Tinnitus information online - does it ring true?

OBJECTIVE: To assess, using standardised tools, the quality and readability of online tinnitus information that patients are likely to access. METHODS: A standardised review was conducted of websites relating to tinnitus and its management. Each website was scored using the DISCERN instrument and the Flesch Reading Ease scale. RESULTS: Twenty-seven unique websites were evaluated. The mean DISCERN score of the websites was 34.5 out of 80 (standard deviation = 11.2). This would be considered 'fair' in quality. Variability in DISCERN score between websites was high (range, 15-57: 'poor' to 'very good'). Website readability was poor, with a mean Flesch Reading Ease score of 52.6 (standard deviation = 7.7); this would be considered 'difficult' to read. CONCLUSION: In general, the quality of tinnitus websites is fair and the readability is poor, with substantial variability in quality between websites. The Action on Hearing Loss and the British Tinnitus Association websites were identified as providing the highest quality information.

Self-motivated learning with gamification improves infant CPR performance, a randomised controlled trial.

Background: Effective paediatric basic life support improves survival and outcomes. Current cardiopulmonary resuscitation (CPR) training involves 4-yearly courses plus annual updates. Skills degrade by 3-6 months. No method has been described to motivate frequent and persistent CPR practice. To achieve this, we explored the use of competition and a leaderboard, as a gamification technique, on a CPR training feedback device, to increase CPR usage and performance. Objective: To assess whether self-motivated CPR training with integrated CPR feedback improves quality of infant CPR over time, in comparison to no refresher CPR training. Design: Randomised controlled trial (RCT) to assess the effect of self-motivated manikin-based learning on infant CPR skills over time. Setting: A UK tertiary children's hospital. Participants: 171 healthcare professionals randomly assigned to self-motivated CPR training (n=90) or no refresher CPR training (n=81) and followed for 26 weeks. Intervention: The intervention comprised 24 h a day access to a CPR training feedback device and anonymous leaderboard. The CPR training feedback device calculated a compression score based on rate, depth, hand position and release and a ventilation score derived from rate and volume. Main outcome measure: The outcome measure was Infant CPR technical skill performance score as defined by the mean of the cardiac compressions and ventilations scores, provided by the CPR training feedback device software. The primary analysis considered change in score from baseline to 6 months. Results: Overall, the control group showed little change in their scores (median 0, IQR -7.00-5.00) from baseline to 6 months, while the intervention group had a slight median increase of 0.50, IQR 0.00-33.50. The two groups were highly significantly different in their changes (p<0.001). Conclusions: A significant effect on CPR performance was demonstrated by access to self-motivated refresher CPR training, a competitive leaderboard and a CPR training feedback device.

Endotracheal DNase for atelectasis in ventilated neonates.

Management of atelectasis and lung collapse in ventilated neonates remains a common challenge in the neonatal intensive care unit. Recombinant human DNase (rhDNase) is an established treatment of atelectasis in cystic fibrosis and its use is also reported in the management of asthma, respiratory syncitial virus bronchiolitis and bronchiectasis to liquefy sputum and aid its clearance from the lungs. We report the use of rhDNase in a subgroup of ventilated neonates with severe end-stage respiratory failure and atelectasis. Three of the four patients showed clinical improvement. A previously undiagnosed lung anomaly was subsequently identified in the fourth patient. Future randomized studies could examine any potential benefits of this emerging therapy.

Dicentric chromosomes and 20q11.2 amplification in MDS/AML with apparent monosomy 20.

FISH analysis of 41 previously karyotyped cases of MDS and AML with apparent monosomy of chromosome 20 revealed a variety of dicentric abnormalities involving chromosome 20. These usually, but not always, involved a breakpoint in the long arm of chromosome 20 and loss of the common deleted region at 20q12. Not one case of true monosomy 20 was confirmed. We found evidence for dicentric chromosome formation in 21 of 24 unbalanced translocations containing chromosome 20 and that were studied in more detail. Subsequent loss of one of the centromeres had occurred in eight of these 24 cases, and was more frequent than centromere inactivation as a means of resolving the inherent instability of a dicentric chromosome. In the three cases with dicentric chromosomes from which proximal 20q had been excised along with the 20 centromere, the excised segment was retained, and in two of these it was amplified. Proximal 20q was clearly retained in all but three cases, and present in three or more copies in 17 of 41 cases. The retention and amplification of proximal 20q provides support for the hypothesis that there is an oncogene located in this region of 20q that is activated in cases of MDS/AML with del(20q). Apparent monosomy 20 in MDS/AML should be treated as evidence of unidentified chromosome 20 abnormalities, and familiarity with the typical G-banded morphology of these derivatives can help with their identification. The reported incidence of dicentric chromosomes is clearly an under-estimate but is increasing in myeloid disorders as more cases are studied with methods allowing their detection.

Energetic optimization of ion conduction rate by the K+ selectivity filter.

The K+ selectivity filter catalyses the dehydration, transfer and rehydration of a K+ ion in about ten nanoseconds. This physical process is central to the production of electrical signals in biology. Here we show how nearly diffusion-limited rates are achieved, by analysing ion conduction and the corresponding crystallographic ion distribution in the selectivity filter of the KcsA K+ channel. Measurements with K+ and its slightly larger analogue, Rb+, lead us to conclude that the selectivity filter usually contains two K+ ions separated by one water molecule. The two ions move in a concerted fashion between two configurations, K+-water-K+-water (1,3 configuration) and water-K+-water-K+ (2,4 configuration), until a third ion enters, displacing the ion on the opposite side of the queue. For K+, the energy difference between the 1,3 and 2,4 configurations is close to zero, the condition of maximum conduction rate. The energetic balance between these configurations is a clear example of evolutionary optimization of protein function.

Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.

Ion transport proteins must remove an ion's hydration shell to coordinate the ion selectively on the basis of its size and charge. To discover how the K+ channel solves this fundamental aspect of ion conduction, we solved the structure of the KcsA K+ channel in complex with a monoclonal Fab antibody fragment at 2.0 A resolution. Here we show how the K+ channel displaces water molecules around an ion at its extracellular entryway, and how it holds a K+ ion in a square antiprism of water molecules in a cavity near its intracellular entryway. Carbonyl oxygen atoms within the selectivity filter form a very similar square antiprism around each K+ binding site, as if to mimic the waters of hydration. The selectivity filter changes its ion coordination structure in low K+ solutions. This structural change is crucial to the operation of the selectivity filter in the cellular context, where the K+ ion concentration near the selectivity filter varies in response to channel gating.

Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.

Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by the channel's cytoplasmic amino terminus. Here we show that the central cavity and inner pore of the K+ channel form the receptor site for both the inactivation gate and small-molecule inhibitors. We propose that inactivation occurs by a sequential reaction in which the gate binds initially to the cytoplasmic channel surface and then enters the pore as an extended peptide. This mechanism accounts for the functional properties of K+ channel inactivation and indicates that the cavity may be the site of action for certain drugs that alter cation channel function.

Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel.

The intracellular C-terminal domain structure of a six-transmembrane K+ channel from Escherichia coli has been solved by X-ray crystallography at 2.4 A resolution. The structure is representative of a broad class of domains/proteins that regulate the conductance of K+ (here referred to as RCK domains) in prokaryotic K+ transporters and K+ channels. The RCK domain has a Rossmann-fold topology with unique positions, not commonly conserved among Rossmann-fold proteins, composing a well-conserved salt bridge and a hydrophobic dimer interface. Structure-based amino acid sequence alignments and mutational analysis are used to demonstrate that an RCK domain is also present and is an important component of the gating machinery in eukaryotic large-conductance Ca2+ activated K+ channels.

Assessing the subjective experience of being a participant in psychiatric research.

OBJECTIVE: To address both clinical and ethical concerns in psychiatric research, the study assessed the subjective experience of being a participant in a feasibility study of outcome in long-term psychodynamic psychotherapy and psychoanalysis. METHOD: A questionnaire assessing positive and negative reactions to three typical research methodologies (self-report questionnaires, structured diagnostic interviews, and tape-recording of sessions) was administered to 23 patient-therapist pairs. RESULTS: Patients reported that questionnaires and interviews were slightly to moderately helpful in promoting self-realization and facilitating therapy, and not at all to slightly intrusive and disruptive. Adjustment to audiotaping of sessions was rapid (within two sessions). Therapists significantly overestimated the negative effects and underestimated the positive benefit patients reported from participating in research. CONCLUSIONS: Traditional objections to research in dynamic psychotherapy on the grounds that patients experience research procedures as significantly intrusive and disruptive appear to be unfounded.

Can we do psychoanalytic outcome research? A feasibility study.

Despite the widespread use of long-term psychodynamic treatments, methodologically rigorous outcome studies have not been conducted. The authors describe the results of a feasibility study designed to (1) investigate whether patients in psychodynamic treatment, including psychoanalysis, could be recruited and retained as research subjects, (2) determine patient and therapist compliance with self-report measures, rater-administered structured interviews and session audiotaping and (3) obtain pilot data on changes in these measures after one year of treatment. Nine patients entering psychoanalysis and fifteen entering psychodynamic psychotherapy were studied at baseline, six months and one year. Major findings were as follows: (1) recruitment rates were 27% (psychoanalysis) and 83% (psychotherapy), (2) all patients who remained in treatment remained in the research protocol, (3) drop-out rates among research participants and non-participants were equivalent, (4) current Axis I (usually affective or anxiety) disorders were found in over 60% of patients, (5) Axis II disorders in the absence of current Axis I disorders were rare, (6) despite a small number (N) of participants, significant positive change was demonstrated on a variety of measures after one year. Results suggest that it is possible to demonstrate a therapeutic effect of psychodynamic treatments, including psychoanalysis, but changing negative clinical perceptions of research is necessary if methodologically rigorous outcome studies are to be possible in the future.

Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K+ channels.

The structure of the cytoplasmic assembly of voltage-dependent K+ channels was solved by x-ray crystallography at 2.1 angstrom resolution. The assembly includes the cytoplasmic (T1) domain of the integral membrane alpha subunit together with the oxidoreductase beta subunit in a fourfold symmetric T1(4)beta4 complex. An electrophysiological assay showed that this complex is oriented with four T1 domains facing the transmembrane pore and four beta subunits facing the cytoplasm. The transmembrane pore communicates with the cytoplasm through lateral, negatively charged openings above the T1(4)beta4 complex. The inactivation peptides of voltage-dependent K(+) channels reach their site of action by entering these openings.

Energetic and structural interactions between delta-dendrotoxin and a voltage-gated potassium channel.

Dendrotoxin proteins isolated from Mamba snake venom block potassium channels with a high degree of specificity and selectivity. Using site-directed mutagenesis we have identified residues that constitute the functional interaction surfaces of delta-dendrotoxin and its voltage-gated potassium channel receptor. delta-Dendrotoxin uses a triangular patch formed by seven side-chains (Lys3, Tyr4, Lys6, Leu7, Pro8, Arg10, Lys26) to block K(+) currents carried by a Shaker potassium channel variant. The inhibitory surface of the toxin interacts with channel residues at Shaker positions 423, 425, 427, 431, and 449 near the pore. Amino acid mutations that interact across the toxin-channel interface were identified by mutant cycle analysis. These results constrain the possible orientation of dendrotoxin with respect to the K(+) channel structure. We propose that dendrotoxin binds near the pore entryway but does not act as a physical plug.

The barium site in a potassium channel by x-ray crystallography.

X-ray diffraction data were collected from frozen crystals (100 degrees K) of the KcsA K(+) channel equilibrated with solutions containing barium chloride. Difference electron density maps (F(barium) - F(native), 5.0 A resolution) show that Ba(2+) resides at a single location within the selectivity filter. The Ba(2+) blocking site corresponds to the internal aspect (adjacent to the central cavity) of the "inner ion" position where an alkali metal cation is found in the absence of the blocking Ba(2+) ion. The location of Ba(2+) with respect to Rb(+) ions in the pore is in good agreement with the findings on the functional interaction of Ba(2+) with K(+) (and Rb(+)) in Ca(2+)-activated K(+) channels (Neyton, J., and C. Miller. 1988. J. Gen. Physiol. 92:549-567). Taken together, these structural and functional data imply that at physiological ion concentrations a third ion may interact with two ions in the selectivity filter, perhaps by entering from one side and displacing an ion on the opposite side.

Isolation of a single carboxyl-carboxylate proton binding site in the pore of a cyclic nucleotide-gated channel.

The pore of the catfish olfactory cyclic nucleotide-gated (CNG) channel contains four conserved glutamate residues, one from each subunit, that form a high-affinity binding site for extracellular divalent cations. Previous work showed that these residues form two independent and equivalent high-pKa (approximately 7.6) proton binding sites, giving rise to three pH-dependent conductance states, and it was suggested that the sites were formed by pairing of the glutamates into two independent carboxyl-carboxylates. To test further this physical picture, wild-type CNG subunits were coexpressed in Xenopus oocytes with subunits lacking the critical glutamate residue, and single channel currents through hybrid CNG channels containing one to three wild-type (WT) subunits were recorded. One of these hybrid channels had two pH-dependent conductance states whose occupancy was controlled by a single high-pKa protonation site. Expression of dimers of concatenated CNG channel subunits confirmed that this hybrid contained two WT and two mutant subunits, supporting the idea that a single protonation site is made from two glutamates (dimer expression also implied the subunit makeup of the other hybrid channels). Thus, the proton binding sites in the WT channel occur as a result of the pairing of two glutamate residues. This conclusion places these residues in close proximity to one another in the pore and implies that at any instant in time detailed fourfold symmetry is disrupted.