Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (-)-hosieine-A.

The affinity and thermodynamic parameters for the interactions of two naturally occurring neurotoxins, (+)-anatoxin-a and (-)-hosieine-A, with acetylcholine-binding protein were investigated using a fluorescence-quenching assay and isothermal titration calorimetry. The crystal structures of their complexes with acetylcholine-binding protein from Aplysia californica (AcAChBP) were determined and reveal details of molecular recognition in the orthosteric binding site. Comparisons treating AcAChBP as a surrogate for human α4ß2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the molecular features involved in ligand recognition and affinity for the protein targets are conserved. The ligands exploit interactions with similar residues as the archetypal nAChR agonist nicotine, but with greater affinity. (-)-Hosieine-A in particular has a high affinity for AcAChBP driven by a favorable entropic contribution to binding. The ligand affinities help to rationalize the potent biological activity of these alkaloids. The structural data, together with comparisons with related molecules, suggest that there may be opportunities to extend the hosieine-A scaffold to incorporate new interactions with the complementary side of the orthosteric binding site. Such a strategy may guide the design of new entities to target human α4ß2 nAChR that may have therapeutic benefit.

Student mental health in higher education: the contextual influence of "cuts, competition & comparison".

BACKGROUND: The mental health of students in UK higher education (HE) is receiving increased attention, and support services for students are under increased pressure. AIMS: Drawing on ecological systems theory (EST), this study sought to explore possible contextual influences, over time, on student distress within HE. METHOD AND SAMPLES: We conducted a two-stage Delphi study, first asking UK professionals (n = 236) from primary, secondary, further education, and HE to provide possible reasons for increases in student distress. The material was reduced to 58 representative statements across all sectors with a further 10 specific to HE. In stage 2, 89 participants rated each statement in terms of whether it: (1) takes place and (2) contributes to distress. RESULTS: The results suggest multiple contextual influences potentially contributing to student distress. They can be summarized using the words: cuts, competition, and comparison. Education professionals in our sample reported that, upstream from HE, pressures on schools and colleges have led to a narrowing of curricula, with a more singular focus on assessment. Reduced teaching teams and pressurized staff unintentionally embed an assessment focus within students who unhelpfully compare themselves with peers while also struggling with wider societal cuts, austerity, and political uncertainty. CONCLUSIONS: The discussion draws on the peer-reviewed literature and relevant reports, discussing them in the context of EST, finding considerable support for these influences. The potential importance of adopting a contextual approach and incorporating this knowledge into the way we understand and tackle students' distress and their preparedness for HE is discussed.

A randomized controlled trial of an online health tool about Down syndrome.

PURPOSE: We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. METHODS: In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs-personalized checklists-are used during annual wellness visits with the patient's PCP. RESULTS: A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. CONCLUSIONS: DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.

Assessment of Specifications Grading in an Undergraduate Dietetics Course.

Assessing student learning is an integral component of teaching undergraduate dietetics students. Traditional grading can be cumbersome for instructors, encouraging extrinsic motivation for students and hindering clear understanding of whether students have met course learning outcomes. Specifications grading is a reimagined assessment paradigm that empowers both students and instructors to focus on achievement of learning objectives. This report examines the deployment of specifications grading in an undergraduate dietetics course, using qualitative methods to determine the impact on students' learning and experiences. Employing specifications grading may help dietetics educators foster self-regulation and mastery learning for students, as well as increase grading transparency.

Engineering a surrogate human heteromeric α/ß glycine receptor orthosteric site exploiting the structural homology and stability of acetylcholine-binding protein.

Protein-engineering methods have been exploited to produce a surrogate system for the extracellular neurotransmitter-binding site of a heteromeric human ligand-gated ion channel, the glycine receptor. This approach circumvents two major issues: the inherent experimental difficulties in working with a membrane-bound ion channel and the complication that a heteromeric assembly is necessary to create a key, physiologically relevant binding site. Residues that form the orthosteric site in a highly stable ortholog, acetylcholine-binding protein, were selected for substitution. Recombinant proteins were prepared and characterized in stepwise fashion exploiting a range of biophysical techniques, including X-ray crystallography, married to the use of selected chemical probes. The decision making and development of the surrogate, which is termed a glycine-binding protein, are described, and comparisons are provided with wild-type and homomeric systems that establish features of molecular recognition in the binding site and the confidence that the system is suited for use in early-stage drug discovery targeting a heteromeric α/ß glycine receptor.

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.

Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen. The resulting ADC consisted of a human αCD11a antibody (based on efalizumab clone hu1124) conjugated to an analog of the highly potent PDE4 inhibitor GSK256066. Both the human αCD11a ADC and a mouse surrogate αCD11a ADC (based on the M17 clone) rapidly internalized into immune cells and suppressed lipololysaccharide (LPS)-induced TNFα secretion in primary human monocytes and mouse peritoneal cells, respectively. In a carrageenan-induced air pouch inflammation mouse model, treatment with the ADC significantly reduced inflammatory cytokine production in the air pouch exudate. Overall, these results provide compelling evidence for the feasibility of delivering drugs with anti-inflammatory activity selectively to the immune compartment via CD11a and the development of tissue-targeted PDE4 inhibitors as a promising therapeutic modality for treating inflammatory diseases.

Rational Design of Dual Agonist-Antibody Fusions as Long-acting Therapeutic Hormones.

Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bifunctional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50-100-fold longer circulating half-lives in rodents compared to the corresponding native peptides/proteins. The efficacy of the leptin/EX4 dual antibody fusion on weight loss, especially fat mass loss, was enhanced in ob/ob mice and DIO mice compared to the antibody fusion of either EX4 or leptin alone. This work demonstrates the versatility of this combinatorial fusion strategy for generating dual antibody agonists with long half-lives.

Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors.

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), glucagon (GCG) receptor (GCGR), and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered peptide agonists for GLP-1R, GCGR, and GIPR were fused to the N-terminus of the heavy chain or light chain of an antibody, either alone or in pairwise combinations. The fusion proteins have similar in vitro biological activities on the cognate receptors as the corresponding peptides, but circa 100-fold longer plasma half-lives. The GLP-1R mono agonist and GLP-1R/GCGR dual agonist antibodies both exhibit potent effects on glucose control and body weight reduction in mice, with the dual agonist antibody showing enhanced activity in the latter.

Neural processing of emotional overinvolvement in borderline personality disorder.

OBJECTIVE: Patients with borderline personality disorder (BPD) fare better clinically if their families are rated as being high in emotional overinvolvement, which is characterized by marked emotionality, anxious concern, and protective behavior. This is not true of patients with disorders such as schizophrenia or major depression. We used functional magnetic resonance imaging methods to explore the link between emotional overinvolvement (EOI) and better clinical outcome in BPD. Specifically, we tested the hypothesis that, unlike healthy controls or people with other psychiatric problems, people with BPD process EOI as an approach-related stimulus. METHOD: Participants with BPD (n = 13) and dysthymia (n = 10) (DSM-IV criteria for both) and healthy controls (n = 11) were imaged using a high field strength (3T) scanner while they listened to a standardized auditory stimulus consisting of either 4 neutral or 4 EOI comments. Participants also rated their mood before and after exposure to the comments. RESULTS: All participants reported increased negative mood after hearing EOI and rated the EOI comments as negative stimuli. However, after subtracting activation to neutral comments, participants with BPD showed higher activation in left prefrontal regions during EOI compared to the other groups. Increased left prefrontal activation during EOI was also correlated with clinical measures indicative of borderline pathology. Participants with dysthymia showed increased amygdala activation during EOI. This was not true for the healthy controls or participants with BPD. CONCLUSIONS: For people with BPD, EOI may be activating neural circuitry implicated in the processing of approach-related stimuli. Increased left prefrontal activation to EOI may be a vulnerability marker for BPD. These findings may also help explain why BPD patients do better clinically in high EOI family environments.

Cortico-limbic response to personally challenging emotional stimuli after complete recovery from depression.

People vulnerable to depression are at increased risk of relapse if they live in highly critical family environments. To explore this link, we used neuroimaging methods to examine cortico-limbic responding to personal criticisms in healthy participants and participants with known vulnerability to major depression. Healthy controls and fully recovered participants with a past history of major depression were scanned while they heard praising, critical, and neutral comments from their own mothers. Prior to scanning, the formerly depressed and the control participants were indistinguishable with respect to self-reported positive, negative, or anxious mood. They also reported similar mood changes after being praised or criticized. However, formerly depressed participants responded to criticism with greater activation in the amygdala and less activation in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) than did controls. During praise and neutral commentary, amygdala activation was comparable in both groups, although lower levels of activation in the DLPFC and ACC still characterized formerly depressed participants. Vulnerability to depression may be associated with abnormalities in cortico-limbic activation that are independent of mood state and that remain even after full recovery. Criticism may be a risk factor for relapse because it activates the amygdala and perturbs the affective circuitry that underlies depression.

Cortico-limbic response to personally challenging emotional stimuli after complete recovery from depression.

People vulnerable to depression are at increased risk of relapse if they live in highly critical family environments. To explore this link, we used neuroimaging methods to examine cortico-limbic responding to personal criticisms in healthy participants and participants with known vulnerability to major depression. Healthy controls and fully recovered participants with a past history of major depression were scanned while they heard praising, critical, and neutral comments from their own mothers. Prior to scanning, the formerly depressed and the control participants were indistinguishable with respect to self-reported positive, negative, or anxious mood. They also reported similar mood changes after being praised or criticized. However, formerly depressed participants responded to criticism with greater activation in the amygdala and less activation in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) than did controls. During praise and neutral commentary, amygdala activation was comparable in both groups, although lower levels of activation in the DLPFC and ACC still characterized formerly depressed participants. Vulnerability to depression may be associated with abnormalities in cortico-limbic activation that are independent of mood state and that remain even after full recovery. Criticism may be a risk factor for relapse because it activates the amygdala and perturbs the affective circuitry that underlies depression.

Israeli civilians under heavy bombardment: prediction of the severity of post-traumatic symptoms.

CONTEXT: The military conflict that occurred between Lebanon and Israel in July and August of 2006 was characterized by the heavy bombardment of specific geographic regions in Israel, resulting in considerable civilian casualties and property damage. OBJECTIVE: Israeli civilians directly and indirectly exposed to bombardment were compared on exposure to the recent bombardment, trauma history, perceived life threat and peri-traumatic dissociation during the recent bombardment, and current post-traumatic stress disorder (PTSD) symptom severity. DESIGN, SETTING, AND PARTICIPANTS: Following the conflict, data were collected by telephone from 317 Israeli residents randomly selected from two towns that were subject to differing levels of exposure to the bombardment. INTERVENTION(S): None MAIN OUTCOME MEASURE(S): Exposure to trauma during the Second Lebanon War, prior trauma exposure, PTSD symptom severity, perceived life threat, and peri-traumatic dissociation. RESULTS: The residents directly affected by the bombardment (Kiryat Shmona; KS) endorsed more trauma exposure, (p <0.01); more prior trauma, (p <0.01); more life threat, (p <0.01); and greater PTSD symptomatology (12 % of KY participants and 38% of KS participants had probable PTSD), compared to residents in the comparison town (Kfar Yona; KY). Both groups reported a similar degree of peri-event dissociation (KS: M = 7.2 +/-3.7; KY: M = 7.3 +/-3.0). Perceived life threat mediated the relationship between exposure to bombardment and PTSD symptomatology. Time spent in bomb shelters was not associated with PTSD symptom severity. Prior shelling-related trauma negatively predicted PTSD. CONCLUSIONS: The terror of bombardment is a risk factor for PTSD among civilians. Although there is considerable resilience in chronically threatened communities, it is prudent to develop and implement public health approaches to prevent those most distressed during and after attacks from developing PTSD. Because, to a small degree, prior trauma exposure buffers the response to bombardment, interventions should consider leveraging citizens' past successful coping.

Trauma and posttraumatic stress disorder in treatment-resistant obsessive-compulsive disorder.

Prior research has indicated a seemingly unique relation between obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) that appears to relate to negative treatment outcome for OCD. However, to date, the prevalence of trauma and PTSD in individuals seeking treatment for OCD is unclear. To begin to address this gap, this study assessed history of traumatic experiences and current PTSD in individuals seeking treatment for treatment-resistant OCD. Trauma predictors of PTSD severity also were examined in this sample. Participants included 104 individuals diagnosed with treatment-resistant OCD who sought treatment over the course of 1 year from OCD specialty treatment facilities. Data were collected via naturalistic retrospective chart reviews of pre-treatment clinical intake files. Findings revealed that 82% of participants reported a history of trauma. Over 39% of the overall sample met criteria for PTSD, whereas almost 50% of individuals with a trauma history met criteria for PTSD. Interpersonal traumas and greater frequency of traumas were most predictive of PTSD severity, and individuals diagnosed with OCD and additional major depressive disorder (MDD) or borderline personality disorder (BPD) appeared at particular risk for a comorbid PTSD diagnosis. PTSD may be relatively common in individuals diagnosed with treatment-resistant OCD; and interpersonal traumas, MDD, and BPD may play a relatively strong predictive role in PTSD diagnosis and severity in such OCD patients.

Repressive coping, emotional adjustment, and cognition in people who have lost loved ones to suicide.

Research indicates that a repressive coping style is psychologically protective against the stress of trauma, yet it is unclear whether this finding generalizes to suicide bereavement. Thus, we assessed cognitive ability and mental health among individuals who lost a loved one to suicide. The results indicate that repressive coping may be associated with greater emotional health during suicide bereavement. Interestingly, "repressors" also had lower scores on both cognitive tasks compared to "nonrepressors," but it is unclear whether their more recent loss accounts for this difference. These results are based on cross-sectional data, and should be interpreted with caution.

Measuring expressed emotion: an evaluation of the shortcuts.

The construct of expressed emotion (EE) is a highly reliable and valid predictor of poor clinical outcomes in patients with major psychopathology. Patients are at early risk for relapse if they live with family members who are classified as high in EE. Conventionally, EE is assessed with the Camberwell Family Interview (CFI), a semistructured interview that is conducted with the patient's key relatives. Unfortunately, training in the CFI is difficult to obtain. The CFI is also time-consuming to administer and labor intensive to rate. In this article, the authors discuss alternative ways of assessing EE. They also evaluate the predictive validity of these measures and make recommendations for researchers and clinicians interested in using these assessments.

Mental illness and suicidality after Hurricane Katrina.

OBJECTIVE: To estimate the impact of Hurricane Katrina on mental illness and suicidality by comparing results of a post-Katrina survey with those of an earlier survey. METHODS: The National Comorbidity Survey-Replication, conducted between February 2001 and February 2003, interviewed 826 adults in the Census Divisions later affected by Hurricane Katrina. The post-Katrina survey interviewed a new sample of 1043 adults who lived in the same area before the hurricane. Identical questions were asked about mental illness and suicidality. The post-Katrina survey also assessed several dimensions of personal growth that resulted from the trauma (for example, increased closeness to a loved one, increased religiosity). Outcome measures used were the K6 screening scale of serious mental illness and mild-moderate mental illness and questions about suicidal ideation, plans and attempts. FINDINGS: Respondents to the post-Katrina survey had a significantly higher estimated prevalence of serious mental illness than respondents to the earlier survey (11.3% after Katrina versus 6.1% before; chi(2)1= 10.9; P < 0.001) and mild-moderate mental illness (19.9% after Katrina versus 9.7% before; chi(2)1 = 22.5; P < 0.001). Among respondents estimated to have mental illness, though, the prevalence of suicidal ideation and plans was significantly lower in the post-Katrina survey (suicidal ideation 0.7% after Katrina versus 8.4% before; chi(2)1 = 13.1; P < 0.001; plans for suicide 0.4% after Katrina versus 3.6% before; chi(2)1 = 6.0; P = 0.014). This lower conditional prevalence of suicidality was strongly related to two dimensions of personal growth after the trauma (faith in one's own ability to rebuild one's life, and realization of inner strength), without which between-survey differences in suicidality were insignificant. CONCLUSION: Despite the estimated prevalence of mental illness doubling after Hurricane Katrina, the prevalence of suicidality was unexpectedly low. The role of post-traumatic personal growth in ameliorating the effects of trauma-related mental illness on suicidality warrants further investigation.

Autobiographical memory specificity in adults reporting repressed, recovered, or continuous memories of childhood sexual abuse.

Some psychotherapists believe that adult survivors of childhood sexual abuse (CSA) are characterised by memory deficits for their childhood. Using the Autobiographical Memory Test (AMT), we asked nonabused control participants and participants who reported either continuous, recovered, or repressed memories of CSA to retrieve a specific personal memory in response to either positive or negative cue words from either childhood or adolescence/adulthood. The results indicated that participants who believed they harboured repressed memories of abuse tended to exhibit the greatest difficulty retrieving specific memories from their childhood. Neither posttraumatic stress disorder (PTSD) nor major depression was related to diminished memory specificity.

Reality monitoring in adults reporting repressed, recovered, or continuous memories of childhood sexual abuse.

People who report either repressed or recovered memories of childhood sexual abuse (CSA) may have deficits in reality monitoring--the process whereby one discriminates memories of percepts from memories of images. Using signal detection methods, the authors found that adults reporting either repressed or recovered memories of CSA were less able to discriminate between words they had seen from words they had imagined seeing than were adults reporting either never having forgotten their CSA or adults reporting no history of CSA. Relative deficits in the ability to discriminate percepts from images (i.e., low d') were apparent on only some tests. The groups did not differ in their criterion--response bias--for affirming having seen versus imagined stimuli.