bluuebunny/crossref_metadata_2025 huggingface dataset:
Cocaine‐specific neuroplasticity in the ventral striatum network is linked to delay discounting and drug relapse
Authors: Contreras‐Rodríguez Oren , Albein‐Urios Natalia , Perales José C. , Martínez‐Gonzalez José M. , Vilar‐López Raquel , Fernández‐Serrano María J. , Lozano‐Rojas Oscar , Verdejo‐García Antonio
Published: July 2015

Aims

To contrast functional connectivity on ventral and dorsal striatum networks in cocaine dependence relative to pathological gambling, via a resting‐state functional connectivity approach; and to determine the association between cocaine dependence‐related neuroadaptations indexed by functional connectivity and impulsivity, compulsivity and drug relapse.

Design

Cross‐sectional study of 20 individuals with cocaine dependence (CD), 19 individuals with pathological gambling (PG) and 21 healthy controls (HC), and a prospective cohort study of 20 CD followed‐up for 12 weeks to measure drug relapse.

Setting and Participants

CD and PG were recruited through consecutive admissions to a public clinic specialized in substance addiction treatment (Centro Provincial de Drogodependencias) and a public clinic specialized in gambling treatment (AGRAJER), respectively; HC were recruited through community advertisement in the same area in Granada (Spain).

Measurements

Seed‐based functional connectivity in the ventral striatum (ventral caudate and ventral putamen) and dorsal striatum (dorsal caudate and dorsal putamen), the Kirby delay‐discounting questionnaire, the reversal‐learning task and a dichotomous measure of cocaine relapse indicated with self‐report and urine tests.

Findings

CD relative to PG exhibit enhanced connectivity between the ventral caudate seed and subgenual anterior cingulate cortex, the ventral putamen seed and dorsomedial pre‐frontal cortex and the dorsal putamen seed and insula (P ≤ 0.001, kE = 108). Connectivity between the ventral caudate seed and subgenual anterior cingulate cortex is associated with steeper delay discounting (P ≤ 0.001, kE = 108) and cocaine relapse (P ≤ 0.005, kE = 34).

Conclusions

Cocaine dependence‐related neuroadaptations in the ventral striatum of the brain network are associated with increased impulsivity and higher rate of cocaine relapse.
Measuring coping style following acquired brain injury: A modification of the Coping Inventory for Stressful Situations Using Rasch analysis
Authors: Simblett Sara K. , Gracey Fergus , Ring Howard , Bateman Andrew
Published: July 2015

Objective

The importance of coping style factors in the process of emotional adjustment following acquired brain injury (ABI) has been gaining increased attention. To assess ways of coping with distress accurately, clear conceptual definitions and measurement precision is vital. The purpose of this study was to investigate the psychometric properties of a well‐known measure of coping, the Coping Inventory for Stressful Situations (CISS), for people who have experienced an ABI; and to modify the CISS, where necessary, to create a more reliable and valid measurement tool for this clinical group.

Methods

Psychometric properties were investigated using Rasch analysis of responses from a sample of adults with ABI (n = 207). The internal consistency reliability and construct validity of the scale were examined.

Results

All originally proposed subscales were not valid or reliable and, as such, were incapable of interval‐level measurement within this sample – Task: χ2(32, N = 207) = 105.1, p < .001; Emotion: χ2(32, N = 204) = 121.9, p < .001; Avoidance: χ2(32, N = 207) = 66.7, p < .001. Three valid and reliable subscales were derived measuring emotion‐, task‐, and avoidance‐oriented coping styles by removing items that provided the most unreliable information and exploring fit to the Rasch model.

Conclusions

The original version of the CISS may not be a valid and reliable measure of coping style following ABI. Modified subscales of the three distinct coping domains have been proposed that would help to improve measurement of coping style following ABI in future research and clinical practice.

Practitioner points

How people cope with difficulties following an ABI has been shown to impact upon emotional outcomes and functional recovery.

The original version of the CISS was found to be an imprecise measure of coping following ABI.

A modified version of the CISS was found to be a valid and reliable measure of three styles of coping (task‐focused, emotion‐focused, and avoidance‐focused) that conforms to the properties of interval‐level measurement as represented by the Rasch model. This structure is in keeping with previous theoretical models of coping.

We advise caution about including items (1, 6, 7, 22, 24, 28, 29, 33, 34, and 46) that were found to diverge from the expectations of the Rasch measurement model in total subscale scores for measuring change in coping style.

A conversion table for the three modified subscales is included in this paper to convert total raw scores into Rasch transformed logit values.

Identifying strengths and weaknesses in coping style could be a means of guiding psychological intervention to promote good recovery following ABI.

The sample included mainly people who had experienced non‐traumatic brain injuries (e.g., a stroke).

This research could be extended to include broader sample of people with differing brain injury aetiologies and neurological disorders.
‘Judging a book by its cover’: An experimental study of the negative impact of a diagnosis of borderline personality disorder on clinicians’ judgements of uncomplicated panic disorder
Authors: Lam Danny C. K. , Salkovskis Paul M. , Hogg Lorna I.
Published: July 2015

Objectives

Diagnosis is ubiquitous in Psychiatry, and whilst it does bring benefits; adverse effects of ‘labelling’ may also be possible. This study aimed to evaluate experimentally whether clinicians’ judgements about a patient with panic disorder were influenced by an inappropriately suggested diagnosis of comorbid borderline personality disorder (BPD).

Design

An experimental design was used to evaluate clinician's judgements when the nature of the information they were given was varied to imply BPD comorbidity.

Methods

Two hundred and sixty‐five clinicians watched a video‐recorded assessment of a woman describing her experience of uncomplicated ‘panic disorder’ and then rated her present problems and likely prognosis. Prior to watching the video recording, participants were randomly allocated to one of three conditions with written information including the following: (1) her personal details and general background; (2) the addition of a behavioural description consistent with BPD; and (3) the further addition of a ‘label’ (past BPD diagnosis).

Results

The BPD label was associated with more negative ratings of the woman's problems and her prognosis than both information alone and a behavioural description of BPD ‘symptoms’.

Conclusions

Regardless of potential actuarial value of such diagnoses, it is concluded that clinicians can be overly influenced by past diagnostic labels in the context of an apparent current comorbid problem, although such biases appear to be less likely if a description of the relevant behaviours is used instead. Thus, the label, rather than the behaviour it denotes, may be stigmatizing in mental health professionals.

Practitioner points

Diagnostic labels can have an inappropriately negative effect on clinicians’ judgements not only of treatment variables such as engagement and response but also risk issues and interpersonal effectiveness.

Diagnostic labels can have a greater effect on clinicians’ judgements than a behavioural description or clinical presentation.

Clinicians should therefore be cautious both in the use of diagnostic labels to describe patients and ensure that these are still valid, and also be mindful of the influence that such labels can have on their own clinical judgements and constantly seek to challenge these.

Behavioural descriptions of difficulties are less likely to result in such negative judgements and predictions.
Theory of mind selectively predicts preschoolers’ knowledge‐based selective word learning
Authors: Brosseau‐Liard Patricia , Penney Danielle , Poulin‐Dubois Diane
Published: July 2015

Children can selectively attend to various attributes of a model, such as past accuracy or physical strength, to guide their social learning. There is a debate regarding whether a relation exists between theory‐of‐mind skills and selective learning. We hypothesized that high performance on theory‐of‐mind tasks would predict preference for learning new words from accurate informants (an epistemic attribute), but not from physically strong informants (a non‐epistemic attribute). Three‐ and 4‐year‐olds (N = 65) completed two selective learning tasks, and their theory‐of‐mind abilities were assessed. As expected, performance on a theory‐of‐mind battery predicted children's preference to learn from more accurate informants but not from physically stronger informants. Results thus suggest that preschoolers with more advanced theory of mind have a better understanding of knowledge and apply that understanding to guide their selection of informants. This work has important implications for research on children's developing social cognition and early learning.
Reappraising Winnicott's The Piggle: A Critical Commentary
Authors: Reeves Christopher
Published: July 2015

This is the second part of an extended paper reviewing the nature of the messages Winnicott wished to communicate to his audience through the psychoanalytic case of The Piggle. ‘Introduction and the Treatment’ (published in BJP 31[2]) set out the work in its theoretical and historical context and reviewed the dialogue which serves as the material for the work. This part provides a discussion and a critical analysis of the case, and an examination of both explicit and less worked‐out conclusions which can be drawn from it. The author considers the case as evidence that therapy with a child can be intensive without being extensive. He highlights Winnicott's emphasis on the importance of play for working through internal conflicts, not merely as providing material for interpretation. Whereas Winnicott held firmly to the efficacy of his commotional interpretations, and the notion that Gabrielle's unconscious dispositions were agentive and intentional, the author argues for an alternative to Winnicott's interpretation, highlighting the use of make‐believe play, the irregular timing of the sessions and the child's own maturational processes as being important elements in her recovery. He suggests that, for Winnicott, these factors were intuitively, rather than conceptually worked out, and, in so being, contribute to the enigmatic nature of the original work.
Lost and Gained in Translation: The Impact of Bilingual Clients' Choice of Language in Psychotherapy
Authors: Byford Annette
Published: July 2015

Bilingual clients in psychotherapy with bilingual therapists have choices as to which language to use. Psychoanalytic case studies suggest that the use of the second language, learned post childhood, reduces access to deeper emotional material and is mainly viewed as a defensive manoeuvre leading to intellectualizing detachment. Linguistic and neurological studies support the view that the use of the second language can lead to a reduced degree of emotionality in the recall of memories. However, this paper suggests that there is a different and enabling dimension to such clients' language choices. Their own and their therapist's bilingualism and biculturalism open a transferential field where language choices are mapped onto deeper inter‐ and intra‐psychic conflicts and can thus allow access to them rather than defensively hide them. Case material from work with bilingual clients is explored to illustrate this.
Confidentiality and Consent Issues in Psychotherapy Case Reports: The Wolf Man, Gloria and Jeremy
Authors: Thomas‐Anttila Kerry
Published: July 2015

In this article I explore the issues surrounding confidentiality and consent in the writing of psychotherapy case reports. An important theme is the challenge of protecting a patient's privacy while furthering knowledge in the field through publication. I discuss some of the complexities as well as the relevance of present day requirements for informed consent, including a consideration of the provisions within the Declaration of Helsinki (1964, last revised 2013). To illustrate the difficulties inherent in writing about our work I give examples of three cases: Freud's patient Sergei Pankejeff (the ‘Wolf Man’), Gloria (the patient in the ‘Gloria Films’), and a contemporary patient, ‘Jeremy’, whose therapist published an account of her work with him. The writing of case material is complex and resists easy solutions; there can be no ‘one‐size‐fits‐all’ approach but instead the therapist writer's careful consideration on a case by case basis of his or her motivations for writing, what the patient is really consenting to, whether patient consent can ever be truly informed, and how writing and publishing a case might impact on the safety and well‐being of the patient (including others connected to the patient), as well as on the therapeutic relationship itself.
Can the Breast Feed the Mother Too? Tracing Maternal Subjectivity inToniMorrison'sBeloved
Authors: Stone Rebecca
Published: July 2015

Breastfeeding tends to elicit strong feelings in mothers as well as impassioned rhetoric in our cultural discourse. Psychoanalytic thinkers have focused extensively on the infant's experience at the breast. Surprisingly, much less theoretical attention has been given to the mother's experience of breastfeeding. I begin with my own experience of struggling with this early stage of motherhood and with understanding why this act seemed to hold such emotional power. By tracing the theme of breastfeeding inToniMorrison'sBeloved, I attempt to draw out ideas about the breastfeeding mother as a subject rather than an object. I argue that the novel's depiction of breastfeeding supports understanding the maternal body as a source of ambivalence and creativity for the mother as well as for the infant. Drawing mainly on the work ofMelanieKlein,DonaldWinnicott andJuliaKristeva, I explore through literary readings how breastfeeding comes to stir up such passionate and often difficult feelings for mothers.
Hopelessness in the Analysis
Authors: Gerrard Jackie
Published: July 2015

The author has written a paper about her sense of hopelessness in working psychoanalytically with two female patients. She found that these feelings were reflected in supervision through the parallel process. She was greatly helped by Betty Joseph's paper, ‘Addiction to near death’, where she found many similarities between that author's patients and her own. Eventually, through consideration of other literature and reflecting on her own experiences, she reached the conclusion that until she could allow herself to be immersed in this sense of hopelessness, it was not possible to genuinely connect with her patients. Any hope to be found, had to be reached through an authentic interaction, which means that the sense of hopelessness had to be tolerated for long periods of time.
Evil, Imagination and the Unrepressed Unconscious: The Value of William Blake's Satanic ‘Error’ for Clinical Practice
Authors: Leader Carol
Published: July 2015

The images and writings of William Blake offer profound insights for the clinician in a form that clearly reveals his visionary ability regarding the unrepressed unconscious. He is particularly helpful with the work of imagination and the presence of evil concerning unconscious process. This paper explores the creative value of Blake's contribution when working with certain patients in the consulting room and for the purposes of psychotherapeutic research: he has inspired many psychoanalytic and Jungian papers in the past. However, in the world of psychotherapy, Blake's complicated but illuminating mythology has been somewhat neglected in favour of interpreting him through the lens of analytic thought. While setting this paper within an analytic frame, the writer aims to offer an overview of Blake's central concepts – particularly those concerning Satan and the state of ‘Error’ – that are revealed in their most refined form in his celebrated ‘Illustrations of the Book of Job’. A number of Blake's paintings and etchings illustrate this paper, providing an additional and vital avenue of communication through image. Clinical vignettes related to psychotic levels of the psyche illustrate the central theme.
Role for engagement of β‐arrestin2 by the transactivated EGFR in agonist‐specific regulation of δ receptor activation of ERK1/2
Authors: Zhang Le‐Sha , Wang Yu‐Jun , Ju Yun‐Yue , Zan Gui‐Ying , Xu Chi , Hong Min‐Hua , Wang Yu‐Hua , Chi Zhi‐Qiang , Liu Jing‐Gen
Published: July 2015

Background and Purpose

β‐Arrestins function as signal transducers linking GPCRs to ERK1/2 signalling either by scaffolding members of ERK1/2s cascades or by transactivating receptor tyrosine kinases through Src‐mediated release of transactivating factor. Recruitment of β‐arrestins to the activated GPCRs is required for ERK1/2 activation. Our previous studies showed that δ receptors activate ERK1/2 through a β‐arrestin‐dependent mechanism without inducing β‐arrestin binding to the δ receptors. However, the precise mechanisms involved remain to be established.

Experimental Approach

ERK1/2 activation by δ receptor ligands was assessed using HEK293 cells in vitro and male Sprague Dawley rats in vivo. Immunoprecipitation, immunoblotting, siRNA transfection, intracerebroventricular injection and immunohistochemistry were used to elucidate the underlying mechanism.

Key Results

We identified a new signalling pathway in which recruitment of β‐arrestin2 to the EGFR rather than δ receptor was required for its role in δ receptor‐mediated ERK1/2 activation in response to H‐Tyr–Tic–Phe–Phe–OH (TIPP) or morphine stimulation. Stimulation of the δ receptor with ligands leads to the phosphorylation of PKCδ, which acts upstream of EGFR transactivation and is needed for the release of the EGFR‐activating factor, whereas β‐arrestin2 was found to act downstream of the EGFR transactivation. Moreover, we demonstrated that coupling of the PKCδ/EGFR/β‐arrestin2 transactivation pathway to δ receptor‐mediated ERK1/2 activation was ligand‐specific and the Ser363 of δ receptors was crucial for ligand‐specific implementation of this ERK1/2 activation pathway.

Conclusions and Implications

The δ receptor‐mediated activation of ERK1/2 is via ligand‐specific transactivation of EGFR. This study adds new insights into the mechanism by which δ receptors activate ERK1/2.
Phosphodiesterase 4D: an enzyme to remember
Authors: Ricciarelli Roberta , Fedele Ernesto
Published: July 2015

Cyclic adenosine monophosphate (cAMP) is one of the second messengers critically involved in the molecular mechanisms underlying memory formation. In the CNS, the availability of cAMP is tightly controlled by phosphodiesterase 4 (PDE4), a family of enzymes that degrades the cyclic nucleotide to inactive AMP. Among the different PDE4 isoforms, in the last few years PDE4D has been hogging the limelight due to accumulating evidence for its crucial role in cognitive processes, which makes this enzyme a promising target for therapeutic interventions in a variety of pathological conditions characterized by memory impairment, such as Alzheimer's disease. In this article, we review the role of the cAMP signal transduction pathway in memory formation with a particular focus on the recent progress in PDE4D research.
δ Subunit‐containing GABAA receptors are preferred targets for the centrally acting analgesic flupirtine
Authors: Klinger Felicia , Bajric Mirnes , Salzer Isabella , Dorostkar Mario M. , Khan Deeba , Pollak Daniela D. , Kubista Helmut , Boehm Stefan , Koenig Xaver
Published: July 2015

Background and Purpose

The Kv7 channel activator flupirtine is a clinical analgesic characterized as ‘selective neuronal potassium channel opener’. Flupirtine was found to exert comparable actions at GABAA receptors and Kv7 channels in neurons of pain pathways, but not in hippocampus.

Experimental Approach

Expression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits. Effects of flupirtine on recombinant and native GABAA receptors were investigated in patch clamp experiments and compared with the actions on Kv7 channels.

Key Results

Immunoblots pointed towards α2, α3, β3 and γ2 subunits as targets, but in all γ2‐containing receptors the effects of flupirtine were alike: leftward shift of GABA concentration‐response curves and diminished maximal amplitudes. After replacement of γ2S by δ, flupirtine increased maximal amplitudes. Currents through α1β2δ receptors were more enhanced than those through Kv7 channels. In hippocampal neurons, flupirtine prolonged inhibitory postsynaptic currents, left miniature inhibitory postsynaptic currents (mIPSCs) unaltered and increased bicuculline‐sensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentration‐response curves for GABA‐induced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABA‐induced currents in the presence of penicillin were more sensitive towards flupirtine than K+ currents. In dorsal horn neurons, currents evoked by the δ‐preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K+ currents.

Conclusions and Implications

Flupirtine prefers δ‐containing GABAA receptors over γ‐containing ones and over Kv7 channels.
Hematopoietic pre‐B cell leukemia transcription factor interacting protein is overexpressed in gastric cancer and promotes gastric cancer cell proliferation, migration, and invasion
Authors: Feng Yingying , Li Ling , Zhang Xiaomei , Zhang Yunjing , Liang Yingchun , Lv Jinjing , Fan Zhongyi , Guo Jing , Hong Tian , Ji Beibei , Ji Quanbo , Mei Guohui , Ding Lihua , Zhang Shu , Xu Xiaojie , Ye Qinong
Published: July 2015

Hematopoietic pre‐B cell leukemia transcription factor interacting protein (HPIP) has been shown to play an important role in the development and progression of some cancers. However, the role of HPIP in gastric cancer (GC) is unclear. Here, we show that HPIP is upregulated in most GC patients and promotes GC cell proliferation, migration, and invasion. In GC patients, HPIP positively associates with tumor size and nodal metastasis, and negatively associates with tumor differentiation. Hematopoietic pre‐B cell leukemia transcription factor interacting protein increases GC cell proliferation through activation of G1/S and G2/M cell cycle transitions, accompanied by a marked increase of the positive cell cycle regulators, including cyclin D1, cyclin A, and cyclin B1. Hematopoietic pre‐B cell leukemia transcription factor interacting protein enhances GC cell migration and invasion, and modulates epithelial–mesenchymal transition, which plays a key role in cancer cell migration and invasion. These data underscore the critical role of HPIP in GC cell proliferation and progression and suggest that HPIP inhibition may be a useful therapeutic strategy for GC treatment.
DDX5 promotes proliferation and tumorigenesis of non‐small‐cell lung cancer cells by activating β‐catenin signaling pathway
Authors: Wang Zhendong , Luo Zhonghua , Zhou Lin , Li Xiaofei , Jiang Tao , Fu Enqing
Published: July 2015

The DEAD‐box‐protein DDX5 is an ATP‐dependent RNA helicase that is frequently overexpressed in various cancers and acts as a transcriptional co‐activator of several transcription factors, including β‐catenin. DDX5 is reported to be involved in cancer progression by promoting cell proliferation and epithelial–mesenchymal transition. However, the clinical significance and biological role of DDX5 in non‐small‐cell lung cancer (NSCLC) remain largely unknown. In this study, we examined the expression of DDX5 in clinical NSCLC samples, investigated its role in regulating NSCLC cell proliferation and tumorigenesis, and explored the possible molecular mechanism. We found that DDX5 was significantly overexpressed in NSCLC tissues as compared with the matched normal adjacent tissues. In addition, overexpression of DDX5 was associated with advanced clinical stage, higher Ki67 index, and shorter overall survival in NSCLC patients. Upregulation of DDX5 promoted proliferation of NSCLC cells in vitro and growth of NSCLC xenografts in vivo, whereas downregulation of DDX5 showed the opposite effects. Furthermore, DDX5 directly interacted with β‐catenin, promoted its nuclear translocation, and co‐activated the expression of cyclin D1 and c‐Myc. β‐catenin silencing significantly abrogated DDX5‐induced cyclin D1 and c‐Myc expression and proliferation in NSCLC cells. Interestingly, DDX5 and cyclin D1 expression followed positive correlation in the same set of NSCLC samples. These findings indicated that DDX5 played an important role in the proliferation and tumorigenesis of NSCLC cells by activating the β‐catenin signaling pathway. Therefore, DDX5 may serve as a novel prognostic marker and potential therapeutic target in the treatment of NSCLC.
Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors
Authors: Yu Man , Lee Carol , Wang Marina , Tannock Ian F.
Published: July 2015

Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration‐dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.
Immunological evaluation of peptide vaccination for cancer patients with the HLA‐A26 allele
Authors: Sakamoto Shinjiro , Matsueda Satoko , Takamori Shinzo , Toh Uhi , Noguchi Masanori , Yutani Shigeru , Yamada Akira , Shichijo Shigeki , Yamada Teppei , Suekane Shigetaka , Kawano Kouichiro , Sasada Tetsuro , Hattori Noboru , Kohno Nobuoki , Itoh Kyogo
Published: July 2015

To develop a peptide vaccine for cancer patients with the HLA‐A26 allele, which is a minor population worldwide, we investigated the immunological responses of HLA‐A26+/A26+ cancer patients to four different CTL epitope peptides under personalized peptide vaccine regimens. In personalized peptide vaccine regimens, two to four peptides showing positive peptide‐specific IgG responses in pre‐vaccination plasma were selected from the four peptide candidates applicable for HLA‐A26+/A26+ cancer patients and administered s.c. Peptide‐specific CTL and IgG responses along with cytokine levels were measured before and after vaccination. Cell surface markers in PBMCs and plasma cytokine levels were also measured. In this study, 21 advanced cancer patients, including seven lung, three breast, two pancreas, and two colon cancer patients, were enrolled. Their HLA‐A26 genotypes were HLA‐A26:01 (n = 24), HLA‐A26:03 (n = 10), and HLA‐A26:02 (n = 8). One, 14, and 6 patients received two, three, and four peptides, respectively. Grade 1 or 2 skin reactions at the injection sites were observed in the majority of patients, but no severe adverse events related to the vaccination were observed. Peptide‐specific CTL responses were augmented in 39% or 22% of patients after one or two cycles of vaccination, respectively. Notably, peptide‐specific IgG were augmented in 63% or 100% of patients after one or two cycles of vaccination, respectively. Personalized peptide vaccines with these four CTL epitope peptides could be feasible for HLA‐A26+ advanced cancer patients because of their safety and higher rates of immunological responses.
Molecular Modeling, Synthesis, and Anti‐HIV Activity of Novel Isoindolinedione Analogues as Potent Non‐nucleoside Reverse Transcriptase Inhibitors
Authors: Kumari Garima , Singh Ramendra K.
Published: July 2015

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti‐HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti‐HIV activity and the molecules having sulfonamide linkages were the most potent HIV‐RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood–brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti‐HIV drugs. In vitro screening was performed using HIV‐1 strain IIIB in MT‐4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV‐1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV‐1.

Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations.
Effect of interferon-β1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients
Authors: Wostradowski T , Gudi V , Pul R , Gingele S , Lindquist J A , Stangel M , Lindquist S
Published: July 2015

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease triggered by infiltration of activated T cells into the central nervous system. Interferon (IFN)-β is an established, safe and effective treatment for patients with relapsing–remitting MS (RRMS). The cytokine can inhibit leucocyte infiltration into the central nervous system; however, little is known about the precise molecular mechanisms. Previously, in vitro application of IFN-β1b was shown to reduce CXCL12/CXCR4-mediated monocyte migration. Here, we analysed the effects of IFN-β1b on CXCR4-dependent T cell function. In vitro exposure to IFN-β1b (1000 U/ml) for 20 h reduced CXCR4-dependent chemotaxis of primary human T cells from healthy individuals and patients with RRMS. Investigating the IFN-β1b/CXCR4 signalling pathways, we found no difference in phosphorylation of ZAP70, ERK1/2 and AKT despite an early induction of the negative regulator of G-protein signalling, RGS1 by IFN-β1b. However, CXCR4 surface expression was reduced. Quantitative real time-PCR revealed a similar reduction in CXCR4-mRNA, and the requirement of several hours' exposure to IFN-β1b supports a transcriptional regulation. Interestingly, T cells from MS patients showed a lower CXCR4 expression than T cells from healthy controls, which was not reduced further in patients under IFN-β1b therapy. Furthermore, we observed no change in CXCL12-dependent chemotaxis in RRMS patients. Our results demonstrate clearly that IFN-β1b can impair the functional response to CXCR4 by down-regulating its expression, but also points to the complex in vivo effects of IFN-β1b therapy.
Neurological and endocrine phenotypes of fragile X carrier women
Authors: Hall D. , Todorova‐Koteva K. , Pandya S. , Bernard B. , Ouyang B. , Walsh M. , Pounardjian T. , Deburghraeve C. , Zhou L. , Losh M. , Leehey M. , Berry‐Kravis E.
Published: July 2015

Women who carry fragile X mental retardation 1 (FMR1)gene premutation expansions frequently report neurological or endocrine symptoms and prior studies have predominantly focused on questionnaire report of medical issues. Premutation carrier (PMC) women (n = 33) and non‐carrier controls (n = 13) were recruited and evaluated by a neurologist, neuropsychologist, and endocrinologist. Blood and skin biopsies were collected for molecular measures. Scales for movement disorders, neuropathy, cognitive function, psychiatric symptoms, sleep, and quality of life were completed. The average age of the women was 51 years (n = 46) and average CGG repeat size was 91 ± 24.9 in the FMR1 PMC women. Seventy percent of the PMC women had an abnormal neurological examination. PMC women had significantly higher scores on the Fragile X‐Associated Tremor Ataxia Syndrome (FXTAS) rating scale, more neuropathy, and difficulty with tandem gait compared to controls. Central sensitivity syndromes, a neuroticism profile on the NEO Personality Profile, and sleep disorders were also prevalent. Discrepancies between subject report and examination findings were also seen. This pilot study suggests that women with the FMR1 premutation may have a phenotype that overlaps with that seen in FXTAS. Additional research with larger sample sizes is warranted to better delineate the clinical features.
Participation in sport and physical activity in head and neck cancer survivors: associations with quality of life
Authors: Sammut L. , Fraser L.R. , Ward M.J. , Singh T. , Patel N.N.
Published: July 2015

Background

Head and neck cancer (HNC), and its treatment, is associated with significant side‐effects which can affect quality of life (QOL). Physical activity (PA) is known to improve a number of QOL measures. We aimed to determine the prevalence of PA pre‐ and post‐treatment of HNC and to determine associations with QOL.

Methods

A questionnaire‐based survey of 172 patients pre‐ and post‐treatment for HNC.

Results

A total of 62.2% of patients met current UK PA guidelines pre‐treatment, reducing to 40.1% following treatment. There was a significant decrease in Metabolic equivalent task minutes/week post‐treatment, with 71% of participants reporting less PA after diagnosis (P < 0.001). Swimming and cycling remained the two most practiced sports. There was a positive correlation between the post‐treatment PA and QOL (P < 0.001).

Conclusion

These data suggest that PA may improve QOL following treatment for HNC. We believe that further studies are warranted.
Ranking Theory and Conditional Reasoning
Authors: Skovgaard‐Olsen Niels
Published: July 2015

Ranking theory is a formal epistemology that has been developed in over 600 pages in Spohn's recent book The Laws of Belief, which aims to provide a normative account of the dynamics of beliefs that presents an alternative to current probabilistic approaches. It has long been received in the AI community, but it has not yet found application in experimental psychology. The purpose of this paper is to derive clear, quantitative predictions by exploiting a parallel between ranking theory and a statistical model called logistic regression. This approach is illustrated by the development of a model for the conditional inference task using Spohn's (2013) ranking theoretic approach to conditionals.
Clinical importance of re‐interpretation of PET/CT scanning in patients referred to a tertiary care medical centre
Authors: Löfgren Johan , Loft Annika , Barbosa de Lima Vinicius Araújo , Østerlind Kell , von Benzon Eric , Højgaard Liselotte
Published: July 2015

Purpose

To evaluate, in a controlled prospective manner with double‐blind read, whether there are differences in interpretations of PET/CT scans at our tertiary medical centre, Rigshospitalet, compared to the external hospitals.

Methods

Ninety consecutive patients referred to our department who had an external F‐18‐FDG PET/CT scan were included. Only information that had been available at the time of the initial reading at the external hospital was available at re‐interpretation. Teams with one radiologist and one nuclear medicine physician working side by side performed the re‐interpretation in consensus. Two oncologists subsequently and independently compared the original reports with the re‐interpretation reports. In case of ‘major discordance’, the oncologists assessed the respective reports validities.

Results

The interpretations were graded as ‘accordant’ in 43 patients (48%), ‘minor discordance’ in 30 patients (33%) and ‘major discordance’ in 17 patients (19%). In 11 (65%) of the 17 cases graded as ‘major discordance’, it was possible to determine which report that was most correct. In 9 of these 11 cases (82%), the re‐interpretation was most correct; in one case, the original report and in another case, both interpretations were incorrect.

Conclusions

Major discordant interpretations were frequent [19% (17 of 90 cases)]. In those cases where follow‐up could assess the validity, the re‐interpretation at Rigshospitalet was most correct in 9 of 11 cases (82%), indicating that there is a difference in expertise in interpreting PET/CT at a tertiary referral hospital compared to primary local hospitals.
Association between blood pressure changes during self‐paced outdoor walking and air temperature
Authors: Otsuki Takeshi , Ishii Nanako
Published: July 2015

Exaggerated elevation of systolic blood pressure (SBP) during exercise is a risk factor for future cardiovascular disease. Although there are differences between the outdoor exercise and exercise tests in the laboratory setting, there is little information regarding SBP changes during practical outdoor exercise. We investigated SBP changes during self‐paced outdoor walking and the relationship to air temperature. Subjects (n = 109, 47–83 years) walked outdoors at their own pace wearing a blood pressure monitor on their wrist. SBP increased during walking compared to rest, but was higher at the 1 km mark than both the 2 and 3 km marks (rest, 124 ± 14 mmHg; 1 km, 140 ± 16 mmHg; 2 km, 136 ± 18 mmHg; 3 km, 135 ± 18 mmHg). SBP at rest, air temperature, body mass index (BMI) and walking intensity during the first 1 km were identified as predictors of SBP at the 1 km mark in the stepwise regression analysis, independent of other confounders (R2 = 0·606). SBP at the 1 km mark was higher in the lower temperature group (11·6–14·3°C, 145 ± 14 mmHg) than in the intermediate (15·1–16·7°C, 140 ± 18 mmHg) and higher (17·0–19·6°C, 136 ± 16 mmHg) temperature groups, independent of SBP at rest, BMI and walking intensity. These results suggest that increases in SBP are higher on lower temperature days and are greater at 1 km than at 2 and 3 km. It is therefore recommended that measures are taken against the cold on lower temperature days to attenuate the SBP response during onset of walking.
Heart rate variability is reduced in underweight and overweight healthy adult women
Authors: Triggiani Antonio Ivano , Valenzano Anna , Ciliberti Michela Anna Pia , Moscatelli Fiorenzo , Villani Stefano , Monda Marcellino , Messina Giovanni , Federici Antonio , Babiloni Claudio , Cibelli Giuseppe
Published: July 2015

Heart rate variability (HRV) is altered in obese subjects, but whether this is true also in underweight (UW) subjects is still under debate. We investigated the HRV profile in a sample of healthy adult women and its association with adiposity. Five‐minute resting state electrocardiographic activity was recorded in 69 subjects grouped according to their body mass index, [23 normal weight (NW), 23 overweight/obese (OW) and 23 UW). Body fat mass (FM) was measured by bio‐impedance. Frequency‐ and time‐domain analyses were performed. Compared to NW, UW and OW subjects showed a significant decrease in HRV indices, as revealed by spectral analysis. No differences were observed between UW and OW subjects. A second‐order polynomial regression unveiled an inverted U‐shaped relationship between FM extent and HRV indices. A decrease of HRV indices was associated with changes in FM extent, proving that in UW and OW subjects, the adaptive flexibility of autonomic cardiac function was reduced. These findings provide important clues to guide future studies addressed to determine how changes in adiposity and autonomic cardiac function may contribute to health risk.
The prediction of total skeletal muscle mass in a Caucasian population – comparison of Magnetic resonance imaging (MRI) and Dual‐energy X‐ray absorptiometry (DXA)
Authors: Geisler Corinna , Pourhassan Maryam , Braun Wiebke , Schweitzer Lisa , Müller Manfred J.
Published: July 2015

Dual‐energy X‐ray (DXA) is an alternative to magnetic resonance imaging (MRI) to measure skeletal muscle mass. DXA assesses lean body mass (LBM), and MRI measures skeletal muscle mass (SMM). Kim et al. (Am J Clin Nutr 2002; 76: 378; J Appl Physiol (1985) 2004; 97: 655) developed MRI‐based algorithms to estimate whole‐body SMM by DXA. These algorithms were based on an ethnically mixed study population (Kim et al., Am J Clin Nutr 2002; 76: 378; J Appl Physiol (1985) 2004; 97: 655). It is unclear whether Kim's algorithms are accurate in an exclusive Caucasian population. The aim of our study was to validate Kim's equation in a Caucasian population of 346 subjects. SMMMRI was assessed using MRI, and LBM and BMCDXA were measured by DXA and fat mass (FMADP) by air‐displacement plethysmographie (ADP). SMMMRI and predicted SMM were highly correlated (r = 0·944; P<0·05). The standard error of estimate of the regression equation was 2·4 kg. However, Bland–Altman plots showed a significant (P<0·001) systematic bias between SMMMRI (median 25·1 kg; IQ 20·2–31·1 kg) and predicted SMM (median 26·3 kg; IQ 22·6–33·0 kg), overestimating SMM by 9·8%. Multiple regression analyses showed that weight explained 4·4% of the variance in the differences between SMMMRI and predicted SMM with the major part unexplained. Kim's algorithm has a systematic unexplained bias and is not recommended in Caucasians.
Sustained benefit of continuous subcutaneous insulin infusion on glycaemic control and hypoglycaemia in adults with Type 1 diabetes
Authors: Beato‐Víbora P. , Yeoh E. , Rogers H. , Hopkins D. , Amiel S. A. , Choudhary P.
Published: July 2015

Aim

To evaluate the sustainability of the benefits of continuous subcutaneous insulin infusion therapy in routine practice in a cohort of adults with diabetes.

Methods

The clinical records of all adults starting continuous subcutaneous insulin infusion over 12 years at our centre were included in this study. Baseline and mean annual HbA1c levels were recorded. The frequency of mild‐to‐moderate and severe hypoglycaemia and hypoglycaemia awareness were analysed in a subgroup.

Results

Adequate data were available from 327 patients, of whom 71% were female. The patients' mean ± sd age was 41 ± 14 years, the mean ± sd (range) follow‐up for continuous subcutaneous insulin infusion was 4.3 ± 2.7 (1–12) years. The mean ± sd HbA1c concentration fell by 8 ± 5 mmol/mol (0.7 ± 0.5%) at year 1 [to 63 ± 12 mmol/mol from 70 ± 18 mmol/mol (7.9 ± 1.1% from 8.6 ± 1.6%); P < 0.0005], sustained to year 5. In patients with initial poor control, HbA1c dropped by 12 ± 11 mmol/mol (1.1 ± 1.0%; P < 0.0005) at year 1, sustained to year 6. The percentage of patients with ≥ 5 mild to moderate hypoglycaemic episodes per week fell from 29 to 12% (n = 163; P = 0.006). In the subgroup (n = 87; follow‐up 2.5 ± mean ± sd 1.1 years), the frequency of severe hypoglycaemia fell from 0.6 ± 1.7 episodes per patient per year to 0.3 ± 0.9 (P = 0.047). Of 24 patients with impaired awareness of hypoglycaemia (Gold score ≥ 4), the mean ± sd Gold score improved from 4.9 ± 0.9 to 3.8 ± 1.7 (P = 0.011). Nine people regained awareness. No deterioration in HbA1c was seen in the hypoglycaemia‐prone groups.

Conclusions

The benefits of continuous subcutaneous insulin infusion with regard to improving glycaemic control and reducing hypoglycaemia frequency, along with improvement in hypoglycaemia awareness without deterioration in glycaemic control, can be sustained over several years in clinical practice.
Durability and tolerability of dapagliflozin over 52 weeks as add‐on to metformin and sulphonylurea in type 2 diabetes
Authors: Matthaei S. , Bowering K. , Rohwedder K. , Sugg J. , Parikh S. , Johnsson E. ,   on behalf of the Study 05 Group
Published: July 2015

Aims

To evaluate the safety and efficacy of dapagliflozin as add‐on therapy to metformin plus sulphonylurea over 52 weeks.

Methods

Patients with type 2 diabetes mellitus (T2DM) using sulphonylurea and metformin received dapagliflozin 10 mg/day or placebo added to therapy for 52 weeks (24‐week randomized, double‐blind period plus 28‐week double‐blind extension).

Results

A total of 219 patients were randomized 1 : 1 to dapagliflozin or placebo. Over 52 weeks, glycated haemoglobin (HbA1c) and fasting plasma glucose levels showed greater improvement from baseline with dapagliflozin (−0.8% and −1.5 mmol/l) than with placebo (−0.1% and 0.6 mmol/l). More patients achieved HbA1c <7.0% with dapagliflozin (27.3%) than with placebo (11.3%) at 52 weeks. Dapagliflozin was associated with greater reductions in body weight and systolic blood pressure (−2.9 kg and −1.0 mmHg) compared with placebo (−1.0 kg and 1.1 mmHg). Greater increases in total, LDL and HDL cholesterol and decreases in triglycerides were observed with dapagliflozin (3.4, 4.8, 6.9 and −8.0%, respectively) versus placebo (1.4, 0.9, 0.6 and 2.9%, respectively). Fewer patients were rescued for failing to reach glycaemic targets with dapagliflozin (9.3%) than with placebo (44.4%). Adverse events and serious adverse events were similar between groups (dapagliflozin: 69.7 and 6.4%; placebo: 73.4 and 7.3%). More hypoglycaemic events were observed with dapagliflozin (15.6%) than with placebo (8.3%). Genital infections were reported in more patients in the dapagliflozin (10.1%) than in the placebo group (0.9%) and urinary tract infection frequency was similar in the two groups (10.1 and 11.0%).

Conclusion

Dapagliflozin as add‐on to metformin plus a sulphonylurea was well tolerated and improvement in glycaemic control was maintained over 52 weeks.