Effects of mexiletine on delayed after-depolarization and triggered activity

Summary The effects of mexiletine on delayed afterdepolarization (DAD) and triggered activity (TA) were studied in the rabbit ventricular muscle using standard microelectrode techniques. First, three kinds of perfusate (modified Tyrode's solution, K⁺-free solution, and 1 mM K⁺ + 5.4 mM Ca²⁺ solution) were used to see whether DAD and TA could be induced by rapid stimulations (cycle lengths of 1000, 600, and 300 ms with trains of 10 and 20 stimuli). The inducibility of DAD and TA in modified Tyrode's solution, in K⁺-free solution, and in low K⁺ + high Ca²⁺ solution was 0%, 8%, and 83%, respectively. The last value was significantly higher than the former values. DAD and TA were induced only by stimulation at the shortest cycle length of 300 ms, and the inducibility was significantly higher with trains of 20 than with those of 10 stimuli. When DAD and/or TA were induced, the effects of mexiletine (5 mg/l) were tested. Mexiletine totally suppressed DAD and TA in 94% of the preparations within 20 min after its addition. Abolition of DAD and TA was associated with a failure of the 1 : 1 response to the stimuli in 53% of the preparations. The drug tended to prolong the coupling interval of DAD and TA, and significantly reduced the DAD amplitude. Possible mechanisms of action are: (1) lowered intracellular Ca²⁺ concentration either via the blocking of the fast Na⁺ current or the reduction of the number of action potentials; and (2) a decrease in the transient inward current due to blockage of the Ca²⁺ current.     

Follow-up study of thyroid function in polytransfused thalassemic patients

The aim of our investigation was to evaluate thyroid function by a follow-up study in 45 polytransfused thalassemic patients, since endocrine abnormalities are frequent consequences of iron overload in thalassemia major. Significant changes of thyroid function have been revealed in the time elapsing the observation, despite unchanged haematological parameters; at the end of the present study five patients were affected by overt hypothyroidism and 15 patients by subclinical hypothyroidism. Ultrasound thyroid volume in 13 randomly selected patients was greatly reduced, while thyroid Magnetic Resonance Imaging (MRI) was not able to detect tissue alterations. Inversely, liver MRI was markedly reduced in 14 patients and negatively related to ferritine levels (P< 0.01). We conclude that polytransfused thalassemics are frequently affected by thyroid disfunction; haepatic haemosiderosis due to iron overload seems influence hormonal peripheral metabolism, although the patients display a moderate compliance with iron chelation therapy. Therefore, periodic thyroid investigation should be carried out in thalassemic subjects in order to detect patients who need hormone replacement therapy.     

Ultrasound activates mechanosensitive TRAAK K+ channels through the lipid membrane

Ultrasound modulates the electrical activity of excitable cells and offers advantages over other neuromodulatory techniques; for example, it can be noninvasively transmitted through the skull and focused to deep brain regions. However, the fundamental cellular, molecular, and mechanistic bases of ultrasonic neuromodulation are largely unknown. Here, we demonstrate ultrasound activation of the mechanosensitive K⁺ channel TRAAK with submillisecond kinetics to an extent comparable to canonical mechanical activation. Single-channel recordings reveal a common basis for ultrasonic and mechanical activation with stimulus-graded destabilization of long-duration closures and promotion of full conductance openings. Ultrasonic energy is transduced to TRAAK through the membrane in the absence of other cellular components, likely increasing membrane tension to promote channel opening. We further demonstrate ultrasonic modulation of neuronally expressed TRAAK. These results suggest mechanosensitive channels underlie physiological responses to ultrasound and could serve as sonogenetic actuators for acoustic neuromodulation of genetically targeted cells.

Manipulating cellular electrical activity is central to basic research and is clinically important for the treatment of neurological disorders including Parkinson’s disease, depression, epilepsy, and schizophrenia (1–4). Optogenetics, chemogenetics, deep brain stimulation (DBS), transcranial electrical stimulation, and transcranial magnetic stimulation are widely utilized neuromodulatory techniques, but each is associated with physical or biological limitations (5). Transcranial stimulation affords poor spatial resolution; deep brain stimulation and optogenetic manipulation typically require surgical implantation of stimulus delivery systems, and optogenetic and chemogenetic approaches necessitate genetic targeting of light- or small-molecule–responsive proteins.Ultrasound was first recognized to modulate cellular electrical activity almost a century ago, and ultrasonic neuromodulation has since been widely reported in the brain, peripheral nervous system, and heart of humans and model organisms (5–12). Ultrasonic neuromodulation has garnered increased attention for its advantageous physical properties. Ultrasound penetrates deeply through biological tissues and can be focused to sub-mm (3) volumes without transferring substantial energy to overlaying tissue, so it can be delivered noninvasively, for example, to deep structures in the brain through the skull. Notably, ultrasound generates excitatory and/or inhibitory effects depending on the system under study and stimulus paradigm (5, 13, 14).The mechanisms underlying the effects of ultrasound on excitable cells remain largely unknown (5, 13). Ultrasound can generate a combination of thermal and mechanical effects on targeted tissue (15, 16) in addition to potential off-target effects through the auditory system (17, 18). Thermal and cavitation effects, while productively harnessed to ablate tissue or transiently open the blood–brain barrier (19), require stimulation of higher power, frequency, and/or duration than typically utilized for neuromodulation (5). Intramembrane cavitation or compressive and expansive effects on lipid bilayers could generate nonselective currents that alter cellular electrical activity (5, 13). Alternatively, ultrasound could activate mechanosensitive ion channels through the deposition of acoustic radiation force that increases membrane tension or geometrically deforms the lipid bilayer (5, 15). Consistent with this notion, behavioral responses to ultrasound in Caenorhabditis elegans require mechanosensitive, but not thermosensitive, ion channels (20), and a number of mechanosensitive (and force-sensitive, but noncanonically mechanosensitive) ion channels have been implicated in cellular responses to ultrasound including two-pore domain K⁺ channels (K2Ps), Piezo1, MEC-4, TRPA1, MscL, and voltage-gated Na⁺ and Ca²⁺ channels (20–24, 25). Precisely how ultrasound impacts the activity of these channels is not known.To better understand mechanisms underlying ultrasonic neuromodulation, we investigated the effects of ultrasound on the mechanosensitive ion channel TRAAK (26, 27). K2P channels including TRAAK are responsible for so called “leak-type” currents because they approximate voltage- and time-independent K⁺-selective holes in the membrane, although more complex gating and regulation of K2P channels is increasingly appreciated (28, 29). TRAAK has a very low open probability in the absence of membrane tension and is robustly activated by force through the lipid bilayer (30–32). Mechanical activation of TRAAK involves conformational changes that prevent lipids from entering the channel to block K⁺ conduction (31). Gating conformational changes are associated with shape changes that expand the channel and make it more cylindrical in the membrane plane upon opening. These shape changes are energetically favored in the presence of membrane tension, resulting in a tension-dependent energy difference between states that favors channel opening (31). TRAAK is expressed in neurons and has been localized exclusively to nodes of Ranvier, the excitable action potential propagating regions of myelinated axons (33, 34). TRAAK is found in most (∼80%) myelinated nerve fibers in both the central and peripheral nervous systems, where it accounts for ∼25% of basal nodal K⁺ currents. As in heterologous systems, mechanical stimulation robustly activates nodal TRAAK. TRAAK is functionally important for setting the resting potential and maintaining voltage-gated Na⁺ channel availability for spiking in nodes; loss of TRAAK function impairs high-speed and high-frequency nerve conduction (33, 34). Changes in TRAAK activity therefore appear well poised to widely impact neuronal excitability.We find that low-intensity and short-duration ultrasound rapidly and robustly activates TRAAK channels. Activation is observed in patches from TRAAK-expressing Xenopus oocytes, in patches containing purified channels reconstituted into lipid membranes, and in TRAAK-expressing mouse cortical neurons. Single-channel recordings reveal that canonical mechanical and ultrasonic activation are accomplished through a shared mechanism. We conclude that ultrasound activates TRAAK through the lipid membrane, likely by increasing membrane tension to promote channel opening. This work demonstrates direct mechanical activation of an ion channel by ultrasound using purified and reconstituted components, is consistent with endogenous mechanosensitive channel activity underlying physiological effects of ultrasound, and provides a framework for the development of exogenously expressed sonogenetic tools for ultrasonic control of neural activity.     

Reliability of mechanical and phased-array designs for serial intravascular ultrasound examinations

Background: Both mechanical and multi-element intravascular ultrasound designs have potential advantages and limitations that may impact on their value for clinical and research purposes. Determination of the reproducibility of measurements is critical before a given system can be used in studies such as regression of atherosclerosis trials. Methods: We performed serial intravascular ultrasound imaging with catheters using mechanical and phased-array designs in stented and non-stented coronary arteries in dogs and in patients. Results: Both systems correlated well for areas (r 0.90, p < 0.0001) and diameters (r 0.84, p < 0.0001) in dogs and in patients. There was a slight difference between multi-element and mechanical designs for measurements of area (mean difference in dogs and in patients: –0.24 and 0.96 mm², p < 0.055) and diameter (–0.08 and 0.16 mm, p < 0.0001). The reproducibility of the multi-element system for reanalysis of the same frames and for analysis of serial pullbacks was similar to the same measurements with the mechanical system (r 0.96 for all measurements). The differences in absolute and relative variability between the mechanical and phased-array designs, both for reanalysis of same frames and serial pullbacks, were very small. Conclusions: Although multi-element and mechanical intravascular ultrasound designs are not strictly interchangeable, their similar reproducibility and the small differences in measurements demonstrate that both designs are acceptable alternatives for trials of regression of atherosclerosis. Determination of the variability for serial pullbacks of both designs was also important to assess the statistical power of such trials.     

Clinical profile,management and outcome of pulmonary embolism in Shahid Gangalal National Heart Centre,Kathmandu, Nepal

Background and aims

Pulmonary embolism (PE) is associated with a significant mortality and morbidity. We aim to study clinical profile, management and outcome of PE at Shahid Gangalal National heart Centre, Kathmandu, Nepal.

Spontaneous coronary artery dissection with pseudoaneurysm formation diagnosed by intravascular ultrasound: a case report

Spontaneous coronary artery dissection is a rare cause of myocardial ischemia. Coronary artery pseudoaneurysm may occur after percutaneous coronary interventions and rarely spontaneously. We present a patient who had spontaneous coronary artery dissection with formation of a pseudoaneurysm diagnosed by intravascular ultrasound.     

Myocardial ischaemia in a case of a solitary coronary ostium in the right aortic sinus with retroaortic course of the left coronary artery: documentation of the underlying pathophysiological mechanisms of ischaemia by intracoronary Doppler and pressure measurements

Only a few cases of a single coronary ostium and retroaortic course of the coronary artery have been described. Almost all cases reported so far had additional coronary artery or valvar disease. However, myocardial ischaemia may be caused by the coronary malformation alone. A 40 year old woman with severe myocardial ischaemia in the absence of clinically relevant coronary atherosclerosis is described. To clarify the origin and mechanisms of ischaemia, intracoronary Doppler, pressure and ultrasound studies were performed using microtransducers. In its outer portion along the course behind the ascending aorta, coronary blood flow velocities were increased, there was an external elliptical compression, and distal coronary flow reserve was reduced. Furthermore, an overshoot in diastolic pressure above aortic pressure was detectable within this portion. Dobutamine stimulation exaggerated the observed intracoronary haemodynamics and induced myocardial ischaemia. The intracoronary diagnostic procedures performed were helpful in clarifying the pathophysiological mechanisms of functional coronary obstruction and ischaemia in this malformation. Bypass surgery was successfully performed with symptomatic improvement.

Keywords: coronary anomaly;  Doppler;  intravascular ultrasound;  single coronary ostium;  congenital disorders     

Elevated Resistive Index in the Hepatic Artery as a Predictor of Fulminant Hepatic Failure in Patients with Acute Viral Hepatitis: A Prospective Study Using Doppler Ultrasound

To assess the sensitivity and specificity of the resistive index of the hepatic artery, which is related to the vascular resistance of the artery, for the prediction of fulminant hepatic failure, we performed Doppler ultrasonography examinations on the hepatic arteries of 72 patients with acute viral hepatitis (25 of whom developed fulminant hepatic failure and 47 of whom recovered without developing fulminant hepatic failure) as well as the hepatic arteries of age- and sex-matched controls. The mean resistive index of the hepatic arteries in patients who developed fulminant hepatic failure was significantly larger than that of patients who recovered without developing fulminant hepatic failure (P < 0.01). When a resistive index cutoff level of 0.74 was used, an 84% sensitivity and a 94% specificity were obtained for the prediction of fulminant hepatic failure. An elevated resistive index of the hepatic artery may be useful for predicting the patient's clinical outcome and determining the need for a liver transplantation in patients with acute viral hepatitis.     

Budesonide Versus Acetazolamide for Prevention of Acute Mountain Sickness

Background

Inhaled budesonide has been suggested as a novel prevention for acute mountain sickness. However, efficacy has not been compared with the standard acute mountain sickness prevention medication acetazolamide.

Associations of multiple unhealthy lifestyle behaviors with overweight/obesity and abdominal obesity among Brazilian adolescents: A country-wide survey

Background and Aims

Physical inactivity, unhealthy diet, smoking and heavy drinking are four key unhealthy lifestyle behaviors (ULB) that may influence body weight and obesity development. More recently, sedentary time has been recognized as another potentially emerging ULB related to obesity. We therefore investigated the association of multiple ULB with overweight/obesity and abdominal obesity among Brazilian adolescents.