO2 (EtCO2) and end-tidal O2 (EtO2) were measured using a metabolic and spirometry module of the medical monitoring system. Wavelet transform analysis was used to assess the relationship between BP and cc-TQ oscillations. RESULTS: HGT evoked an increase in BP (+15.9%; P<0.001), HR (14.7; P<0.001), SaO2 (+0.5; P<0.001) EtO2 (+2.1; P<0.05) RR (+9.2%; P = 0.05) and MV (+15.5%; P<0.001), while sas-TQ was diminished (-8.12%; P<0.001), and a clear trend toward cc-TQ decline was observed (-11.0%; NS). CBFV (+2.9%; NS) and EtCO2 (-0.7; NS) did not change during HGT. CT evoked an increase in BP (+7.4%; P<0.001), sas-TQ (+3.5%; P<0.05) and SaO2(+0.3%; P<0.05). HR (+2.3%; NS), CBFV (+2.0%; NS), EtO2 (-0.7%; NS) and EtCO2 (+0.9%; NS) remained unchanged. A trend toward decreased cc-TQ was observed (-5.1%; NS). The sas-TQ response was biphasic with elevation during the first 40 seconds (+8.8% vs. baseline; P<0.001) and subsequent decline (+4.1% vs. baseline; P<0.05). No change with respect to wavelet coherence and wavelet phase coherence was found between the BP and cc-TQ oscillations. CONCLUSIONS: Short sympathetic activation does not affect the cardiac and respiratory contribution to the relationship between BP-cc-TQ oscillations. HGT and CT display divergent effects on the width of the subarachnoid space, an indirect marker of changes in intracranial pressure.

Effect of oxygen on neuronal excitability measured by critical flicker fusion frequency is dose dependent.

INTRODUCTION: Reactive oxygen species are involved in the functional changes necessary for synaptic plasticity, memory, and cognitive function. It is far from clear whether the increased excitability, and which forms of neuronal excitability, should be considered a part of the learning process or, rather, cellular manifestation of neuronal oxygen poisoning. It is yet to be elucidated whether oxygen (O2)-induced learning and poisoning use the same or distinct cellular pathways. PURPOSE: We hypothesized that O2-induced neuronal excitability might use the same or an intertwined signaling cascade as the poisoning cellular pathway. METHOD: Eighty-one healthy, young males, mean age 27.7 ± 4.1 (SD) years, were exposed in the hyperbaric chamber to 0.7 atmosphere absolute (ATA) O2, 1.4 ATA O2, and 2.8 ATA O2. The critical flicker fusion frequency (CFFF), oxyhemoglobin saturation (SiO2), and heart rate (HR) were measured before exposure, after 30 min of oxygen breathing while still at pressure and then after exposure. RESULTS: Normobaric (0.7 ATA) O2 exposure did not affect CFFF and HR. Medium hyperbaric O2 exposure (1.4 ATA) decreased CFFF but HR remained unchanged. High hyperbaric O2 exposure (2.8 ATA) increased CFFF and diminished HR. SiO2 was similar in all investigated groups. A correlation between CFFF, HR, and SiO2 was observed only at low oxygen (0.7 ATA). CONCLUSIONS: The effect of O2 on neuronal excitability measured by CFFF in young healthy men was dose dependent: 0.7 ATA O2 did not affect CFFF; CFFF were significantly jeopardized at 1.4 ATA O2, while CFFF recovered at 2.8 ATA. With 2.8 ATA O2, the CFFF and oxygen poisoning transduction pathways seemed to be intertwined.

Effects of diving and oxygen on autonomic nervous system and cerebral blood flow.

Recreational scuba diving is a popular leisure activity with the number of divers reaching several millions worldwide. Scuba diving represents a huge challenge for integrative physiology. In mammalian evolution, physiological reflexes developed to deal with lack of oxygen, rather than with an excess, which makes adaptations to scuba diving more difficult to describe and understand than those associated with breath-hold diving. The underwater environment significantly limits the use of equipment to register the organism's functions, so, in most instances, scientific theories are built on experiments that model real diving to some extent, like hyperbaric exposures, dive reflexes or water immersion. The aim of this review is to summarise the current knowledge related to the influence exerted by physiological conditions specific to diving on the autonomic nervous system and cerebral blood flow. The main factors regulating cerebral blood flow during scuba diving are discussed as follows: 1) increased oxygen partial pressure; 2) immersion-related trigemino-cardiac reflexes and 3) exposure to cold, exercise and stress. Also discussed are the potential mechanisms associated with immersion pulmonary oedema.