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Recent studies implicate a strong association between elevated plasma branched-chain amino acids (BCAAs) and insulin resistance (IR). However, a causal relationship and whether interrupted BCAA homeostasis can serve as a therapeutic target for diabetes remain to be established experimentally. In this study, unbiased integrative pathway analyses identified a unique genetic link between obesity-associated IR and BCAA catabolic gene expression at the pathway level in human and mouse populations. In genetically obese (ob/ob) mice, rate-limiting branched-chain α-keto acid (BCKA) dehydrogenase deficiency (i.e., BCAA and BCKA accumulation), a metabolic feature, accompanied the systemic suppression of BCAA catabolic genes. Restoring BCAA catabolic flux with a pharmacological inhibitor of BCKA dehydrogenase kinase (BCKDK) ( a suppressor of BCKA dehydrogenase) reduced the abundance of BCAA and BCKA and markedly attenuated IR in ob/ob mice. Similar outcomes were achieved by reducing protein (and thus BCAA) intake, whereas increasing BCAA intake did the opposite; this corroborates the pathogenic roles of BCAAs and BCKAs in IR in ob/ob mice. Like BCAAs, BCKAs also suppressed insulin signaling via activation of mammalian target of rapamycin complex 1. Finally, the small-molecule BCKDK inhibitor significantly attenuated IR in high-fat diet-induced obese mice. Collectively, these data demonstrate a pivotal causal role of a BCAA catabolic defect and elevated abundance of BCAAs and BCKAs in obesity-associated IR and provide proof-of-concept evidence for the therapeutic validity of manipulating BCAA metabolism for treating diabetes.

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure.

BackgroundAlthough metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied.Methods and resultsTranscriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload. Suppression of branched-chain amino acid (BCAA) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids was identified as a significant signature of metabolic reprogramming in mouse failing hearts and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor Krüppel-like factor 15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated branched-chain α-keto acids directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain α-keto acid dehydrogenase activity significantly blunted cardiac dysfunction after pressure overload.ConclusionsBCAA catabolic defect is a metabolic hallmark of failing heart resulting from Krüppel-like factor 15-mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.

Elia Gabarron,1 Enrique Dorronzoro,2 Meghan Bradway,1,3 Octavio Rivera-Romero,2 Rolf Wynn,3,4 Eirik Årsand1,3 1Norwegian Centre for E-health Research, University Hospital of North Norway, Tromsø, Norway; 2Department of Electronic Technology, Universidad de Sevilla, Seville, Spain; 3Department of Clinical Medicine, Faculty of Health Sciences, UiT – Arctic University of Norway, Tromsø, Norway; 4Division of Mental Health and Addictions, University Hospital of North Norway, Tromsø, Norway Background: Nowadays, rapid and accessible participatory research on diabetes can be carried out using social media platforms. The objective of this study was to identify preferences and interests of diabetic social media users regarding a health-promotion intervention targeting them. Methods: Social media followers of the Norwegian Diabetes Association were invited to participate in the creation of a health-promotion intervention on diabetes by expressing their opinions through an online questionnaire posted on Facebook, Twitter, and Instagram. The questionnaire asked participants about their demographics and preferences regarding type of health content: format, frequency, and channels to deliver content. Questions regarding the perceived quality of diabetes-related information and satisfaction with content on social media were also included. Results: The questionnaire was answered by 346 participants: 332 (96%) of those were reached via Facebook, 66.5% of respondents (n=230) identified themselves as women, 54% (n=187) as individuals diagnosed with type 1 diabetes, and 71% (n=235) were aged 30–64 years. The preferred type of content was “research and innovation on diabetes”, selected by 78.0% of the respondents. “Text format” was the choice for 93.4%, and 97.3% would prefer to find health-promotion content on Facebook. There was heterogeneity in the desired frequency of this content. In a scale ranging from 0 to 100, the perceived quality of diabetes-related information on social media was 62.0±1.2 and satisfaction with such content 61.9±1.3. Conclusion: The approach used in this study was successful in reaching and involving participants quickly, and could also potentially increase diabetes patients’ engagement and satisfaction with health-promotion interventions, enhance their sense of community, and thus help people attain healthier lifestyles. It is a limitation that our sample might not have been fully representative, as the most interested social media users might have chosen to participate. Keywords: community-based participatory research, diabetes, health promotion, health education, social media

Lars Henrik Myklebust,1 Knut Sørgaard,1,2 Rolf Wynn21Psychiatric Research Centre of North Norway, Nordland Hospital Trust, Bodø, 2Department of Clinical Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, NorwayObjectives: In the last few decades, there has been a restructuring of the psychiatric services in many countries. The complexity of these systems may represent a challenge to patients that suffer from serious psychiatric disorders. We examined whether local integration of inpatient and outpatient services in contrast to centralized institutions strengthened continuity of care.Methods: Two different service-systems were compared. Service-utilization over a 4-year period for 690 inpatients was extracted from the patient registries. The results were controlled for demographic variables, model of service-system, central inpatient admission or local inpatient admission, diagnoses, and duration of inpatient stays.Results: The majority of inpatients in the area with local integration of inpatient and outpatient services used both types of care. In the area that did not have beds locally, many patients that had been hospitalized did not receive outpatient follow-up. Predictors of inpatients' use of outpatient psychiatric care were: Model of service-system (centralized vs decentralized), a diagnosis of affective disorder, central inpatient admission only, and duration of inpatient stays.Conclusion: Psychiatric centers with local inpatient units may positively affect continuity of care for patients with severe psychiatric disorders, probably because of a high functional integration of inpatient and outpatient care.Keywords: psychiatry, hospitalization, decentralization, outpatients, continuity of care, health service research, affective

Martin Bystad,1,2 Camilla Bystad,3 Rolf Wynn1,3 1Division of Addictions and Specialized Psychiatric Services, University Hospital of North Norway, 2Institute of Psychology, 3Institute of Clinical Medicine, Faculty of Health Sciences, Arctic University of Norway, Tromsø, Norway Abstract: Placebo effects are documented in a number of clinical and experimental studies. It is possible to benefit from placebo effects in clinical practice by using them as effects additive to those of documented and effective treatments. The purpose of this paper is to discuss how doctors and other health workers may benefit from placebo effects within an ethical framework. A narrative review of the literature relating to placebo effects in clinical practice was performed. We searched PubMed and selected textbooks on placebo effects for articles and book chapters relating to placebo effects in clinical practice. By drawing on placebo effects, doctors may access patients’ self-healing potentials. In practice, doctors may best benefit from placebo effects by influencing the patient’s expectations through communication. An important principle is to give the patient information stating that a particular treatment is effective, as long as this is based on realistic optimism. A patient-centered style involving elements such as developing trust and respect, exploring the patient’s values, speaking positively about treatments, and providing reassurance and encouragement might aid in activating placebo effects. The total effect of a documented treatment will partly depend on how well the placebo effects have been activated. Thus, placebo effects can be understood as a form of supplemental treatment. Keywords: placebo effects, doctor-patient communication, expectations, biopsychosocial model

Helene Persen Storjord,1 Mari Mjønes Teodorsen,1 Jan Bergdahl,1 Rolf Wynn,2,3 Jan-Are Kolset Johnsen1 1Department of Clinical Dentistry, 2Department of Clinical Medicine, UiT - The Arctic University of Norway, 3Division of Addictions and Specialized Psychiatric Services, University Hospital of North Norway, Tromsø, Norway Introduction: Dental anxiety is an important challenge for many patients and clinicians. It is thus of importance to know more about dental students' own experiences with dental anxiety and their understanding of dental anxiety. The aim was to investigate differences in dental anxiety levels between dental students, psychology students, and biology students at a Norwegian university. Materials and methods: A total of 510 students of dentistry, psychology, and biology at the University of Tromsø received a questionnaire consisting of the Modified Dental Anxiety Scale, demographic questions, and questions relating to their last visit to the dentist/dental hygienist; 169 students gave complete responses. Nonparametric tests were used to investigate differences between the student groups. Results: The respondents were 78% female and 22% male; their mean age was 24 years. The dental students showed a significantly lower degree of dental anxiety than the psychology (P

Jan-Are K Johnsen,1 Sara M Vambheim,2 Rolf Wynn,3,4 Silje C Wangberg3,51Department of Clinical Dentistry, University of Tromsø, 2Department of Psychology, University of Tromsø, 3Division of Addiction and Specialized Psychiatry, University Hospital of North-Norway, 4Department of Clinical Medicine, University of Tromsø, Tromsø, 5Narvik University College, Narvik, NorwayAbstract: The present study describes a novel approach to the identification of the motivational processes in text data extracted from an Internet support group (ISG) for smoking cessation. Based on the previous findings that a “prevention” focus might be more relevant for maintaining behavior change, it was hypothesized that 1) language use (ie, the use of emotional words) signaling a “promotion” focus would be dominant in the initiating stages of the ISG, and 2) that the proportion of words signaling a prevention focus would increase over time. The data were collected from the ISG site, spanning 4 years of forum activity. The data were analyzed using the Linguistic Inquiry and Word Count application. The first hypothesis – of promotion focus dominance in the initiating stages – was not supported during year 1. However, for all the other years measured, the data showed that a prevention failure was more dominant compared with a promotion failure. The results indicate that content analysis could be used to investigate motivational and language-driven processes in ISGs. Understanding the interplay between self-regulation, lifestyle change, and modern communication channels could be of vital importance in providing the public with better health care services and interventions.Keywords: self-regulation, behavior change, emotion, prevention