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  • 1. Al-Ani, Amer
    et al.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Säff, Maria
    Neander, Gustaf
    Blomfeldt, Richard
    Ekström, Wilhelmina
    Hedström, Margareta
    Low bone mineral density and fat free mass in young and middle-aged patients with a femoral neck fracture2015In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 45, no 8, p. 800-806Article in journal (Refereed)
    Abstract [en]

    Background

    Reduced bone mineral density (BMD) together with muscle wasting and dysfunction, that is sarcopenia, emerges as a risk factor for hip fracture. The aim of this study was to examine body composition and BMD and their relationship with trauma mechanisms in young and middle-aged patients with femoral neck fracture.

    Materials and methods

    Altogether, 185 patients with femoral neck fracture aged 20–69 were included. BMD, body composition and fat-free mass index (FFMI) were determined by dual-X-ray absorptiometry (DXA), and trauma mechanisms were registered.

    Results

    Ninety per cent of the whole study population had a femoral neck BMD below the mean for age. In the young patients (< 50 years), 27% had a Z-score of BMD ≤ −2 SD. More than half of the middle-aged patients (50–69 years) had osteopenia, that is T-score −1 to −2·5, and 35% had osteoporosis, that is T-score < −2·5, at the femoral neck. Patients with low-energy trauma, sport injury or high-energy trauma had a median standardised BMD of 0·702, 0·740 vs. 0·803 g/cm2 (= 0·03), and a median FFMI of 15·9, 17·7 vs. 17·5 kg/m2 (< 0·001), respectively. FFMI < 10th percentile of an age- and gender-matched reference population was observed in one-third.

    Conclusions

    A majority had low BMD at the femoral neck, and one-third had reduced FFMI (i.e. sarcopenia). Patients with fracture following low-energy trauma had significantly lower femoral neck BMD and FFMI than patients with other trauma mechanisms. DXA examination of both BMD and body composition could be of value especially in those with low-energy trauma.

  • 2. Al-Ani, Amer N.
    et al.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Saaf, Maria
    Neander, Gustaf
    Blomfeldt, Richard
    Ekstrom, Wilhelmina
    Hedstrom, Margareta
    Low bone mineral density and fat-free mass in younger patients with a femoral neck fracture2015In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 45, no 8, p. 800-806Article in journal (Refereed)
    Abstract [en]

    Background Reduced bone mineral density (BMD) together with muscle wasting and dysfunction, that is sarcopenia, emerges as a risk factor for hip fracture. The aim of this study was to examine body composition and BMD and their relationship with trauma mechanisms in young and middle-aged patients with femoral neck fracture. Materials and methods Altogether, 185 patients with femoral neck fracture aged 20-69 were included. BMD, body composition and fat-free mass index (FFMI) were determined by dual-X-ray absorptiometry (DXA), and trauma mechanisms were registered. Results Ninety per cent of the whole study population had a femoral neck BMD below the mean for age. In the young patients (<50years), 27% had a Z-score of BMD-2 SD. More than half of the middle-aged patients (50-69years) had osteopenia, that is T-score -1 to -25, and 35% had osteoporosis, that is T-score<-25, at the femoral neck. Patients with low-energy trauma, sport injury or high-energy trauma had a median standardised BMD of 0702, 0740 vs. 0803g/cm(2) (P=003), and a median FFMI of 159, 177 vs. 175kg/m(2) (P<0001), respectively. FFMI<10th percentile of an age- and gender-matched reference population was observed in one-third. Conclusions A majority had low BMD at the femoral neck, and one-third had reduced FFMI (i.e. sarcopenia). Patients with fracture following low-energy trauma had significantly lower femoral neck BMD and FFMI than patients with other trauma mechanisms. DXA examination of both BMD and body composition could be of value especially in those with low-energy trauma.

  • 3.
    Bellomo, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Gahman, T. C.
    Ludwig Canc Res, La Jolla, CA USA..
    Shiau, A. K.
    Ludwig Canc Res, La Jolla, CA USA..
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    TGF beta and the nuclear receptor LXR alpha crosstalk on lipid metabolism and epithelial to mesenchymal transition in hepatocellular carcinoma2016In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 46, p. 36-36Article in journal (Other academic)
  • 4.
    Carlstedt, F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wide, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Rastad, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Serum levels of parathyroid hormone are related to the mortality and severity of illness in patients in the emergency department1997In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 27, no 12, p. 977-981Article in journal (Refereed)
    Abstract [en]

    Hypocalcaemia is a common finding in intensive care patients. In addition, raised levels of parathyroid hormone (PTH) have been described. The explanation and clinical importance of these findings are yet to be revealed. To investigate the occurrence of hypocalcaemia and elevated PTH levels and their relationship to morality and the severity of disease, serum levels of PTH, ionized calcium (Ca2+) and the cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were measured on arrival in the emergency department in a broad spectrum of 140 acutely ill patients patients suffering from common diseases such as stroke, acute abdominal disorders, obstructive lung diseases, heart failure, acute myocardial infarction, angina pectoris, trauma and infectious diseases. A score (APACHE II) was calculated to assess the severity of disease. Elevated PTH levels (> 55 pg ml-1) were seen in 16% of the patients, being most frequent in patients with myocardial infarction (28%) and congestive heart failure (42%). The levels were significantly correlated with the APACHE II score (r = 0.48, P < 0.0001) and with the length of stay in hospital (r = 0.26, P < 0.002). PTH was also significantly (P < 0.03) elevated in non-survivors compared with survivors and was found to be a stronger predictor of mortality (P < 0.01) than the APACHE II score (P < 0.02) in Cox's proportional hazard analysis. No close relationships were found between the cytokine levels and the indices of calcium metabolism. In conclusion, a rise in serum levels of PTH was common and related to the severity of disease and mortality in a mixed emergency department population.

  • 5.
    Christoffersson, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evalina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Massena, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Powers, A. C.
    Opdenakker, G.
    Phillipson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    A distinct subset of proangiogenic CD11b(+)/Gr-1(+)/CXCR4(+)/MMP-9(hi) neutrophils are recruited by VEGF-A to transplanted hypoxic tissue2013In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 43, no SI, p. 9-9Article in journal (Other academic)
  • 6.
    Cunningham, Janet L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Janson, Eva T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    The biological hallmarks of ileal carcinoids2011In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 12, p. 1353-1360Article, review/survey (Refereed)
    Abstract [en]

    Endocrine tumours derived from the small intestine, ileal carcinoids, produce and secrete the hormones tachykinins and serotonin, which induces the specific symptoms related to the tumour. Because of their low proliferation rate, they are often discovered at late stages when metastases have occurred. The biology that characterizes these tumours differs in many ways from what is generally recognized for other malignancies. In this overview, the current knowledge on the development and progression of ileal carcinoids is described.

  • 7. Emilsson, Louise
    et al.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ludvigsson, Jonas F.
    Ischaemic heart disease in first-degree relatives to coeliac patients2014In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 44, no 4, p. 359-364Article in journal (Refereed)
    Abstract [en]

    ObjectiveCoeliac disease (CD) has been linked to an increased risk of ischaemic heart disease (IHD). We examined the risk of IHD in first-degree relatives and spouses to coeliac patients to ascertain the genetic contribution to IHD excess risk. Study design and settingCoeliac disease was defined as having a biopsy-verified villous atrophy (Marsh grade 3) in 1969-2008 (n=29096). Coeliac patients were matched to 144522 controls. Through Swedish registers, we identified all first-degree relatives and spouses to coeliac patients and their controls, in total 87622 unique coeliac relatives and 432655 unique control relatives. Our main outcome measure was IHD defined according to relevant international classification of disease codes in the Swedish Inpatient Registry or in the Cause of Death Registry. Hazard ratios (HR) and confidence intervals (CI) were estimated through Cox regression adjusted for sex, age-group and calendar year at study entry of the relative. ResultDuring a median follow-up of 10<bold>8</bold>years, 2880 coeliac relatives and 13817 control relatives experienced IHD. First-degree relatives of coeliac patients were at increased risk of IHD (HR=1<bold>05</bold>; 95% CI=1<bold>00</bold>-1<bold>09</bold>, P-value=0<bold>04</bold>), while spouses were at no increased risk (HR=0<bold>99</bold>; 95% CI=0<bold>87</bold>-1<bold>12</bold>). The excess risk of IHD in coeliac first-degree relatives aged 40-59years was 70/100000 person-years. ConclusionFirst-degree relatives to coeliac patients seem to be at an increased risk of IHD but the excess risk is so small that it has little clinical relevance.

  • 8.
    Farrokhnia, Nasim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Ericsson, A.
    Terént, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    MEK-inhibitor U0126 in hyperglycaemic focal ischaemic brain injury in the rat2008In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 38, no 9, p. 679-85Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hyperglycaemia aggravates ischaemic brain injury, possibly due to activation of signalling pathways involving mitogen-activated protein kinases (MAPK). In this study, the activation of MAPK/ERK was inhibited using the upstream inhibitor of MAPK-ERK-kinase (MEK) U0126, and the effects on focal brain ischaemia were evaluated during normo- and hyperglycaemia. MATERIALS AND METHODS: Temporary (90 min) middle cerebral artery occlusion (MCAO) was induced in five groups of rats. U0126 (400 microg kg(-1)) or vehicle was given as 60-min intravenous infusions starting either 30 min prior to MCAO or 30 min prior to reperfusion. The infarct size was determined by perfusion with tetrazolium red after 24 h of survival, and the neurology was tested with the 4-level scale of Bederson and performance on an inclined plane. The inhibitory effect on the targeted MEK enzyme was investigated by analysing the phosphorylation of the downstream target ERK with western immunoblotting. Two subgroups were investigated with magnetic resonance imaging (MRI), including diffusion-weighted (DWI) and perfusion-weighted imaging (PWI). RESULTS: U0126 effectively reduced the infarct size and improved neurology in hyperglycaemic rats both when given before and after ischemic onset. This effect was not accompanied by any detectable changes in cerebral blood flow on MRI. Normoglycaemic rats had generally milder injuries compared with the hyperglycaemic and there was a nonsignificant trend for U0126 to reduce damage also in the nonhyperglycaemic groups. CONCLUSIONS: In conclusion, U0126 appears to be neuroprotective in this model of hyperglycaemic ischaemic brain injury. The findings support the pathogenic importance of the MEK-ERK pathway in hyperglycaemic-ischaemic brain injury.

  • 9.
    Farrokhnia, Nasim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Roos, Magnus W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Differential early mitogen-activated protein kinase activation in hyperglycemic ischemic brain injury in the rat2005In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 35, no 7, p. 457-463Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hyperglycemia aggravates brain injury induced by focal ischemia-reperfusion. The mitogen-activated protein kinase (MAPK) members extracellular-signal regulated kinase (Erk) and c-Jun N-terminal kinase (JNK) have been proposed as mediators of ischemic brain injury, and Erk is strongly activated by combined hyperglycemia and transient global ischemia. It is unclear whether similar MAPK activation appears in focal brain ischemia with concomitant hyperglycemia. DESIGN: Hyperglycemia was induced in rats by an intraperitoneal bolus of glucose (2 g kg(-1)). The rats were then subjected to 90 min of transient middle cerebral artery occlusion (MCAO). Erk and JNK activation were investigated with immunofluorescence and Western blot along with infarct size measurement based on tetrazolium staining and neurological score. RESULTS: The hyperglycemic rats showed increased tissue damage and impaired neurological performance after 1 day compared with controls. The hyperglycemia was generally moderate (< 15 mM). Erk activation was increased after 30 min of reperfusion in the ischemic cortex of the hyperglycemic rats, while JNK activation was present on the contralateral side. Phospho-Erk immunofluorescence revealed marked neuronal activation of Erk in the ischemic cortex of hyperglycemic rats compared with controls. CONCLUSION: Besides confirming the detrimental effects of hyperglycemia on focal ischemia-reperfusion, this study shows that hyperglycemia strongly activates the pathogenic mediator Erk in the ischemic brain in the early phase of reperfusion. JNK activation at this stage is present in the nonischemic hemisphere. The functional relevance of these findings needs further investigation.

  • 10.
    Giannelli, Gianluigi
    et al.
    Univ Bari, Dept Biomed Sci & Human Oncol, Sch Med, Bari, Italy..
    Mikulits, Wolfgang
    Med Univ Vienna, Ctr Comprehens Canc, Div Inst Canc Res, Dept Med 1, Vienna, Austria..
    Dooley, Steven
    Mannheim Heidelberg Univ, Fac Med, Dept Med 2, Heidelberg, Germany..
    Fabregat, Isabel
    Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain..
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    ten Dijke, Peter
    Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, Postbus 9600, NL-2300 RC Leiden, Netherlands..
    Portincasa, Piero
    Univ Bari, Dept Biomed Sci & Human Oncol, Sch Med, Bari, Italy..
    Winter, Peter
    GenXPro GmbH, Frankfurt, Germany..
    Janssen, Richard
    Galapagos, Leiden, Netherlands..
    Leporatti, Stefano
    CNR, NANOTEC Inst Nanotechnol, Lecce, Italy..
    Herrera, Blanca
    Univ Complutense, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Dept Bioquim & Biol Mol 2, E-28040 Madrid, Spain..
    Sanchez, Aranzazu
    Univ Complutense, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Dept Bioquim & Biol Mol 2, E-28040 Madrid, Spain..
    The rationale for targeting TGF-beta in chronic liver diseases2016In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 46, no 4, p. 349-361Article, review/survey (Refereed)
    Abstract [en]

    BackgroundTransforming growth factor (TGF)- is a pluripotent cytokine that displays several tissue-specific biological activities. In the liver, TGF- is considered a fundamental molecule, controlling organ size and growth by limiting hepatocyte proliferation. It is involved in fibrogenesis and, therefore, in worsening liver damage, as well as in triggering the development of hepatocellular carcinoma (HCC). TGF- is known to act as an oncosuppressor and also as a tumour promoter in HCC, but its role is still unclear. DesignIn this review, we discuss the potential role of TGF- in regulating the tumoural progression of HCC, and therefore the rationale for targeting this molecule in patients with HCC. ResultsA considerable amount of experimental preclinical evidence suggests that TGF- is a promising druggable target in patients with HCC. To support this hypothesis, a phase II clinical trial is currently ongoing using a TGF- pathway inhibitor, and results will soon be available. ConclusionsThe identification of new TGF- related biomarkers will help to select those patients most likely to benefit from therapy aimed at inhibiting the TGF- pathway. New formulations that may provide a more controlled and sustained delivery of the drug will improve the therapeutic success of such treatments.

  • 11.
    Herrera Hidalgo, Carmen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ullsten, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Parv, Kristel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Liu, Haoyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Effect of neonatal infections on pancreatic macrophages, islet development and long-term glucose homeostasis2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 83-83Article in journal (Other academic)
  • 12.
    Ingelsson, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hulthe, J
    Lind, L
    Inflammatory markers in relation to insulin resistance and the metabolic syndrome2008In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 38, no 7, p. 502-509Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Inflammation has repeatedly been demonstrated to be associated with the metabolic syndrome (MetS) and insulin resistance, but the relative importance of different aspects of the inflammatory process is largely unexplored. DESIGN: We measured circulating interleukins (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10); other cytokines (tumour necrosis factor-alpha, interferon gamma and monocyte chemotactic protein-1), cell adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, E-selectin, P-selectin, l-selectin], and systemic inflammation markers [C-reactive protein (CRP) and leukocyte count] in 943 70 year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. We related these biomarkers to MetS and the homeostasis model assessment insulin resistance index (HOMA-IR). RESULTS: In a multivariable model including all inflammatory markers conjointly together with sex, log VCAM-1 [odds ratio (OR), 1.45; 95% confidence interval (CI), 1.22-1.72 per 1 SD increase; P < 0.0001], log E-selectin (OR, 1.33; 95% CI, 1.12-1.57 per 1SD increase; P = 0.001), and log CRP (OR, 1.41; 95% CI, 1.20-1.66 per 1-SD increase; P < 0.0001) were independently associated with MetS. These biomarkers were also independently associated with HOMA-IR. CONCLUSIONS: Among 17 inflammatory biomarkers, most of them previously not examined in relation to MetS and insulin resistance, VCAM-1, E-selectin and CRP demonstrated the strongest associations with MetS and insulin resistance in our community based sample of the elderly. The relative importance of these biomarkers in predicting the development of MetS, insulin resistance and cardiovascular disease needs to be further examined in a longitudinal setting.

  • 13. Jansson, P-A
    et al.
    Eliasson, B
    Lindmark, S
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients--potential role of steroid hormones and leptin in the development of insulin resistance.2002In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 32, no 3, p. 172-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: First-degree relatives of type 2 diabetes patients are at risk of developing diabetes and they display several metabolic and hormonal perturbations. The interplay between insulin resistance, steroid hormones and circulating leptin is, however, still not fully explored in this group.

    DESIGN: Thirty-three healthy first-degree relatives of type 2 diabetic patients (relatives; M/F 19/14) were compared to 33 healthy subjects without a family history of diabetes (controls) and the groups were matched for gender, age and body mass index (BMI). We performed euglycaemic hyperinsulinaemic clamps and blood was sampled for hormone analyses.

    RESULTS: Relatives exhibited decreased insulin sensitivity (index of metabolic clearance rate of glucose; MCRI) but when genders were analysed separately, this difference was significant only in males (11.3 +/- 1.3 vs. 15.0 +/- 1.5 units, means +/- SEM, P = 0.030). In male relatives morning cortisol and testosterone levels were lower, whereas leptin was higher than in male controls (P = 0.018, 0.008 and 0.063, respectively). In male relatives plasma testosterone levels were significantly associated with insulin sensitivity (r = 0.48, P = 0.040). Circulating leptin levels were inversely correlated with insulin sensitivity in all subject groups (r-values -0.49 to -0.66; P < 0.05, except in female control subjects P = 0.063). These associations were present also when age and BMI or waist:hip ratio were included in stepwise multiple regression analyses.

    CONCLUSION: Male subjects genetically predisposed for type 2 diabetes display several endocrine abnormalities including leptin, cortisol and testosterone levels. Dysregulation of these hormones may be important in the development of insulin resistance and type 2 diabetes.

  • 14. Kahan, Thomas
    et al.
    Forslund, Lennart
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Björkander, Inge
    Billing, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Diabetes Nursing Research.
    Eriksson, Sven V
    Näsman, Per
    Rehnqvist, Nina
    Hjemdahl, Paul
    Risk prediction in stable angina pectoris2013In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 43, no 2, p. 141-151Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Although stable angina pectoris often carries a favourable prognosis, it remains important to identify patients with an increased risk of cardiovascular (CV) complications. Many new markers of disease activity and prognosis have been described. We evaluated whether common and easily accessible markers in everyday care provide sufficient prognostic information.

    MATERIALS AND METHODS:

    The Angina Pectoris Prognosis Study in Stockholm treated 809 patients (248 women) with stable angina pectoris with metoprolol or verapamil double blind during a median follow-up of 3·4 years, with a registry-based extended follow-up after 9·1 years. Clinical and mechanistic variables, including lipids and glucose, renal function, ambulatory and exercise-induced ischaemia, heart rate variability, cardiac and vascular ultrasonography, and psychosocial variables were included in an integrated analysis. Main outcome measures were nonfatal myocardial infarction (MI) and CV death combined.

    RESULTS:

    In all, 139 patients (18 women) suffered a main outcome. Independent predictive variables were (odds ratio [95% confidence intervals]), age (1·04 per year [1·00;1·08], P = 0·041), female sex (0·33 [0·16;0·69], P = 0·001), fasting blood glucose (1.29 per mM [1.14; 1.46], P < 0·001), serum creatinine (1·02 per μM [1·00;1·03], P < 0·001) and leucocyte counts (1·21 per 106 cells/L [1·06;1·40], P = 0·008). Smoking habits, lipids and hypertension or a previous MI provided limited additional information. Impaired fasting glucose was as predictive as manifest diabetes and interacted adversely with serum creatinine. Sexual problems were predictive among men.

    CONCLUSIONS:

    Easily accessible clinical and demographic variables provide a good risk prediction in stable angina pectoris. Impaired glucose tolerance and an elevated serum creatinine are particularly important.

  • 15.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carlsson, Axel C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, S-14152 Huddinge, Sweden..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Dalarna Univ, Dept Hlth & Social Sci, S-79188 Falun, Sweden..
    Impact of physical activity on cardiovascular status in obesity2017In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 47, no 2, p. 167-175Article in journal (Refereed)
    Abstract [en]

    Background We have recently shown that being physically active (PA) counteracts, but not eliminates the increased risk of future cardiovascular disease in overweight and obese subjects. To investigate this further, we studied the impact of being normal weight, overweight and obese on multiple markers of subclinical cardiovascular disease in relation to physical activity. Materials and methods At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Being PA was defined as performing regular heavy exercise (self-reported). According to body mass index (BMI)/PA groups, the participants were categorized as PA/normal weight (BMI < 25 kg/m(2), n = 104), non-PA/normal weight (n = 234), PA/overweight (BMI 25-29.9 kg/m(2), n = 133), non-PA/overweight (n = 295), PA/obese (BMI = 30 kg/m(2), n = 54) and non-PA/obese (n = 169). Several different measurements of endothelial reactivity and arterial compliance (plethysmography and ultrasound), cartotid artery atherosclerosis and echocardiography were performed, and seven markers of coagulation/ fibrinolysis were measured. Results Physically active subjects with obesity showed impaired vasoreactivity in the forearm resistance vessels, increased left ventricular mass and impaired left ventricular systolic and diastolic functions, together with impaired coagulation/fibrinolysis when compared to PA/normal-weight subjects (P < 0.05 to < 0.001). The majority of these disturbances were seen also in PA/overweight subjects when compared to PA/normal-weight subjects (P < 0.05 to < 0.001). Conclusions Our data provide additional support for the notion that an increased level of self-reported physical activity does not fully eliminate the deleterious cardiovascular consequences associated with overweight and obesity.

  • 16.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fugmann, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Millgård, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ageing impairs insulin-mediated vasodilatation but not forearm glucose uptake2001In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 31, no 10, p. 860-864Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: It is unclear if insulin-mediated vasodilatation is altered by ageing and if this affects insulin-mediated glucose uptake. MATERIAL AND METHODS: A 2-h euglycaemic hyperinsulinaemic clamp (56 mU m(-2) min(-1)) was performed in 10 healthy, nonobese elderly men (70-75 years) and 13 young men (23-28 years). Forearm blood flow (FBF) was measured by venous occlusion plethysmography and forearm glucose uptake was calculated by arterial and venous serum glucose determinations in the forearm. RESULTS: Insulin induced an increase in FBF in the younger men (from 3.9 +/- 1.1 SD to 5.9 +/- 2.2 mL min(-1) 100(-1)mL tissue, P < 0.001), but this insulin-mediated vasodilatation was completely blunted in the elderly subjects. Glucose extraction during the clamp was significantly higher in the elderly subjects (1.2 +/- 0.76 vs. 0.82 +/- 0.37 mmol L(-1) at 120 min, P < 0.01), resulting in a similar forearm glucose uptake in the two groups. On the other hand, whole-body glucose uptake was significantly decreased in the elderly subjects (5.3 +/- 1.8 vs. 8.0 +/- 1.1 mg kg(-1) min(-1), P < 0.001). CONCLUSION: The present study showed that the ability of insulin to induce vasodilatation is blunted in the forearm in healthy, nonobese elderly subjects. However, the elderly compensate for this impairment with an increased glucose extraction from arterial blood to maintain an unaltered forearm glucose uptake.

  • 17.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Methylation-based estimated biological age and cardiovascular disease2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no 2, article id e12872Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DNA methylation changes over life at specific sites in the genome, which can be used to estimate "biological age." The aim of this population-based longitudinal cohort study was to investigate the association between estimated biological age and incident cardiovascular disease (CVD).

    MATERIALS AND METHODS: Based on formulas published by Hannum et al and Horvath et al, "biological age" was calculated using data from the Illumina 450k Bead Methylation chip in 832 participants free from cardiovascular disease in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between estimated biological and chronological age was calculated (DiffAge).

    RESULTS: During 10 years of follow-up, 153 incident cases of cardiovascular disease occurred. In the sex-adjusted analyses, the Horvath estimation of DiffAge was significantly related to incident cardiovascular disease (HR 1.040, 95% CI 1.010-1.071, P = .0079). Thus, for each year of increased biological age, a 4% increased risk of future cardiovascular disease was observed. This relationship was still significant following adjustment for the traditional risk factors sex, BMI, diabetes, HDL and LDL-cholesterol, systolic blood pressure and smoking (HR 1.033, 95% CI 1.004-1.063, P = .024). No such significant association was found using the Hannum formula.

    CONCLUSIONS: DNA methylation-based estimation of "biological age" per Horvath was associated with incident cardiovascular disease.

  • 18.
    Lindell, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Variable Expression of CYP and Pgp Genes in the Human Small Intestine2003In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 33, no 6, p. 493-499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome p450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes.

    METHODS:

    The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed.

    RESULTS:

    Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively.

    CONCLUSIONS:

    Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.

  • 19.
    Lindqvist, Ulla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Westerberg, G
    Bergström, M
    Torsteindottir, I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gustafson, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. University Hospital, Uppsala, Sweden.
    Långström, Bengt
    [11C]Hyaluronan uptake with positron emission tomography in liver disease2000In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 30, no 7, p. 600-607Article in journal (Other academic)
    Abstract [en]

    Background

    A hyaluronan-loading test has been developed for assessment of hyaluronan kinetics and applied in patients with liver and joint diseases. This test describes the metabolic process of hyaluronan but cannot define the specific contribution of different organs. A method for labelling of hyaluronan with the short-lived positron-emitting radionuclide 11C has been published and in this study applied in healthy subjects and liver diseases.

    Materials and methods

    Positron emission tomography (PET) was used for the regional assessment and quantification of [11C]hyaluronan uptake in three healthy subjects, four patients with alcoholic liver cirrhosis, one with alcoholic hepatitis and one with liver steatosis. After intravenous administration of 60 MBq of 11C-labelled hyaluronan, a 55-min PET scan was performed over the liver and plasma radioactivity was analysed. Rate constants describing the transport of the [11C]hyaluronan tracer from plasma to the liver were calculated.

    Results

    High uptake was observed in the liver combined with a rapid elimination of tracer from plasma. The liver uptake rate (k1) was significantly lower in patients (0.018 min−1) than in healthy subjects (0.043 min−1, P = 0.002). The rate constants seem to be related to the severity of the disease as defined by the Child–Pugh score.

    Conclusions

    The study suggests that PET with [11C]hyaluronan could be an accurate method by which to assess liver dysfunction, in conditions where endothelial cell function is impaired. The possibility of quantification over extended portions of the body also opens up possibilities to explore regional differences in liver function and to assess other elimination routes of hyaluronan.

  • 20.
    Lofton Tomenius, Hava
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Öhnstedt, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Mortier, A.
    Katholieke Univ Leuven, Leuven, Belgium.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    A novel drug-delivery system and drug candidate: using probiotic bacteria as bioreactors for delivery of therapeutic chemokines in wound healing2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 79-79Article in journal (Other academic)
  • 21.
    Lomei, Jalal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Characterization of pro-angiogenic neutrophils2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 81-81Article in journal (Other academic)
  • 22.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eriksson, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lundberg, Jon O
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension2011In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 8, p. 889-897Article in journal (Refereed)
    Abstract [en]

    Background Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysedexhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PHaetiology.Methods Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in22 patients with PH and 21 healthy controls. Alveolar NO (CalvNO) and bronchial flux (J’awNO) were calculatedusing the slope–intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH)and PH WHO Groups II–IV, according to the WHO clinical classification of PH.Results Exhaled NO was reduced at flow-rates in the range of 20)200 mL s)1 in patients with PAH (n = 13) vs.PH WHO Group II–IV (n = 9) (P < 0Æ05 all). Patients with PAH had higher CalvNO than healthy controls [2Æ61(2Æ23, 3Æ36) vs. 1.97 ppb (1Æ22, 2Æ49), P = 0Æ03] and similar to PH WHO Group II–IV (P = 0Æ51). Patients with PAHhad lower J’awNO than patients with PH WHO Group II–IV or healthy controls [430 (371, 702) vs. 807 (557, 993)or 731 pL s)1 (580, 818), P < 0Æ05 both]. Subjects with PAH were characterized by higher levels of salivary andplasma nitrite than healthy controls (P < 0Æ05 both).Conclusions Patients with PAH have lower bronchial NO flux compared to healthy controls and patients withPH WHO Group II–IV along with elevated salivary and plasma nitrite compared to controls. This implies reducedbronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects withPH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in thealveoli.

  • 23.
    Massena, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gustafsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kutschera, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The mechanisms of VEGF-A-induced recruitment of pro-angiogenic neutrophils2013In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 43, no SI, p. 27-27Article in journal (Other academic)
  • 24. Mastellos, Dimitrios C.
    et al.
    Yancopoulou, Despina
    Kokkinos, Petros
    Huber-Lang, Markus
    Hajishengallis, George
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lupu, Florea
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Risitano, Antonio M.
    Ricklin, Daniel
    Lambris, John D.
    Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention2015In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 45, no 4, p. 423-440Article, review/survey (Refereed)
    Abstract [en]

    There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational wet' and in silico synthetic approaches and an array of biophysical, structural and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogues that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception.

  • 25. Mischak, Harald
    et al.
    Ioannidis, John P. A.
    Argiles, Angel
    Attwood, Teresa K.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Broenstrup, Mark
    Charonis, Aristidis
    Chrousos, George P.
    Delles, Christian
    Dominiczak, Anna
    Dylag, Tomasz
    Ehrich, Jochen
    Egido, Jesus
    Findeisen, Peter
    Jankowski, Joachim
    Johnson, Robert W.
    Julien, Bruce A.
    Lankisch, Tim
    Leung, Hing Y.
    Maahs, David
    Magni, Fulvio
    Manns, Michael P.
    Manolis, Efthymios
    Mayer, Gert
    Navis, Gerjan
    Novak, Jan
    Ortiz, Alberto
    Persson, Frederik
    Peter, Karlheinz
    Riese, Hans H.
    Rossing, Peter
    Sattar, Naveed
    Spasovski, Goce
    Thongboonkerd, Visith
    Vanholder, Raymond
    Schanstra, Joost P.
    Vlahou, Antonia
    Implementation of proteomic biomarkers: making it work2012In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 42, no 9, p. 1027-1036Article in journal (Refereed)
    Abstract [en]

    While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.

  • 26. Montella, Silvia
    et al.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Maniscalco, Mauro
    Sofia, Matteo
    De Stefano, Sara
    Raia, Valeria
    Santamaria, Francesca
    Measurement of nasal nitric oxide by hand-held and stationary devices2011In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 10, p. 1063-1070Article in journal (Refereed)
    Abstract [en]

    Background Nasal nitric oxide (nNO) is assessed by nasal aspiration/insufflation via one nostril or by nasal silent exhalation through a facemask and is also measured during humming, a manoeuvre that results in increased nNO in the presence of a patent osteomeatal complex. Humming nNO peak is absent in primary ciliary dyskinesia (PCD) and in cystic fibrosis (CF). Hand-held devices are used successfully for exhaled or nNO analysis. No study compared nNO during silent and humming exhalation using hand-held and stationary analysers. Methods Thirty-eight subjects (14 PCD; 11 CF; 13 healthy individuals) measured nNO with a stationary and a hand-held analyser during silent and humming exhalations. Results No difference between nNO obtained from stationary or hand-held analyser during silent and humming exhalation was found (P > 0 05). Patients with PCD exhibited lower silent and humming nNO than CF or controls (P < 0 001). During both silent and humming exhalation, there was a significant correlation between nNO from the two analyzers both in the whole study population and within each group (r >= 0.7, P < 0 01). Bland-Altman plots confirmed this agreement. Using the hand-held device during humming, nNO values of 50, 81 and 21 ppb had sensitivity and specificity > 90% for discriminating PCD or CF from healthy subjects, and patients with PCD from patients with CF, respectively. Conclusions The hand-held device is as effective as the stationary analyzer for assessing nNO during silent and humming exhalation. Its wider use might result in an increased number of subjects suspected to have PCD.

  • 27.
    Nilsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    C3 And C4 Are Strongly Related To Adipose Tissue Variables And Cardiovascular Risk Factors2014In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 44, no 6, p. 587-596Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In several reports C3 and C4 have been linked to diabetes and cardiovascular disease (CVD). Here we investigate this link and the degree of C3 activation in elderly individuals.

    METHODS: In the present study, C3 and C4 and the activation fragment C3a-desArg were analyzed in 1016 subjects aged 70, in which blood pressure, lipid variables and fasting blood glucose were assessed.

    RESULTS: C3 levels were related to all the investigated classical cardiovascular risk factors and the metabolic syndrome (BMI, waist circumference, fat distribution, blood pressure, blood glucose levels, TG) except total cholesterol and LDL-cholesterol in a highly significant fashion (Spearman up to 0,5; p<0.0001). C4 and C3a-desArg were associated in the same fashion but less significantly, while the ratios C4/C3 or C3a-desArg/C3 were not, indicating that the association was not directly related to complement activation. The levels C3 and to a lesser degree C4 and C3a-desArg, were associated particularly to CRP, but also to E-selectin and ICAM-1. In addition, C3 and C4 levels were shown to decline significantly in 15 female subjects enrolled in a weight-reduction program over 4 months.

    CONCLUSION: A strong relation between C3, C4 and C3a-desArg levels, adipose tissue and risk factors of CVD was established. The data support that the adipose tissue produces complement components and generates initiators of inflammation, such as C3a and C5a, able to trigger a cyto/chemokine response, in proportion to the amount of adipose tissue. This corroborates the concept that complement contributes to the low-grade inflammation associated with obesity. This article is protected by copyright. All rights reserved.

  • 28.
    Nilsson, Erik
    et al.
    Orebro Univ, Sch Med Sci, Dept Internal Med, Orebro, Sweden;Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med & Baxter Novum, Stockholm, Sweden.
    Rudholm, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Stenvinkel, Peter
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med & Baxter Novum, Stockholm, Sweden.
    Arnlov, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Pregnancy-associated plasma protein A and mortality in haemodialysis2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no 8, article id e12959Article in journal (Refereed)
    Abstract [en]

    BackgroundElevated pregnancy-associated plasma protein A (PAPP-A) levels are associated with increased risk of death in ischaemic heart disease as well as in haemodialysis patients. Previous research indicates that the prognostic value of PAPP-A may be stronger in patients with concomitant diabetes mellitus or signs of inflammation. We studied the association between PAPP-A and outcomes in prevalent haemodialysis patients and hypothesized that diabetes mellitus and inflammation status act as effect modifiers. Materials and MethodsCirculating PAPP-A levels were quantified using ELISA. Cox proportional hazards and quantile regression models were used for associations between PAPP-A and mortality. PAPP-A levels were log-transformed for Normality. ResultsDuring 60-month follow-up, 37 (40%) of the 92 participants died. Higher PAPP-A was associated with increased risk of mortality in unadjusted analysis (HR per SD=1.4, 95% CI=1-1.9, P=.03) and when adjusted for confounders and cardiovascular risk factors (HR=1.8, 95% CI=1.18-2.73, P=.006). An interaction between PAPP-A levels and diabetes mellitus on mortality was found (HR for the multiplicative interaction term=2.74 95% CI=1.02-7.37, P=.05). In a quantile regression adjusted for age and sex, one SD increase in PAPP-A was associated with 22months shorter estimated time until 25% of the patients died (95% CI -35 to -9.1months). ConclusionsIncreased PAPP-A levels are associated with higher all-cause mortality in prevalent haemodialysis patients with concomitant diabetes mellitus.

  • 29.
    Parv, Kristel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Elucidating the dynamics and role of peri-vascular macrophages2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 82-83Article in journal (Other academic)
  • 30.
    Pujari, Shiuli
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Hoess, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Shen, J.
    Thormann, A.
    Heilmann, A.
    Tang, L.
    Karlsson-Ott, Miriam
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Effect of nanoporosity on inflammatory cells2014In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 44, no S1, p. 36-36Article in journal (Other academic)
  • 31. Rolla, Giovanni
    et al.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Badiu, Iuliana
    Heffler, Enrico
    Petrarulo, Michele
    Bucca, Caterina
    Brussino, Luisa
    The increase in exhaled NO following allergen challenge is not associated with airway acidification2011In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 4, p. 411-416Article in journal (Refereed)
    Abstract [en]

    Background: Exhaled nitric oxide (NO), commonly accepted marker of airways inflammation, may be generated both by specific enzymes, NO synthases, as well as by nonenzymatic reduction in its metabolites. During asthma exacerbations, owing to lower airways pH, it has been reported that nitrite reduction may contribute to the increase in exhaled NO. Allergen exposure, an important cause of asthma exacerbations, is also known to increase exhaled NO. Design To investigate whether cat allergen exposure of cat-sensitized asthmatics leads to airway acidification, which could explain the expected increase in exhaled NO. Twelve nonsmoking, cat-sensitized patients (nine women) aged 33·5 (22-54) years with mild intermittent asthma performed a cat allergen challenge. Exhaled NO at 50-200mLs-1, nasal NO, exhaled breath condensate (EBC) pH, nitrite and nitrate were measured before, 8 and 24h after allergen challenge. Results A significant increase in FENO 50 was observed 24h after allergen challenge compared to baseline: 110ppb (34, 143) vs. 60ppb (19, 122), P=0·006. This was mainly explained by an increase in bronchial NO flux (P=0·02), while no changes in EBC pH were observed (P=0·35). Conclusions: Allergen exposure is not associated with airways acidification, implying that the observed increase in exhaled NO is probably because of enzymatic NO production.

  • 32. Ruge, T
    et al.
    Sukonina, V
    Myrnäs, T
    Lundgren, M
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Olivecrona, G
    Lipoprotein lipase activity/mass ratio is higher in omental than in subcutaneous adipose tissue.2006In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 36, no 1, p. 16-21Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Lipoprotein lipase (LPL) is important for lipid deposition in adipose tissue (AT) and responds rapidly to changes in the nutritional state. Animal experiments indicate that short-term regulation of LPL is mainly post-translational. Different processing of LPL in different AT depots may play a role in the distribution of lipids in the body.

    MATERIALS AND METHODS: Lipoprotein lipase mRNA, mass and activity were measured in pieces of omental adipose tissue (OAT) and subcutaneous adipose tissue (SAT) from 15 subjects undergoing gastrointestinal surgery (four male and 11 female subjects, mean age 54 +/- 5 years, BMI 28 +/- 2 kg m(-2)).

    RESULTS: Lipoprotein lipase activity was higher in OAT than in SAT (18 +/- 2.1 compared with 12 +/- 1.6 mU g(-1), P < 0.01), whereas LPL mass was lower in OAT than in SAT (100 +/- 9 compared with 137 +/- 16 mU g(-1), P < 0.05). Consequently, the specific LPL activity (ratio of activity over mass) was approximately twofold greater in OAT compared with SAT. There was correlation between LPL mRNA and LPL activity in SAT (P < 0.05) and a similar tendency in OAT (P = 0.08). There were strong correlations (P < 0.01) for mRNA abundance as well as for LPL activity between the two depots. In contrast there was no correlation between the LPL mass and LPL mRNA or activity in any of the depots.

    CONCLUSIONS: These results indicate that long-term regulation, as reflected in the mRNA abundance, is similar in the two types of adipose tissue. The displayed activity reflects the mRNA abundance and the fraction of newly synthesized LPL molecules which the post-translational mechanism allows to become/remain active. This fraction was on average twofold greater in OAT compared with SAT.

  • 33. Ruge, T
    et al.
    Svensson, A
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Olivecrona, T
    Olivecrona, G
    Food deprivation increases post-heparin lipoprotein lipase activity in humans.2001In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 31, no 12, p. 1040-7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the effect of fasting on lipoprotein lipase (LPL) activity in human post-heparin plasma, representing the functional pool of LPL.

    DESIGN: Fourteen healthy volunteers were recruited for the study. The subjects were fasted for 30 h. Activities of LPL and hepatic lipase (HL), and LPL mass, were measured in pre- and post-heparin plasma in the fed and in the fasted states, respectively. For comparison, LPL and HL activities were measured in pre- and post-heparin plasma from fed and 24-h-fasted guinea pigs.

    RESULTS: Fasting caused a significant drop in the levels of serum insulin, triglycerides and glucose in the human subjects. Post-heparin LPL activity increased from 79 +/- 6.4 mU mL-1 in the fed state to 112 +/- 10 mU mL-1 in the fasted state (P < 0.01), while LPL mass was 361 +/- 29 in the fed state and 383 +/- 28 in the fasted state, respectively (P = 0.6). In contrast, fasting of guinea pigs caused an 80% drop in post-heparin LPL activity. The effect of fasting on human and guinea pig post-heparin HL activity were moderate and statistically not significant.

    CONCLUSIONS: In animal models such as rats and guinea pigs, post-heparin LPL activity decreases on fasting, presumably due to down-regulation of adipose tissue LPL. In humans, fasting caused increased post-heparin LPL activity.

  • 34. Ruge, T
    et al.
    Svensson, M
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Olivecrona, G
    Tissue-specific regulation of lipoprotein lipase in humans: effects of fasting.2005In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 35, no 3, p. 194-200Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously reported that the activity of lipoprotein lipase (LPL) measured in postheparin plasma from humans fasted for 30 h is increased relative to the fed state. This is in contrast to laboratory animals, where the strong down-regulation of LPL in their adipose tissue on fasting is reflected in decreased levels of LPL activity in postheparin plasma.

    MATERIALS AND METHODS: To search for the tissue source of the increase in LPL activity on fasting of humans, young, healthy subjects were fasted for 10, 20 or 30 h, and LPL was measured in plasma (pre- and postheparin) and in biopsies from subcutaneous adipose tissue (abdominal) and from a skeletal muscle (tibialis anterior). Both LPL activity and LPL protein mass were measured in the tissue homogenates. Values after fasting were compared with values from postprandial samples obtained 2 h after a meal.

    RESULTS: Fasting for up to 30 h did not alter LPL activity in basal plasma (preheparin). LPL activity in postheparin plasma remained unchanged after 10 and 20 h of fasting, but was increased by 50% after 30 h (P < 0.05). Ten hours of fasting caused a 25% (P < 0.05) decrease in LPL activity in subcutaneous adipose tissue, while LPL activity in skeletal muscle remained unchanged. After 30 h of fasting, both LPL activity and mass had decreased by approximately 50% (P < 0.05) in adipose tissue, but had increased by approximately 100% (P < 0.05) in muscle.

    CONCLUSIONS: The increase in postheparin plasma LPL activity after 30 h of total food deprivation of healthy human subjects seemed to reflect an increased activity and mass of LPL in skeletal muscle.

  • 35.
    Seignez, Cedric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Tissue hypoxia induces the mobilisation from the spleen of pro-angiogenic neutrophils through the activation of sympathetic nerves2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 78-78Article in journal (Other academic)
  • 36.
    Simonsson, Ulrika S.H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Raffalli-Mathieu, Francoise
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Lannerbro, Angela
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Honkakoski, Paavo
    University of Kuopio, Kuopio, Finland .
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin2006In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 36, no 9, p. 647-653Article in journal (Refereed)
    Abstract [en]

    Backround Artemisinin (a sesquiterpene lactone endoperoxide) has become important in multi-drug treatment of malaria. There is evidence that artemisinin induces drug metabolism which could result in drug-drug interactions. The objective of this study was to characterize the inductive properties of artemisinin on drug-metabolizing cytochrome P450 (CYP450) enzymes. Materials and methods The possibility of artemisinin to induce CYP450 was studied in artemisinin-treated (orally for four days) and vehicle-treated rats using reverse transcriptase polymerase chain reaction (RT-PCR). The effect on enzymatic activities in mouse microsomes from multiple artemisinin administration (intraperitonally) to mice were also studied as well as the effect on the expression in mouse primary hepatocytes and HEK293 cells. Results Increased CYP2B1 mRNA levels in rats could be seen after artemisinin treatment as well as a weak but reproducible increase in the intensity of CYP1A2. Administration of artemisinin to mice up-regulated hepatic CYP2B10-dependent, and to a lesser extent, CYP2A5-dependent enzyme activities. In primary hepatocyte culture, artemisinin significantly increased the CYP2B10 mRNA levels whereas the CYP2A5 mRNA levels were increased to a lesser extent. No significant changes were seen in the levels of other CYP enzymes. Artemisinin was an activator of constitutive androstane receptor (CAR) but not pregnane X receptor (PXR) in HEK293 cells. Conclusions The results demonstrate that the drug exerts its effects on drug metabolism via the CAR receptor that results in up-regulation of genes such as the Cyp2b. The weaker up-regulation of CYP2A5 might also be CAR-dependent or alternatively, a consequence of artemisinin toxicity. The results of this study are of importance when predicting potential drug-drug interactions in multi-drug therapies with artemisinin.

  • 37.
    Steer, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endothelial vasodilatory function is related to the proportions of saturated fatty acids and alpha-linolenic acid in young men, but not in women2003In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 33, no 5, p. 390-396Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fatty acid composition of serum lipids is associated with cardiovascular disease. As attenuated endothelium-dependent vasodilation (EDV) is an early event in atherosclerosis, we investigated the relationships between endothelial vasodilatory function and the proportion of serum fatty acids, reflecting dietary fat quality, in 74 healthy men and women, aged 20-30 years.

    DESIGN: Endothelium-dependent vasodilation and endothelium-independent vasodilation (EIDV) was studied in the forearm during local administration of methacholine (2 and 4 micro g min-1) and nitroprusside (5 and 10 micro g min-1). Forearm blood flow was determined with venous occlusion plethysmography. An endothelial function index was calculated as the EDV/EIDV ratio.

    RESULTS: The endothelial function index was inversely related to the total proportion of saturated fatty acids (r = -0.41, P < 0.05), in particular lauric and myristic acid (r = -0.37 and r = -0.36, respectively, P < 0.05 for both), and was positively related to the proportion of alpha-linolenic acid (r = 0.45, P < 0.01) in men only. Total serum nonesterified fatty acid (NEFA) concentration was not significantly related to endothelial vasodilatory function. By multiple stepwise regression analysis, including age, blood pressure, body mass index, and serum cholesterol, triglyceride and NEFA as confounders, myristic acid and alpha-linolenic acid were independent predictors of the endothelial function index in men only (r = -0.39 and r = 0.47, respectively, P < 0.01 for both).

    CONCLUSIONS: We conclude that serum fatty acid composition predicts endothelial vasodilatory dysfunction independently of serum NEFA and cholesterol levels in young, healthy men in their third decade of life, whereas fatty acid composition seems to be less important in women at this age. As a result of the large number of analyses performed, these findings need to be verified by other studies.

  • 38. Svensson, M
    et al.
    Yu, Z-W
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    A small reduction in glomerular filtration is accompanied by insulin resistance in type I diabetes patients with diabetic nephrophathy.2002In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 32, no 2, p. 100-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Insulin sensitivity and insulin clearance are compromised in end-stage renal disease but it has not been fully established whether they are altered in earlier stages of diabetic nephropathy.

    DESIGN: We studied three groups of patients with type 1 diabetes; 10 with no sign of nephropathy, 11 with albuminuria (> 20 microg min-1) but normal glomerular filtration rate (GFR) and eight with a small reduction in GFR, (43-73 mL min-1 1.73 m-2). The groups were matched for age (range 36-61 years), body mass index (BMI), diabetes duration and glycaemic control. The euglycaemic hyperinsulinaemic clamp technique was utilized to study insulin sensitivity (M-value) and metabolic clearance rate for insulin. Needle biopsies from abdominal subcutaneous fat tissue were obtained to study insulin binding, insulin degradation, insulin-stimulated glucose uptake and anti-lipolysis in adipocytes in vitro.

    RESULTS: Patients with reduced GFR were more insulin-resistant (M-value 5.7 +/- 0.7 mg kg LBM-1 min-1) than those without nephropathy (9.6 +/- 0.7, P = 0.001) and those with only albuminuria (8.9 +/- 1.2, P = 0.044). In all subjects taken together there was a strong association between insulin sensitivity and GFR (r = 0.46, P = 0.012). Patients with reduced GFR displayed no significant difference in insulin clearance (12.2 +/- 1.6 mL kg-1 min-1) compared to controls (13.8 +/- 1.3) but a slightly lower insulin clearance than patients with only albuminuria (16.6 +/- 1.0, P = 0.027). There were no significant differences between patient groups in the adipocyte studies in vitro, i.e. with respect to insulin binding, insulin degradation and the effects of insulin on glucose uptake and lipolysis. This is compatible with humoral factors causing whole-body insulin resistance and in the group with reduced GFR, we found that serum parathyroid hormone, interleukin-6 and tumour necrosis factor-alpha levels were elevated whereas the morning cortisol was decreased.

    CONCLUSIONS: In type 1 diabetes, the appearance of albuminuria does not seem to alter insulin sensitivity and clearance. A marked insulin resistance but no consistent impairment in insulin clearance seems to accompany progression to a stage with a slight reduction in GFR. These alterations are not accompanied by general defects in insulin target cells. Instead, alterations in the regulation of insulin-antagonistic hormones and cytokines could potentially contribute to the development of insulin resistance in diabetic nephropathy.

  • 39.
    Vågesjö, Evalina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Strategic recruitment of proangiogenic leukocytes to the ischemic hindlimb increases functional tissue perfusion2013In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 43, no SI, p. 27-27Article in journal (Other academic)
  • 40.
    Vågesjö, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Seignez, Cedric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Christoffersson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Herrera Hidalgo, Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Giraud, Antoine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rundqvist, H.
    Karolinska Inst, Cell & Mol Biol Dept, Solna, Sweden.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Johnson, R.
    Karolinska Inst, Cell & Mol Biol Dept, Solna, Sweden; Univ Cambridge, Physiol Dev & Neurosci Dept, Cambridge, England.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Perivascular macrophages regulate blood flow following tissue damage2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 44-45Article in journal (Other academic)
  • 41.
    Wiklund, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Ronquist, Göran
    Roomans, G M
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Waldenström, A
    Response of myocardial cellular energy metabolism to variation of buffer composition during open-chest experimental cardiopulmonary resuscitation in the pig.1997In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 27, no 5, p. 417-26Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate possible relationships in piglets between myocardial energy-related metabolites and intracellular electrolytes during open-chest cardiopulmonary resuscitation (OCCPR) supplemented by the administration of alkaline buffers with varying sodium content. Our hypothesis was that an increasing myocardial intracellular sodium content would decrease the intracellular energy stores. In addition to haemodynamics, acid-base and blood gas variables were analysed, and myocardial biopsies were collected before and during OCCPR as well as after the return of spontaneous circulation. After a period of 4 min of untreated ventricular fibrillation (VF). 25 piglets were randomly allocated to one of four groups: OCCPR with normal saline (n = 5); OCCPR with sodium bicarbonate (SB) (n = 7); OCCPR with Tris buffer mixture (TBM) (n = 7); and a totally untreated control group (n = 6). The results showed that 4 min of untreated VF almost eradicated creatine phosphate (CrP) and that the ATP/ADP ratio decreased to 1.5-2.0. During OCCPR with normal saline, the myocardial content of CrP increased, whereas lactate, ATP and ADP levelled off and AMP decreased, causing an increased ATP/ADP ratio. The adenosine and inosine contents increased, whereas inosine monophosphate was unchanged at a low level, the adenosine and inosine contents being inversely correlated with the total content of adenine nucleotides. In both buffered groups, the increase in most energy-related metabolites (CrP, ATP, ADP, AMP and the ATP/ADP quotient) was less and in lactate more pronounced than in the group not being buffered, with no difference between the groups receiving SB or TBM. Although the intracellular potassium content was unaltered, the sodium, chloride and calcium concentration increased, more so in the group receiving SB. The intracellular content of sodium was correlated with that of calcium. Thus, buffering increased the myocardial AMP degradation during OCCPR by increasing the flux via the 5'-nucleotidase reaction, and SB increased the intracellular contents of sodium and calcium to a greater extent than did TBM.

  • 42.
    Öhnstedt, E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vågesjö, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Lofton Tomenius, Hava
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Phillipson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Bioengineering of the local wound environment accelerates wound healing by increasing macrophage density and induces a phenotype shift in the wound macrophages2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no S1, p. 79-79Article in journal (Other academic)
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