"I want to know what it is used for": Clients' perspectives on completing a routine outcome measure (ROM) while undergoing psychotherapy.

Objectives: Within mental health care, the use of routine outcome measure (ROMs) has increased. So far, clients' perspectives on ROMs in the context of long-term psychotherapy remain largely unexplored. The present study aimed to explore clients' perspectives on completing the CORE-OM throughout psychotherapy. Method: Eight clients attending a psychiatric outpatient clinic in Sweden were interviewed and the data were analyzed according to the principles of interpretative phenomenological analysis. Results: The results included three main themes. The clients described an uncertainty of the purpose and usage of the CORE-OM, which gave room for interpretations regarding possible consequences of the results. The theme self-reporting in a relational context describes the clients' reflections about the CORE-OM, both as a measure and as a means for communication requiring continuous feedback. The CORE-OM as part of the treatment indicated that completing the questionnaire was useful for clients by evoking feelings and increasing awareness of inner states.Conclusions: ROMs should be used with great care in the treatment process and openness about the purpose of the instrument might increase the validity of the results. The use of ROMs as both an outcome measure on group level and a therapeutic tool is discussed.

Tracking a complete voltage-sensor cycle with metal-ion bridges.

Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 Å along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

Intracellular K+ concentration decrease is not obligatory for apoptosis.

K(+) efflux is observed as an early event in the apoptotic process in various cell types. Loss of intracellular K(+) and subsequent reduction in ionic strength are suggested to release the inhibition of proapoptotic caspases. In this work, a new K(+)-specific microelectrode was used to study possible alterations in intracellular K(+) in Xenopus laevis oocytes during chemically induced apoptosis. The accuracy of the microelectrode to detect changes in intracellular K(+) was verified with parallel electrophysiological measurements. In concordance with previous studies on other cell types, apoptotic stimuli reduced the intracellular K(+) concentration in Xenopus oocytes and increased caspase-3 activity. The reduction in intracellular K(+) was prevented by dense expression of voltage-gated K (Kv) channels. Despite this, the caspase-3 activity was increased similarly in Kv channel-expressing oocytes as in oocytes not expressing Kv channels. Thus, in Xenopus oocytes caspase-3 activity is not dependent on the intracellular concentration of K(+).

Electrostatic tuning of cellular excitability.

Voltage-gated ion channels regulate the electric activity of excitable tissues, such as the heart and brain. Therefore, treatment for conditions of disturbed excitability is often based on drugs that target ion channels. In this study of a voltage-gated K channel, we propose what we believe to be a novel pharmacological mechanism for how to regulate channel activity. Charged lipophilic substances can tune channel opening, and consequently excitability, by an electrostatic interaction with the channel's voltage sensors. The direction of the effect depends on the charge of the substance. This was shown by three compounds sharing an arachidonyl backbone but bearing different charge: arachidonic acid, methyl arachidonate, and arachidonyl amine. Computer simulations of membrane excitability showed that small changes in the voltage dependence of Na and K channels have prominent impact on excitability and the tendency for repetitive firing. For instance, a shift in the voltage dependence of a K channel with -5 or +5 mV corresponds to a threefold increase or decrease in K channel density, respectively. We suggest that electrostatic tuning of ion channel activity constitutes a novel and powerful pharmacological approach with which to affect cellular excitability.

Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids.

Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We report that omega-3 and omega-6 all-cis-PUFAs affected the voltage dependence of the Shaker K channel by shifting the conductance versus voltage and the gating charge versus voltage curves in negative direction along the voltage axis. Uncharged methyl esters of the PUFAs did not affect the voltage dependence, whereas changes of pH and charge mutations on the channel surface affected the size of the shifts. This suggests an electrostatic effect on the channel's voltage sensors. Monounsaturated and saturated fatty acids, as well as trans-PUFAs did not affect the voltage dependence. This suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. We believe this provides a new approach for pharmacological treatment that is voltage sensor pharmacology.

Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: a putative mechanism of antiseizure action.

PURPOSE: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. METHODS: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (beta-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. RESULTS: We found that PUFAs at concentrations down to 21microM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. CONCLUSIONS: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels.

Nodule detection in digital chest radiography: effect of nodule location.

Most detection studies in chest radiography treat the entire chest image as a single background or divided into the two regions parenchyma and mediastinum. However, the different parts of the lung show great variations in attenuation and structure, leading to different amounts of quantum noise and scattered radiation as well as different complexity. Detailed data on the difference in detectability in the different regions are of importance. The purpose of this study was to quantify the difference in detectability between different regions of a chest image. The chest X ray was divided into six different regions, where each region was considered to be uniform in terms of detectability. Thirty clinical chest images were collected and divided into the different regions. Simulated designer nodules with a full-width-at-fifth-maximum of 10 mm but with varying contrast were added to the images. An equal number of images lacking pathology were included and a receiver operating characteristic (ROC) study was conducted with five observers. Results show that the image contrast needed to obtain a constant value of A(z) (area under an ROC curve) differs by more than a factor of four between different regions.

Nodule detection in digital chest radiography: effect of system noise.

Apart from the image content that is the reproduction of anatomy and possible lesions, an X-ray image also contains system noise due to the limited number of photons and other internal noise sources in the system (image plate artefacts, electronic noise, etc.). The aim of this study was to determine the extent to which the system noise influences the detection of subtle lung nodules in five different regions of the chest. This was done by conducting a receiver operating characteristic (ROC) study with five observers on two different sets of images; clinical chest X-ray images and images of a LucAl phantom at similar dose levels found in the different regions of the chest. In both image types, mathematically simulated nodules (with a full-width-at-fifth-maximum of 10 mm) were added to the images at varying contrast levels. As a measure of the influence of system noise on the detection of subtle lung nodules, the ratio between the contrast needed to obtain an area under the ROC curve of 0.80 in the system noise images to that needed in the clinical images was used. The contrast ratio between system noise images and clinical images ranged from approximately 0.02 (in the hilar region) to 0.18 (in the lower mediastinal region). The maximum difference in contrast needed for the corresponding system noise images, collected at the lowest and the highest dose represented in the anatomical image, was a factor of 2. These results indicate that probably no region in a chest X-ray image is limited by the number of quanta to the detector for the detection of 10 mm lung nodules when a radiation dose corresponding to a system with speed class 200 (leading to a detector dose of approximately 9 muGy behind the parenchyma) is used.

A software tool for increased efficiency in observer performance studies in radiology.

Observer performance studies are time-consuming tasks, both for the participating observers and for the scientists collecting and analysing the data. A possible way to optimise such studies is to perform them in a completely digital environment. A software tool-ViewDEX (Viewer for Digital Evaluation of X-ray images)-has been developed in Java, enabling it to function on almost any computer. ViewDEX is designed to handle several types of studies, such as visual grading analysis (VGA), image criteria scoring (ICS) and receiver operating characteristics (ROC). The results from each observer are saved in a log file, which can be exported for further analysis in, for example, a special software for analysing ROC results. By using ViewDEX for an ROC experiment, an evaluation rate of approximately 200 images per hour can be achieved, compared to approximately 25 images per hour using hard copy evaluation. The results are obtained within minutes of completion of the viewing. The risk of human errors in the process of data collection and analysis is also minimised. The viewer has been used in a major trial containing approximately 2700 images.

Nodule detection in digital chest radiography: introduction to the RADIUS chest trial.

Most digital radiographic systems of today have wide latitude and are hence able to provide images with a small constraint on dose level. This opens up for an unprejudiced dose optimisation. However, in order to succeed in the optimisation task, good knowledge of the imaging and detection processes is needed. As a part of the European-wide research project 'unification of physical and clinical requirements for medical X-ray imaging'-governed by the Radiological Imaging Unification Strategies (RADIUS) Group-a major image quality trial was conducted by members of the group. The RADIUS chest trial was focused on the detection of lung nodules in digital chest radiography with the aims of determining to what extent (1) the detection of a nodule is dependent on its location, (2) the system noise disturbs the detection of lung nodules, (3) the anatomical noise disturbs the detection of lung nodules and (4) the image background and anatomical background act as pure noise for the detection of lung nodules. The purpose of the present paper is to give an introduction to the trial and describe the framework and set-up of the investigation.

Nodule detection in digital chest radiography: part of image background acting as pure noise.

There are several factors that influence the radiologist's ability to detect a specific structure/lesion in a radiograph. Three factors that are commonly known to be of major importance are the signal itself, the system noise and the projected anatomy. The aim of this study was to determine to what extent the image background acts as pure noise for the detection of subtle lung nodules in five different regions of the chest. A receiver operating characteristic (ROC) study with five observers was conducted on two different sets of images, clinical chest X-ray images and images with a similar power spectrum as the clinical images but with a random phase spectrum, resulting in an image background containing pure noise. Simulated designer nodules with a full-width-at-fifth-maximum of 10 mm but with varying contrasts were added to the images. As a measure of the part of the image background that acts as pure noise, the ratio between the contrast needed to obtain an area under the ROC curve of 0.80 in the clinical images to that in the random-phase images was used. The ratio ranged from 0.40 (in the lateral pulmonary regions) to 0.83 (in the hilar regions) indicating that there was a large difference between different regions regarding to what extent the image background acted as pure noise; and that in the hilar regions the image background almost completely acted as pure noise for the detection of 10 mm nodules.

Nodule detection in digital chest radiography: effect of anatomical noise.

The image background resulting from imaged anatomy can be divided into those components that are meaningful to the observers, in the sense that they are recognised as separate structures, and those that are not. These latter components (reffered to as anatomical noise) can be removed using a method developed within the RADIUS group. The aim of the present study was to investigate whether the removal of the anatomical noise results in images where lung nodules with lower contrast can be detected. A receiver operating characteristic (ROC) study was therefore conducted using two types of images: clinical chest images and chest images in which the anatomical noise had been removed. Simulated designer nodules with a full-width-at-fifth-maximum of 10 mm but with varying contrast were added to the images. The contrast needed to obtain an area under the ROC curve of 0.80, C0.8, was used as a measure of detectability (a low value of C0.8 represents a high detectability). Five regions of the chest X ray were investigated and it was found that in all regions the removal of anatomical noise led to images with lower C0.8 than the original images. On average, C0.8 was 20% higher in the original images, ranging from 7% (the lateral pulmonary regions) to 41% (the upper mediastinal regions).

Nodule detection in digital chest radiography: summary of the RADIUS chest trial.

As a part of the Europe-wide research project 'Unification of physical and clinical requirements for medical X-ray imaging'-governed by the Radiological Imaging Unification Strategies (RADIUS) Group-a major image quality trial was conducted by members of the group. The RADIUS chest trial aimed at thoroughly examining various aspects of nodule detection in digital chest radiography, such as the effects of nodule location, system noise, anatomical noise, and anatomical background. The main findings of the RADIUS chest trial concerning the detection of a lung nodule with a size in the order of 10 mm can be summarised as: (1) the detectability of the nodule is largely dependent on its location in the chest, (2) the system noise has a minor impact on the detectability at the dose levels used today, (3) the disturbance of the anatomical noise is larger than that of the system noise but smaller than that of the anatomical background and (4) the anatomical background acts as noise to a large extent and is the major image component affecting the detectability of the nodule.

The free energy barrier for arginine gating charge translation is altered by mutations in the voltage sensor domain.

The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3(10)-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C1), modeled from experimental constraints. We show that conformations within 3 Å of the X-ray structure are obtained in simulations starting from the C1 model, and directly observe the previously suggested sliding 3(10)-helix region in S4. Through systematic free energy calculations, we show that the C1 state is a stable intermediate conformation and determine free energy profiles for moving between the states without constraints. Mutations indicate several residues in a narrow hydrophobic band in the voltage sensor contribute to the barrier between the open and C1 states, with F233 in the S2 helix having the largest influence. Substitution for smaller amino acids reduces the transition cost, while introduction of a larger ring increases it, largely confirming experimental activation shift results. There is a systematic correlation between the local aromatic ring rotation, the arginine barrier crossing, and the corresponding relative free energy. In particular, it appears to be more advantageous for the F233 side chain to rotate towards the extracellular side when arginines cross the hydrophobic region.

Dampening of hyperexcitability in CA1 pyramidal neurons by polyunsaturated fatty acids acting on voltage-gated ion channels.

A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (K(A)) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channel's steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the K(A) channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of K(A) channels, and the resting potential can be an effective treatment of epilepsy.

An electrostatic potassium channel opener targeting the final voltage sensor transition.

Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study, we have localized the site of action for PUFAs on the voltage-gated Shaker K channel by introducing positive charges on the channel surface, which potentiated the PUFA effect. Furthermore, we found that PUFA mainly affects the final voltage sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.

Structure, function, and modification of the voltage sensor in voltage-gated ion channels.

Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensor domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensor domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves approximately 13 A outwards and rotates approximately 180 degrees, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane. This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.