Søren-Peter Olesen

Optically pumped magnetometers are becoming a promising alternative to cryogenically-cooled superconducting magnetometers for detecting and imaging biomagnetic fields. Magnetic field detection is a completely non-invasive method, which allows one to study the function of excitable human organs with a sensor placed outside the human body. For instance, magnetometers can be used to detect brain activity or to study the activity of the heart. We have developed a highly sensitive miniature optically pumped magnetometer based on cesium atomic vapor kept in a paraffin-coated glass container. The magnetometer is optimized for detection of biological signals and has high temporal and spatial resolution. It is operated at room- or human body temperature and can be placed in contact with or at a mm-distance from a biological object. With this magnetometer, we detected the heartbeat of an isolated guinea-pig heart, which is an animal widely used in biomedical studies. In our recordings of the magnetocardiogram, we can detect the P-wave, QRS-complex and T-wave associated with the cardiac cycle in real time. We also demonstrate that our device is capable of measuring the cardiac electrographic intervals, such as the RR- and QT-interval, and detecting drug-induced prolongation of the QT-interval, which is important for medical diagnostics.

Aim: We investigated the effect of variants in genes encoding sodium channel modifiers SNTA1 and GPD1L found in early onset atrial fibrillation (AF) patients. Patients & methods: Genetic screening in patients with early onset lone AF revealed three variants in GPD1L and SNTA1 in three AF patients. Functional analysis was performed by patch-clamp electrophysiology. Results: Co-expression of GPD1L or its p.A326E variant with NaV1.5 did not alter INa density or current kinetics. SNTA1 shifted the peak-current by -5 mV. The SNTA1-p.A257G variant significantly increased INa. SNTA1-p.P74L did not produce functional changes. Conclusion: Although genetic variation of sodium channel modifiers may contribute to development of AF at a molecular level, it is unlikely a monogenic cause of the disease.

Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.SIGNIFICANCE STATEMENTOur study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.

Background: Evidence has emerged that small-conductance Ca ²⁺ -activated K ⁺ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. Methods and Results: A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. Conclusions: SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

In several European countries there is an increasing trend within social and labour market policy to implement employment-oriented policies. In some countries, this turn towards employment has opened up a new professional arena for social workers, so called employment-oriented social work. The chapter examines the challenges that this development has brought to the social work profession, especially in regard to how knowledge and decision-making is negotiated in relation to clients and other professions within the same policy arena. The chapter is based on Danish, Italian and Austrian data including register data, semi-structured interviews, observations and sound recordings.

Aim: In this study, we investigate the impact of altered action potential durations (APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K⁺‐channel‐interacting protein 2 (KChIP2^−/− and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia.Methods: Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time (AT), APD and repolarization time (=AT + APD) were measured in isolated hearts using floating microelectrodes.Results: Proarrhythmia in WT and KChIP2^−/− was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2^−/− hearts compared to WT hearts. Isolated WT hearts had large apico‐basal dispersion of repolarization time, whereas hearts from KChIP2^−/− mice had large left‐to‐right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2^−/− mice in vivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice.Conclusion: Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and the amplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability.

Magnetic fields generated by human and animal organs, such as the heart, brain and nervous system carry information useful for biological and medical purposes. These magnetic fields are most commonly detected using cryogenically-cooled superconducting magnetometers. Here we present the first detection of action potentials from an animal nerve using an optical atomic magnetometer. Using an optimal design we are able to achieve the sensitivity dominated by the quantum shot noise of light and quantum projection noise of atomic spins. Such sensitivity allows us to measure the nerve impulse with a miniature room-temperature sensor which is a critical advantage for biomedical applications. Positioning the sensor at a distance of a few millimeters from the nerve, corresponding to the distance between the skin and nerves in biological studies, we detect the magnetic field generated by an action potential of a frog sciatic nerve. From the magnetic field measurements we determine the activity of the nerve and the temporal shape of the nerve impulse. This work opens new ways towards implementing optical magnetometers as practical devices for medical diagnostics.

Background and Purpose: KCNQ‐encoded voltage‐dependent potassium channels (K_v7) are involved in the regulation of vascular tone. In this study we evaluated the influence of K_v7 channel activation on smooth muscle relaxation in rat penile arteries and corpus cavernosum from normal and spontaneously hypertensive, heart failure‐prone (SHHF) rats – a rat model of human metabolic syndrome.Experimental Approach: Quantitative PCR and immunohistochemistry were used to determine the expression of KCNQ isoforms in penile tissue. Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from normal and SHHF rats.Key Results: Transcripts for KCNQ3, KCNQ4 and KCNQ5 were detected in penile arteries and corpus cavernosum. KCNQ1 was only found in corpus cavernosum. Immunofluorescence signals to K_v7.4 and K_v7.5 were found in penile arteries, penile veins and corpus cavernosum. The K_v7.2–7.5 activators, ML213 and BMS204352, relaxed pre‐contracted penile arteries and corpus cavernosum independently of nitric oxide synthase or endothelium‐derived hyperpolarization. Relaxations to sildenafil, a PDE5 inhibitor, and sodium nitroprusside (SNP), an nitric oxide donor, were reduced by blocking K_v7 channels with linopirdine in penile arteries and corpus cavernosum. In SHHF rat penile arteries and corpus cavernosum, relaxations to ML213 and BMS204352 were attenuated, and the blocking effect of linopirdine on sildenafil‐induced and SNP‐induced relaxations reduced. KCNQ3, KCNQ4 and KCNQ5 were down‐regulated, and KCNQ1 was up‐regulated in corpus cavernosum from SHHF rats. KCNQ1–5 transcripts remained unchanged in penile arteries from SHHF rats.Conclusions and Implications: These data suggest that K_v7 channels play a role in erectile function and contribute to the pathophysiology of erectile dysfunction, an early indicator of cardiovascular disease.