The Interplay between NF-kappaB and E2F1 Coordinately Regulates Inflammation and Metabolism in Human Cardiac Cells

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, thus suggesting that additional transcription factors are regulating PDK4. Interestingly, a recent study has demonstrated that the transcription factor E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Given that NF-κB may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-κB can downregulate PDK4 expression in human cardiac AC16 cells through E2F1 inhibition. Protein coimmunoprecipitation indicated that PDK4 downregulation entailed enhanced physical interaction between the p65 subunit of NF-κB and E2F1. Chromatin immunoprecipitation analyses demonstrated that p65 translocation into the nucleus prevented the recruitment of E2F1 to the PDK4 promoter and its subsequent E2F1-dependent gene transcription. Interestingly, the NF-κB inhibitor parthenolide prevented the inhibition of E2F1, while E2F1 overexpression reduced interleukin expression in stimulated cardiac cells. Based on these findings, we propose that NF-κB acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription

To return or not return? Predictive factors for return to work in persons with musculoskeletal disorders – prospective studies over a 10-year period

Background: Musculoskeletal disorders (MSD) are a major reason for sick leave and results in individual suffering as well as economical consequences for both the individual and society. It is important to study variables from a multidimensional perspective to predict sustainable return to work (RTW). The overall aim was to identify multidimensional predictors and psychosocial characteristics for RTW in persons with musculoskeletal disorders (MSD), over a 10-year period. Study I: Aim: To identify predictive factors for RTW in patients with MSD. Design: Prospective. Method: Persons aged 18-65 years (n=377), were divided into two groups due to sickness certification one year after rehabilitation. The groups were compared with each other regarding predictive factors for RTW using logistic regression analysis. Result: Predictive factors for RTW were gender, age, education, number of sick-listed days before rehabilitation, physical capacity, self-rated pain, self-rated functional capacity and self-rated Quality of Life (QoL). Implication: Identifying predictors for RTW is an essential task for designing a suitable individual rehabilitation. Study II: Aim: To identify multidimensional predictive factors for sustainable RTW in a long-term follow-up study of persons with MSD. Design: Prospective. Method: Persons aged 18-65 years (n=183) were divided into “working full-time” and “sick-listed” groups five and ten years after a rehabilitation program. The groups were compared with each other regarding predictive factors for RTW using stepwise logistic regression. Result: Long-term predictive factors were number of sick-listed days before rehabilitation, age, self-rated pain, life events, gender, physical capacity, self-rated functional capacity, educational level, and light physical labour. Implication: Sustained RTW can be facilitated by early planning of the sick leave period using instruments that take these predictors into account. Study III: Aim: To describe thoughts and feelings of future working life related to RTW in persons who are sick-listed due to MSD and to compare these descriptions with the person’s actual working situation to create predictors for RTW. Design: Prospective and explorative. Method: Persons aged 18-65 years (n=320) answered an open-ended question about thoughts and feelings of their future working life before participating in a rehabilitation program. The answers were analysed using qualitative content analysis. The emerging categories were compared with the persons working situation one, five and ten years after the rehabilitation program using Pearson’s chi-squared test. Result: Three categories; “motivation and optimism”, “limitations to overcome” and “hindrance and hesitation”, and nine subcategories, were defined. Persons in the subcategories driving force, new possibilities and demand another job had changed job. Those in the reduced work-time subcategory were working part-time after a five-year period. Implication: Persons with a motivation for RTW and those expressing some kind of hindrance should have different types of support. Study IV: Aim: To compare psychosocial factors between healthy and sick-listed persons, both groups with MSD ten years ago. Design: Prospective. Method: Ten years after a rehabilitation program persons aged 18-65 years (n=183) were divided into a healthy group and a sick-listed group. The groups were compared with each other in regards to psychosocial factors using logistic regression analysis and Pearson’s chi-squared test. Result: The healthy group had a higher QoL, more control over the working situation, better sense of coherence (SOC) and more life events. Implication: Using the knowledge about the characteristics of the healthy group, adequate rehabilitation can be given. General conclusion and implications: The focus of this thesis has been on healthy factors for RTW in line with the salutogenic theory. When predicting RTW for persons with MSD we must have a multidimensional perspective and physical, psychosocial and occupational factors must be considered. The instruments in this thesis can be used to predict RTW. Taking all dimensions and all predictive factors into account, sick leave can be reduced by directing the person to the correct amount rehabilitation, not more and not less. Keywords: Certified sick leave, functional capacity, job strain, motivation, musculoskeletal disorders, pain, physical capacity, qualitative content analysis, quality of life, return to work, sense of coherence, working life ISBN 978-91-628-8061-3 Abstract To return or not return? Predictive factors for return to work in persons with musculoskeletal disorders - prospective factors over a 10-year period Marie Lydell, Sahlgrenska School of Public Health and Community Medicine, Department of Primary Health Care, University of Gothenburg. Background: Musculoskeletal disorders (MSD) are a major reason for sick leave and results in individual suffering as well as economical consequences for both the individual and society. It is important to study variables from a multidimensional perspective to predict sustainable return to work (RTW). The overall aim was to identify multidimensional predictors and psychosocial characteristics for RTW in persons with musculoskeletal disorders (MSD), over a 10-year period. Study I: Aim: To identify predictive factors for RTW in patients with MSD. Design: Prospective. Method: Persons aged 18-65 years (n=377), were divided into two groups due to sickness certification one year after rehabilitation. The groups were compared with each other regarding predictive factors for RTW using logistic regression analysis. Result: Predictive factors for RTW were gender, age, education, number of sick-listed days before rehabilitation, physical capacity, self-rated pain, self-rated functional capacity and self-rated Quality of Life (QoL). Implication: Identifying predictors for RTW is an essential task for designing a suitable individual rehabilitation. Study II: Aim: To identify multidimensional predictive factors for sustainable RTW in a long-term follow-up study of persons with MSD. Design: Prospective. Method: Persons aged 18-65 years (n=183) were divided into “working full-time” and “sick-listed” groups five and ten years after a rehabilitation program. The groups were compared with each other regarding predictive factors for RTW using stepwise logistic regression. Result: Long-term predictive factors were number of sick-listed days before rehabilitation, age, self-rated pain, life events, gender, physical capacity, self-rated functional capacity, educational level, and light physical labour. Implication: Sustained RTW can be facilitated by early planning of the sick leave period using instruments that take these predictors into account. Study III: Aim: To describe thoughts and feelings of future working life related to RTW in persons who are sick-listed due to MSD and to compare these descriptions with the person’s actual working situation to create predictors for RTW. Design: Prospective and explorative. Method: Persons aged 18-65 years (n=320) answered an open-ended question about thoughts and feelings of their future working life before participating in a rehabilitation program. The answers were analysed using qualitative content analysis. The emerging categories were compared with the persons working situation one, five and ten years after the rehabilitation program using Pearson’s chi-squared test. Result: Three categories; “motivation and optimism”, “limitations to overcome” and “hindrance and hesitation”, and nine subcategories, were defined. Persons in the subcategories driving force, new possibilities and demand another job had changed job. Those in the reduced work-time subcategory were working part-time after a five-year period. Implication: Persons with a motivation for RTW and those expressing some kind of hindrance should have different types of support. Study IV: Aim: To compare psychosocial factors between healthy and sick-listed persons, both groups with MSD ten years ago. Design: Prospective. Method: Ten years after a rehabilitation program persons aged 18-65 years (n=183) were divided into a healthy group and a sick-listed group. The groups were compared with each other in regards to psychosocial factors using logistic regression analysis and Pearson’s chi-squared test. Result: The healthy group had a higher QoL, more control over the working situation, better sense of coherence (SOC) and more life events. Implication: Using the knowledge about the characteristics of the healthy group, adequate rehabilitation can be given. General conclusion and implications: The focus of this thesis has been on healthy factors for RTW in line with the salutogenic theory. When predicting RTW for persons with MSD we must have a multidimensional perspective and physical, psychosocial and occupational factors must be considered. The instruments in this thesis can be used to predict RTW. Taking all dimensions and all predictive factors into account, sick leave can be reduced by directing the person to the correct amount rehabilitation, not more and not less. Keywords: Certified sick leave, functional capacity, job strain, motivation, musculoskeletal disorders, pain, physical capacity, qualitative content analysis, quality of life, return to work, sense of coherence, working life ISBN 978-91-628-8061-

Ventricular pacing site separation by cardiac computed tomography: validation for the prediction of clinical response to cardiac resynchronization therapy

© 2017, Springer Science+Business Media Dordrecht. Cardiac Resynchronization Therapy (CRT) fails to provide benefit in up to one-third of patients. Maximizing the geographic separation of right and left ventricular pacing lead sites has been suggested as one way to improve response. Cardiac CT provides an opportunity to explore 3-dimensional inter-lead distance (ILD) measures for the prediction of CRT response. The objective of this study was to investigate associations between standardized measures of ILD by cardiac CT and echocardiographic response to CRT. Forty-two consecutive patients undergoing CRT had serial clinical and echocardiographic evaluations performed in addition to a post-procedural cardiac-gated CT with blinded measurement of direct and circumferential (via the myocardium) ILD measures. Clinical response to CRT, the primary clinical outcome, was defined as a ≥15% reduction in LVESV using echocardiography at 6-months. The mean age and ejection fraction was 63.6 ± 8.9 years and 25.2 ± 7.8%, respectively. The primary outcome occurred in 35 of 42 patients (83%). Both direct and circumferential CT-based ILD measures were associated with the primary outcome by univariate analysis. Receiver Operator Characteristic analysis identified Circumferential ILD to have the strongest predictive accuracy (AUC 0.78). Inter- and intra-observer reproducibility of CT-derived ILD measures was excellent. Circumferential ILD measures on cardiac CT are predictive of clinical response to CRT. Incorporation of these measures into the selection of optimal pacing targets, particularly from pre-procedural CT coronary vein imaging may be of therapeutic benefit and warrants further investigation

Erratum to: Ventricular pacing site separation by cardiac computed tomography: validation for the prediction of clinical response to cardiac resynchronization therapy (The International Journal of Cardiovascular Imaging, (2017), 33, 9, (1433-1442), 10.1007/s10554-017-1120-4)

© 2017, Springer Science+Business Media Dordrecht. The original publication contained an incorrect Fig. 2. The correct Fig. 2 is shown here.(Figure Presented)

Social transmission of food preferences among norway rats by marking of food sites and by gustatory contact

Three experiments were conducted to investigate the social learning and transmission of food preferences by excretory marking among adult male Norway rats. The experiments extend our earlier findings that rats prefer to eat from a food bowl marked by the excretory deposits of conspecifics and that this mechanism can result in the communication and social learning of food preferences (Laland &amp; Plotkin, 1991). Here we investigate whether a tradition of food and food site preferences can become established by these means. Experiment 1 established that the residual cues deposited by rats lose their powers of communication as "markers" of food sites over a 72-h period. Experiment 2 showed that while a socially enhanced preference for one flavored diet could be transmitted from one animal to the next along a chain, it was unstable for an alternative diet. This suggests that social transmission may be more stable when it reinforces a prior preference than when it conflicts with one. In Experiment 3, the stability of socially transmitted food preferences was bolstered by the addition of a second process for the communication of diet preferences-namely, gustatory cues on the demonstrator's breath. This finding suggests that when a socially transmitted trait is mediated by more than one process, the processes may interact, and the diffusion is likely to be more stable.</p

Genomic imprinting mediates sexual experience-dependent olfactory learning in male mice

Mammalian imprinted genes are generally thought to have evolved as a result of conflict between parents; however, recent knockout studies suggest that coadaptation between mother and offspring may have been a significant factor. We present evidence that the same imprinted gene that regulates mammalian maternal care and offspring development also regulates male sexual behavior and olfaction. We have shown that the behavior of male mice carrying a knockout of the imprinted gene Peg3 does not change with sexual experience and that the mice are consequently unable to improve their copulatory abilities or olfactory interest in female odor cues after mating experience. Forebrain activation, as indexed by female odor-induced c-Fos protein induction, fails to increase with sexual experience, providing a neural basis for the behavioral deficits that the male mice display. The behavioral and neural effects of the Peg3 knockout show that this imprinted gene has evolved to regulate multiple and varied aspects of reproduction, from male sexual behavior to female maternal care, and the development of offspring. Moreover, sexual experience-driven behavioral changes may represent an adaptive response that enables males to increase their reproductive potential over their lifespan, and the effects we have found suggest that the evolution of genomic imprinting has been influenced by coadaptation between males and females as well as between females and offspring