New measurements indicate that the public are being exposed, without their knowledge, to airborne ultrasound. Existing guidelines are insufficient for such exposures; the vast majority refers to ...occupational exposure only (where workers are aware of the exposure, can be monitored and can wear protection). Existing guidelines are based on an insufficient evidence base, most of which was collected over 40 years ago by researchers who themselves considered it insufficient to finalize guidelines, but which produced preliminary guidelines. This warning of inadequacy was lost as nations and organizations issued ‘new’ guidelines based on these early guidelines, and through such repetition generated a false impression of consensus. The evidence base is so slim that few reports have progressed far along the sequence from anecdote to case study, to formal scientific controlled trials and epidemiological studies. Early studies reported hearing threshold shifts, nausea, headache, fatigue, migraine and tinnitus, but there is insufficient research on human subjects, and insufficient measurement of fields, to assess what health risk current occupational and public exposures might produce. Furthermore, the assumptions underpinning audiology and physical measurements at high frequencies must be questioned: simple extrapolation of approaches used at lower frequencies does not address current unknowns. Recommendations are provided.
A number of queries regarding the paper ‘Are some people suffering as a result of increasing mass exposure of the public to ultrasound in air?’ (Leighton 2016 Proc. R. Soc. A 472, 20150624 ...(doi:10.1098/rspa.2015.0624)) have been sent in from readers, almost all based around some or all of a small set of questions. These can be grouped into issues of engineering, human factors and timeliness. Those issues (represented by the most typical wording used in queries) and my responses are summarized in this comment.
The heart has the ability to adjust to changing mechanical loads. The Frank–Starling law and the Anrep effect describe exquisite intrinsic mechanisms the heart has for autoregulating the force of ...contraction to maintain cardiac output under changes of preload and afterload. Although these mechanisms have been known for more than a century, their cellular and molecular underpinnings are still debated. How does the cardiac myocyte sense changes in preload or afterload? How does the myocyte adjust its response to compensate for such changes? In cardiac myocytes Ca2+ is a crucial regulator of contractile force and in this review we compare and contrast recent studies from different labs that address these two important questions. The ‘dimensionality’ of the mechanical milieu under which experiments are carried out provide important clues to the location of the mechanosensors and the kinds of mechanical forces they can sense and respond to. As a first approximation, sensors inside the myocyte appear to modulate reactive oxygen species while sensors on the cell surface appear to also modulate nitric oxide signalling; both signalling pathways affect Ca2+ handling. Undoubtedly, further studies will add layers to this simplified picture. Clarifying the intimate links from cellular mechanics to reactive oxygen species and nitric oxide signalling and to Ca2+ handling will deepen our understanding of the Frank–Starling law and the Anrep effect, and also provide a unified view on how arrhythmias may arise in seemingly disparate diseases that have in common altered myocyte mechanics.
Surface and internal mechanosensors link to NO and ROS signalling and to Ca2+ handling. Surface (blue) and internal (red and green) mechanosensors are depicted as springs. In experimental systems where the myocyte is in bathing solution that offers little mechanical resistance, the surface mechanosensors experience little or no strain (change in length divided by original length) as shown in the left panel. The internal mechanosensors experience strain and can produce reactive oxygen species (ROS) that affect Ca2+ handling. In other experimental systems the myocyte is adherent to a stretchable membrane or encased in a viscoelastic gel that provides mechanical resistance as the cell contracts or stretches; this mechanical loading causes surface mechanosensor strain as shown in the right panel. In these systems both internal and surface mechanosensors are activated. We and others have shown that this can result in activation of nitric oxide synthase (NOS) and production of nitric oxide (NO), which affects Ca2+ handling. Experimental systems represented by the left and right panels are complementary and enable study of surface and internal mechanosensors and their mechano‐chemo‐transduction pathways.
Abstract
The expansion and potential rupture of the swim bladder due to rapid decompression, a major cause of barotrauma injury in fish that pass through turbines and pumps, is generally assumed to ...be governed by Boyle’s Law. In this study, two swim bladder expansion models are presented and tested in silico. One based on the quasi-static Boyle’s Law, and a Modified Rayleigh Plesset Model (MRPM), which includes both inertial and pressure functions and was parametrised to be representative of a fish swim bladder. The two models were tested using a range of: (1) simulated and (2) empirically derived pressure profiles. Our results highlight a range of conditions where the Boyle’s Law model (BLM) is inappropriate for predicting swim bladder size in response to pressure change and that these conditions occur in situ, indicating that this is an applied and not just theoretical issue. Specifically, these conditions include any one, or any combination, of the following factors: (1) when rate of pressure change is anything but very slow compared to the resonant frequency of the swim bladder; (2) when the nadir pressure is near or at absolute zero; and (3) when a fish experiences liquid tensions (i.e. negative absolute pressures). Under each of these conditions, the MRPM is more appropriate tool for predicting swim bladder size in response to pressure change and hence it is a better model for quantifying barotrauma in fish.
Cardiac excitation‐contraction (E‐C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Figure). Here we review the mechanical effects on ...cardiomyocytes that include mechano‐electro‐transduction (commonly referred to as mechano‐electric coupling, MEC) and mechano‐chemo‐transduction (MCT) mechanisms at cell and molecular levels which couple to Ca2+‐electro and E‐C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano‐transduction to the Ca2+ homeodynamics and to the electrical excitation are essential for understanding the E‐C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca2+ dynamics). Of course, such separation is artificial since Ca2+ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium.
figure legend Cardiac excitation‐contraction coupling and feedback pathways by mechano‐electro‐ and mechano‐chemo‐transduction.
Deterrents that use acoustics to guide fish away from dangerous areas depend on the elicitation of avoidance in the target species. Acoustic deterrents select the optimum frequency based on an ...assumption that highest avoidance is likely to occur at the greatest sensitivity. However, such an assumption may be unfounded. Using goldfish (Carassius auratus) as a suitable experimental model, this study tested this as a null hypothesis. Under laboratory conditions, the deterrence thresholds of individual goldfish exposed to 120 ms tones at six frequencies (250-2000 Hz) and four Sound Pressure Levels (SPL 115-145 dB) were quantified. The deterrence threshold defined as the SPL at which 25% of the tested population startled was calculated and compared to the hearing threshold obtained using Auditory Evoked Potential and particle acceleration threshold data. The optimum frequency to elicit a startle response was 250 Hz; different from the published hearing and particle acceleration sensitivities based on audiograms. The difference between the deterrence threshold and published hearing threshold data varied from 47.1 dB at 250 Hz to 76 dB at 600 Hz. This study demonstrates that information obtained from audiograms may poorly predict the most suitable frequencies at which avoidance behaviours are elicited in fish.
Late Na+ current (INaL) significantly contributes to shaping cardiac action potentials (APs) and increased INaL is associated with cardiac arrhythmias. β-adrenergic receptor (βAR) stimulation and its ...downstream signaling via protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathways are known to regulate INaL. However, it remains unclear how each of these pathways regulates INaL during the AP under physiological conditions. Here we performed AP-clamp experiments in rabbit ventricular myocytes to delineate the impact of each signaling pathway on INaL at different AP phases to understand the arrhythmogenic potential. During the physiological AP (2 Hz, 37 °C) we found that INaL had a basal level current independent of PKA, but partially dependent on CaMKII. βAR activation (10 nM isoproterenol, ISO) further enhanced INaL via both PKA and CaMKII pathways. However, PKA predominantly increased INaL early during the AP plateau, whereas CaMKII mainly increased INaL later in the plateau and during rapid repolarization. We also tested the role of key signaling pathways through exchange protein activated by cAMP (Epac), nitric oxide synthase (NOS) and reactive oxygen species (ROS). Direct Epac stimulation enhanced INaL similar to the βAR-induced CaMKII effect, while NOS inhibition prevented the βAR-induced CaMKII-dependent INaL enhancement. ROS generated by NADPH oxidase 2 (NOX2) also contributed to the ISO-induced INaL activation early in the AP. Taken together, our data reveal differential modulations of INaL by PKA and CaMKII signaling pathways at different AP phases. This nuanced and comprehensive view on the changes in INaL during AP deepens our understanding of the important role of INaL in reshaping the cardiac AP and arrhythmogenic potential under elevated sympathetic stimulation, which is relevant for designing therapeutic treatment of arrhythmias under pathological conditions.
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•Measure the dynamic profile of INaL under cardiac AP during β-adrenergic stimulation•Reveal the differential contributions of PKA and CaMKII pathways in modulating INaL•Pacing-induced CaMKII activation upregulates basal INaL under AP-clamp.•Both PKA and CaMKII upregulate INaL during β-adrenergic stimulation.•PKA increases INaL in phase 2 and CaMKII increases INaL in phase 3 of the AP.•Reactive oxygen species and nitric oxide may contribute to PKA and CaMKII effects.
Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of ...electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell’s action potential (AP) under physiologically relevant conditions using selfAP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na⁺ current, Ca2+-activated K⁺ current, Ca2+-activated Cl⁻ current, decreased rapid delayed rectifier K⁺ current, and altered Na⁺/Ca2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca2+ current, decrease of inward rectifier K⁺ current, and Ca2+ release-dependent delayed after-depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF.
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