Metabolite profiling of obese individuals before and after a one year weight loss program.

OBJECTIVE: We and others have previously characterized changes in circulating metabolite levels following diet-induced weight loss. Our aim was to investigate whether baseline metabolite levels and weight-loss-induced changes in these are predictive of or associated with changes in body mass index (BMI) and metabolic risk traits. METHODS: Serum metabolites were analyzed with gas and liquid chromatography/mass spectrometry in 91 obese individuals at baseline and after participating in a 1 year non-surgical weight loss program.ResultsA total of 137 metabolites were identified and semi-quantified at baseline (BMI 42.7±5.8, mean±s.d.) and at follow-up (BMI 36.3±6.6). Weight-loss-induced modification was observed for levels of 57 metabolites in individuals with ⩾10% weight loss. Lower baseline levels of xylitol was predictive of a greater decrease in BMI (ß=0.06, P<0.01) and ⩾10% weight loss (odds ratio (OR)=0.2, confidence interval (CI)=0.07-0.7, P=0.01). Decreases in levels of isoleucine, leucine, valine and tyrosine were associated with decrease in BMI (ß>0.1, P<0.05) and ⩾10% weight loss (isoleucine: OR=0.08, CI=0.01-0.3, leucine: OR=0.1, CI=0.01-0.6, valine: OR=0.1, CI=0.02-0.5, tyrosine: OR=0.1, CI=0.03-0.6, P<0.02). CONCLUSIONS: Diet-induced weight loss leads to mainly reduced levels of metabolites that are elevated in obese insulin resistant individuals. We identified multiple new associations with metabolic risk factors and validated several previous findings related to weight loss-mediated metabolite changes. Levels of specific metabolites, such as xylitol, may be predictive of the response to non-surgical weight loss already at baseline.

Spontaneous activity and stretch-induced contractile differentiation are reduced in vascular smooth muscle of miR-143/145 knockout mice.

AIM: Stretch is essential for maintaining the contractile phenotype of vascular smooth muscle cells, and small non-coding microRNAs are known to be important in this process. Using a Dicer knockout model, we have previously reported that microRNAs are essential for stretch-induced differentiation and regulation of L-type calcium channel expression. The aim of this study was to investigate the importance of the smooth muscle-enriched miR-143/145 microRNA cluster for stretch-induced differentiation of the portal vein. METHODS: Contractile force and depolarization-induced calcium influx were determined in portal veins from wild-type and miR-143/145 knockout mice. Stretch-induced contractile differentiation was investigated by determination of mRNA expression following organ culture for 24 h under longitudinal load by a hanging weight. RESULTS: In the absence of miR-143/145, stretch-induced mRNA expression of contractile markers in the portal vein was reduced. This was associated with decreased amplitude of spontaneous activity and depolarization-induced contractile and intracellular calcium responses, while contractile responses to 5-HT were largely maintained. We found that these effects correlated with a reduced basal expression of the pore-forming subunit of L-type calcium channels and an increased expression of CaMKIIδ and the transcriptional repressor DREAM. CONCLUSION: Our results suggest that the microRNA-143/145 cluster plays a role in maintaining stretch-induced contractile differentiation and calcium signalling in the portal vein. This may have important implications for the use of these microRNAs as therapeutic targets in vascular disease.

The societal cost of depression: evidence from 10,000 Swedish patients in psychiatric care.

OBJECTIVE: Depression cost studies have mainly taken a primary care perspective and should be completed with cost estimates from psychiatric care. The objectives of this study were to estimate the societal per-patient cost of depression in specialized psychiatric care in Sweden, and to relate costs to disease severity, depressive episodes, hospitalization, and patient functioning. METHODS: Retrospective resource use data in inpatient and outpatient care for 2006-2008, as well as ICD-10 diagnoses and Global Assessment of Functioning (GAF), were obtained from the Northern Stockholm psychiatric clinic (covering half of Stockholm's population aged 18 years and above). As a complement, data from national registers on pharmaceuticals and sick leave were used in order to estimate the societal cost of depression. RESULTS: Based on 10,430 patients (63% women), the mean annual per-patient cost was €17,279 in 2008. The largest cost item was indirect costs due to productivity losses (88%), followed by outpatient care (6%). Patients with mild and severe depression had average costs of €14,200 and €21,500, respectively. Total costs were substantially higher during depressive episodes, among patients with co-morbid psychosis or anxiety, for hospitalized patients, and for patients with poor functioning. LIMITATIONS: Primary care costs and costs for reduced productivity at work were not included. CONCLUSIONS: The main cost item among depression patients in psychiatric care was indirect costs. Costs were higher than previously reported for primary care, and strongly related to hospitalization, depressive episodes, and low functioning. This suggests that effective treatment that avoids depressive episodes and hospitalization may reduce society's costs for depression.

Ergonomics action research I: shifting from hypothesis testing to experiential learning.

This paper presents the case for the need for 'Action Research' (AR) approaches to gain understanding of how ergonomics considerations can best be integrated into the design of new work systems. The AR researchers work collaboratively with other stakeholders to solve a real-world problem: gaining insight into the problem and factors influencing solution building from an embedded position in the development process. This experience is interpreted in terms of available theory and can support further theory development. This non-experimental approach can help provide practical new approaches for integrating ergonomics considerations into real work system design processes. The AR approach suffers from a lack of acceptance by conventionally trained scientists. This paper aims to help overcome this weakness by developing the underlying theory and rationale for using AR approaches in ergonomics research. We propose further development of hybrid approaches which incorporate other evaluation techniques to extend the knowledge gains from AR projects. PRACTITIONER SUMMARY: Researchers should engage directly with organisations in ergonomics projects so that they can better understand the challenges and needs of practitioners who are trying to apply available scientific knowledge in their own unique context. Such 'Action Research' could help develop theory and approaches useful to improve mobilisation and application of ergonomics knowledge in organisations.

Cost effectiveness of cardiac resynchronization therapy in Greece: an analysis based on the CArdiac REsychronization in Heart Failure trial.

AIMS: Health economic considerations have become increasingly important in healthcare. The aim of this study was to investigate the incremental cost effectiveness of cardiac resynchronization therapy (CRT) plus medical therapy compared with medical therapy alone in the Greek health-care system. METHODS AND RESULTS: The health economic analysis was based on the CARE-HF trial, a randomized clinical trial estimating the efficacy of adding CRT (n = 409) to optimal pharmacological treatment (n = 404) in patients with moderate-to-severe heart failure with markers of cardiac dyssynchrony. Health care resource use from CArdiac REsychronization in Heart Failure was combined with costs for CRT implantation and hospitalization from publicly available sources. The analysis was based on a lifetime perspective, with the life expectancy estimated from the clinical trial data. Shorter time horizons were explored in the sensitivity analysis. The cost per quality-adjusted life year (QALY) gained with CRT was €6,045 in Greece, with a 95% confidence interval for the cost-effectiveness ratio of €4,292-9,411 per QALY gained. CONCLUSIONS: The results of the economic evaluation of CRT in Greek health-care setting indicate that it is a cost-effective treatment compared with traditional pharmacological therapy. Cardiac resynchronization therapy can therefore be recommended for routine use in patients with moderate-to-severe heart failure and markers of dyssynchrony.

Diameter and compliance of the greater saphenous vein - effect of age and nitroglycerine.

OBJECTIVES: The greater saphenous vein (GSV) is commonly used in autologous vein graft surgery. GSV diameter has proven to influence graft patency, and furthermore venous compliance might be of importance. The purpose of the study was to evaluate the effect of age on GSV diameter and compliance, and to evaluate the effect of nitroglycerine (NTG). METHODS: The diameter and compliance of the GSV, with and without NTG, were examined with B-mode ultrasound in 12 elderly (70·3 ± 1·2 year) and 15 young (25·1 ± 0·6 year) men. The GSV diameter at the thigh and calf level was measured at rest, after 6 min of venous stasis (60 mmHg) and after NTG administration. Pressure-area curves during a linear venous pressure decrease were produced. Venous compliance was calculated using the quadratic regression equation (area) = ß(0) + ß(1) (cuff pressure) + ß(2) (cuff pressure)(2) . RESULTS: GVS diameter between the groups showed significant lower diameter in elderly compared to young men (P<0·05). Venous occlusion increased GSV diameter in elderly men (P<0·01) as well as young men (P<0·001). NTG increased GSV diameter in elderly men (P<0·01) with an equal trend in young men. During venous occlusion, after administration of NTG, GSV diameter increased further in both elderly (P<0·01) and young men (P<0·001). GSV compliance was decreased in elderly (ß(1) , 0·037 ± 0019, ß(2,) -0·000064 ± 00017) versus young men (ß(1) , 0·128 ± 0·013, ß(2) , -0·00010 ± 000018) [P<0·001 (ß(1) ), P<0·02 (ß(2) )]. CONCLUSIONS: Baseline GSV diameter as well as GSV compliance is decreased in elderly men compared to the young subjects. As reduced GSV diameter as well as reduced compliance is related to decreased graft patency, these findings might be of importance for the uses of GSV as graft material in cardiovascular bypass surgery. The clinical value has to be clarified in future studies.

Health-economic evaluation of three imaging strategies in patients with suspected colorectal liver metastases: Gd-EOB-DTPA-enhanced MRI vs. extracellular contrast media-enhanced MRI and 3-phase MDCT in Germany, Italy and Sweden.

The purpose of this study was to perform an economic evaluation of hepatocyte-specific Gd-EOB-DTPA enhanced MRI (PV-MRI) compared to extracellular contrast-media-enhanced MRI (ECCM-MRI) and three-phase-MDCT as initial modalities in the work-up of patients with metachronous colorectal liver metastases. The economic evaluation was performed with a decision-tree model designed to estimate all aggregated costs depending on the initial investigation. Probabilities on the need for further imaging to come to a treatment decision were collected through interviews with 13 pairs of each a radiologist and a liver surgeon in Germany, Italy and Sweden. The rate of further imaging needed was 8.6% after initial PV-MRI, 18.5% after ECCM-MRI and 23.5% after MDCT. Considering the cost of all diagnostic work-up, intra-operative treatment changes and unnecessary surgery, a strategy starting with PV-MRI with 959 Euro was cost-saving compared to ECCM-MRI (1,123 Euro) and MDCT (1,044 Euro) in Sweden. In Italy and Germany, PV-MRI was cost-saving compared to ECCM-MRI and had total costs similar to MDCT. In conclusion, our results indicate that PV-MRI can lead to cost savings by improving pre-operative planning and decreasing intra-operative changes. The higher cost of imaging with PV-MRI is offset in such a scenario by lower costs for additional imaging and less intra-operative changes.

Thrombin generation assay: a useful routine check-up tool in the management of patients with haemophilia?

Severity assessment of patients with haemophilia A (HA) is traditionally based on FVIII activity (FVIII:C). Clinical phenotype of HA patients often differs between individuals with the same FVIII:C determined with clotting and chromogenic assays. The aim of this study was to assess the influence of the FVIII:C on thrombin generation (TG) assay parameters both in vitro and ex-vivo postinfusion plasma. For in-vitro approach, influence of FVIII:C was evaluated on TG parameters in several dilutions of a normal plasma pool with commercial FVIII-depleted-plasma (FVIIIDP) and in others experiments, adding increasing amounts of different commercial FVIII concentrates (Fanhdi, Haemate-P, Hemofil-M and Kogenate Bayer) to FVIIIDP. In a series of 50 postinfusion samples, from HA patients of different severity, we assayed TG and FVIII:C (chromogenic and clotting). In vitro experiments, the 50% of maximum TG peak (TGMP) was achieved using only 5% FVIII:C and the TGMP was obtained with 40% of normal VIII:C. Impaired response compared with normal plasma was found in FVIIIDP using addition of increasing amounts of different commercial FVIII concentrates. An overall good correlation between the two FVIII assays was observed (y = 0.9115x - 0.273, r = 0.975, P < 0.001); TGMP and the Lag-Phase-Time (LPT) provided some discrepant results when compared with the total range of FVIII:C measurements. In contrast, correlations for TGMP, LPT and endogenous thrombin potential were improved in samples restricted to FVIII:C <5%. We conclude that TG parameters tentatively could be a tool to tailor the global haemostatic capacity in haemophilic patients.

Expression of both oestrogen receptor alpha and beta in human skeletal muscle tissue.

There are two oestrogen receptors (ERs), ERalpha and ERbeta. ERbeta protein is expressed in human skeletal muscle in the nuclei of both myofibres and endothelial cells, whether ERalpha protein is present in this tissue is unknown. We studied the expression of ERalpha protein in human skeletal muscle biopsies taken from vastus lateralis from four men, four women, two children and two postmenopausal women. Immunohistochemistry was used to determine the proportions of nuclei that were positively stained for ERalpha, the proportion of ERalpha-positive nuclei located in the muscle fibres and in capillaries and to test for possible co-expression of ERalpha and ERbeta. Both ERs were expressed in all subjects. Of all nuclei, 63% stained for ERalpha with no sex difference. ERalpha was localised both in myofibres and in endothelial cells of the capillaries, 25% of the ERalpha-positive nuclei were located in the capillaries. ERalpha and ERbeta were generally expressed in the same nuclei. The present study shows for the first time the expression of ERalpha protein in human skeletal muscle independently of age and sex. These results might improve understanding of the physiological role of oestrogen in human skeletal muscle and raise new questions about activation of ERs in skeletal muscle.

An in vitro model for studying neuromuscular transmission in the mouse pharynx.

The muscles of the pharynx are controlled by networks of neurons under the control of specific regions in the brain stem, which have been fairly well studied. However, the transmission between these neurons and the pharyngeal muscles, at the motor end plates, is less well understood. Therefore, an in vitro model for the study of neuromuscular transmission in the pharyngeal muscle of the mouse was developed. Ring preparations from the inferior constrictor and the cricopharyngeus muscles were isolated and mounted for isometric force recording at physiologic temperature. Preparations from the diaphragm and the soleus muscles were examined in parallel. The muscles were stimulated at supramaximal voltage with short tetani at 100 Hz. Following direct stimulation of the muscle fibers, using a longer pulse duration, the rate of force development of the pharyngeal muscles was similar to that of the diaphragm and faster than that of the soleus muscle. By varying the duration of the stimulation pulses, conditions where the nerve-mediated activation contributed to a major extent of the contractile responses were identified. Gallamine completely inhibited the nerve-mediated responses. In separate experiments the dose dependence of gallamine inhibition was examined, showing similar sensitivity in the inferior pharyngeal constrictor compared to the diaphragm and soleus muscles. We conclude that reproducible contractile responses with an identifiable nerve-induced component can be obtained from the mouse inferior pharyngeal constrictor. The pharyngeal muscles have contractile characteristics similar to those of the faster diaphragm. The sensitivity to the neuromuscular blocking agent gallamine of the inferior pharyngeal constrictor was in the same concentration range as that of the diaphragm and soleus muscles.

Cost effectiveness of cardiac resynchronization therapy in the Nordic region: an analysis based on the CARE-HF trial.

BACKGROUND: The aim of this study was to investigate the cost-effectiveness of cardiac resynchronization therapy (CRT) in Denmark, Finland and Sweden. The analysis was based on the CARE-HF trial, a randomised clinical trial investigating the efficacy of adding CRT (n=409) to optimal pharmacological treatment (n=404) in patients with moderate to severe heart failure with markers of cardiac dyssynchrony. The average follow-up time was 29.4 months. METHODS: The health effects were measured in terms of quality-adjusted life years (QALYs) gained. Data on health care resource consumption from CARE-HF was combined with costs for CRT implantation and hospitalisation from university hospitals in Denmark, Finland and Sweden. Calculations were based on patients' expected life time. The expected device lifetime (6 years) was used for CRT, and no additional gains in clinical effects were assumed after the 6 years. RESULTS: The cost-effectiveness ratio per QALY gained was 4800 euros in Denmark, 3600 euros in Finland and 6700 euros in Sweden. The 95% confidence intervals for the cost per QALY gained varied between a lower limit of 1169 euros in Finland to an upper limit of 17,482 euros in Sweden. These values were all below the threshold for being cost-effective in Denmark, Finland and Sweden. CONCLUSIONS: The study indicates that CRT is a cost-effective treatment in Scandinavian health care settings compared to traditional pharmacological therapy and can therefore be recommended for routine use in patients with moderate to severe heart failure and markers of dyssynchrony.

Cost-effectiveness of irbesartan/hydrochlorothiazide in patients with hypertension: an economic evaluation for Sweden.

Irbesartan, an angiotensin-II inhibitor, has been shown to be an effective antihypertensive agent in clinical trials. The purpose of this study was to assess the cost-effectiveness of irbesartan in combination with hydrochlorothiazide (HCTZ) in Swedish health-care setting by predicting clinical events and life years based upon observed reductions in blood pressure in clinical trials. The cost-effectiveness of antihypertensive treatment with irbesartan compared with placebo and to other selected angiotensin-II inhibitors (losartan, valsartan, candesartan) in combination with HCTZ was estimated using a Markov model. The incidence of cardiovascular disease was obtained from the Swedish inpatient registry, whereas the risk reductions associated with antihypertensive therapy were taken from the medical literature. Costs for antihypertensive therapy and for treatment of cardiovascular events were included, and the health effects were measured in terms of quality-adjusted life years (QALYs). The study was conducted from a health-care payer perspective. For a 55-year-old male, irbesartan 150 mg/HCTZ 12.5 mg was a dominant strategy (better health effects at lower costs) when compared with losartan 50 mg/HCTZ 12.5 mg and valsartan 80 mg/HCTZ 12.5 mg, and the cost-effectiveness ratio compared with placebo was 3500 euros per QALY gained. In moderate-to-severe hypertension, irbesartan was cost-effective compared with losartan, whereas the results compared with candesartan were mixed. High-dose combination therapy of irbesartan was also found to be cost-effective compared with low-dose combination therapy. The results from the model indicate that irbesartan provides a cost-effective antihypertensive treatment strategy compared with both placebo, and to valsartan and losartan.

The cost-utility of maintenance treatment with venlafaxine in patients with recurrent major depressive disorder.

AIMS: The Prevention of Recurrent Episodes of Depression with venlafaxine XR for Two Years trial has reported advantages with maintenance treatment for patients with recurrent depressive disorder. The aim of this study was to assess the cost-utility of maintenance treatment with venlafaxine in patients with recurrent major depressive disorder, based on a recent clinical trial. METHODS: A Markov simulation model was constructed to assess the cost-utility of maintenance treatment for 2 years in recurrently depressed patients in Sweden. Risk of relapse and recurrence was based on a recent randomised clinical trial assessing the efficacy and tolerability of maintenance treatment with venlafaxine over 2 years. Costs and quality of life estimations were retrieved from a naturalistic longitudinal observational study conducted in Sweden. Health effects were quantified as quality-adjusted life-years (QALYs). Sensitivity analyses were conducted on key parameters employed in the model. RESULTS: In the base-case analysis, the cost per QALY gained of venlafaxine compared with no treatment was estimated at $18,500 over 2 years. In a probabilistic sensitivity analysis, we found that maintenance treatment with venlafaxine is cost-effective with 90% probability at a willingness to pay per QALY of $67,000 or less. Our long-term analyses also indicate that even under conservative assumptions about future risks of recurrences, maintenance treatment is cost-effective. CONCLUSION: The present study indicates that maintenance treatment for 2 years with venlafaxine is cost-effective in patients with recurrent major depressive disorder.

Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation.

In order to describe the haemostatic role of a variation in inhibitor reactivity with different factor VIII (FVIII) concentrates, we have compared inhibitor titres against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested in vitro in mixing experiments with inhibitor plasmas from 11 patients with severe haemophilia A: Fanhdi, which contains von Willebrand factor (VWF) with a final ratio of approximately 1:1 (VWF IU per IU FVIII:C); Haemate-P with a ratio of 2.5:1 and Hemofil-M containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer containing no VWF was included. Inhibitor titres and the capacity to generate thrombin were measured. A statistically significant difference in measured titres was found with the highest titres recorded against Hemofil-M. The inhibitor titres needed to inhibit 50% maximum thrombin generation were the lowest for Kogenate Bayer and the highest and similar for Fanhdi and Haemate-P with intermediate titres needed for inhibition of Hemofil-M. In this study, the thrombin generation assay provides additional indications for the role of VWF in the treatment of patients with inhibitors. The VWF-containing concentrates Fanhdi and Haemate-P, added to FVIII-deficient plasma with the presence of inhibitor, generate more thrombin than do the purified concentrates Hemofil-M and Kogenate Bayer.

Resource use and costs associated with patients treated for depression in primary care.

We investigated medical resource consumption, productivity loss and costs associated with patients treated with antidepressants for depression in primary care in Sweden. Patients on treatment for depression were followed naturalistically for six-months, and data on patients' characteristics, daily activity and resource-use were collected. The total cost per patient was estimated at euro 5,500 (95%CI euro 5,000-6,100) over six months in 2005 prices. Direct costs were estimated at euro 1,900 (euro 1,700-2,200), 35% of total costs, and indirect costs at euro 3,600 (euro 3,100-4,100), 65% of total costs. The cost for antidepressants represented only 4% of the total costs. We conclude that the burden of depression is high, both to the individual as well as to wider society, and there seems to be a particular need for therapies that have the potential to improve productivity in depressed patients.

The mission is remission: health economic consequences of achieving full remission with antidepressant treatment for depression.

The aim of the present study was to determine the magnitude of the impact of treating depression to full remission on cost and health-related quality of life. In a naturalistic longitudinal survey recordings of resource use and quality of life were carried out among depressed patients treated with antidepressant therapy in 56 Swedish primary care clinics. We found that a total of 52% of the patients achieved full remission during the study period. Remitting patients had, on average, three outpatient visits less than non-remitting patients (p < 0.01), 22 fewer sick leave days (p = 0.01), which translated into a significantly lower total cost (Euro 2700) compared with non-remitting patients (p < 0.01). Health-related quality-of-life scores improved by 40% for remitting patients when compared with non-remitting ones (p < 0.01). We conclude that remission has a substantial health economic impact on patients treated for depression, which further strengthens the importance of aiming for full remission in the treatment of depression.

Expression of oestrogen receptor alpha and beta is higher in skeletal muscle of highly endurance-trained than of moderately active men.

AIM: Two known oestrogen receptors (ERs), ERalpha and the recently cloned ERbeta, are expressed in the human skeletal muscle of both males and females. The effects of oestrogen and the role of ERs in skeletal muscle tissue are not well known. Oestrogen receptors and some of their target genes are involved in angiogenic processes. It was hypothesized that ERs are expressed at a higher level in a group with higher oxidative capacity, and that such an enhanced expression would parallel expression of the angiogenic factor -- vascular endothelial growth factor (VEGF). METHOD: Muscle biopsies were taken from vastus lateralis in 10 highly endurance-trained males and 10 moderately active males and analysed for the expression of ERs and VEGF. RESULTS: The major findings in the present study were the higher mRNA levels of ERalpha, ERbeta and VEGF in the highly endurance-trained than in the moderately active group. CONCLUSION: These data suggest that the greater mRNA expression of ERalpha and ERbeta and the oestrogen-associated angiogenic factor VEGF support the hypothesis of an involvement of ERs in the adaptation of skeletal muscle to endurance training.