Elevated Amygdala Responses During De Novo Pavlovian Conditioning in Alcohol Use Disorder Are Associated With Pavlovian-to-Instrumental Transfer and Relapse Latency

BACKGROUND: Contemporary learning theories of drug addiction ascribe a key role to Pavlovian learning mechanisms in the development, maintenance, and relapse of addiction. In fact, cue-reactivity research has demonstrated the power of alcohol-associated cues to activate the brain’s reward system, which has been linked to craving and subsequent relapse. However, whether de novo Pavlovian conditioning is altered in alcohol use disorder (AUD) has rarely been investigated. METHODS: To characterize de novo Pavlovian conditioning in AUD, 62 detoxified patients with AUD and 63 matched healthy control participants completed a Pavlovian learning task as part of a Pavlovian-to-instrumental transfer paradigm during a functional magnetic resonance imaging session. Patients were followed up for 12 months to assess drinking behavior and relapse status. RESULTS: While patients and healthy controls did not differ in their ability to explicitly acquire the contingencies between conditioned and unconditioned stimuli, patients with AUD displayed significantly stronger amygdala responses toward Pavlovian cues, an effect primarily driven by stronger blood oxygen level–dependent differentiation during learning from reward compared with punishment. Moreover, in patients compared with controls, differential amygdala responses during conditioning were positively related to the ability of Pavlovian stimuli to influence ongoing instrumental choice behavior measured during a subsequent Pavlovian-to-instrumental transfer test. Finally, patients who relapsed within the 12-month follow-up period showed an inverse association between amygdala activity during conditioning and relapse latency. CONCLUSIONS: We provide evidence of altered neural correlates of de novo Pavlovian conditioning in patients with AUD, especially for appetitive stimuli. Thus, heightened processing of Pavlovian cues might constitute a behaviorally relevant mechanism in alcohol addiction

Does immediate dentin sealing influence postoperative sensitivity in teeth restored with indirect restorations? A systematic review and meta-analysis

Objective: This study comprehensively reviewed clinical trials that investigated the effect of immediate dentin sealing (IDS) technique on postoperative sensitivity (POS) and clinical performance of indirect restorations. Materials and methods: The systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses statement, and was guided by the PICOS strategy. Clinical trials in which adult patients received at least one indirect restoration cemented with IDS approach and one restoration cemented following the delayed dentin sealing (DDS) were considered. Results: Following title screening and full-text reading, four studies met the inclusion criteria and were included for qualitative synthesis, while two studies were selected for quantitative synthesis. According to Risk of bias-2 tool, two studies were classified as “some concerns” for the outcome POS. No statistically significant differences were found between teeth restored with indirect restorations using the IDS and DDS approach for POS (p > 0.05), neither at the baseline (very low certainty of evidence according to GRADE) nor after 2 years of follow-up (low certainty of evidence according to GRADE). Conclusion: There is low-certainty evidence that IDS does not reduce POS in teeth restored with indirect restorations. Clinical significance: There is no clinical evidence to favor IDS over DDS when restoring teeth with indirect restorations

The Role of Appearance in Adolescents’ Experiences of Neurofibromatosis Type 1: A Survey of Young People and Parents

© 2016, National Society of Genetic Counselors, Inc. Neurofibromatosis type 1 (NF1) is a genetic condition which can result in varying degrees of visible difference (disfigurement). Adolescence is a time when appearance concerns become more salient for many young people and is acknowledged as a particularly challenging time for individuals with NF1. There is currently little research into the psychosocial impact of the appearance changes associated with NF1 during this stage of life. In order to address this, surveys of young people with NF1 aged 14–24years (n=73), and parents of young people with NF1 (n=55) were developed following interview studies with these groups. The surveys included the Perceived Stigma Questionnaire, Social Comfort Questionnaire, Body Esteem Scale (appearance subscale) and the Subjective Happiness Scale. Young people and parents identified appearance as central to young peoples’ experience of NF1, however no significant difference was found on measures of body esteem, happiness, stigma or social comfort between those young people who reported their NF1 was noticeable to others and those who reported it was not. Findings from the parent survey indicated that their reports of greater perceived noticeability did relate to greater perceived stigma and lower levels of social comfort. Findings highlight the importance of attending to young people’s concerns around appearance in general and managing the possibility of future appearance changes, rather than the current noticeability of NF1

HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study

Background: X linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20-40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes. Methods: 2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes. Results: We identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation. Conclusions: As we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.Michael J Friez, Susan Sklower Brooks, Roger E Stevenson, Michael Field, Monica J Basehore, Lesley C Adès, Courtney Sebold, Stephen McGee, Samantha Saxon, Cindy Skinner, Maria E Craig, Lucy Murray, Richard J Simensen, Ying Yzu Yap, Marie A Shaw, Alison Gardner, Mark Corbett, Raman Kumar, Matthias Bosshard, Barbara van Loon, Patrick S Tarpey, Fatima Abidi, Jozef Gecz, Charles E Schwart

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Optimisation of processing and microstructural parameters of LSM cathodes to improve the electrochemical performance of anode-supported SOFCs

To improve the electrochemical performance of LSM-based anode-supported single cells, a systematic approach was taken for optimising processing and materials parameters. Four parameters were investigated in more detail: (1) the LSM/YSZ mass ratio of the cathode functional layer, (2) the grain size of LSM powder for the cathode current collector layer, (3) the thickness of the cathode functional layer and the cathode current collector layer, and (4) the influence of calcination of YSZ powder used for the cathode functional layer. Results from electrochemical measurements performed between 700 and 900 degrees C with H-2 (3 vol.% H2O) as fuel gas and air as the oxidant showed that the performance was the highest using an LSM/YSZ mass ratio of 50/50. A further increase of the electrochemical performance was obtained by increasing the grain size of the outer cathode current collector layer: the highest performance was achieved with non-ground LSM powder. In addition, it was found that the thickness of the cathode functional layer and cathode current collector layer also affects the electrochemical performance, whereas no obvious detrimental effects occurred with the different qualities of YSZ powder for the cathode functional layer. The highest performance, i.e. 1.50 +/- 0.05 A cm(-2) at 800 degrees C and 700 mV, was obtained with a cathode functional layer, characterised by an LSM/YSZ mass ratio of 50/50, a d(90) of the LSM powder of 1.0 mu m, non-calcined YSZ powder, and a thickness of about 30 mu m, and a cathode current collector layer, characterised by d(90) of the LSM powder of 26.0 mu m (non-ground), and a thickness of 50-60 mu m. Also interesting to note is that the use of non-ground LSM for the cathode current collector layer and non-calcined YSZ powder for the cathode functional layer obviously simplifies the production route of this type of fuel cell. (c) 2004 Elsevier B.V. All rights reserved