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Background Non-adherence to preventive guidelines on cardiovascular disease calls for an interdisciplinary approach acknowledging psychological factors of relevance for risk communication and lifestyle modification. Evidence is building up regarding the advantage of sharing arterial imaging evidence of subclinical atherosclerosis with asymptomatic individuals, but there is limited understanding of how this relates to mechanisms of importance for behavioural change. Longitudinal studies on associations between patients’ reactions and lifestyle modification are missing. The population-based randomized controlled trial VIPVIZA investigates the impact of pictorial information about subclinical atherosclerosis, added to traditional risk factor-based communication. The intervention includes a personalized, colour-coded and age-related risk communication strategy and a motivational conversation, and has been shown to reduce cardiovascular disease risk. In the present study we assessed cognitive and emotional reactions to the intervention, and how these reactions are associated to lifestyle modification. Methods The participants’ evaluation of the risk communication was assessed in the intervention group (n = 1749). Lifestyle modification was assessed with a lifestyle index based on physical activity, diet, smoking and alcohol consumption at baseline and after 3 years. Associations between cognitive and emotional response and lifestyle modification were tested with analyses of covariance in a subset of participants (n = 714–857). Results The intervention increased understanding of personal CVD risk, the possibility to influence the risk, and how to influence the risk. Severity of atherosclerosis was associated with emotional reactions, but emotions of strong negative valance were uncommon. Cognitive response and emotional arousal evoked by the intervention were positively associated with lifestyle modification, whereas negative emotions in isolation were not. High level of cognitive response in combination with high level of emotional arousal was found to be most beneficial for lifestyle modification. Conclusions The results demonstrate the potential of communicating asymptomatic atherosclerosis with a pictorial, colour-coded and age-related strategy, also including a motivational conversation. Furthermore, the results show the importance of CVD risk communication evoking engagement, and that an interaction between cognitive and emotional reactions might be central for sustained lifestyle modification. Our results also indicate that, in an asymptomatic population, atherosclerosis screening may strengthen disease prevention and health promotion. Trial registration: ClinicalTrials.gov identifier: NCT01849575. Registration date 08/05/2013.

Background and Aims: Cholangiocarcinoma (CCA) is a malignancy arising from biliary epithelial cells of intra- and extrahepatic bile ducts with dismal prognosis and few nonsurgical treatments available. Despite recent success in the immunotherapy-based treatment of many tumor types, this has not been successfully translated to CCA. Mucosal-associated invariant T (MAIT) cells are cytotoxic innate-like T cells highly enriched in the human liver, where they are located in close proximity to the biliary epithelium. Here, we aimed to comprehensively characterize MAIT cells in intrahepatic (iCCA) and perihilar CCA (pCCA). Approach and Results: Liver tissue from patients with CCA was used to study immune cells, including MAIT cells, in tumor-affected and surrounding tissue by immunohistochemistry, RNA-sequencing, and multicolor flow cytometry. The iCCA and pCCA tumor microenvironment was characterized by the presence of both cytotoxic T cells and high numbers of regulatory T cells. In contrast, MAIT cells were heterogenously lost from tumors compared to the surrounding liver tissue. This loss possibly occurred in response to increased bacterial burden within tumors. The residual intratumoral MAIT cell population exhibited phenotypic and transcriptomic alterations, but a preserved receptor repertoire for interaction with tumor cells. Finally, the high presence of MAIT cells in livers of iCCA patients predicted long-term survival in two independent cohorts and was associated with a favorable antitumor immune signature. Conclusions: MAIT cell tumor infiltration associates with favorable immunological fitness and predicts survival in CCA.

Aims Health literacy, the degree to which individuals understand and act upon health information, may have a pivotal role in the prevention of cardiovascular disease (CVD), with low health literacy potentially explaining poorer adherence to prevention guidelines. We investigated the associations between health literacy, ultrasound-detected carotid atherosclerosis and cardiovascular risk factors. Methods Baseline data (cross-sectional analysis) from a randomized controlled trial, integrated within the Västerbotten Intervention Program, Northern Sweden, was used. We included 3459 individuals, aged 40 or 50 years with ≥1 conventional risk factor or aged 60 years old. The participants underwent clinical examination, blood sampling, carotid ultrasound assessment of intima-media wall thickness (CIMT) and plaque formation, and answered a questionnaire on health literacy – the Brief Health Literacy Screen. The European Systematic Coronary Risk Evaluation and Framingham Risk Score were calculated. Results About 20% of the participants had low health literacy. Low health literacy was independently associated with the presence of ultrasound-detected carotid artery plaques after adjustment for age and education, odds ratio (95% confidence interval) 1.54 (1.28–1.85), demonstrating a similar level of risk as for smoking. Health literacy was associated with CIMT in men. Low health literacy was associated with higher CVD risk scores. Sensitivity analyses with low health literacy set to 9% or 30% of the study sample, respectively, yielded essentially the same results. Conclusions Low health literacy was independently associated with carotid artery plaques and a high level of CVD risk scores. Presenting health information in a fashion that is understood by all patients may improve preventive efforts.

BACKGROUND: Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasou ...

Bile acids (BAs) are detergents essential for intestinal absorption of lipids. Disruption of BA homeostasis can lead to severe liver damage. BA metabolism is therefore under strict regulation by sophisticated feedback mechanisms. The hormone-like protein Fibroblast growth factor 19 (FGF19) is essential for maintaining BA homeostasis by down regulating BA synthesis. Here, the impact of both FGF19 and chenodeoxycholic acid (CDCA) on primary human hepatocytes was investigated and a possible autocrine/paracrine function of FGF19 in regulation of BA synthesis evaluated. Primary human hepatocytes were treated with CDCA, recombinant FGF19 or conditioned medium containing endogenously produced FGF19. RNA sequencing revealed that treatment with CDCA causes deregulation of transcripts involved in BA metabolism, whereas treatment with FGF19 had minor effects. CDCA increased FGF19 mRNA expression within 1 h. We detected secretion of the resulting FGF19 protein into medium, mimicking in vivo observations. Furthermore, medium enriched with endogenously produced FGF19 reduced BA synthesis by down regulating CYP7A1 gene expression. However, following knockdown of FGF19, CDCA still independently decreased BA synthesis, presumably through the regulatory protein small heterodimer partner (SHP). In summary, we show that in primary human hepatocytes CDCA regulates BA synthesis in an FGF19-independent manner.

Childhood obesity is increasing in Sweden. All children are offered regularly spread health visits to a school nurse. As health visits include a measure of height and weight and a health dialogue, school nurses can discover, disclose, and treat a child's weight gain. The aim of this study was to describe school nurses’ experiences and challenges in working with childhood obesity. This qualitative study collected data through focus-group discussion and semi-structured interviews with ten female school nurses from six municipalities. Data were analysed inductively using manifest qualitative content analysis. The study was reported using the COREQ guidelines. Stigmatization and lack of resources are major challenges for school nurses working with childhood obesity, and they experience frustration, powerlessness and feel that they provide unequal treatment. The present study concludes that obesity stigmatization is a widespread challenge for school nurses. They cannot alone generate all the resources needed or conquer all challenges. Evidence-based guidelines, increased knowledge, time for reflections and peer support could potentially empower school nurses, reduce frustration, and improve the quality of and equality in childhood obesity treatment.

Background ABO blood group antigens in the liver are expressed mainly on endothelial cells or biliary epithelial cells but not on hepatocytes. This suggests that ABO-incompatible hepatocyte transplantation (ABOi-HTx) is theoretically feasible. However, the effects of stress on ABO blood group antigen expression caused by isolation and intraportal infusion require thorough investigation before ABOi-HTx can be implemented in clinical settings. Methods Human hepatocytes were isolated from liver tissue obtained from liver resection or deceased donor livers. The expression of blood group antigens on cryopreserved human liver tissues and isolated hepatocyte smear specimens were examined by immunofluorescent staining. The effect of proinflammatory cytokines on blood group antigen expression of hepatocytes was evaluated by flow cytometry. Instant blood-mediated inflammatory reaction after hepatocyte incubation with ABO-incompatible whole blood was examined using the tubing loop model. Results Blood group antigens were mainly expressed on vessels in the portal area. In hepatocyte smear specimens, isolated hepatocytes did not express blood group antigens. In contrast, a subset of cells in the smear specimens of nonparenchymal liver cells stained positive. In the flow cytometry analysis, isolated hepatocytes were negative for blood group antigens, even after 4-h incubation with cytokines. Platelet counts and complement activation were not significantly different in ABO-identical versus ABO-incompatible settings in the tubing loop model. Conclusion Our study showed that blood group antigens were not expressed on hepatocytes, even after isolation procedures or subsequent incubation with cytokines. This finding is an important step toward removing the restriction of ABO matching in hepatocyte transplantation. Our results suggest that ABOi-HTx is a feasible therapeutic option, especially in patients who require urgent treatment with freshly isolated hepatocytes, such as those with acute liver failure.

Until three decades, ago 3,5-diiodothyronine (3,5-T2) and 3,3'-diiodothyronine (3,3'-T2) were considered products of thyroid hormone catabolism without biological activity. Some metabolic effects have been described in rodents, but the physiological relevance in humans and the mechanisms of action are unknown. Aim of this work was to investigate the role and the mechanisms of action of 3,5-T2 and 3,3'-T2 in the regulation of metabolic homeostasis in human liver. We used primary human hepatocytes freshly isolated from donors and grown on Matrigel as the golden standard in vitro model to study human hepatic metabolism. Results show that diiodothyronines in the range of plasma physiological concentrations reduced hepatic lipid accumulation, by modulating the activity of the mTORC1/Raptor complex through an AMPK-mediated mechanism, and stimulated the mTORC2/Rictor complex-activated pathway, leading to the down regulation of the expression of key gluconeogenic genes. Hence, we propose that diiodothyronines act as key regulators of hepatic metabolic homeostasis in humans.

Introduction: The incidence of chronic disease and treatment costs have been steadily increasing in the United States over the past few decades. Primary prevention and healthy lifestyle counseling have been identified as important strategies for reducing health-care costs and chronic disease prevalence. This article seeks to examine decision-makers’ experiences and self-perceived roles in guideline and lifestyle counseling implementation in a primary care setting in the United States. Methods: Qualitative interviews were conducted with administrators at a health-care network in Upstate New York and with state-level administrators, such as insurers. Decision-makers were asked to discuss prevention guidelines and healthy lifestyle counseling, as well as how they support implementation of these initiatives. Interviews were analyzed using a thematic analysis framework and relevant sections of text were sorted using a priori codes. Results: Interviews identified numerous barriers to guideline implementation. These included the complexity and profusion of guidelines, the highly politicized nature of health-care provision, and resistance from providers who sometimes prefer to make decisions autonomously. Barriers to supporting prevention counseling included relatively time-limited patient encounters, the lack of reimbursement mechanisms for counseling, lack of patient resources, and regulatory complexities. Conclusions: Our research indicates that administrators and administrative structures face barriers to supporting prevention activities such as guideline implementation and healthy lifestyle counseling in primary care settings. They also identified several solutions for addressing existing primary prevention barriers, such as relying on nurses to provide healthy lifestyle support to patients. This article provides an important assessment of institutional readiness to support primary prevention efforts.

Background & Aims Bile duct tumors are rare and have poor prognoses. Natural killer (NK) cells are frequent in human liver and infiltrate these tumors but do not control their progression. Responses of NK cells are regulated by NK immunoglobulin-like receptors (KIRs), which interact with HLA class I ligands. We aimed to characterize the features of the KIR gene loci and their ligands in patients with bile duct cancer (BDC). Methods We performed combined multidimensional characterization of genes that encode KIRs and their ligands in blood samples from patients with BDC from Sweden, followed for up to 8 years after diagnosis (n = 148), in 2 geographically matched cohorts of healthy individuals from Northern Europe (n = 204 and n = 900), and in healthy individuals from 6 geographically unrelated populations (n = 2917). We used real-time polymerase chain reaction, RNA sequencing, immunohistochemistry, and flow cytometry to evaluate NK-cell presence, as well as KIR and KIR-ligand expression in bile duct tumors and control tissues. Results Patients with bile duct tumors had multiple alterations at the KIR gene loci. KIR loci are grouped into genotypes that encode more inhibitory (group A) and more activating (group B) receptors, which can be subdivided into centromeric and telomeric fragments. Patients with BDC had a lower prevalence of KIR2DL3, which was linked to disequilibrium in centromeric A/B and B/B genotypes, compared with control individuals. The associations between KIRs and KIR ligands differed between patients with BDC and control individuals; patients had an altered balance between activating and inhibitory KIRs. KIR-positive NK cells infiltrated biliary tumors that expressed matched KIR ligands. Conclusions In a multidimensional analysis of DNA from blood samples of patients with BDC in Europe, we found patients to have multiple alterations at the KIR and HLA gene loci compared with control individuals. These alterations might affect NK-cell tumor surveillance. NK cells from bile duct tumors expressed KIRs and were found in tumors that expressed cognate ligands. This should be considered in development of immune-based therapies for BDC.

Liver X receptor (LXR) agonists have the potential to alleviate obesity related diseases, particularly atherosclerosis. However, LXRs are transcriptional regulators that induce de novo lipogenesis and lipid accumulation in hepatocytes which represents a serious adverse effect. In this work, we sought to characterize the LXR agonist GW3965 effects on fatty acid (FA) and phospholipid (PL) remodelling and the correlation with gene expression in order to better understand the underlying effects leading to hepatic pathology upon LXR activation. Human primary hepatocytes treated for 48 h with GW3965 were analysed for changes in lipid metabolism gene expression by qPCR, variations in the FA profile was evaluated by GC-FID and in PL profiles using thin layer chromatography, ESI-MS and MS/MS analysis. Changes in cell membrane biochemical properties were studied using bilayer models generated with CHARMM-GUI. ELOLV6 and SCD1 mRNA increase was consistent with higher C16:1 and C18:1n9 at the expense of C16:0 and C18:0. The reduction of C18:2n6 and increase in C20:2n6 was in agreement with ELOVL5 upregulation. Phosphatydilethanolamine (PE) levels tended to decrease and phosphatidylinositol to increase; although differences did not reach significance, they correlated with changes in AGXT2L1, CDS1 and LPIN1 mRNA levels that were increased. The overall effect of GW3965 on PEs molecular profiles was an increase of long-chain polyunsaturated FA chains and a decrease of C16/C18 saturated and monounsaturated FAs chains. Additionally, PC (32:1) and PC (34:2) were decreased, and PC (36:1) and PC (34:1) were increased. AGXT2L1 is an enzyme with strict substrate specificity for phosphoethanolamine, which is converted into ammonia in GW3965-treated hepatocytes and could explain the PE reduction. In summary, LXR activation by GW3965 targets PE biosynthesis and FA elongation/desaturation, which tends to decrease PE in relation to total PL levels, and remodelling of PC and PE molecular species. We identified the human AGXT2L1 gene as induced by LXR activation by both synthetic and endogenous agonist treatment. The increase in acetaldehyde-induced oxidative stress, and in the lipid species identified have the potential to enhance the inflammatory process and impair membrane function. Future studies should focus on inhibition of AGXT2L1 activity with the aim of reverting the steatosis induced by LXR activation.

AimThe aim of this study is to explore the perceptions among primary health center staff concerning competencies, values, skills and resources related to team-based diabetes management and to describe the availability of needed resources for team-based approaches.BackgroundThe diabetes epidemic challenges services available at primary health care centers in the Middle East. Therefore, there is a demand for evaluation of the available resources and team-based diabetes management in relation to the National Diabetes Management Guidelines.MethodA cross-sectional study was conducted with 26 public primary health care centers in Muscat, the capital of Oman. Data were collected from manual and electronic resources as well as a questionnaire that was distributed to the physician-in-charge and diabetes management team members.FindingsThe study revealed significant differences between professional groups regarding how they perceived their own competencies, values and skills as well as available resources related to team-based diabetes management. The perceived competencies were high among all professions. The perceived team-related values and skills were also generally high but with overall lower recordings among the nurses. This pattern, along with the fact that very few nurses have specialized qualifications, is a barrier to providing team-based diabetes management. Participants indicated that there were sufficient laboratory resources; however, reported that pharmacological, technical and human resources were lacking. Further work should be done at public primary diabetes management clinics in order to fully implement team-based diabetes management.

Background: There is limited knowledge about the mechanisms behind the unparalleled growth of the future liver remnant (FLR) linked to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). In this study, liver regenerative markers were examined in patients subjected to ALPPS. Methods: Ten patients with colorectal liver metastases treated with neoadjuvant chemotherapy and ALPPS were included. Plasma was sampled at 6 time points and biopsies from both liver lobes were collected at both stages of ALPPS. The levels of interleukin (IL)-6, hepatocyte growth factor (HGF), tumor necrosis factor-α, epidermal growth factor, and vascular endothelial growth factor in plasma were measured at each time point. Expression of mRNA for markers of proliferation and apoptosis was studied in the biopsies from both liver lobes taken at both stages. Results: ALPPS resulted in a peak of IL-6 after stage 1 (p = 0.004), which decreased rapidly and did not increase again after stage 2. HGF also increased after stage 1 (p = 0.048), and the HGF levels correlated significantly with the degree of growth of the FLR before stage 2 (p = 0.02, r2 = 0.47). There was a correlation between peak levels of IL-6 and HGF (p = 0.03, r2 = 0.84). Conclusions: IL-6 and HGF seem to be early mediators of hypertrophy after stage 1 in the ALPPS procedure. The peak HGF plasma level correlates with the degree of FLR growth in patients subjected to ALPPS.

Background: The role of primary care professionals in lifestyle counseling is receiving attention at the national level in many countries. The U.S. and Sweden are two countries currently establishi ...

Background Bile acid homeostasis is essential and imbalance may lead to liver damage and liver failure. The bile acid induced intestinal factor fibroblast growth factor 19 (FGF19) has been identified as a key protein for mediating negative feedback inhibition of bile acid synthesis. The aim of the study was to define FGF19 and bile acid concentrations in portal and systemic blood in the fasted and postprandial state. We also addressed the question if physiological portal levels of FGF19 can be extrapolated from the concentration in systemic blood. Methods Portal and systemic blood was collected from 75 fasted patients undergoing liver surgery and from three organ donors before and after enteral nutrition. Serum concentration of FGF19 was determined with ELISA and bile acid concentration with gas chromatography–mass spectrometry. Results Concentration of bile acids was twice as high in portal compared to systemic blood in the fasted group and 3–5 times higher in the postprandial group. FGF19 increased after enteral nutrition but did not differ between portal and systemic blood, in either group. In addition, a strong, positive correlation between bile acids and FGF19 was found. Conclusion Our results confirm that bile acids drive the postprandial increase of circulating FGF19 but a hepatic clearance of FGF19 is unlikely. We conclude that systemic concentrations of FGF19 reflect portal concentrations of FGF19.

The main goal of the therapy with purified human plasma alpha1-antitrypsin (A1AT) is to increase A1AT levels and to prevent lungs from elastolytic activity in patients with PiZZ (Glu342Lys) A1AT deficiency-related emphysema. Potential hepatic gains of this therapy are unknown. Herein, we investigated the effect of A1AT therapy on SERPINA1 (gene encoding A1AT) expression. The expression of SERPINA1 was determined in A1AT or A1AT plus Oncostatin M (OSM) treated primary human hepatocytes isolated from liver tissues from A1AT deficient patients and control liver tissues. In addition, SERPINA1 mRNA was assessed in lung tissues from PiZZ emphysema patients with and without A1AT therapy, and in adherent human peripheral blood mononuclear cells (PBMC) isolated from healthy PiMM donors. In a dose-dependent manner purified A1AT lowered SERPINA1 expression in hepatocytes. This latter effect was more prominent in hepatocytes stimulated with OSM. Although it did not reach statistical significance (P = 0.0539)-analysis of lung tissues showed lower SERPINA1 expression in PiZZ emphysema patients receiving augmentation therapy relative to those without therapy. Finally, exogenously added purified A1AT (1mg/ml) reduced SERPINA1 expression in naive as well as in lipopolysaccharide (LPS)-stimulated human adherent PBMCs. Exogenous A1AT protein reduces its own endogenous expression. Hence, augmentation with native M-A1AT protein and a parallel reduction in expression of dysfunctional mutant Z-A1AT may be beneficial for PiZZ liver, and this motivates further studies.

Background: Interventions that support patient efforts at lifestyle changes that reduce tobacco use, hazardous use of alcohol, unhealthy eating habits and insufficient physical activity represent important areas of development for health care. Current research shows that it is challenging to reorient health care toward health promotion. The aim of this study was to explore the extent of health care professional work with lifestyle interventions in Swedish primary health care, and to describe professional knowledge, attitudes and perceived organizational support for lifestyle interventions. Methods: The study is based on a cross-sectional Web-based survey directed at general practitioners, other physicians, residents, public health nurses and registered nurses (n = 315) in primary health care. Results: Fifty-nine percent of the participants indicated that lifestyle interventions were a substantial part of their duties. A majority (77%) would like to work more with patient lifestyles. Health professionals generally reported a thorough knowledge of lifestyle intervention methods for disease prevention. Significant differences between professional groups were found with regard to specific knowledge and extent of work with lifestyle interventions. Alcohol was the least addressed lifestyle habit. Management was supportive, but structures to sustain work with lifestyle interventions were scarce, and a need for national guidelines was identified. Conclusions: Health professionals reported thorough knowledge and positive attitudes toward lifestyle interventions. When planning for further implementation of lifestyle interventions in primary health care, differences between professional groups in knowledge, extent of work with promotion of healthy lifestyles and lifestyle issues and provision of organizational support such as national guidelines should be considered.

Background: Despite various guidelines, shortcomings in lifestyle counseling in primary care have been demonstrated. Comparisons between countries may provide insight on how to improve such counseling. To the best of our knowledge, studies comparing patients’ views of lifestyle counseling beween the United States (US) and European countries have not been reported. Objectives: To quantify and compare patients’ perspectives in the US and Sweden on primary care providers’ counseling on weight, eating habits, physical activity, smoking, and alcohol consumption. Methods: In a cross-sectional study, 629 patients from Sweden and the US completed a telephone interview about their experiences after a visit to a physician in primary care. The survey focused on patients’ perception of the importance of healthy lifestyle habits, their need to change, their desire to receive support from primary care, and the support they had actually received. Data were analyzed using chi-square or Fisher’s exact test. Results: For three of the four lifestyle habits, the proportion saying they needed to change was higher in the US. The exception was for alcohol, where Swedish subjects indicated a greater need to change. Among those stating a need to change, the proportion saying that they would like to have support from primary care was generally above 80% in both countries. The proportion of US patients reporting that their primary care provider had initiated a discussion of lifestyle modification was, with the exception of alcohol, roughly double the level reported by the Swedish patients. Conclusions: This study demonstrates high and quite similar patient expectations concerning lifestyle counseling in both countries, but more frequent initiation of discussions of most lifestyle issues in US primary care. Further studies, e.g. qualitative interviews with physicians, and medical record reviews, are required to better understand what can explain the differences between countries indicated by the study. © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Helene Johansson1,2, Lars Weinehall1, Maria Emmelin11Epidemiology and Global Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 2Ersboda Health Care Centre, Umeå, SwedenAim: With the overall objective to develop future strategies for a more health-promoting health service in Sweden, the aim of this paper was to describe how health personnel view barriers and possibilities for having a health-promoting role in practice.Materials and methods: Seven focus group discussions were carried out with a total of 34 informants from both hospital and primary health care settings in Sweden. The informants represented seven professional groups; counselors, occupational therapists, assistant nurses, midwives, nurses, physicians, and physiotherapists. The data were analyzed using qualitative content analysis.Results: The analysis resulted in one major theme “If we only got a chance”. The theme captures the health professionals’ positive view about, and their willingness to, develop a healthpromoting and/or preventive role, while at the same time feeling limited by existing values, structures, and resources. The four categories, “organizational commitment to a paradigm shift”, “recognition of staff as health-promoting instruments”, “a balance between resources and tasks”, and “freedom of action” capture what is needed for implementing and increasing health promotion and preventive efforts in the health services.Conclusions: The study indicates that an organizational setting that support health promotion is still to be developed. There is a need for a more explicit leadership with a clear direction towards the goal of “a more health–promoting health service” and with enough resources for achieving this goal.Keywords: qualitative methods, health promotion, health care professionals, health service, perceptions

It is well known that reduced glomerular filtration rate (GFR) leads to an increased risk of dyslipidemia, insulin resistance, and cardiovascular mortality. The liver is a central organ for metabolism, but its function in the uremic setting is still poorly characterized. We used human primary hepatocytes isolated from livers of nine donors with normal renal function to investigate perturbations in key metabolic pathways following exposure to uremic ( n = 8) or healthy ( n = 8) sera, and to serum-free control medium. Both uremic and healthy elicited consistent responses from hepatocytes from multiple donors and compared with serum-free control. However, at physiological insulin concentrations, uremic cells accumulated 56% more intracellular lipids. Also, when comparing uremic with healthy medium after culture, it contained more very-low-density lipoprotein-triglyceride and glucose. These changes were accompanied by decreased phosphorylation of AktS473. mRNA levels of key regulators of gluconeogenesis in uremic sera-treated hepatocytes such as phospho enolpyruvate carboxykinase 1 and glucose 6-phosphate were elevated. We also found increased expression of 11β-hydroxysteroid dehydrogenase mRNA in uremic cells, along with high phosphorylation of downstream p53 and phospholipase C-γ1Y783. Thus our ex vivo data suggest that the uremic hepatocytes rapidly develop a glycogenic and lipogenic condition accompanied by perturbations in a large number of signaling networks.

Primary hepatocytes isolated from human, mouse and rat liver as well as cell lines, such as HepG2 cells, are frequently used in vitro systems in liver research. In regenerative medicine, stem cells are used for differentiation towards hepatocyte-like cells with the goal of creating differentiated functional hepatocytes. It is therefore important to measure the quality and function of highly specialized hepatocyte-specific functions using appropriate methods. In this chapter, we describe an assay to assess conjugation and excretion of labeled bile acids in cultured hepatocytes.

Although NK cells are considered innate, recent studies in mice revealed the existence of a unique lineage of hepatic CD49a+DX5− NK cells with adaptive-like features. Development of this NK cell lineage is, in contrast to conventional NK cells, dependent on T-bet but not Eomes. In this study, we describe the identification of a T-bet+Eomes−CD49a+ NK cell subset readily detectable in the human liver, but not in afferent or efferent hepatic venous or peripheral blood. Human intrahepatic CD49a+ NK cells express killer cell Ig-like receptor and NKG2C, indicative of having undergone clonal-like expansion, are CD56bright, and express low levels of CD16, CD57, and perforin. After stimulation, CD49a+ NK cells express high levels of inflammatory cytokines but degranulate poorly. CD49a+ NK cells retain their phenotype after expansion in long-term in vitro cultures. These results demonstrate the presence of a likely human counterpart of mouse intrahepatic NK cells with adaptive-like features.

Primary hepatocytes isolated from human, mouse and rat liver as well as cell lines, such as HepG2 cells, are frequently used in vitro systems in liver research. In regenerative medicine, stem cells are used for differentiation towards hepatocyte-like cells with the goal of creating differentiated functional hepatocytes. It is therefore important to measure the quality and function of highly specialized hepatocyte-specific functions using appropriate methods. In this chapter, we describe an assay to assess conjugation and excretion of labeled bile acids in cultured hepatocytes.

The intrathecal (i.t.) injection of 3.0 fmol nociceptin (orphanin FQ) elicited scratching, biting and licking responses in mice. N-terminal fragments of nociceptin, nociceptin (1-7), nociceptin (1-9) and nociceptin (1-13), induced no characteristic behavioral response. When these N-terminal fragments of nociceptin were injected simultaneously with nociceptin, the behavioral response induced by nociceptin was reduced dose-dependently. Nociceptin (1-13) was much more potent than nociceptin (1-7) and nociceptin (1-9) and antagonized nociceptin-induced response at equimolar doses. No significant effects of the N-terminal fragments were observed against the scratching, biting and licking response elicited by i.t. administration of substance P or N-methyl-D-aspartate. These results suggest that N-terminal fragments formed endogenously in the spinal cord may have an antagonistic effect on nociceptin-induced behavioral responses.

Background The challenge of an aging population in the society makes it important to find strategies to promote health for all. The aim of this study is to evaluate if repeated health coaching in terms of motivational interviewing, and an offer of wide range of activities, will contribute to positive lifestyle modifications and health among persons aged 60–75 years, with moderately elevated risk for cardiovascular disease (CVD), diabetes, or mild depression. Methods/Design Men and women between 60 and 75 are recruited in four regions in Sweden if they fulfill one or more of the four inclusion criteria. •Current reading of blood pressure (140-159/90-99) without medication. •Current reading of blood sugar (Hba1c 42–52 mmol/mol) without medication. •A current waist-circumference of ≥94 cm for men and ≥80 for women. •A minor/mild depression (12–20 points) according to Montgomery-Åsberg Depression Rating Scale without medication. Individuals with a worse result than inclusion criteria are treated according to regular guidelines at the PHCs and therefore not included. Exclusion criteria for the study are dementia, mental illness or other condition deemed unsuitable for participation. All participants fill out a questionnaire at baseline, and at the 6-, 12- and 18-month follow-ups containing questions on demographic characteristics, social life, HRQoL, lifestyle habits, general health/medication, self-rated mental health, and sense of coherence. At the 12-month follow-up, the health coach will give each participant a second questionnaire to capture attitudes and perceptions related to health coaching and venues/activities offered. Qualitative data will be collected twice to obtain a deeper understanding of perceptions and attitudes related to health and lifestyle/lifestyle modifications. A health economic assessment will be performed. Individual costs for health care utilisation will be collected and QALY-scores will be estimated. Discussion Several drawbacks can be identified when conducting research in real life. However, many of the identified problems can diminish the positive results of the intervention and if the intervention shows positive effects they might be underestimated. Trial registration Current Controlled Trials ISRCTN01396033.

Refined methods for maintaining specific functions of isolated hepatocytes under xeno-free and chemical defined conditions is of great importance for the development of hepatocyte research and regenerative therapy. Laminins, a large family of heterotrimeric basement membrane adhesion proteins, are highly cell and tissue type specific components of the extracellular matrix and strongly influence the behavior and function of associated cells and/or tissues. However, detailed biological functions of many laminin isoforms are still to be evaluated. In this study, we determined the distribution of laminin isoforms in human liver tissue and isolated primary human hepatocytes by western blot analysis, and investigated the efficacy of different human recombinant laminin isoforms on hepatic functions during culture. Protein expressions of laminin-chain α2, α3, α4, β1, β3, γ1, and γ2 were detected in both isolated human hepatocytes and liver tissue. No α1 and α5 expression could be detected in liver tissue or hepatocytes. Hepatocytes were isolated from five different individual livers, and cultured on human recombinant laminin isoforms -111, -211, -221, -332, -411, -421, -511, and -521 (Biolamina AB), matrigel (extracted from Engelbreth-Holm-Swarm sarcoma), or collagen type IV (Collagen). Hepatocytes cultured on laminin showed characteristic hexagonal shape in a flat cell monolayer. Viability, double stranded DNA concentration, and Ki67 expression for hepatocytes cultured for six days on laminin were comparable to those cultured on EHS and Collagen. Hepatocytes cultured on laminin also displayed production of human albumin, alpha-1-antitrypsin, bile acids, and gene expression of liver-enriched factors, such as hepatocyte nuclear factor 4 alpha, glucose-6-phosphate, cytochrome P450 3A4, and multidrug resistance-associated protein 2. We conclude that all forms of human recombinant laminin tested maintain cell viability and liver-specific functions of primary human hepatocytes, and that recombinant laminin is a promising xeno-free and chemical defined strategy for preservation of hepatocyte specific function in vitro.

Background The role of health services must be re-oriented towards health promotion to more effectively contribute to population health. One of the objectives of the Swedish public health policy is that health promotion and disease prevention should be an integral part of the health care system and an important component of all care and treatment. However, the uncertainty about what the concepts of health and health promotion mean poses a challenge for implementation. Depending on how these concepts are interpreted, the attitudes of health professionals toward health promoting practices will differ. Thus, a more in-depth understanding of health professionals' views can be a starting point for a discussion about the values and attitudes that influence the current health care system and about the barriers and possibilities for future development of a health promoting health service. Methods Seven focus group discussions (n = 34) were carried out with health professionals, from different health care settings, to understand how they communicate about health and health promotion. The data were analyzed using qualitative content analysis. Results The analysis of health professional's general understanding of the concept of health resulted in the category; a multi-facetted concept, whilst the category; a subjective assessment describes what health means to themselves. A third category; health is about life, the whole life. describes their understanding of health as an outcome of a multiplicity of contextually dependent determinants. The health professional's multiple ways of associating health promotion to disease prevention suggest a concept that is diffuse, elusive and difficult to apply in practice. Despite a shared view of health, the health professionals described their health promotion role very differently depending partly on how the concept of health promotion was interpreted. The analysis resulted in the development of three ideal types, labelled the demarcater, the integrater and the promoter describing different strategies for handling a health promotion role in practice Conclusion The study suggests that different interpretations of what constitutes health promotion can lead to unnecessary misunderstandings and pose barriers to further development of a health promoting practice.

Helene Johansson1,3, Hans Stenlund1, Lena Lundström2, Lars Weinehall11Epidemiology and Global Health, Department of Public Health and Clinical Medicine, 2Medical Rehabilitation, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden; 3Ersboda Health Care Centre, Umeå, SwedenAim: The objective of this study is to analyze the commitment to a more health-promoting health service and to illuminate important barriers for having a health-promoting role in daily practice, among Swedish health care professionals.Material and method: Out of a total of 3751 health professionals who are working daytime in clinical practice in the province of Västerbotten, 1810 were invited to participate in a survey. The health professionals represented eight different occupational groups: counselors, dieticians, midwives, nurses, occupational therapists, physical therapists, psychologists, and physicians. A questionnaire that operationalized perceptions found in a previous qualitative study was mailed to residential addresses of the participants.Results: The majority believed that health services play a major role in long-term health development in the population and saw a need for health orientation as a strategy to provide more effective health care. Willingness to work more in health promotion and disease prevention was reported significantly more often by women than men, and by primary health care personnel compared to hospital personnel. Among the professional groups, psychologists, occupational therapists, and physiotherapists most frequently reported willingness. The most common barriers to health promotion roles in daily practice were reported to be heavy workload, lack of guidelines, and unclear objectives.Conclusions: This study found strong support for reorientation of health services in the incorporation of a greater health promotion. A number of professions that are not usually associated with health promotion practices are knowledgeable and wish to focus more on health promotion and disease prevention. Management has a major role in creating opportunities for these professionals to participate in health promotion practices. Men and physicians reported less positive attitudes to a more health-promoting health service and often possess high positions of power. Therefore, they may play an important role in the process of change toward more health promotion in health services.Keywords: health promotion, health care professionals, health service, attitudes, barriers

Degradation of methyl mercury by mink was investigated in a series of experiments. Mink were fed daily with a diet containing methyl mercury-contaminated fish. Contents of total mercury, methyl mercury and selenium were determined in different tissues from the animals, as were the contents in faces. Of the total amount of mercury detected, only about 73% was found as methyl mercury. In liver and kindney the proportions were and 55%, respectively. Selenium contents were low compared with those found in marine mammals where equivalent amounts of mercury and selenium on a molar basis been reported. The conditions in mink are compared with earlier studies on cats and marine mammals.

BACKGROUND: The role of primary care professionals in lifestyle counseling for smoking, alcohol consumption, physical activity, and diet is receiving attention at the national level in many countries. The U. S. and Sweden are two countries currently establishing priorities in these areas. A previously existing international research collaboration provides a unique opportunity to study this issue. METHODS: Data from a national survey in Sweden and a study in rural Upstate New York were compared to contrast the perspectives, attitudes, and practice of primary care professionals in the two countries. Answers to four key questions on counseling for tobacco use, alcohol consumption, physical activity, and eating habits were compared. RESULTS: The response rates were 71% (n = 180) and 89% (n = 86) in the Sweden and the U.S. respectively. U.S. professionals rated counseling "very important" significantly more frequently than Swedish professionals for tobacco (99% versus 92%, p