Sensitivity enhancement of plasmonic grating in the local field.

A plasmonic grating consisting of parallel gold or silver nanowires on the glass substrate is an excellent sensor for refractive index measurement of a gas or liquid medium. We suggest measuring the local field in a gap between the wires to increase the sensitivity. The local electric field contains more information on the environment since it includes the evanescent waves. Calculation by the boundary element method confirms a substantial improvement of sensitivity owing to a sharp cusp-like gap resonance in the angular dependence. The local field measurement under the frustration of total internal reflection has promising prospects for the development of modern biomedical and chemical sensors.

Effects of imperfect angular adjustment on plasmonic force.

The attractive plasmonic force between two metallic walls due to electromagnetic wave in the slit has been studied earlier for parallel plates and normal incidence. In present paper the effects of imperfectly adjusted plates and laser beam are analyzed. The change of force for non-parallel plates is shown to be of the first order in angle when the wedge is oriented along wave propagation and of the second order for the transverse case. Beam inclination decreases the force due to an antisymmetric mode excited in the slit.

Method for computing the optimal signal distribution and channel capacity.

An iterative method for computing the channel capacity of both discrete and continuous input, continuous output channels is proposed. The efficiency of new method is demonstrated in comparison with the classical Blahut - Arimoto algorithm for several known channels. Moreover, we also present a hybrid method combining advantages of both the Blahut - Arimoto algorithm and our iterative approach. The new method is especially efficient for the channels with a priory unknown discrete input alphabet.

The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.

BACKGROUND: Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS: After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS: In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133-237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS: This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.

New light on disordered ensembles: ab initio structure determination of one particle from scattering fluctuations of many copies.

We report on the first experimental ab initio reconstruction of an image of a single particle from fluctuations in the scattering from an ensemble of copies, randomly oriented about an axis. The method is applicable to identical particles frozen in space or time (as by snapshot diffraction from an x-ray free electron laser). These fluctuations enhance information obtainable from an experiment such as conventional small angle x-ray scattering.

X-ray diffraction from membrane protein nanocrystals.

Membrane proteins constitute > 30% of the proteins in an average cell, and yet the number of currently known structures of unique membrane proteins is < 300. To develop new concepts for membrane protein structure determination, we have explored the serial nanocrystallography method, in which fully hydrated protein nanocrystals are delivered to an x-ray beam within a liquid jet at room temperature. As a model system, we have collected x-ray powder diffraction data from the integral membrane protein Photosystem I, which consists of 36 subunits and 381 cofactors. Data were collected from crystals ranging in size from 100 nm to 2 µm. The results demonstrate that there are membrane protein crystals that contain < 100 unit cells (200 total molecules) and that 3D crystals of membrane proteins, which contain < 200 molecules, may be suitable for structural investigation. Serial nanocrystallography overcomes the problem of x-ray damage, which is currently one of the major limitations for x-ray structure determination of small crystals. By combining serial nanocrystallography with x-ray free-electron laser sources in the future, it may be possible to produce molecular-resolution electron-density maps using membrane protein crystals that contain only a few hundred or thousand unit cells.

An assessment of the resolution limitation due to radiation-damage in x-ray diffraction microscopy.

X-ray diffraction microscopy (XDM) is a new form of x-ray imaging that is being practiced at several third-generation synchrotron-radiation x-ray facilities. Nine years have elapsed since the technique was first introduced and it has made rapid progress in demonstrating high-resolution three-dimensional imaging and promises few-nm resolution with much larger samples than can be imaged in the transmission electron microscope. Both life- and materials-science applications of XDM are intended, and it is expected that the principal limitation to resolution will be radiation damage for life science and the coherent power of available x-ray sources for material science. In this paper we address the question of the role of radiation damage. We use a statistical analysis based on the so-called "dose fractionation theorem" of Hegerl and Hoppe to calculate the dose needed to make an image of a single life-science sample by XDM with a given resolution. We find that for simply-shaped objects the needed dose scales with the inverse fourth power of the resolution and present experimental evidence to support this finding. To determine the maximum tolerable dose we have assembled a number of data taken from the literature plus some measurements of our own which cover ranges of resolution that are not well covered otherwise. The conclusion of this study is that, based on the natural contrast between protein and water and "Rose-criterion" image quality, one should be able to image a frozen-hydrated biological sample using XDM at a resolution of about 10 nm.

Powder diffraction from a continuous microjet of submicrometer protein crystals.

Atomic-resolution structures from small proteins have recently been determined from high-quality powder diffraction patterns using a combination of stereochemical restraints and Rietveld refinement [Von Dreele (2007), J. Appl. Cryst. 40, 133-143; Margiolaki et al. (2007), J. Am. Chem. Soc. 129, 11865-11871]. While powder diffraction data have been obtained from batch samples of small crystal-suspensions, which are exposed to X-rays for long periods of time and undergo significant radiation damage, the proof-of-concept that protein powder diffraction data from nanocrystals of a membrane protein can be obtained using a continuous microjet is shown. This flow-focusing aerojet has been developed to deliver a solution of hydrated protein nanocrystals to an X-ray beam for diffraction analysis. This method requires neither the crushing of larger polycrystalline samples nor any techniques to avoid radiation damage such as cryocooling. Apparatus to record protein powder diffraction in this manner has been commissioned, and in this paper the first powder diffraction patterns from a membrane protein, photosystem I, with crystallite sizes of less than 500 nm are presented. These preliminary patterns show the lowest-order reflections, which agree quantitatively with theoretical calculations of the powder profile. The results also serve to test our aerojet injector system, with future application to femtosecond diffraction in free-electron X-ray laser schemes, and for serial crystallography using a single-file beam of aligned hydrated molecules.

Three-dimensional coherent x-ray diffraction imaging of a ceramic nanofoam: determination of structural deformation mechanisms.

Ultralow density polymers, metals, and ceramic nanofoams are valued for their high strength-to-weight ratio, high surface area, and insulating properties ascribed to their structural geometry. We obtain the labrynthine internal structure of a tantalum oxide nanofoam by x-ray diffractive imaging. Finite-element analysis from the structure reveals mechanical properties consistent with bulk samples and with a diffusion-limited cluster aggregation model, while excess mass on the nodes discounts the dangling fragments hypothesis of percolation theory.

The effectiveness of computerized cognitive behavioural therapy in routine care.

OBJECTIVES AND DESIGN: The efficacy of a Computerized Cognitive Behavioural Therapy (CCBT) package, Beating the Blues, has been demonstrated in a large randomized controlled trial. The current study tests the generalizability of this finding in a naturalistic non-randomized trial. METHOD: 219 patients with anxiety and/or depression were recruited to receive CCBT in routine care. The Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) and Work and Social Adjustment scale (WSA) were administered pre-treatment, immediately on completing treatment and at 6 months post-treatment. Single-item self-report measures of anxiety and depression were also collected during each treatment session. RESULTS: Completer and intention-to-treat analysis demonstrated statistically and clinically significant improvements on the CORE-OM, WSA and in self-reported anxiety and depression. Intention-to-treat analysis indicated an average 0.29-point drop on the CORE-OM, equating to an uncontrolled pre-post effect size of 0.50. Research completers achieved an average 0.61-point drop equating to an uncontrolled pre-post size of 1.00 on the same measure. Where data was available (18%), these benefits were maintained at week 32 (6 months follow-up). CONCLUSION: CCBT can be an effective first line tool within a stepped care framework for the management of common mental health problems.

The effectiveness of psychological treatments for treatment-resistant depression: a systematic review.

OBJECTIVE: A systematic review of all studies (controlled and uncontrolled) to evaluate psychological interventions with treatment-resistant depression. METHOD: A systematic search to identify studies evaluating a psychological intervention with adults with a diagnosis of major depressive disorder who had not responded to at least one course of antidepressant medication. RESULTS: Twelve studies met inclusion criteria, of which four were controlled and eight uncontrolled. Treatment effect sizes were computable for four studies and ranged from 1.23 to 3.10 with a number of better quality studies demonstrating some improvements in patients following a psychological intervention. CONCLUSION: Psychological treatments for depression are commonly delivered and often recommended following the failure of medication. The paucity of evidence for their effectiveness in these situations is a significant problem. There is a need for studies with a strong controlled design investigating the effectiveness of psychological treatments for patients with treatment-resistant depression.

Computerized cognitive-behaviour therapy for anxiety and depression: a practical solution to the shortage of trained therapists.

Computerized cognitive-behaviour therapy (CCBT) programmes have been developed to help meet the enormous need for evidence-based psychological treatment of common mental health problems in the context of a severe shortage of trained therapists to meet that need. Randomized controlled trials have confirmed the efficacy of such programmes. We present the experience of a community mental health team (CMHT) resource centre with one such programme, Beating the Blues, together with outcome data on a small sample of its clients. We conclude that experience and data, taken together, demonstrate the practical benefits of CCBT in routine practice.

Exploring and enhancing engagement to the psychosocial intervention 'Preparing for Parenthood'.

BACKGROUND: Poor compliance by participants consenting to be randomised to receive both physical and mental health promotion interventions represents a potentially serious threat to external and internal validity of those interventions. Quantitative and qualitative investigation of possible predictors of engagement forms an appropriate basis for efforts to enhance it. METHODS: Eight 'Preparing for Parenthood' intervention courses of a randomized controlled trial (RCT) underpinned a quantitative study. One 'Preparing for Parenthood' (PFP) intervention course, run upon completion of the RCT, formed a qualitative study. All nine courses followed identical procedures to enable clear comparisons. The three factors quantitatively explored with respect to engagement in health promoting behaviours were: locus of control (LOC), psychosocial support, and life events. The qualitative study utilised grounded theory analysis, the participants reflecting upon their experiences of the intervention and/or their reasons for not attending the course; nine interviews were completed. RESULTS: Participants in the quantitative and qualitative studies were divided into three sub-groups: compliant, non-compliant, and refusers. None of the three health promoting variables predicted compliance to a statistically significant degree. However, a variable from the trial analysis was found to reach significance; those women who had had less contact with the National Health Service in the 12 months prior to the baseline assessment were more likely to refuse the invitation to PFP. The qualitative study produced nine main themes that had influenced participant engagement at both the initial recruitment stage and during the course itself. CONCLUSIONS: In combination these findings may contribute to the future design of both effective and acceptable interventions to prevent postnatal depression. One such modified intervention is described and its impact on engagement outlined.

Practice development in psychological interventions: mental health nurse involvement in the Conversational Model of psychotherapy.

This paper describes a mental health nurse led practice development initiative in psychotherapy. Four mental health nurses have been trained to deliver the Conversational Model of psychotherapy (also known as psychodynamic-interpersonal (PI) psychotherapy) a non-cognitive behavioural therapy (CBT) with a robust evidence base. We report on the robust range of both processes and outcome measures being used to evaluate this initiative. We conclude that good quality evidence-based practice requires careful planning and preparation, adequate financial resources from Trusts, as well as commitment and motivation from the staff expected to be involved in such initiatives.

Personal reflections of mental health nurses training to use Hobson's Conversational Model (psychodynamic-interpersonal) of psychotherapy.

Current mental health policy documents highlight the need for mental health nurses to become increasingly involved in the delivery of evidence-based psychological interventions. However, substantial evidence exists indicating that there is a paucity of training to adequately equip nurses to deliver these interventions and, even when training is available, there are barriers to their implementation into routine clinical practice. This paper reports on the personal reflections and experiences of a group of four mental health nurses undertaking training in the Conversational Model of psychotherapy (also known as psychodynamic-interpersonal 'PI' psychotherapy). These reflections highlight the rewards and challenges arising from the effort to undertake training in an evidence-based model of psychological intervention and from attempting to implement and sustain this training into routine practice.

First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes.

OBJECTIVE: To evaluate the safety of IDN-6556, a novel anti-apoptotic pan-caspase inhibitor, administered in single and multiple ascending doses in normal volunteers and patients with hepatic dysfunction. MATERIALS AND METHODS: IDN-6556 was administered as a 30-minute intravenous infusion in rising doses to 3 groups: Group A, normal volunteers, given as a single infusion, Group B, normal volunteers, given q.i.d. for 7 days, Group C, patients with hepatic impairment (elevated transaminases, alanine transaminase, ALT and aspartate transaminase, AST), given q.i.d. for 7 days. RESULTS: The drug was well tolerated up to 10 mg/kg/infusion for a single dose, and 1.5 mg/kg/infusion q.i.d. for 7 days, with the dose-limiting adverse event of phlebitis or inflammation at the site of the infusion. This toxicity was predicted from animal studies. Clinically and statistically meaningful dose-related falls in transaminases were seen in all but 1 of the hepatic impaired patients. Two-way ANOVA analyses of the changes for all the IDN-6556 groups combined versus placebo were: ALT absolute change: p < 0.0001 and % change: p = 0.012, AST absolute and % changes: p < 0.0001. After discontinuation of the drug (after 7 days of dosing), the transaminases rapidly returned to the pre-treatment levels. CONCLUSIONS: Following intravenous administration of a novel anti-apoptotic caspase inhibitor, adverse events were mild-to-moderate in severity, resolved in a few days and did not result in any subject terminating treatment prematurely. The effects in hepatic impaired patients appear to be consistent with both the administration and subsequent abrupt withdrawal of an effective hepatoprotective drug that delays cell death in hepatocytes.

Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism.

We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.

Client interpersonal and cognitive styles as predictors of response to time-limited cognitive therapy for depression.

This study examined the relationship between cognitive and interpersonal styles and outcome among 24 clients who received time-limited cognitive therapy for depression. The authors hypothesized that this relationship would be mediated by therapeutic alliance. They found that clients' interpersonal style, particularly an underinvolved style, was predictive of treatment outcome. As predicted, the impact of this style on outcome was mediated through the therapeutic alliance.

Experience of aversive tension and dissociation in female patients with borderline personality disorder -- a controlled study.

Assuming that the experience of strong aversive tension might be an indicator of the extent of affect dysregulation within patients with borderline personality disorder (BPD), we sought to operationalize the duration and intensity of these phenomena. In addition we studied the relationship between aversive tension and the experience of dissociative features. Seventy-two female patients with BPD, together with 55 healthy controls, completed a self-rating questionnaire covering the previous 24 h. Substantial and highly significant differences with regard to the duration and intensity of the subjectively perceived states of aversive tension were found. Amongst patients with BPD there was a strong correlation between duration and intensity of tension, and experience of dissociative features, both somatoform and psychological. The findings underline the clinical importance of states of aversive tension in BPD particularly with regard to stress-related induction of dissociative features.

Discovery of a novel member of the histamine receptor family.

We report the discovery, tissue distribution and pharmacological characterization of a novel receptor, which we have named H4. Like the three histamine receptors reported previously (H1, H2, and H3), the H4 receptor is a G protein-coupled receptor and is most closely related to the H3 receptor, sharing 58% identity in the transmembrane regions. The gene encoding the H4 receptor was discovered initially in a search of the GenBank databases as sequence fragments retrieved in a partially sequenced human genomic contig mapped to chromosome 18. These sequences were used to retrieve a partial cDNA clone and, in combination with genomic fragments, were used to determine the full-length open reading frame of 390 amino acids. Northern analysis revealed a 3.0-kb transcript in rat testis and intestine. Radioligand binding studies indicated that the H4 receptor has a unique pharmacology and binds [(3)H]histamine (K(d) = 44 nM) and [(3)H]pyrilamine (K(d) = 32 nM) and several psychoactive compounds (amitriptyline, chlorpromazine, cyproheptadine, mianserin) with moderate affinity (K(i) range of 33-750 nM). Additionally, histamine induced a rapid internalization of HA-tagged H4 receptors in transfected human embryonic kidney 293 cells.