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.

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.

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.

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.

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.

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.

Social support and life events in working class women. Stress buffering or independent effects?

Several authors have suggested that social support reduces the risk of psychiatric disorder by providing a "buffer" against the adverse effects of stressful events. Others have proposed, in contrast, that social support is beneficial irrespective of life stress. We addressed this issue in a community survey of 193 working class mothers by measuring social support, threatening life events, psychiatric symptomatology, and psychological well-being via a detailed assessment combining a standardized interview and case-identification procedure with self-report questionnaires yielding continuous measures of distress and well-being. Subject selection minimized confounding between support and events. The effects of life stress and social support were found to be largely independent of one another, although detailed analysis suggested that the conclusions drawn in such studies are affected by the measures and statistics used.

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.

Extended-release felodipine in patients with mild to moderate hypertension. Felodipine ER Dose-Response Study Group.

Two hundred eighty-six patients with mild to moderate hypertension who had untreated diastolic blood pressure while seated of 95 to 115 mm Hg were randomized to receive placebo or once-daily doses of 2.5, 5, or 10 mg of the dihydropyridine calcium channel blocker felodipine extended release (ER). Blood pressure was measured 24 hours after dosing (at trough). Mean reductions in diastolic blood pressure after 8 weeks of double-blind treatment were significantly greater in each of the ER felodipine treatment groups (2.5, 5, and 10 mg ER felodipine: -7.8, -9.5, and -11.3 mm Hg, respectively) than in the placebo group (-5.3 mm Hg). The effect was dose dependent for both diastolic and systolic blood pressure. Moreover, much of the peak antihypertensive effect was still present at trough, confirming the 24-hour efficacy of the drug. Felodipine was well tolerated.

Cytogenetic diagnosis of the fragile X syndrome: efficiency, utilization, and trends.

In order to assess the impact of the increasing awareness of the fra(X) syndrome and a broader approach to fra(X) testing, we analyzed our laboratory experience for 1980-1988. In 1981-1986, there was an average of 80 cases/year (62 male; 18 female). The 103 (74 male; 29 female) cases in 1987 represent a 45% increase over the prior 3 years; this sustained in 1988 with 106 cases. The fra(X) positive yield decreased from a high of 49% in 1980 to an average of 20% (range 15-24%) in 1981-1984, 10% (range 9-11%), in 1985-1987 and 7% in 1988. The positive rate for males and females was nearly identical in both time periods. The positive yield for mentally retarded individuals with a family history of mental retardation dropped from an average of 20% for 1981-1984 and 33% for 1985-87 to 13% for 1988; however, the positive fra(X) rate for mentally retarded individuals decreased from an average of 23% in 1981-1984 to 9% in 1985-1987 and 7% in 1988. The decreasing fra(X) yield and increasing case load are directly attributable to the relaxation of criteria for referral and testing related to the referral of all mentally retarded patients, and to the perceived malpractice liability for not doing a "complete" evaluation. Although the burden for cytogenetic laboratories is considerable, the yield of positive fra(X) cases is still worthwhile, and may be maximized by the use of improved screening criteria.

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.

Disabuse of the drug metaphor: psychotherapy process-outcome correlations.

The drug metaphor suggests that if a process component (e.g., interpretation) is an active ingredient of a successful psychotherapy, then administering a relatively high level of it should yield a relatively positive outcome, and levels of the process component and the outcome should be correlated across clients. Measures of 5 theoretically relevant, reliably measured verbal process components were compared with the rate of change in 3 standard symptom intensity measures across the brief treatments of 39 (mainly depressed) psychotherapy clients. The expected significant process-outcome correlations were not found. These results are discussed as they illuminate some misleading assumptions that underlie many conventional studies of psychotherapy process and outcome.

Verbal exchange structure of brief psychodynamic-interpersonal and cognitive-behavioral psychotherapy.

A verbal exchange is a set of 2 people's co-occurring speech-act categories that accomplish some subtask within an interpersonal encounter. Factor analysis of verbal response mode (speech act) frequencies in 1,630 segments (each approximately 10 to 12 min) drawn from the brief psychodynamic-interpersonal or cognitive-behavioral treatment of 39 mainly depressed clients identified 6 exchanges in each treatment--4 that were the same in both treatments (Revealing, Storytelling, Explaining, and Inquiring) and 2 that distinguished each treatment (Exploring and Interpreting in psychodynamic-interpersonal treatment; Prescribing and Reframing in cognitive-behavioral treatment). The exchanges showed distinctive temporal patterns across segments of sessions and across sessions of each time-limited treatment. The verbal exchange is a midsize concept that links atomistic verbal codes with clinical or theoretical concepts.

Coding system of therapeutic focus on action and insight.

This study (a) used an established comprehensive process measure to uncover a latent pattern of therapeutic focus in cognitive-behavioral and psychodynamic-interpersonal sessions; (b) used these results to develop the coding system of Therapeutic Focus on Action and Insight, which makes it possible to evaluate therapists' relative emphasis on the Constructing Meaning and Facilitating Action domains of in-session focus; and (c) evaluated its reliability and validity.

The shape of change in psychotherapy: longitudinal assessment of personal problems.

We propose 4 parameters that describe the course of change in the subjective intensity of personal problems during psychotherapy: (a) the problem's initial severity; (b) its rate of change (deterioration or improvement); (c) its instability (day-to-day variability in intensity); and (d) its curve (change in the rate of change during treatment). We constructed indexes of these parameters for 10 individualized personal problems rated 3 times per week by each of 40 clients (most were diagnosed as depressed) over the course of their 16-session treatment and associated assessment periods. Initial severity predicted problems' reported salience to clients. The rate of change parameter was correlated (across clients) with traditional pretreatment to posttreatment outcome measures. Instability was high, and problems dealing with tension symptoms and mood were more unstable than were problems dealing with relationships or self-esteem. Cutting across problem content were large individual differences among clients in the patterns of change.

Psychotherapy in two-plus-one sessions: outcomes of a randomized controlled trial of cognitive-behavioral and psychodynamic-interpersonal therapy for subsyndromal depression.

A total of 116 clients with a range of subsyndromal depression received 3 therapy sessions: 2 sessions 1 week apart followed by a 3rd session 3 months later (the 2 + 1 model). Clients were stratified for severity on the Beck Depression Inventory (BDI) as stressed, subclinical, or low-level clinically depressed. In a 2 x 2 design, they received either cognitive-behavioral (CB) or psychodynamic-interpersonal (PI) therapy, either immediately or after a 4-week delay. An initial advantage for the immediate condition disappeared once the delayed-condition clients received treatment. Improvement rates at the end of treatment were 67% (stressed), 72% (subclinical), and 65% (low-level clinically depressed). There were no significant differences between CB and PI treatment methods, with the exception at 1-year follow-up, when the BDI showed a significant advantage for CB. Implications for designing very brief planned interventions are discussed.

Acceleration of changes in session impact during contrasting time-limited psychotherapies.

Following the suggestion that therapeutic change is accelerated in time-limited psychotherapy, this study investigated the across-session patterns of session impact in the treatments of 117 depressed clients who were randomly allocated to 8 or 16 sessions of cognitive-behavioral (CB) or psychodynamic-interpersonal (PI) therapy. After each session, all clients completed the Session Evaluation Questionnaire and 75 of the clients completed the Session Impacts Scale. Session ratings indicated that sessions were perceived increasingly positively on most impact dimensions (e.g., session depth and smoothness, relationship with the therapist, feelings of understanding and problem solving, postsession positive mood) as treatment progressed. Early in treatment, PI therapy sessions were less smooth (i.e., more tense and uncomfortable) and less focused on problem solving, but PI sessions changed more rapidly than CB sessions on these dimensions, so that later in treatment, sessions of both treatments were equivalently positive. In both treatments, the trend toward more positive sessions was more rapid (i.e., the across-session slope was steeper) in 8-session treatments than in 16-session treatments. Such accelerated changes in session impact may reflect the suggested acceleration of therapeutic change associated with shorter time limits.

Impact of Cluster C personality disorders on outcomes of contrasting brief psychotherapies for depression.

Twenty-seven of 114 depressed clients, stratified for severity of depression, obtained a Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; DSM-III; American Psychiatric Association, 1980) diagnosis of Cluster C personality disorder--that is, avoidant, obsessive-compulsive or dependent personality disorder (PD clients)--whereas the remaining 87 did not (non-personality-disorder [NPD] clients). All clients completed either 8 or 16 sessions of cognitive-behavioral (CB) or psychodynamic-interpersonal (PI) psychotherapy. On most measures, PD clients began with more severe symptomatology than NPD clients. Among those who received PI therapy, PD clients maintained this difference posttreatment and at 1-year follow-up. Among those who received CB therapy, posttreatment differences between PD and NPD groups were not significant. Treatment length did not influence outcome for PD clients. PD clients whose depression was also relatively severe showed significantly less improvement after treatment than either PD clients with less severe depression or NPD clients.