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  • 201. Pazaitou-Panayiotou, Kalliopi
    et al.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Koletsa, Triantafyllia
    Kotoula, Vassiliki
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Karkavelas, Georgios
    Karayannopoulou, Georgia
    Somatostatin receptor expression in non-medullary thyroid carcinomas2012In: Hormones, ISSN 1109-3099, Vol. 11, no 3, p. 290-296Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Peptide receptor radionuclide therapy (PRRT) is dependent upon binding of radiolabelled peptides to their respective receptor expressing cells. The main objective of this study was to characterize the expression of somatostatin receptor (SSTR) subtypes in non-medullary thyroid cancers in order to be able to recommend the use of PRRT as a treatment option in patients with progressive local or metastatic disease.

    DESIGN:

    We constructed tissue microarrays from paraffin blocks prepared from 47 cases of non-medullary thyroid carcinomas and related normal thyroid tissue. Immunohistochemical staining was performed with five different polyclonal SSTR antibodies.

    RESULTS:

    SSTR subtypes sst2 and sst3 were expressed in all non-medullary thyroid carcinomas, sst1 and sst5 in 75%, and sst4 in 38%. Coexpression of more than three subtypes was detected in 36 of the 47 cases. The expression of SSTR subtypes in normal thyroid tissue was low or absent.

    CONCLUSIONS:

    Non-medullary thyroid carcinomas frequently express all SSTR subtypes. This expression provides a basis for further studies with the aim of exploring PRRT as a possible new treatment for iodine-131 refractory metastatic non-medullary thyroid carcinomas.

  • 202.
    Peterson, Christer G. B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wagner, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lettesjö, H.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis2007In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 67, no 8, p. 810-820Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    A prominent feature of inflammatory bowel disease (IBD) is the presence of inflammatory cells in the gut mucosa, and which contribute to the ongoing inflammatory process. The aim of the study was to evaluate fecal neutrophil, eosinophil, mast cell and macrophage markers in the assessment of disease activity in patients with ulcerative colitis (UC).

    METHODS:

    Twenty-eight patients with active UC; 4 with proctitis, 16 with left-side colitis and 8 with total colitis, were included in the study. Patient history, endoscopy and histopathology were examined and fecal and serum samples were evaluated at inclusion and after 4 and 8 weeks of treatment. Fecal samples were analysed for myeloperoxidase (MPO), eosinophil protein X (EPX), mast cell tryptase, IL-1beta and TNF-alpha using immunoassays. Blood samples were analysed for MPO, EPX, C-reactive protein, orosomucoid and leucocyte counts.

    RESULTS:

    Fecal MPO and IL-1beta levels were elevated in all patients at inclusion despite different disease extensions. Striking reductions in fecal levels of MPO, EPX, tryptase and IL-1beta were observed after 4 weeks of treatment in 20/28 patients with complete remission after 8 weeks. No further reductions were seen in 20/27 patients at 8 weeks. Endoscopic score correlated to IL-1beta at all visits (p<0.01), to MPO at visits 2 and 3 (p<0.05, p<0.001), EPX at visit 2 (p<0.05) and tryptase at visit 3 (p<0.01). Levels of fecal markers also related to histological indices of the disease.

    CONCLUSIONS:

    Measurements of fecal MPO, EPX and IL-1beta could be objective complements to endoscopical and histopathological evaluations in the daily care of patients with UC.

  • 203. Plewako, Halina
    et al.
    Wosinska, Katarzyna
    Arvidsson, Monica
    Bjökander, Janne
    Skov, Per Stahl
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rak, Sabina
    Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy2006In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 141, no 4, p. 346-353Article in journal (Refereed)
    Abstract [en]

    Background: Studies using rush immunotherapy (RIT) have shown that rapid protection can be achieved using protocols allowing a fast increment of allergen dose. We examined the early effects of RIT on basophil numbers and expression of CD203c, production of interleukin (IL)-4 and IL-13 and histamine release by basophils in the peripheral blood of patients treated with immunotherapy and controls. Methods: Twelve patients treated with RIT and 4 untreated controls were included in the study. Any adverse events were evaluated during the incremental phase of RIT. Mononuclear cells were isolated before the start of RIT and 3 days, I week, 4 weeks and 3 months after the beginning of the treatment. Histamine release upon allergen stimulation, expression of CD203c and allergen-induced production of IL-4 and IL-13 by basophils were examined. Results: Significant decreases in blood basophil count (p = 0.02) were observed early in the treatment, returning to baseline values 1 week after the start of RIT. Similarly, histamine release decreased at day 3 (p = 0.02), but returned to pretreatment levels after I week. Also, the percentage of IL-4+ and IL-13+ basophils and levels of CD203c expression were markedly reduced early in the treatment. IL-4 and IL-13 production correlated with histamine release and CD203c expression. Histamine release and production of IL-4 and IL-13 by basophils before the treatment correlated with the severity of adverse events during the incremental phase of RIT. Conclusion: We report the decrease in blood basophil numbers, their lower activation status and the reduced production of IL-4 and IL-13 early in the course of RIT. This early suppression of basophil activation could be one mechanism behind the protective effect of RIT.

  • 204.
    Portela-Gomes, G. M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gayen, J. R.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Mahata, S. K.
    The importance of chromogranin A in the development and function of endocrine pancreas2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 151, no 1-3, p. 19-25Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chromogranin (Cg) A is expressed in neuroendocrine and neuronal tissues. It is involved in the generation of secretory granules and is cleaved to form biologically active peptides. Targeted ablation of the Chga gene resulted in increased plasma catecholamines, high blood pressure, and decreased size and number of adrenal medullary chromaffin granules. The aim of this study was to determine whether Chga null mice display changes in the morphology and function of the endocrine pancreas. MATERIALS AND METHODS: Sections of pancreata from Chga-/-, Chga+/- and Chga+/+ mice, were immunostained with antibodies against synaptophysin, CgA, CgB, secretogranin II and the four major pancreatic islet hormones. Plasma was analysed for glucose, insulin, glucagon, somatostatin and pancreatic polypeptide (PP). RESULTS: CgA epitopes were undetectable in the islets of Chga-/- animals. CgB and secretogranin II epitopes were expressed in the islets of all animal groups albeit with decreased expression in Chga-/- islets. The islet number and size were decreased in the Chga-/- animals compared with Chga+/+. The proportion of insulin cells was decreased but somatostatin and PP cells were increased in Chga-/- mice compared to Chga+/+ mice. The nuclear size was decreased in insulin cells and increased in somatostatin cells in Chga-/- mice. Plasma insulin level was markedly decreased in the Chga-/- mice although fasting plasma glucose and glucagon were normal. CONCLUSION: Ablation of the Chga gene affected the islet volume, the composition, distribution and nuclear size of islet cell types and plasma insulin concentration. Our data indicate decreased insulin cell function and increased glucagon cell function. Our study shows that CgA exerts a significant influence on the endocrine pancreas with importance in maintaining islet volume, cellular composition and function.

  • 205. Portela-Gomes, Guida M.
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Immunohistochemical and Biochemical Studies with Region-Specific Antibodies to Chromogranins A and B and Secretogranins II and III in Neuroendocrine Tumors2010In: Cellular and Molecular Neurobiology, New York, USA: SPRINGER/PLENUM PUBLISHERS , 2010, Vol. 30, no 8, p. 1147-1153Conference paper (Refereed)
    Abstract [en]

    This short review deals with our investigations in neuroendocrine tumors (NETs) with antibodies against defined epitopes of chromogranins (Cgs) A and B and secretogranins (Sgs) II and III. The immunohistochemical expression of different epitopes of the granin family of proteins varies in NE cells in normal human endocrine and non-endocrine organs and in NETs, suggesting post-translational processing. In most NETs one or more epitopes of the granins were lacking, but variations in the expression pattern occurred both in benign and malignant NETs. A few epitopes displayed patterns that may be valuable in differentiating between benign and malignant NET types, e.g., well-differentiated NET types expressed more CgA epitopes than the poorly differentiated ones and C-terminal secretoneurin visualized a cell type related to malignancy in pheochromocytomas. Plasma concentrations of different epitopes of CgA and CgB varied. In patients suffering from carcinoid tumors or endocrine pancreatic tumors the highest concentrations were found with epitopes from the mid-portion of CgA. For CgB the highest plasma concentrations were recorded for the epitope 439-451. Measurements of SgII showed that patients with endocrine pancreatic tumors had higher concentrations than patients with carcinoid tumors or pheochromocytomas. SgIII was not detectable in patients with NETs.

  • 206. Portela-Gomes, Guida M.
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Granins and granin-related peptides in neuroendocrine tumours2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 165, no 1, p. 12-20Article, review/survey (Refereed)
    Abstract [en]

    This review focus on neuroendocrine tumours (NETs), with special reference to the immunohistochemical analysis of granins and granin-related peptides and their usefulness in identifying and characterizing the great diversity of NET types. Granins, their derived peptides, and complex protein-processing enzyme systems that cleave granins and prohormones, have to some extent cell-specific expression patterns in normal and neoplastic NE cells. The marker most commonly used in routine histopathology to differentiate between non-NETs and NETs is chromogranin (Cg) A, to some extent CgB. Other members of the granin family may also be of diagnostic value by identifying special NET types, e.g. secretogranin (Sg) VI was only found in pancreatic NETs and phaeochromocytomas. SgIII has recently arisen as an important NET marker; it was strongly expressed in NETs, with some exceptions - phaeochromocytomas expressed few cells and parathyroid adenomas none. Some expression patterns of granin-related peptides seem valuable in differentiating between some benign and malignant NETs, some may also provide prognostic information, among which: well-differentiated NET types expressed more CgA epitopes than the poorly differentiated ones, except insulinomas, where the opposite was noted; medullary thyroid carcinomas containing few cells immunoreactive to a CgB antibody were related to a bad prognosis; C-terminal secretoneurin visualized a cell type related to malignancy in phaeochromocytomas. Further research will probably establish new staining patterns with marker functions for granins in NETs which may be of histopathological diagnostic value.

  • 207.
    Portela-Gomes, Guida Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas2008In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 146, no 1-3, p. 117-124Article in journal (Refereed)
    Abstract [en]

    Prohormone convertases (PCs) are proteinases that cleave inactive prohormones to biologically active peptides. Seven PCs have been identified; two of them, PC1/3 and PC2, have only been localized in neuroendocrine (NE) tissues; a third, furin, in both endocrine and exocrine tissues. We have studied the immunoreactivity of PC1/3, PC2 and furin in the four major NE cell types of the human pancreas by using double immunofluorescence techniques. The study also included the expression of NE secretory protein 7B2 (secretogranin V), a member of the granin family, which influences the function of PC2. The results showed that the three PCs and 7B2 were expressed only in endocrine pancreas, furin also in exocrine cells. Insulin (B) cells harboured PC1/3 and PC2, but not furin. Glucagon (A) cells were immunoreactive to all three PCs; all glucagon cells expressed PC2, but one subpopulation showed PC1/3 immunoreactivity and another furin. Only a few somatostatin (D) cells contained PC2, but no other proconvertase. Pancreatic polypeptide (PP) cells were non-reactive to all three PCs. 7B2 occurred only in insulin and glucagon cells. A varying co-localization pattern was observed between PCs and between PCs and 7B2, with the exception of PC1/3 and furin which were not co-localized. In conclusion, our study shows that PCs are localized in insulin and glucagon cells and do seem to be important in these cell types for processing of hormone and other protein precursors, especially chromogranins, but for the two other major cell types probably other enzymes are of importance.

  • 208. Portela-Gomes, Guida Maria
    et al.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Secretogranin III in human neuroendocrine tumours A comparative immunohistochemical study with chromogranins A and B and secretogranin II2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 165, no 1, p. 30-35Article in journal (Refereed)
    Abstract [en]

    Background: Different epitopes of the granin family of proteins, chromogranin (Cg) A, CgB and secretogranin (Sg) II, have been demonstrated in normal human pancreas, gastrointestinal tract, adrenal medulla and in several neuroendocrine tumours (NETs). SgIII has been recently reported in endocrine pancreas. The aim of the present study was to examine the expression of SgIII in different NETs and compare it with the expression of CgA. CgB and SgII epitopes. Material and methods: Tissue specimens from 47 NETs were analyzed. Antibodies to CgA 250-284, CgB 244-255. SgII 172-186 (C-terminal secretoneurin) and SgIII 348-361 were used for immunostaining. Results: SgIII was expressed in 41 of 47 NETs. The expression of SgIII agreed well with that of CgA, CgB and SgII, with exceptions of phaeochromocytomas, where more CgB and SgII immunoreactive cells were observed and parathyroid adenomas, which were only stained by CgA. In rectal NETs more cells expressed SgIII than CgA. Conclusions: This is the first report on SgIII expression in various NETs. A majority of tumours studied displayed SgIII immunostaining, which indicates a functional relationship with the other granins.

  • 209.
    Portela-Gomes, Guida Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rorstad, Otto
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas: predominance of receptor subtype 42007In: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 18, no 2, p. 79-85Article in journal (Refereed)
    Abstract [en]

    Insulinomas constitute a subgroup of pancreatic endocrine tumors showing B cell differentiation and clinical symptoms related to inappropriate insulin secretion (WHO). Many endocrine tumors express somatostatin receptors (sstrs), which can be visualized by octreotide scintigraphy; however, about half of all insulinomas are reported to be negative. Previous immunohistochemical investigations with antibodies to sstr subtypes 1, 2, 3, and 5 have revealed differences in expression between various neuroendocrine tumors. In the present study, the immunoreactivity to all five human sstr was studied in ten benign and six malignant human insulinomas. Sstr4 was the receptor subtype most frequently expressed in both benign and malignant tumors. A difference in the immunohistochemical sstr5 expression pattern was seen between benign and malignant tumors: Three of the six malignant tumors, but none of the benign tumors, expressed sstr5. The other receptor subtypes were expressed in low numbers with no difference between benign and malignant tumors. The finding of a strong expression of sstr4 in both benign and malignant insulinomas suggests that this receptor subtype could be of importance for diagnostic and therapeutic use.

  • 210.
    Raffalli-Mathieu, Françoise
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Orre, Carolina
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson Edalat, Maryam
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Mannervik, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells2008In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 414, no 1, p. 103-109Article in journal (Refereed)
    Abstract [en]

    hGSTA3-3 (human Alpha-class glutathione transferase 3-3) efficiently catalyses steroid Delta(5)-Delta(4) double-bond isomerization in vitro, using glutathione as a cofactor. This chemical transformation is an obligatory reaction in the biosynthesis of steroid hormones and follows the oxidation of 3beta-hydroxysteroids catalysed by 3beta-HSD (3beta-hydroxysteroid dehydrogenase). The isomerization has commonly been ascribed to a supplementary function of 3beta-HSD. The present study is the first to provide evidence that hGSTA3-3 contributes to this step in steroid hormone biosynthesis in complex cellular systems. First, we find glutathione-dependent Delta(5)-Delta(4) isomerase activity in whole-cell extracts prepared from human steroidogenic cells. Secondly, effective inhibitors of hGSTA3-3 dramatically decrease the conversion of Delta(5)-androstene-3,17-dione into Delta(4)-androstene-3,17-dione in cell lysates. Thirdly, we show that RNAi (RNA interference) targeting hGSTA3-3 expression decreases by 30% the forskolin-stimulated production of the steroid hormone progesterone in a human placental cell line. This effect is achieved at low concentrations of two small interfering RNAs directed against distinct regions of hGSTA3-3 mRNA, and is weaker in unstimulated cells, in which hGSTA3-3 expression is low. The results concordantly show that hGSTA3-3 makes a significant contribution to the double-bond isomerization necessary for steroid hormone biosynthesis and thereby complements the indispensable 3beta-hydroxysteroid oxidoreductase activity of 3beta-HSD. The results indicate that the lower isomerase activity of 3beta-HSD is insufficient for maximal rate of cellular sex hormone production and identify hGSTA3-3 as a possible target for pharmaceutical intervention in steroid hormone-dependent diseases.

  • 211. Rafik Hamad, Rangeen
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Pernow, John
    Bremme, Katarina
    Eriksson, Maria J.
    Assessment of left ventricular structure and function in preeclampsia by echocardiography and cardiovascular biomarkers2009In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 27, no 11, p. 2257-2264Article in journal (Refereed)
    Abstract [en]

    AIM: To assess left ventricular (LV) structure and function in preeclampsia, a serious vascular-related pregnancy disorder, by Doppler tissue imaging (DTI) in combination with the levels of cardiovascular biomarkers. MATERIAL AND METHODS: Thirty-five pregnant women with preeclampsia and 30 with normal pregnancy, matched for age and gestational age were examined during pregnancy and 3-6 months after delivery. Transthoracic echocardiography and DTI were performed and blood levels of amino-terminal pro-brain natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), cystatin C and troponin I were analyzed. RESULTS: There were significant differences in LV and left atrial dimensions and function between the groups. A higher septal and lateral E/E' ratio (E = early transmitral diastolic flow velocity and E' = early diastolic myocardial velocity) (P < 0.0001, 0.0008) and higher levels of NT-pro-BNP, cystatin C, and lower cystatin C estimated GFR in ml/min per 1.73 m (P < 0.0001) were seen in the preeclampsia both during pregnancy and at follow-up. In addition the levels of E/E' ratio lateral and NT-pro-BNP were higher in pregnant women with early-onset preeclampsia necessitating delivery before 34 weeks of gestation than those who developed preeclampsia and delivered at or after 34 weeks (P = 0.0004, 0.005). CONCLUSION: In pregnancies complicated by preeclampsia, especially early-onset preeclampsia, the diastolic LV function is impaired and levels of biomarkers, NT-pro-BNP and cystatin C, are increased in comparison to normal pregnancy.

  • 212.
    Ridefelt, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Axelsson, John
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Diurnal variability of total calcium during normal sleep and after an acute shift of sleep2012In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 50, no 1, p. 147-151Article in journal (Refereed)
    Abstract [en]

    Background: Serum total calcium is becoming a widely used test when screening for hyperparathyroidism (HPT) and other causes of hypercalcemia, even if serum calcium is tightly regulated in the body it is unclear whether the reference values are correct for tests taken at different times of the day or for individuals with altered sleep patterns. Thus, the aim was to investigate how timing of testing and sleep affects serum calcium.

    Methods: The diurnal variation of total calcium in serum during night-time and day-time conditions was studied in seven healthy volunteers. Serum samples for calcium measurements were collected every hour (48 samples per individual) to evaluate the effect of sampling times, sleep and food intake on the test results.

    Results: The median intra-individual coefficients of variations for calcium were 3.3% during night-time sleep and 2.8% during day-time sleep conditions. There was a clear diurnal variation in serum calcium, with a trough at 08.00 h in the morning after night-time sleep and a difference of approximately 0.07 mmol/L between trough and peak. Calcium was lower around the end of the sleep periods, for both night-time and day-time sleep. Food intake did not affect calcium concentrations.

    Conclusions: Evaluation of serum calcium results should take diurnal variation into account and allow slightly higher calcium values in the afternoon in comparison with samples collected in the morning.

  • 213.
    Ridefelt, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rehman, Javaid-ur
    Karolinska Institutet.
    Axelsson, John
    Karolinska Institutet.
    Influences of sleep and the circadian rhythm on iron-status indices2010In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 43, no 16-17, p. 1323-1328Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim was to study the influence of sampling time, food intake and sleep on tests used to screen for and monitor conditions of iron deficiency and overload. DESIGN AND METHODS: The 24 h variations of iron, transferrin, transferrin saturation (TS) and ferritin were studied in seven healthy individuals during standardised food intake, and during night or day sleep. RESULTS: Iron and TS showed clear diurnal variations, with peaks at 12.6 h and 12.8 h respectively, during night sleep, and at 19.7 h and 19.3 h, respectively, during day sleep. Ferritin did not demonstrate any circadian variation. Transferrin and ferritin were unaffected by sleep-condition. Meals did not have any effect except a slight decline of transferrin. CONCLUSIONS: Time of day and sleeping patterns had great influence on iron and TS, whereas no or only minor effects are seen on the concentration of ferritin and transferrin. Meals have limited effects.

  • 214.
    Ronquist, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Frithz, Göran
    Wang, Yu-Hui
    Lindeborg, Torsten
    Captopril may reduce biochemical (prostate-specific antigen) failure following radical prostatectomy for clinically localized prostate cancer2009In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 43, no 1, p. 32-36Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A prior report suggested that individuals medicated with captopril showed a decreased incidence of prostate cancer. This study therefore investigated whether captopril given postoperatively had any preventive effect on biochemical recurrence for patients treated with radical prostatectomy. MATERIAL AND METHODS: Data were prospectively reviewed for 62 men subjected to radical retropubic prostatectomy due to biopsy-confirmed, clinically localized prostate cancer and comparisons were made between two groups, those receiving captopril postoperatively (12.5 mg twice daily; captopril group, n=32) and those not receiving any captopril (control group, n=30). One surgeon carried out the surgery. RESULTS: The two groups were comparable as regards age at surgery, prostate volume, preoperative prostate-specific antigen values, pathological stage, Gleason score, organ-confined disease, occurrence of positive surgical margins and extraprostatic extension. The incidence of biochemical failure was three out of 32 patients in the captopril group and 10 out of 30 in the control group (p=0.034) during a mean observational time of 29 months. CONCLUSIONS: A lower rate of biochemical recurrence was observed in men subjected to radical prostatectomy treated with captopril postoperatively than in those not receiving captopril. These results were based on only 32 observations; a larger study may show no evidence of an association.

  • 215.
    Ronquist, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    García Rodríguez, LA
    Ruigómez, A
    Johansson, Saga
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Frithz, G
    Svärdsudd, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Association between captopril, other antihypertensive drugs and risk of prostate cancer2004In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 58, no 1, p. 50-56Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    There has been some debate on the existence of an association between hypertension, antihypertensive medications and cancer risk.

    METHODS

    We performed a nested case-control study to assess the association between the risk of prostate cancer and the use of the angiotensin converting enzyme (ACE)-inhibitor captopril, and other antihypertensive drugs. We used data from the General Practice Research Database in UK.

    RESULTS

    We found an incidence rate of prostate cancer of 1.61 per 1,000 person-years among male patients aged 50–79 years old. Patients with a history of benign prostatic hyperplasia and/or prostatism carried a two-fold greater risk of prostate cancer than those without such antecedents. None of the other studied co-morbidities were associated with prostate cancer. We found that users of captopril had a relative risk of 0.7 (95% CI: 0.4–1.2) to develope prostate cancer. None of the other studied individual ACE-inhibitors shared a similar effect with the one observed for captopril.

    CONCLUSIONS

    No clear association was apparent between the use of antihypertensive drugs and prostate cancer. However, specific focus on users of captopril showed a lower risk of subsequent prostate cancer. Further research is needed to explore this association.

  • 216.
    Ronquist, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Theodorsson, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Inherited, non-spherocytic haemolysis due to deficiency of glucose-6-phosphate dehydrogenase2007In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 67, no 1, p. 105-111Article, review/survey (Refereed)
    Abstract [en]

    The about 400 million individuals worldwide suffering from a hereditary deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) may experience different degrees of haemolytic anaemia. Haemoglobin is present in very high concentrations in the erythrocyte cytoplasm, at risk of falling out of solution if the internal environment or the haemoglobin itself is changed. G6PD is a crucial enzyme producing reduced glutathione in the erythrocyte cytoplasm for the purpose of protecting haemoglobin against oxidative damage. The presence of unopposed oxidizing agents leading to oxidation of the sulfhydryl bridges between parts of the haemoglobin molecule decrease the solubility of haemoglobin, leading to precipitations called Heinz bodies. The laboratory investigation of G6PD deficiency is commonly done by a quantitative spectrophotometric analysis or by a rapid fluorescent spot test detecting the generation of NADPH from NADP. Genetic tests based on polymerase chain reaction detect specific mutations and may be used for population screening, family studies, or prenatal diagnosis.

  • 217.
    Ronquist, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Some Characteristics of Human Prostasomes and Their Relationship to Prostate Cancer2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The secretory epithelial cells of the prostate gland use sophisticated vehicles named prostasomes to relay important information to sperm cells in semen. This prostasome-forming and secretory ability of the epithelial cells is also preserved in poorly differentiated prostate cancer cells.

    Aim: The aim of this thesis was to examine different characteristics of prostasomes, especially those derived from malignant prostate cells, linked to their potential role in diagnosis and prognostication of prostate cancer.

    Results: Serum samples of prostate cancer patients contained autoantibodies against seminal prostasomes in a higher concentration than did control sera. These autoantibodies were most frequently directed against 25 prostasome-associated proteins, but no one was prostate specific. Clusterin was one of the most frequently occurring prostasomal proteins. Elevated titers were however seen in both patients´ and control sera. Clusterin turned out to be a major antigen of seminal prostasomes. No prostate specific or prostate cancer specific protein was discovered upon proteomic analysis of prostasomes deriving from malignant cells of vertebral metastases of prostate cancer patients. Human chromosomal DNA was identified in both seminal prostasomes and PC-3 cell prostasomes and strong evidence existed that the DNA was localized inside the prostasomes. Four out of 13 DNA clones of seminal prostasomes featured gene sequences (31%). The corresponding figures for PC-3 cell prostasomes were 4 out of 16 clones (25%).

    Conclusions: Prostasomes are immunogenic and give rise to serum autoantibodies. The most frequently occurring autoantibodies were directed against 25 prostasomal proteins but none of these was exclusively prostate specific. Thirty different proteins were identified in prostate cancer metastasis-derived prostasomes but none of these proteins was prostate cancer specific. Human chromosomal DNA was identified in prostasomes of both normal and malignant cell origin.

  • 218.
    Ronquist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Sten
    Karolinska University Hospital, Department of Oncology and Pathology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prostasome-derived proteins capable of eliciting an immune response in prostate cancer patients2006In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 119, no 4, p. 847-853Article in journal (Refereed)
    Abstract [en]

    Prostate cancer consistently remains a difficult clinical enigma. Therefore, the development of novel strategies for diagnosis and treatment (e.g. immunotherapy) of prostate cancer is essential. We tried to identify the prostasome-derived proteins that were immunogenic in prostate cancer patients. Prostate cancer patients’ sera (n 5 44) with high enzyme-linked immunosorbent assay (ELISA) titers against prostasomes were selected for immunoblotting against purified seminal prostasomes. The SDS-PAGE and immunoblotting experiments were performed with Bio-Rad systems. Twenty-five of the recognized proteins were isolated and analyzed by means of mass spectrometry. Out of 44 patients’ sera, 31 (70%) demonstrated in immunoblotting experiments reactivity against several prostasomal protein bands in the molecular weight range of 10– 200 kDa. Some of the bands (55, 70 and 170 kDa) were more frequently recognized by the patients’ sera. Concomitantly run control sera generated only very weak or no bands at all. The most frequently occurring prostasomal proteins were identified as heat shock proteins (HSP 70, 71) and clusterin. This study identified the most important molecular targets of autoantibodies against prostasomes generated in connection with the development of prostate cancer in man. These immunogenic prostasomal proteins could be appropriate target molecules for specific immunotherapy of prostate cancer patients.

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

  • 219.
    Ronquist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Semjonow, Axel
    Department of Urology-Prostate Centre, University Clinic, Mu¨nster,.
    Wülfing, Christian
    Department of Urology-Prostate Centre, University Clinic, Mu¨nster,.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Serum antibodies against prostasomal clusterin in prostate cancer patients2008In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 68, no 3, p. 219-227Article in journal (Refereed)
    Abstract [en]

    Objective. Clusterin is a ubiquitous secretory sulphated glycoprotein present in prostasomes. It is an antiapoptotic mediator in prostate cancer and is among the most frequently occurring prostasomal proteins immunogenic in prostate cancer patients. The aim of the present study was to investigate the occurrence of anticlusterin antibodies in the serum of patients with prostate cancer and whether there is a relationship between anticlusterin antibody titres and other clinico-pathological variables. Material and methods. Serum samples were collected from 391 consecutive patients with suspected prostate cancer (150 benign prostate and 241 prostate cancer). The patients’ serum samples were used in an ELISA where microtitre wells were coated with purified clusterin from serum of a healthy volunteer. Flow cytometric studies of clusterin and prostasomes were performed. Results. Flow cytometric analyses revealed the presence of clusterin on the surface of seminal prostasomes. Anti-clusterin ELISA titres in sera of patients did not differ significantly from those of a control group. A significant ‘‘inverse’’ correlation existed between anti-clusterin ELISA titres and lymph node metastases (p50.047), but only 11 out of 161 patients had metastases. These titres correlated significantly with total prostate (p50.021) and transitional zone (p50.015) volumes of the patients. Conclusions. The correlation between serum anti-clusterin antibody titres and other clinico-pathological variables was generally weak in prostate cancer patients, although clusterin has been assigned an important role in tumourigenesis and progression of prostate cancer. However, the anti-clusterin antibody titre appeared to be related to prostate volume, correlating to both transitional zone volume and total volume of the prostate.

  • 220.
    Ronquist, Göran K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hreinsson, Julius
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Prostasomal DNA Characterization and Transfer Into Human Sperm2011In: Molecular Reproduction and Development, ISSN 1040-452X, E-ISSN 1098-2795, Vol. 78, no 7, p. 467-476Article in journal (Refereed)
    Abstract [en]

    Human prostasomes, exosome-like microvesicles secreted by acinar cells of the prostate gland, contain chromosomal DNA. Agarose gel electrophoresis of DNA from seminal prostasomes displayed fragments of over 12 kb and smaller, with a distinct band around 1 kb that was excised, cloned, and sequenced. The sequences showed 8 out of 25 clones (32%) originating from genes. We elaborated the concept further by carrying out a genome-wide DNA copy number analysis of prostasomal DNA, hypothesizing that human prostasomes contain fragments of DNA randomly selected from the entire genome. Acridine orange-stained prostasomes were incubated with freshly prepared sperm for different times, and a transfer of acridine orange-stained prostasomal DNA to sperm (preferentially the head region) was observed. Fluorescence microscopy of slices in the center of 14 optical slides of the sperm head displayed an even fluorescence rather than a halo-like one, indicating DNA-uptake rather than just binding along the sperm head membrane.

  • 221.
    Ronquist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human Prostasomes Contain Chromosomal DNA2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 7, p. 737-743Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. The aim of this study was to perform a comprehensive evaluation of the occurrence of DNA in human prostasomes. METHODS. Prostasomes were purified from seminal fluid (seminal prostasomes) and from PC-3-cells (PC-3 cell prostasomes). DNA extracted from both sources of prostasomes was visualized on agarose gels. Further, theDNAwas cloned and sequenced (13 clones from seminal prostasomal DNAand 16 clones from PC-3 cell prostasomal DNA) and identified by alignment in the BLAST-nucleotide search database. In order to decide if the DNA was internally or externally located in/on prostasomes, prostasomes were treated with nuclease (DNase) and A260 was measured before and after treatment. Additionally, flow cytometric studies were performed with membrane permeable and membrane impermeable DNA stains. RESULTS. We identified human chromosomal DNA in purified prostasomes from both sources and treatment with DNase demonstrated that the prostasome-shielded DNA was protected from enzyme attack. Membrane-permeable DNA stain raised the fluorescence contrary to membrane-impermeable stain. Clearly discernible nucleic acid of prostasomes was separated on 1% agarose gel yieldingDNAfragments of about 13 kbp and below with a marked band at about 1 kbp. Cloning and sequencing of 13 fragments from seminal prostasomes and 16 from PC-3 cell prostasomes revealed a chromosomal origin of the DNA. In purified seminal prostasomes, 4 out of 13 DNA clones featured gene sequences (31%). The corresponding figure for PC3-derived prostasomes was 4 out of 16 clones featuring gene sequences (25%). CONCLUSION. Human prostasomes contain chromosomal DNA. Both nuclease treatment and differential DNA stainings indicated an inside location of the prostasomal DNA. Our findings suggest a DNA-delivery function of prostasomes to sperm cells.

  • 222.
    Ronquist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Proteomic analysis of prostate cancer metastasis: derived prostasomes2010In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 30, no 2, p. 285-290Article in journal (Refereed)
    Abstract [en]

    The secretory epithelial cells of the prostate gland use sophisticated vehicles in the form of prostasomes to relay important information to sperm cells in semen. This prostasome-forming and secretory ability of the epithelial cells is also preserved in poorly differentiated prostate cancer cells. We investigated prostasomes from vertebral metastases of prostate cancer, taken from the operating field at surgery, directly taken care of under protease inhibitory conditions for later 2-dimensional electrophoresis and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) protein characterization. A total of 104 spots were punched out for identification. Twenty five unique protein spots had a MALDI-TOF above 49 and another 5 proteins were determined by MS/MS. The remaining 74 spots were either identical to already determined proteins or had no reliable score. Annexins A1, A3, and A5 as well as dimethylarginine dimethylaminohydrolase 1 were among the identified proteins. The annexins and dimethylarginine dimethylaminohydrolase 1 found in cancer-derived prostasomes can act, among other things, as angiogenic factors and can increase the vascular development in the neighborhood of the tumor. Cancer-derived prostasomes may play an important role in the interaction between tumor cells and their environment.

  • 223.
    Ronquist, K Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ek, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human prostasomes express glycolytic enzymes with capacity for ATP production2013In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 304, no 6, p. E576-E582Article in journal (Refereed)
    Abstract [en]

    Prostasomes are prostate-derived, exosome-like microvesicles that transmit signaling complexes between the acinar epithelial cells of the prostate and sperm cells. A vast majority of prostasomes has a diameter of 30 - 200 nm and they are generally surrounded by a classical membrane bilayer. Using a selected proteomic approach, it became increasingly clear that prostasomes harbor distinct subsets of proteins that may be linked to adenosine triphosphate (ATP) metabolic turnover that in turn might be of importance in the role of prostasomes as auxiliary instruments in the fertilization process. Among the 21 proteins identified most of the enzymes of anaerobic glycolysis were represented and three of the glycolytic enzymes present are among the ten top proteins found in most exosomes, once again linking prostasomes to the exosome family. Other prostasomal enzymes involved in ATP turnover were adenylate kinase, ATPase, 5'-nucleotidase and hexose transporters. The identified enzymes in their prostasomal context were operational for ATP formation when supplied with substrates. The net ATP production was low due to a high prostasomal ATPase activity that could be partially inhibited by vanadate that was utilized in order to profile the ATP forming ability of prostasomes. Glucose and fructose were equivalent as glycolytic substrates for prostasomal ATP formation and the enzymes involved were apparently surface-located on prostasomes, since an alternative substrate not being membrane-permeable (glyceraldehyde 3-phosphate) was operative, too. There is no clear cut function linked to this subset of prostasomal proteins but some possible roles are discussed.

  • 224.
    Rubin, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zagai, Ulrika
    Blom, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Trulson, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The coding ECP 434(G>C) gene polymorphism determines the cytotoxicity of ECP but has minor effects on fibroblast-mediated gel contraction and no effect on RNase activity2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 1, p. 445-451Article in journal (Refereed)
    Abstract [en]

    Eosinophil cationic protein (ECP) is a secretory protein of the eosinophil granulocyte, a cell involved in innate immunity. Functional studies have implicated ECP in numerous processes, such as tissue remodeling in allergic inflammation and cytotoxicity toward a variety of pathogens. Recent genetic studies have suggested that the ECP 434(G>C) polymorphism resulting in an arg97thr substitution would alter the function of ECP in vivo. Functional (in vitro) studies of ECP up until now have either been conducted with native preparations containing an unknown mixture of the ECP(97arg) and ECP(97thr) variants, or with recombinant proteins. Therefore, we have now for the first time extracted the native ECP(97arg) and ECP(97thr) variants from healthy blood donors and tested them functionally in vitro. Our results show that the arg97thr shift dramatically alters the cytotoxic capacity of ECP in vitro; the tested ECP(97arg) variants were cytotoxic toward the small-cell lung cancer cell line NCI-H69, whereas ECP(97thr) was noncytotoxic. RNase activity was unaffected by the arg97thr substitution. Both ECP(97arg) and ECP(97thr) stimulated fibroblast-mediated collagen gel contraction, an experimental model, which depicts wound healing, in a dose-dependent manner. In conclusion, our results demonstrate that the ECP 434(G>C) gene polymorphism affects the functional properties of native ECP, but also that there is a dissociation between different biological activities; the arg97thr substitution impairs the cytotoxic potential of ECP but less the gel contraction and not at all the RNase activity.

  • 225. Rudolphi, Olle
    et al.
    Brattsand, Göran
    Waldenström, Anders
    Nilsson, Anna-Lena
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ovanlig typ av hemolys vid Taruis sjukdom i två familjer av västerbottniskt ursprung2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 9, p. 657-60Article in journal (Refereed)
  • 226.
    Rundström, Gerd
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Surface Biotechnology.
    Jonsson, Ann
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology, Centre for Surface Biotechnology.
    Mårtensson, Ola
    Mendel-Hartvig, Ib
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lateral Flow Immunoassay Using Europium (III) Chelate Microparticles and Time-Resolved Fluorescence for Eosinophils and Neutrophils in Whole Blood2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 2, p. 342-348Article in journal (Refereed)
    Abstract [en]

    Background: A simple point-of-care method for measuring leukocyte counts in a doctor’s office or emergency room could be of great importance. We developed a protocol for measuring cell count by disrupting the cell membrane and analyzing specific proteins within the cells and used it to analyze proteins from eosinophils and neutrophils.

    Methods: Lateral immunochromatographic (ICR) assays have been developed for eosinophil protein X (EPX) and human neutrophil lipocalin (HNL) as measures of the concentration of eosinophils and neutrophils. The correlation between the lateral ICR assays and cell counting of eosinophils and neutrophils was performed manually and with an automated cell counter. RIA assays measuring the same analytes were also compared with the results from cell counting and lateral ICR assays.

    Results: The optimized assays showed analytical detection limits below the clinical ranges of 3.36 µg/L and 2.05 µg/L for EPX and HNL, respectively. The recovery was 114.8%–122.8% for EPX and 94.5%–96.9% for HNL. The imprecision was 3%–17% CV for EPX over the whole range and 5%–16% CV for HNL. The correlation coefficients between manually counted cells and lateral ICR assays were 0.9 and 0.83 for EPX and HNL, respectively.

    Conclusion: The numbers of eosinophils and neutrophils in small amounts of blood can be estimated in the point-of-care setting by means of fast lateral ICR assays of EPX and HNL.

  • 227.
    Rönquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prostasomer och exosomer - cellbudbärare med terapeutisk potentia2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 10, p. 784-786Article in journal (Refereed)
    Abstract [en]

    Prostasomes and exosomes are kindred natures. They are small organellar structures harboured in multivesicular bodies (”storage vesicles”) and released by exocytosis into the extracellular space. They are surrounded by a complex bilayered, sometimes multilayered, membrane. The pluripotency of prostasomes favours the normal reproductive process in different ways and later on in life they may be involved in the propagation of prostate cancer.Exosomes can function in a multitude of processes, e.g. intercellular communication during immune response and they can indirectly stimulate the immune system. They are being used in clinical trials as tumour antigen bearers to trigger tumour rejection by the body.

  • 228. Sabina, Richard L.
    et al.
    Waldenström, Anders
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The contribution of Ca+ calmodulin activation of human erythrocyte AMP deaminase (isoform E) to the erythrocyte metabolic dysregulation of familial phosphofructokinase deficiency2006In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 91, no 5, p. 652-5Article in journal (Refereed)
    Abstract [en]

    Erythrocyte membrane leakage of Ca2+ in familial phosphofructokinase deficiency results in a compensatory increase of Ca2+-ATPase activity that depletes ATP and leads to diminished erythrocyte deformability and a higher rate of hemolysis. Lowered ATP levels in circulating erythrocytes are accompanied by increased IMP, indicating that activated AMP deaminase plays a role in this metabolic dysregulation. Exposure to a calmodulin antagonist significantly slows IMP accumulation during experimental energy imbalance in patients' cells to levels that are similar to those in untreated controls, implying that Ca2+-calmodulin is involved in erythrocyte AMP deaminase activation in familial phosphofructokinase deficiency. Therapies directed against activated isoform E may be beneficial in this compensated anemia.

  • 229.
    Sahlén, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Nilsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Norlén, Bo Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Secretions from seminal vesicles lack characteristic markers for prostasomes2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 2, p. 107-112Article in journal (Refereed)
    Abstract [en]

    Background. Prostasomes are suggested to be produced in the prostate gland. Although biochemical studies support this, some immunohistochemical findings indicate that also the seminal vesicles could be a source of prostasomes. Therefore, we have compared the secretion of the vesicles with that of the prostate using biochemical and ultrastructural techniques. Methods. Ultracentrifuged pellets of substance from seminal vesicle secretions were analysed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and flow cytometry. The secretory cells of the seminal vesicles were examined with transmission electron microscopy. These findings were then compared with published results from similar studies of the prostate secretory cells. Results. In SDS-PAGE, the seminal vesicle pellets lacked the three prostasome-characteristic CD-markers, namely CD10, CD13, and CD26, but expressed two proteins of about 55 kDa and 70 kDa, corresponding to clusterin and heat shock protein (HSP70). Flow cytometry showed the presence of secretion particles in the seminal pellet, although of a smaller size than that of the prostasomes. Electron microscopy of the luminal part of the cells in the seminal vesicles demonstrated many secretion granules, each enclosed in a vesicle with a size of about 1 mum. Conclusions. Pelleted seminal vesicle secretion is different to prostate secretion in several ways. No prostasome characteristics were detected in the pelleted seminal vesicle secretion.

  • 230. Salem, Rany M.
    et al.
    Cadman, Peter E.
    Chen, Yuqing
    Rao, Fangwen
    Wen, Gen
    Harnilton, Bruce A.
    Rana, Brincla K.
    Smith, Douglas W.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ward, Harry J.
    Mahata, Manjula
    Mahata, Sushi K.
    Bowden, Donald W.
    Hicks, Pamela J.
    Freeclman, Barry I.
    Schork, Nicholas J.
    O'Connor, Daniel T.
    Chromogranin a polymorphisms are associated with hypertensive renal disease2008In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 19, no 3, p. 600-614Article in journal (Refereed)
    Abstract [en]

    Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic “braking” system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5′) region, G-462A→T-415C→C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3′-end, C11825T (3′-UTR, C+87T)→G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3′-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.

  • 231. Seveus, Lahja
    et al.
    Amin, Kawa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Human Anatomy.
    Peterson, Christer
    Roomans, Godfried
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Human Anatomy.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human neutrophil lipocalin (HNL) is a specific granule constituent of the neutrophil granulocyte: Studies in bronchial and lung parenchymal tissue and peripheral blood cells1997In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 107, no 5, p. 423-432, article id 9208334Article in journal (Refereed)
    Abstract [en]

    The neutrophilic granulocyte is a cytotoxic and potentially tissue-injuring cell participating in the destructive processes and symptoms seen in a variety of inflammatory diseases. Sensitive immunoassays have been introduced to measure the levels of specific secretory proteins of various inflammatory cells in blood and other body fluids. The aim has been to develop highly specific markers for each cell type. The results obtained by immunoassay have indicated that human neutrophil lipocalin (HNL) is a protein unique to the neutrophil. The present study investigated the specificity of HNL as a neutrophil marker in peripheral blood and lung tissue by using flow cytometry and immunocytochemistry. Flow cytometry and immunocytochemistry on peripheral blood showed that monoclonal antibodies to HNL only react with neutrophils and not with other types of leukocytes. Immunocytochemistry on plastic-embedded sections and on frozen sections of lung tissue showed that a cocktail of six monoclonal antibodies to HNL specifically reacts with neutrophils and not with epithelial cells or macrophages. By immunoelectron microscopical studies performed on healthy human neutrophils after low temperature embedding in Lowicryl K4M following aldehyde fixation and partial dehydration, it could be shown that HNL colocalized with lactoferrin (a known marker for secondary or specific granules) and that myeloperoxidase was localized in the primary or azurophil granules. The results confirm that HNL is a unique component of the secondary granules of the neutrophil granulocyte.

  • 232. Shlipak, Michael G.
    et al.
    Weekley, Cristin C.
    Li, Yongmei
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Whooley, Mary
    Comparison of Cardiovascular Prognosis by 3 Serum Cystatin C Methods in the Heart and Soul Study2011In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 57, no 5, p. 737-745Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cystatin C is a promising new biomarker to estimate glomerular filtration (eGFR). However, the Siemens' cystatin C assay (Siemens), used in many longitudinal studies, has had limited clinical applicability because it requires a specific, dedicated instrument. Other companies, including Gentian and Roche, have developed cystatin C assays that can be used with most routine clinical chemistry analyzers. METHODS: We compared the agreement of Gentian and Roche with Siemens in 948 participants at the baseline visit of the Heart and Soul Study, a cohort of participants with established coronary artery disease who were followed for an average of 8 years. We then compared associations of all 3 cystatin C measures and eGFR-Modification of Diet in Renal Disease (MDRD) with clinical outcomes. RESULTS: The Gentian assay had higher correlation with Siemens (r = 0.96) than did Roche (r = 0.93, P < 0.001). After cross-tabulating quartiles of each cystatin C measure, agreements (κ statistic) were higher for Siemens and Gentian (0.73, 95% CI 0.72-0.75) than for Roche and Siemens (0.64, 0.63-0.66) or for Roche and Gentian (0.69, 0.65-0.71). These differences in agreement had minimal impact on associations with clinical outcomes; the hazard ratios (HRs) for mortality comparing the high vs low quartiles were 3.2 (95% CI 2.1-4.8) for Siemens, 3.1 (CI 2.1-4.7) for Gentian, 3.1 (CI 2.1-4.7) for Roche, and 1.6 (CI 1.1-2.3) for eGFR-MDRD, after multivariate adjustment. CONCLUSIONS: In summary, agreement with the Siemens' assay was modestly higher for the Gentian compared with the Roche assay, although all 3 methods for cystatin C measurement had similar utility as predictors of clinical outcomes.

  • 233.
    Siegbahn, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Johnell, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nordin, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Velling, Teet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    TF/FVIIa transactivate PDGFRbeta to regulate PDGF-BB-induced chemotaxis in different cell types: involvement of Src and PLC2008In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 1, p. 135-41Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously reported the potentiation of PDGF-BB-induced chemotaxis of fibroblasts, vascular smooth muscle cells, and endothelial cells by FVIIa. Here we studied the role of TF/FVIIa and the induced signaling pathways in regulation of chemotaxis of human monocytes, fibroblasts, and porcine aorta endothelial cells. METHODS AND RESULTS: Human monocytes were obtained by using Ficoll-Paque gradient and the MACS system (for highly purified population), fibroblasts and PAE cells have been characterized previously. Inhibitors of selected signaling intermediates were used, and the effect of TF/FVIIa on the migratory response of all cells to chemotactic agents was analyzed. The induced signaling was studied by immunoprecipitation and Western blotting. TF/FVIIa complex selectively enhanced PDGF-BB-induced chemotaxis in a Src-family, PLC, and PAR-2-dependent manner. Using PAE cells we identified c-Src and c-Yes as the Src-family members activated by TF/FVIIa. We report for the first time the PAR-2 and Src family-dependent transactivation of PDGFRbeta by TF/FVIIa involving phosphorylation of a subset of PDGFRbeta tyrosines. CONCLUSIONS: The described transactivation is a likely mechanism of TF/FVIIa-mediated regulation of PDGF-BB-induced chemotaxis. Similar behavior of 3 principally different cell types in our experimental setup may reflect a general function of TF in regulation of cell migration.

  • 234. Skagius, E
    et al.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Henriksson, A E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Fibrinolysis in patients with abdominal aortic aneurysm with special emphasis on rupture and shock2007In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 1, p. 147-150Article in journal (Refereed)
    Abstract [en]

    Background: A ruptured abdominal aortic aneurysm (AAA) is associated with high mortality. Postoperative complications such as hemorrhage, multiple organ failure, myocardial infarction, and thromboembolism are common. An active and balanced hemostatic system is essential to avoid bleeding as well as thrombosis. When these activities are not properly regulated the patient is at risk of developing either excessive bleeding or thrombosis-related complications. Previous studies have shown a state of activated coagulation in patients with ruptured AAA. However, there are conflicting results regarding the fibrinolytic response. Objectives: The aim of the present study was to investigate the fibrinolytic state pre-operatively in patients with ruptured and non-ruptured AAA in relation to the clinical outcome with special regard to the influence of shock. Methods: A prospective study was performed on 95 patients who underwent surgery for a ruptured AAA with shock (n = 43), a ruptured AAA without shock (n = 12), and a non-ruptured AAA (n = 40). Forty-one controls without an aneurysm were matched to the AAA patients according to age, gender and smoking habits. Plasma levels of tissue plasminogen activator antigen (tPAag), and plasminogen activator inhibitor type-1 (PAI-1) were measured as markers of fibrinolytic activity. D-dimer, a marker of fibrin turnover, was also measured. Results: D-dimer was significantly higher in patients with a non-ruptured AAA compared with controls without AAA. There were significantly higher levels of D-dimer, tPAag, and PAI-1 in patients operated for ruptured compared with non-ruptured AAA. tPAag was also significantly higher in ruptured AAA patients with shock compared with without shock. No deaths occurred in patients operated on for a non-ruptured AAA or ruptured AAA without shock. There were 12 deaths after repair of a ruptured AAA with shock, of which two patients died from bleeding and the remaining 10 from multiple organ failure and cardiac failure. Conclusion: Our results indicate a state of activated coagulation in patients with a non-ruptured AAA, the state being intensified by rupture. The present data show normal fibrinolytic activities in patients with a non-ruptured AAA, but increased systemic fibrinolysis, as demonstrated by elevated tPAag level, in patients with a ruptured AAA. The elevated PAI-1 level indicates a simultaneous inhibition of the systemic fibrinolysis. Furthermore, the hyperfibrinolytic state was reinforced by shock in this study. However, the clinical outcome, with a relatively high incidence of thrombosis-related deaths, indicate a prothrombotic state instead of a hyperfibrinolytic state as a major point of attention in patients with shock as a result of a ruptured AAA.

  • 235.
    Skalkidou, Alkistis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sylvén, Sara M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Papadopoulos, Fotios C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Risk of postpartum depression in association with serum leptin and interleukin-6 levels at delivery: a nested case-control study within the UPPSAT cohort2009In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 34, no 9, p. 1329-1337Article in journal (Refereed)
    Abstract [en]

    Although postpartum depression (PPD) is a common condition, it often goes undiagnosed and untreated, with devastating consequences for the woman's ability to perform daily activities, to bond with her infant and to relate to the infant's father. Leptin, a protein synthesised in the adipose tissue and involved in regulation of food intake and energy expenditure has been related to depressive disorders, but studies report conflicting results. The aim of this study was to evaluate the association between serum leptin levels at the time of delivery and the subsequent development of postpartum depression in women, using data from a population-based cohort of delivering women in Uppsala, Sweden. Three hundred and forty seven women from which serum was obtained at the time of delivery filled out at least one of three structured questionnaires containing the Edinburgh Scale for Postnatal Depression (EPDS) at five days, six weeks and six months after delivery. Mean leptin levels at delivery did not significantly differ between the 67 cases of PPD and the 280 controls. Using linear regression analysis and adjusting for maternal age, body-mass index, smoking, interleukin-6 levels, duration of gestation and gender of the newborn, the EPDS scores at six weeks and six months after delivery were found to be negatively associated with leptin levels at delivery (p<0.05). Serum leptin levels at delivery were found to be negatively associated with self-reported depression during the first six months after delivery. No such association was found concerning serum IL-6 levels at delivery. If these finding are replicated by other studies, leptin levels at delivery could eventually serve as a biological marker for the prediction of postpartum depression.

  • 236.
    Skogseid, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lundqvist, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lörelius, Lars Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wide, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Multiple endocrine neoplasia type 1: a ten year prospective screening study in four kindreds1991In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 73, no 2, p. 281-287Article in journal (Refereed)
    Abstract [en]

    A total of 80 individuals in 4 kindreds with multiple endocrine neoplasia type 1 (MEN 1) have been subjected to repeated biochemical screening during a 10-yr period with the principal aim being to analyze characteristics of the developing pancreatic lesion. Age at presentation of the MEN 1 trait averaged 18 yr in 7 previously unaffected individuals, and this effect of the screening procedure represented a lowering by almost 2 decades. Pancreatic endocrine involvement was recognized at a mean age of 25 yr and constituted the presenting lesion in a majority of the patients. A standardized meal test and basal values of serum pancreatic polypeptide, insulin, proinsulin, and gastrin were the most efficient markers for the pancreatic lesion and preceded signs of pancreatic tumors upon radiological examinations by a mean of 3.5 yr. A 75% penetrance of the islet cell disease and 90% for primary hyperparathyroidism within the affected individuals equalled the prevalences reported in autopsy studies. Two of the kindreds showed signs of intrafamilial homogeneity with respect to the profile of peptide excess (P less than 0.05) and considerable discrepancy in the malignant potential of the pancreatic lesions. The results of early detection and surgical intervention of the pancreatic tumors in MEN 1 suggested an impact on morbidity, while any effect on the mortality of these individuals remains to be clarified.

  • 237.
    Sköldenberg, Erik G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Jakobson, Åke
    Hedborg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kogner, Per
    Christofferson, Rolf H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Azarbayjani, Faranak
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The angiogenic growth factors HGF and VEGF in serum and plasma from neuroblastoma patients2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 8, p. 3311-3319Article in journal (Refereed)
    Abstract [en]

    AIM: To determine whether concentrations of the angiogenic growth factors hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A) correlate with clinical and genetic markers in samples taken at diagnosis in children with neuroblastoma (NB). PATIENTS AND METHODS: Heparin plasma (P-) and serum (S-) samples of healthy controls (n=73, mean age +/- SD 3.5+/-2.1; females/males: 23/50) and patients with NB (n=62; 2.2+/-1.8; 26/36) were collected between 1988 and 1999. Clinical data included age at diagnosis, gender, stage, outcome, amplification of the oncogene MYCN, loss of heterozygosity at the short arm of chromosome 1 (1p LOH) and ploidy. RESULTS: HGF and S-VEGF-A were elevated in NB as compared to controls (38/62 patients, p<0.0001 and p<0.05, Mann-Whitney U test). HGF concentrations were higher in high-stage (stage 3-4) as compared to low-stage (stage 1-2) disease (p<0.01). P-HGF was elevated in patients with 1p LOH (p<0.01), MYCN amplification (p<0.001) and di- or tetraploidy (p<0.001). S-HGF concentration was elevated in patients MYCN-amplified tumors only. Plasma and S-HGF concentrations were higher in the deceased group (p<0.05), but not P or S-VEGF-A. CONCLUSION: This study showed that concentrations of HGF and S-VEGF-A are elevated in patients with NB. Furthermore, HGF and S-VEGF-A concentrations correlate to higher stage disease and HGF correlates to genetic markers known to indicate a poor outcome. These observations imply that HGF and VEGF-A have biological roles in NB and suggest the possibility of interference with HGF or VEGF-A signaling as a therapeutic strategy.

  • 238.
    Sohrabian, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Noraddin, Feria Hikmet
    Flodin, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Fredricsson, Annika
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Particle enhanced turbidimetric immunoassay for the determination of urine cystatin C on Cobas c5012012In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 45, no 4-5, p. 339-344Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Urinary cystatin C has been reported to be a good marker for tubular damage and acute kidney injury. The aim of this study was to develop a high throughput assay for the quantification of urine cystatin C.

    METHODS:

    Antigen-excess, imprecision, interference, linearity, recovery, sample stability and reference values were evaluated on Cobas c501.

    RESULTS:

    The assay was linear over the dynamic range of the study (R(2)=0.9994). The total assay imprecision was below 5%. The assay recovery was estimated at 87-100%. No tendency to antigen-excess (up to 35mg/L), nor interference with haemoglobin (1.25-10g/L) was observed. Cystatin C was stable for 1day at ambient temperature (19-23°C) but for 2days at +4°C. The reference interval for cystatin C in urine was <0.414mg/L.

    CONCLUSIONS:

    The urinary cystatin C assay verified to be a reliable assay with convenient performance characteristics, enabling routine testing on clinical chemistry platforms.

  • 239.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kristiansson, Gudjon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Measurements of chromogranin B can serve as a complement to chromogranin A2007In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 139, no 1-3, p. 80-83Article in journal (Refereed)
    Abstract [en]

    Objective

    CgA has been shown to be an excellent marker for neuroendocrine tumours. However, there are two major drawbacks with CgA measurements; elevated levels are common in patients with decreased renal function and in patients on treatment with proton pump inhibitors. These problems are not seen with CgB measurements. We have recently presented the development of 13 region-specific radioimmunoassays for measurements of CgB. A region-specific assay was identified, which measured higher concentrations of CgB than the other assays and seemed to be very useful as a marker for neuroendocrine tumours. The aim of the present study was therefore to further explore the diagnostic potential of this assay in the clinical management of patients with neuroendocrine tumours.

    Methods

    Measurements of CgB with two methods were compared with CgA in plasma samples from patients investigated for neuroendocrine tumours (N = 86), patients with decreased renal function (N = 35) and patients on treatment with proton pump inhibitors (N = 29).

    Results

    The diagnostic sensitivity for the new CgB assay was almost as good as that for CgA. Furthermore, with CgB measurements we could avoid the falsely elevated levels of CgA found in patients with decreased renal function and treatment with proton pump inhibitors.

    Conclusions

    We conclude that the new CgB assay can serve as a complement to CgA measurements as an important tumour marker for neuroendocrine tumours.

  • 240.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Lundqvist, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Islet amyloid polypeptide (IAPP) in patients with neuroendocrine tumours1995In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 55, no 2, p. 119-131Article in journal (Refereed)
    Abstract [en]

    Although IAPP was first discovered and isolated from amyloid deposits in an endocrine pancreatic tumour (EPT), surprisingly few reports have investigated the potential use of IAPP as a marker for neuroendocrine tumour growth. In this study we present results from plasma measurements of IAPP in 102 patients with neuroendocrine tumours. Four of 35 patients (11%) with midgut carcinoid tumours, but none of the patients (4 and 5, respectively) with lung carcinoids or with rectal carcinoids displayed elevated plasma levels of IAPP. Five of 31 patients (16%) with sporadic EPT and 3 of 27 patients (11%) with EPT and multiple endocrine neoplasia type 1 syndrome disclosed elevated IAPP levels. Within the different syndromes, 1/11 individuals with insulinoma, 2/16 with gastrinoma, 0/2 with glucagonoma, 0/3 with VIPoma and 5/26 with non-functioning tumours showed elevated plasma levels of IAPP. In two patients, the plasma IAPP levels were extremely elevated. These patients also exhibited altered glucose homeostasis. In response to a standardised mixed meal test, IAPP increased in parallel to the insulin, pancreatic polypeptide, gastrin and glucose responses. In MEN1 patients with hypercalcaemia due to increased secretion of parathyroid hormone, the plasma levels of IAPP were significantly higher before than after surgical removal of the parathyroid adenomas. However in normocalcaemic patients, no correlation between the blood calcium and plasma IAPP levels was found. Immunocytochemical staining of tumour tissue showed that 9/13 (69%) of insulin producing tumours, 4/14 (29%) of non-functioning tumours and 1/9 (11%) of gastrin producing tumours were IAPP immunoreactive. Amyloid deposits were always IAPP immunoreactive. In conclusion, increased circulating levels of IAPP occurred in 12% of 102 patients with neuroendocrine tumours. In 2 patients with extremely elevated plasma levels of IAPP, effects on glucose homeostasis were recorded. Thus, IAPP may be useful as an additional marker for neuroendocrine tumour growth in selected cases.

  • 241.
    Stridsberg, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Portela-Gomes, G M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Immunohistochemical staining of human islet cells with region-specific antibodies against secretogranins II and III2008In: Journal of Anatomy, ISSN 0021-8782, E-ISSN 1469-7580, Vol. 212, no 3, p. 229-234Article in journal (Refereed)
    Abstract [en]

    Chromogranins and secretogranins belong to the granin family of proteins, which are expressed in neuroendocrine and nervous tissue. In earlier publications we have described the development of region-specific antibodies against CgA and CgB. In this study we describe antibodies to SgII and SgIII and their usefulness for immunohistochemical staining. Peptides homologous to defined parts of secretogranins II and III were selected and synthesized. Antibodies were raised and immunostainings were performed on normal human pancreas. The SgII 154-165 (N-terminal secretoneurin), SgII 172-186 (C-terminal secretoneurin) and SgIII antibodies immunostained all insulin-immunoreactive cells, most of the glucagon cells and some of the pancreatic polypeptide cells. The SgII 225-242 antibody immunostained only the insulin-containing cells. None of the antibodies immunostained the somatostatin cells. This study is the first observation of the expression of SgIII in human tissues, where we show expression of SgIII in three of the four major islet cell types in human pancreas.

  • 242.
    Sundelöf, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Helmersson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnemaa, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Degerman-Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Systemic inflammation and the risk of Alzheimer's disease and dementia: a prospective population-based study2009In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 18, no 1, p. 79-87Article in journal (Refereed)
    Abstract [en]

    Inflammation is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 1062 and age 77, n = 749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2alpha (PGF2alpha) metabolite levels were analyzed at age 77 in this cohort. Two serial samples (at ages 70 and 77) were available from 704 individuals. Using Cox regression analyses, associations between serum IL-6, hsCRP, SAA and PGF2alpha metabolite levels and risk of AD, any type of dementia (all-cause dementia) and non-AD dementia were analyzed. On follow-up (median, 11.3 years) in the age 70 cohort, 81 subjects developed AD and 165 subjects developed all-cause dementia. Serum IL-6, hsCRP, SAA, or PGF2alpha levels were not associated with risk of AD. At age 70, high IL-6 levels were associated with an increased risk of non-AD dementia (Hazard ratio 2.21 for above vs. below/at median, 95%confidence interval 1.23-3.95, p-value = 0.008). A longitudinal change in CRP or IL-6 levels was not associated with AD ordementia. In conclusion, Serum IL-6, hsCRP, SAA, and PGF2alpha levels are not associated with the risk of AD. High serum IL-6 levels may be associated with increased risk of non-AD dementia.

  • 243.
    Sundelöf, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Helmersson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnemaa, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Degerman-Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Systemic tocopherols and F2-isoprostanes and the risk of Alzheimer's disease and dementia: a prospective population-based study2009In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 18, no 1, p. 71-78Article in journal (Refereed)
    Abstract [en]

    Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer's disease (AD). In this study, serum alpha- and gamma-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 616 and age 77, n = 761). In addition, urinary F2-isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n = 679). Cox regression analyses were used to examine associations between serum alpha-, gamma-tocopherol and urinary F2-isoprostane levels and AD, any type of dementia (all-cause dementia) and non-AD dementia. On follow-up (median, 12.3 years), 40 subjects developed AD and 86 subjects developed all-cause dementia. Serum alpha- and gamma-tocopherol or urinary F2-isoprostane levels were not associated with the future risk of AD or dementia. In conclusion, systemic serum alpha- and gamma-tocopherol and urinary F2-isoprostane levels are not associated with the future risk of AD or dementia and do not seem to be useful predictors of clinical AD or dementia.

  • 244.
    Sundelöf, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansson, Oskar
    Eriksdotter-Jönhagen, Maria
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Degerman-Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Minthon, Lennart
    Blennow, Kaj
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cystatin C Levels are Positively Correlated with both Aβ42 and Tau Levels in Cerebrospinal Fluid in Persons with Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 21, no 2, p. 471-478Article in journal (Refereed)
    Abstract [en]

    Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Abeta42, and tau levels across disease groups were investigated. Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 mumol/L +/- 1.7), MCI (5.4 mumol/L +/- 1.48), and controls (5.6 mumol/L +/- 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61-0.81, p< 0.0001) and Abeta42 (r=0.35-0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Abeta42 levels in CSF independent of age, gender, and APOE genotype.

  • 245.
    Sundelöf, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, J.
    Ingelsson, E.
    Sundström, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Irizarry, M. C.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rönnemaa, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Degerman-Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hyman, B. T.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Serum cystatin C and the risk of Alzheimer disease in elderly men2008In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 14, p. 1072-1079Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). METHODS: Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. RESULTS: On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). CONCLUSIONS: Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.

  • 246.
    Sundström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cardiac troponin-I and risk of heart failure: a community-based cohort study2009In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 30, no 7, p. 773-781Article in journal (Refereed)
    Abstract [en]

    AIMS: We examined if circulating levels of cardiac troponin-I (cTnI) predict subsequent heart failure in the community. METHODS AND RESULTS: Using Cox proportional hazards models, we examined the risk of a first hospitalization for heart failure during a maximum of 11.4 years in a community-based sample of 1089 70-year-old men without heart failure, valvular disease, or electrocardiographic left ventricular hypertrophy. Adjusting for smoking, systolic blood pressure, antihypertensive medication use, diabetes, body mass index, serum cholesterol, and myocardial infarction before baseline or during follow-up, 0.01 microg/L higher cTnI conferred a hazard ratio (HR) of 1.26 (95% confidence interval 1.15-1.38) for subsequent heart failure. Persons with cTnI > or =0.03 microg/L had an HR of 5.25 (2.00-13.77) compared with persons with cTnI <0.01 microg/L. Adjusting additionally for serum NTproBNP attenuated the estimates somewhat [HR 1.22 (1.11-1.34) per 0.01 microg/L of cTnI]. Excluding persons with myocardial infarction before baseline and censoring at time of myocardial infarction during follow-up, 0.01 microg/L higher cTnI was associated with a multivariable-adjusted HR of 1.31 (1.16-1.47) for heart failure. CONCLUSION: In a community-based sample, a direct measure of cardiomyocyte damage, cTnI, indicated a substantially increased risk of heart failure, accounting for other risk factors. Studies investigating the clinical utility of measuring cTnI in asymptomatic individuals are warranted.

  • 247.
    Swenne, Ingemar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Bone metabolism markers in adolescent girls with eating disorders and weight loss: effects of growth, weight trend, developmental and menstrual status2012In: Archives of Osteoporosis, ISSN 1862-3514, Vol. 7, no 1-2, p. 125-133Article in journal (Refereed)
    Abstract [en]

    SUMMARY:

    Serum concentrations of osteocalcin (OC) decrease and those of C-terminal telopeptide of type 1 collagen (CTX) increase during weight loss in adolescent girls with eating disorders (ED). The impact of weight loss on bone metabolism markers is greatest in premenarcheal girls.

    INTRODUCTION:

    Adolescents with ED stand a risk of not reaching optimal peak bone mass and develop osteoporosis. Previous investigations are contradictory as to how markers of bone formation and resorption change during weight loss and nutritional rehabilitation.

    METHODS:

    Serum OC and CTX were measured at assessment of 461 adolescent girls with ED and during treatment of 55 girls with anorexia nervosa. Bone metabolism was related to weight, weight change and growth rate.

    RESULTS:

    At assessment, OC concentrations were positively correlated with growth rate and inversely with age and (rate of) weight loss. Growth rate was the only predictor of CTX concentrations in premenarcheal girls. In postmenarcheal girls, CTX concentrations were inversely correlated with age and rate of weight loss. During weight gain, there was an increase of OC concentrations. CTX concentrations decreased at the onset of weight gain and increased when near normal weight was reached.

    CONCLUSIONS:

    Bone formation markers decrease and resorption markers increase during weight loss. The effects are independent of menstrual status but the impact on bone formation markers is greater in young, premenarcheal girls. Markers are normalised during weight gain but it is conceivable that repeated and/or prolonged weight loss in adolescents reduces peak bone mass.

  • 248.
    Swenne, Ingemar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Thurfjell, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Rosling, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Triiodothyronine Is an Indicator of Nutritional Status in Adolescent Girls with Eating Disorders2009In: Hormone Research, ISSN 0301-0163, E-ISSN 1423-0046, Vol. 71, no 5, p. 268-275Article in journal (Refereed)
    Abstract [en]

    Aim: Circulating thyroid hormone concentrations are influenced by nonthyroidal disease and changes in nutritional status. We studied thyroid hormones as possible indicators of nutrition in adolescent girls with eating disorders. Method: Blood samples for analyses of thyroid hormones were obtained at 360 assessments of 298 patients and biweekly during 42 treatment periods in 36 patients. Results: At assessment, when most of the girls were on a weight losing course, serum triiodothyronine (T3) concentrations were low. Great weight loss and rapid rate of weight loss were the most important predictors of low T3 concentrations. Serum free thyroxine concentrations were in the lower normal range. In premenarcheal girls, weight loss was the most important predictor of free thyroxine but this relationship was weaker in postmenarcheal girls. Serum TSH concentrations were within the normal range and only weakly related to weight changes. During treatment, T3 increased in parallel with weight but was also influenced by the short-term weight trend. Conclusion: Serum T3 concentration is an indicator of nutritional status in adolescent girls with eating disorders. It is sensitive to short-term weight changes and could be used to monitor progress throughout nutritional rehabilitation.

  • 249.
    Söderberg, Ewa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Anestesi och intensivvård.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Anestesi och intensivvård.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Anestesi och intensivvård.
    The impact of hydrocortisone on neutrophil granulocyte activation in porcine endotoxemic shockManuscript (preprint) (Other academic)
  • 250.
    Taha, Yesuf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Raab, Yngve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lördal, Mikael
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Thörn, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Steroids reduce local inflammatory mediator secretion and mucosal permeability in collagenous colitis patients2006In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 12, no 43, p. 7012-7018Article in journal (Refereed)
    Abstract [en]

    AIM: To study the effect of oral steroids upon clinical response and rectal mucosa secretion of eosinophil cationic protein (ECP), myeloperoxiclase (MPO), basic fibroblast growth factor (bFGF), vascular enclothelial growth factor (VEGF) and albumin in patients with collagenous colitis (CC).

    METHODS: A segmental perfusion technique was used to collect perfusates from rectum of CC patients once before and twice (one and four weeks) after the start of steroid treatment. Clinical data was monitored and ECP, MPO, bFGF, VEGF and albumin concentrations were analyzed by immunochernical methods in perfusates and in serum.

    RESULTS: Steroids reduced the number of bowel movements by more than five times within one week and all patients reported improved subjective wellbeing at wk 1 and 4. At the same time, the median concentrations of ECP, bFGF, VEGF and albumin in rectal perfusates decreased significantly. MPO values were above the detection limit in only 3 patients before treatment and in none during treatment. VEGF, bFGF, ECP and albumin concentrations correlated with each other with the exception of ECP and albumin. A decrease of serum ECP and VEGF concentrations was also seen even if the overtime reduction was not significant.

    CONCLUSION: Oral steroid treatment in CC patients induced a simultaneous reduction of bowel movements and rectal release of ECP, bFGF, VEGF and albumin, suggesting that these polypeptides and increased mucosal permeability are important components of the pathophysiology in collagenous colitis.

23456 201 - 250 of 295
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