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  • 1. Abraham, N G
    et al.
    Brunner, E J
    Eriksson, J W
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Robertson, R P
    Metabolic syndrome: psychosocial, neuroendocrine, and classical risk factors in type 2 diabetes2007In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1113, p. 256-275Article in journal (Refereed)
    Abstract [en]

    This article summarizes some aspects of stress in the metabolic syndrome at the psychosocial, tissue, and cellular levels. The metabolic syndrome is a valuable research concept for studying population health and social-biological translation. The cluster of cardiovascular risk factors labeled the metabolic syndrome is linked with low socioeconomic status. Systematic differences in diet and physical activity contribute to social patterning of the syndrome. In addition, psychosocial factors including chronic work stress are linked with its development. Psychosocial factors could lead to metabolic perturbations and increase cardiovascular risk via activation of neuroendocrine responses, for example, in the autonomic nervous system and in several hormonal pathways. High glucocorticoid levels will promote lipid storage in visceral rather than subcutaneous adipose tissue. Adipocytes secrete several proinflammatory cytokines, which considered major contributors to increase in oxidants and cell injury. Upregulation of heme oxygenase 1 (HO-1) and peroxidase in the early development of diabetes produces a decrease in oxidative-mediated injury. Increased HO activity is associated with a significant decrease in superoxide, endothelial cell shedding and blood pressure. Finally, it is proposed that overexpression of glutathione peroxidase in beta cells may protect beta cell deterioration from oxidative stress during development of diabetes and hyperglycemia and this may result in attenuation of beta cell failure. If this proves to be the case, then the scene will be set to develop glutathione peroxidase mimetics for use in preclinical and clinical trials.

  • 2. Araç, Demet
    et al.
    Aust, Gabriela
    Calebiro, Davide
    Engel, Felix B
    Formstone, Caroline
    Goffinet, André
    Hamann, Jörg
    Kittel, Robert J
    Liebscher, Ines
    Lin, Hsi-Hsien
    Monk, Kelly R
    Petrenko, Alexander
    Piao, Xianhua
    Prömel, Simone
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schwartz, Thue W
    Stacey, Martin
    Ushkaryov, Yuri A
    Wobus, Manja
    Wolfrum, Uwe
    Xu, Lei
    Langenhan, Tobias
    Dissecting signaling and functions of adhesion G protein-coupled receptors2012In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1276, no 1, p. 1-25Article in journal (Refereed)
    Abstract [en]

    G protein-coupled receptors (GPCRs) comprise an expanded superfamily of receptors in the human genome. Adhesion class G protein-coupled receptors (adhesion-GPCRs) form the second largest class of GPCRs. Despite the abundance, size, molecular structure, and functions in facilitating cell and matrix contacts in a variety of organ systems, adhesion-GPCRs are by far the most poorly understood GPCR class. Adhesion-GPCRs possess a unique molecular structure, with extended N-termini containing various adhesion domains. In addition, many adhesion-GPCRs are autoproteolytically cleaved into an N-terminal fragment (NTF, NT, α-subunit) and C-terminal fragment (CTF, CT, β-subunit) at a conserved GPCR autoproteolysis-inducing (GAIN) domain that contains a GPCR proteolysis site (GPS). These two features distinguish adhesion-GPCRs from other GPCR classes. Though active research on adhesion-GPCRs in diverse areas, such as immunity, neuroscience, and development and tumor biology has been intensified in the recent years, the general biological and pharmacological properties of adhesion-GPCRs are not well known, and they have not yet been used for biomedical purposes. The "6th International Adhesion-GPCR Workshop," held at the Institute of Physiology of the University of Würzburg on September 6-8, 2012, assembled a majority of the investigators currently actively pursuing research on adhesion-GPCRs, including scientists from laboratories in Europe, the United States, and Asia. The meeting featured the nascent mechanistic understanding of the molecular events driving the signal transduction of adhesion-GPCRs, novel models to evaluate their functions, and evidence for their involvement in human disease.

  • 3.
    Brocki, Karin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Placing neuroanatomical models of executive function in a developmental context: Imaging and imaging-genetic strategies2008In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1129, p. 246-255Article in journal (Refereed)
  • 4. Chaplin-Kramer, Rebecca
    et al.
    Jonell, Malin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Natural Resources and Sustainable Development.
    Guerry, Anne
    Lambin, Eric F
    Morgan, Alexis J
    Pennington, Derric
    Smith, Nathan
    Franch, Jane Atkins
    Polasky, Stephen
    Ecosystem service information to benefit sustainability standards for commodity supply chains2015In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1355, p. 77-97Article in journal (Refereed)
    Abstract [en]

    The growing base of information about ecosystem services generated by ecologists, economists, and other scientists could improve the implementation, monitoring, and evaluation of commodity-sourcing standards being adopted by corporations to mitigate risk in their supply chains and achieve sustainability goals. This review examines various ways that information about ecosystem services could facilitate compliance with and auditing of commodity-sourcing standards. We also identify gaps in the current state of knowledge on the ecological effectiveness of sustainability standards and demonstrate how ecosystem-service information could complement existing monitoring efforts to build credible evidence. This paper is a call to the ecosystem-service scientists to engage in this decision context and tailor the information they are generating to the needs of the standards community, which we argue would offer greater efficiency of standards implementation for producers and enhanced effectiveness for standard scheme owners and corporations, and should thus lead to more sustainable outcomes for people and nature.

  • 5. Do Rego, Jean-Luc
    et al.
    Seong, Jae Young
    Burel, Delphine
    Luu-The, Van
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Tsutsui, Kazuyoshi
    Pelletier, Georges
    Tonon, Marie-Christine
    Vaudry, Hubert
    Steroid biosynthesis within the frog brain: a model of neuroendocrine regulation2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1163, p. 83-92Article in journal (Refereed)
    Abstract [en]

    There is now clear evidence that the brain, similar to the adrenal gland, gonads, and placenta, is a steroidogenic organ. Notably in the frog brain, the presence of various steroidogenic enzymes has been detected by immunohistochemistry in specific populations of neurons and/or glial cells. These steroidogenic enzymes are biologically active, as shown by the ability of brain tissue explants to convert [(3)H]pregnenolone into various radiolabeled steroids. The frog brain has also been extensively used as a model to study the mechanism of regulation of neurosteroidogenesis by neurotransmitters and neuropeptides. It has been demonstrated that the biosynthesis of neurosteroids is inhibited by gamma-aminobutyric acid (GABA), acting through GABA(A) receptors, and neuropeptide Y, acting through Y1 receptors, and is stimulated by the octadecaneuropeptide (ODN), acting through central-type benzodiazepine receptors, triakontatetraneuropeptide (TTN), acting through peripheral-type benzodiazepine receptors, and vasotocin, acting through V1a-like receptors. These data indicate that some of the neurophysiological effects of neurotransmitters and neuropeptides may be mediated through modulation of neurosteroid biosynthesis.

  • 6.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Bergström, Mats
    Sundin, Anders
    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 Radiology, Oncology and Radiation Science, Radiology.
    Juhlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. onk endo.
    Långström, Bengt
    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 Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    The role of PET in localization of neuroendocrine and adrenocortical tumors2002In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 970, p. 159-169Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) supplies a range of labeled compounds to be used for the characterization of tumor biochemistry. Some of these have proved to be of value for clinical diagnosis, treatment follow up, and clinical research. The first routinely used PET tracer in oncology, 18F-labeled deoxyglucose (FDG), was successfully used for diagnosis of cancer, reflecting increased expression of glucose transporter in cancerous tissue. This tracer, however, usually does not show sufficient uptake in well-differentiated tumors such as neuroendocrine tumors. We developed a tracer more specific to neuroendocrine tumors—the serotonin precursor 5-hydroxytryptophan (5-HTP) labeled with 11C—and demonstrated increased uptake and irreversible trapping of this tracer in carcinoid tumors. The uptake was so selective and the resolution was so high that we could detect more liver and lymph node metastases with PET than with CT or octreotide scintigraphy. To further improve the method, especially to reduce the high renal excretion of the tracer producing streaky artifacts in the area of interest, we introduced premedication by the decarboxylase inhibitor carbidopa, leading to a six-fold decreased renal excretion while the tumor uptake increased three-fold, hence improving the visualization of the tumors.

    11C-labeled l-DOPA was evaluated as an alternative tracer, especially for endocrine pancreatic tumors, which usually do not demonstrate enhanced urinary serotonin metabolites. However, only half of the EPTs, mainly functioning tumors, could be detected with l-DOPA. Instead 5-HTP seems to be a universal tracer for EPT and foregut carcinoids. With new, more sensitive PET cameras, larger field of view and procedures for whole-body coverage, the PET examination with 5-HTP is now routinely performed as reduced whole-body PET examinations with coverage of the thorax and abdomen. With this method we have been able to visualize small neuroendocrine lesions in the pancreas and thorax (e.g., ACTH-producing bronchial carcinoids) not detectable by any other method, including octreotide scintigraphy, MRI, and CT. Another tracer, the 11β-hydroxylase inhibitor, metomidate labeled with 11C, was developed to simplify diagnosis and follow-up of patients with incidentalomas. A large series of patients with incidentally found adrenal masses have been investigated and so far all lesions of adrenocortical origin have been easily identified because of exceedingly high uptake of 11C-metomidate, whereas noncortical lesions showed very low uptake. In addition, adrenocortical cancer shows high uptake, suggesting that this PET tracer can be used for staging purposes.

  • 7.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lilja, A
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergström, M
    Lindner, Karin J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Positron-emission tomography as a radiological technique in neuroendocrine gastrointestinal tumors1994In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 733, p. 446-452Article in journal (Refereed)
  • 8.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Farmakologi 3.
    Pharmacological characterization of melanocortin receptors in fish suggests an important role for ACTH2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1040, no Apr, p. 337-9Article in journal (Refereed)
    Abstract [en]

    Abstract: The melanocortin (MC) receptor subtypes have distinctive characteristic binding profiles. We found that the trout and Fugu MC4 receptors have similar affinity for α-MSH and β-MSH and a much higher affinity for ACTH than does the human MC4 receptor. The Fugu MC1 and the trout and Fugu MC5 receptors also have higher affinity for ACTH-derived peptides than α-, β-, or γ-MSH. It is tempting to speculate that ACTH-derived peptides may have played an important role as “original” ligands at the MC receptors, while the specificity of the different subtypes for the α-, β-, and γ-MSH peptides may have appeared at later stages during vertebrate evolution.

  • 9.
    Kapusta, Aurelie
    et al.
    Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA..
    Suh, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Evolution of bird genomes-a transposon's-eye view2017In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1389, no 1, p. 164-185Article, review/survey (Refereed)
    Abstract [en]

    Birds, the most species-rich monophyletic group of land vertebrates, have been subject to some of the most intense sequencing efforts to date, making them an ideal case study for recent developments in genomics research. Here, we review how our understanding of bird genomes has changed with the recent sequencing of more than 75 species from all major avian taxa. We illuminate avian genome evolution from a previously neglected perspective: their repetitive genomic parasites, transposable elements (TEs) and endogenous viral elements (EVEs). We show that (1) birds are unique among vertebrates in terms of their genome organization; (2) information about the diversity of avian TEs and EVEs is changing rapidly; (3) flying birds have smaller genomes yet more TEs than flightless birds; (4) current second-generation genome assemblies fail to capture the variation in avian chromosome number and genome size determined with cytogenetics; (5) the genomic microcosm of bird-TE "arms races" has yet to be explored; and (6) upcoming third-generation genome assemblies suggest that birds exhibit stability in gene-rich regions and instability in TE-rich regions. We emphasize that integration of cytogenetics and single-molecule technologies with repeat-resolved genome assemblies is essential for understanding the evolution of (bird) genomes.

  • 10.
    Kristiansson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Holding, C
    Hughes, S
    Haynes, D
    Does human relaxin-2 affect peripheral blood mononuclear cells to increase inflammatory mediators in pathologic bone loss?2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1041, p. 317-9Article in journal (Refereed)
    Abstract [en]

    This study was designed to test the hypothesis that relaxin stimulates bone resorption by regulating the production of several mediators that stimulate osteoclast formation. The levels of mediators were measured in response to differing relaxin concentrations in supernatants from peripheral blood mononuclear cells (PBMCs), MCF-7 breast cancer cells, and normal human osteoblasts. Although all cell types expressed mRNA for the relaxin receptor (LGR7), only PBMCs responded to relaxin at physiologic levels by increasing tumor necrosis factor-α and interleukin-1β secretion. The findings indicate that PBMCs should be studied in relation to the effect of relaxin on inflammation and bone destruction caused by osteoclasts.

  • 11. Kristiansson, Per
    et al.
    Holding, Christopher
    Hughes, S
    Haynes, David
    Does human relaxin-2 affect peripheral blood mononuclear cells to increase inflammatory mediators in pathologic bone loss?2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1041, p. 317-319Article in journal (Other academic)
  • 12.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Dreborg, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Tomas A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Early duplications of opioid receptor and Peptide genes in vertebrate evolution2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1163, p. 451-453Article in journal (Refereed)
    Abstract [en]

    The opioid receptor family in mammals has four members called delta, kappa, mu, and NOP (the nociceptin/orphanin receptor). We show here that they arose from a common ancestral gene through quadruplication of a large chromosomal region, presumably in the two basal vertebrate tetraploidizations. The four opioid peptide precursor genes have a more complicated evolutionary history involving chromosomal rearrangements but nevertheless seem to have arisen in the same time period as the receptors. Thus the system of opioid peptides and receptors was already established approximately 450 Ma at the dawn of gnathostome evolution.

  • 13.
    Larhammar, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Dreborg, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Ocampo Daza, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larsson, Tomas A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Major genomic events and their consequences for vertebrate evolution and endocrinology2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1163, no 1, p. 201-208Article in journal (Refereed)
    Abstract [en]

    Comparative studies of proteins often face the problem of distinguishing a true orthologue (species homologue) from a paralogue (a gene duplicate). This identification task is particularly challenging for endocrine peptides and neuropeptides because they are short and usually have several invariant positions. For some peptide families, this has led to a terminology with peptide names relating to the first species where a specific peptide sequence was determined, such as chicken or salmon gonadotropin-releasing hormone, or names that highlight amino acid differences, e.g., Lys-vasopressin. With accumulating information from multiple species, such a terminology becomes almost impenetrable for nonexperts and difficult even for aficionados. The sequenced genomes offer a new way to distinguish orthologues and paralogues, namely by location of the genes relative to neighboring genes on the chromosomes. In addition, the genome databases can ideally provide a complete listing of the family members in each species. Many vertebrate gene families have expanded in the two basal tetraploidizations (2R) and the teleost fish third tetraploidization (3R), after which some vertebrate lineages have lost some of the duplicates. We review here some peptide families (neuropeptide Y, oxytocin-vasopressin, and somatostatin) where genomic information helps simplify nomenclature. This approach is useful also for other gene families, such as peptide receptors.

  • 14. Liebscher, Ines
    et al.
    Ackley, Brian
    Araç, Demet
    Ariestanti, Donna M
    Aust, Gabriela
    Bae, Byoung-Il
    Bista, Bigyan R
    Bridges, James P
    Duman, Joseph G
    Engel, Felix B
    Giera, Stefanie
    Goffinet, André M
    Hall, Randy A
    Hamann, Jörg
    Hartmann, Nicole
    Lin, Hsi-Hsien
    Liu, Mingyao
    Luo, Rong
    Mogha, Amit
    Monk, Kelly R
    Peeters, Miriam C
    Prömel, Simone
    Ressl, Susanne
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sigoillot, Séverine M
    Song, Helen
    Talbot, William S
    Tall, Gregory G
    White, James P
    Wolfrum, Uwe
    Xu, Lei
    Piao, Xianhua
    New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors2014In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1333, p. 43-64Article in journal (Refereed)
    Abstract [en]

    The class of adhesion G protein-coupled receptors (aGPCRs), with 33 human homologs, is the second largest family of GPCRs. In addition to a seven-transmembrane α-helix-a structural feature of all GPCRs-the class of aGPCRs is characterized by the presence of a large N-terminal extracellular region. In addition, all aGPCRs but one (GPR123) contain a GPCR autoproteolysis-inducing (GAIN) domain that mediates autoproteolytic cleavage at the GPCR autoproteolysis site motif to generate N- and a C-terminal fragments (NTF and CTF, respectively) during protein maturation. Subsequently, the NTF and CTF are associated noncovalently as a heterodimer at the plasma membrane. While the biological function of the GAIN domain-mediated autocleavage is not fully understood, mounting evidence suggests that the NTF and CTF possess distinct biological activities in addition to their function as a receptor unit. We discuss recent advances in understanding the biological functions, signaling mechanisms, and disease associations of the aGPCRs.

  • 15. Muresanu, Dafin F.
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Diabetes aggravates heat stress-induced blood-brain barrier breakdown, reduction in cerebral blood flow, edema formation, and brain pathology: Possible neuroprotection with growth hormone2010In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1199, p. 15-26Article in journal (Refereed)
    Abstract [en]

    The possibility that diabetes influences the outcome of heat stress-induced brain pathology was examined in our experimental rat model. Because growth hormone (GH) deficiency is an important factor in diabetes, the possible neuroprotective role of GH supplements was also examined in diabetic rats following heat stress. Rats receiving streptozotocine once daily for three days (50 mg/kg, i.p.) and allowed to survive four weeks resulted in diabetes (blood glucose level 18 and 20 mMol/L) compared to controls (blood glucose 4-6 mMol/L). Control or diabetic rats when subjected to four hours' heat stress at 38 degrees C in a biological oxygen demand incubator (BOD) showed profound disruption of the blood-brain barrier (BBB), reduction in cerebral blood flow (CBF), brain edema formation, and cell injury. These effects were most pronounced in diabetic rats. Pretreatment with GH (50 mu g/kg/min for 10 min before heat stress) significantly attenuated brain pathology in normal animals subjected to hyperthermia. On the other hand, almost a double dose of the growth hormone (80 to 120 mu g/g/min for 10 min) is needed in diabetic rats to induce considerable neuroprotection following heat stress. These observations are the first to suggest that diabetic rats are more vulnerable to heat stress-induced brain pathology and further show that the efficacy of neuroprotective drugs is also severely reduced in diabetic rats. Taken together, our results demonstrate that the dosage of neuroprotective drugs requires adjustment to enhance neuroprotection depending on the patient's endocrine or metabolic status, for example, diabetes mellitus, a finding not reported earlier.

  • 16.
    Nilsson, J. Lars G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Stenberg, Pål
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Ljunggren, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Hoffman, Kurt-Jürgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Lundén, Ragnar
    Eriksson, Olle
    Lorand, Lazlo
    Fibrin-Stabilizing Factor Inhibitors1972In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 202, no DEC8, p. 286-296Article in journal (Refereed)
  • 17.
    Ocampo Daza, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larsson, Tomas A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Evolution of the growth hormone-prolactin-somatolactin system in relation to vertebrate tetraploidizations2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1163, no 1, p. 491-493Article in journal (Refereed)
    Abstract [en]

    Gene sequences from several species representing major vertebrate groups were used to create phylogenetic trees for the growth hormone family of peptide hormones as well as the growth hormone receptor family. These analyses show that both the peptide and receptor families were formed through local duplications in early vertebrate evolution and chromosome duplications.

  • 18. Olsson, S B
    et al.
    Blomström, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blomström-Lundqvist, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wohlfart, B
    Endocardial monophasic action potentials: Correlations with intracellular electrical activity1990In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 601, p. 119-127Article in journal (Refereed)
  • 19.
    Rostedt Punga, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Circulating microRNAs as potential biomarkers in myasthenia gravis patients.2018In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1412, no 1, p. 33-40Article, review/survey (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are small noncoding RNA molecules that bind to specific mRNA targets and regulate a wide range of important biological processes within cells. Circulating miRNAs are released into the extracellular space and can be measured in most biofluids, including blood serum and plasma. Recently, circulating miRNAs have emerged as easily accessible markers in various body fluids with different profiles and quantities specific for different human disorders, including autoimmune diseases. In myasthenia gravis (MG), diagnostic tests such as titers of serum autoantibodies specific for either the acetylcholine receptor (AChR+) or muscle‐specific tyrosine kinase (MuSK+) do not necessarily reflect disease progression, and there is a great need for reliable objective biomarkers to monitor the disease course and therapeutic response. Recent studies in AChR+ MG revealed elevated levels of the immuno‐miRNAs miR‐150‐5p and miR‐21‐5p. Of particular importance, levels of miR‐150‐5p were lower in immunosuppressed patients and in patients with clinical improvement following thymectomy. In MuSK+ MG, another profile of circulating miRNAs was found, including upregulation of the let‐7 family of miRNAs. Here, we summarize the potential role of circulating miRNAs as biomarkers in general and in MG, and highlight important considerations for the analysis of circulating miRNA.

  • 20.
    Sanjeevi, Carani B.
    et al.
    Dept. of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Sedimbi, Saikiran K.
    Landin-Olsson, Mona
    Kockum, Ingrid
    Lernmark, Åke
    Aili, M.
    Dept. of Pediatrics, Halmstad, Sweden.
    Bååth, L.E.
    Dept. of Pediatrics, Östersund, Sweden.
    Carlsson, E.
    Dept. of Pediatrics, Kalmar, Sweden.
    Edenwall, H.
    Dept. of Pediatrics, Karlskrona, Sweden.
    Forsander, G.
    Dept. of Pediatrics, Falun, Sweden.
    Granström, B.W.
    Dept. of Pediatrics, Gällivare, Sweden.
    Gustavsson, I.
    Dept. of Pediatrics, Skellefteå, Sweden.
    Hanås, R.
    Dept. of Pediatrics, Uddevalla, Sweden.
    Hellenberg, L.
    Dept. of Pediatrics, Nyköping, Sweden.
    Hellgren, H.
    Dept. of Pediatrics, Linköping, Sweden.
    Holmberg, E.
    Dept. of Pediatrics, Umeå, Sweden.
    Hörnell, H.
    Dept. of Pediatrics, Hudiksvall, Sweden.
    Ivarsson, Sten-A.
    Dept. of Pediatrics, Malmö, Sweden.
    Johansson, C.
    Dept. of Pediatrics, Jönköping, Sweden.
    Jonsell, G.
    Dept. of Pediatrics, Karlstad, Sweden.
    Kockum, K.
    Dept. of Pediatrics, Ystad, Sweden.
    Lindblad, B.
    Dept. of Pediatrics, Mölndal, Sweden.
    Lindh, A.
    Dept. of Pediatrics, Borås, Sweden.
    Ludvigsson, J.
    Dept. of Pediatrics, Linköping, Sweden.
    Myrdal, U.
    Dept. of Pediatrics, Västerås, Sweden.
    Neiderud, J.
    Dept. of Pediatrics, Helsingborg, Sweden.
    Segnestam, K.
    Dept. of Pediatrics, Eskilstuna, Sweden.
    Sjöblad, S.
    Dept. of Pediatrics, Lund, Sweden.
    Skogsberg, L.
    Dept. of Pediatrics, Boden, Sweden.
    Strömberg, L.
    Dept. of Pediatrics, Norrköping, Sweden.
    Ståhle, U.
    Dept. of Pediatrics, Ängelholm, Sweden.
    Thalme, B.
    Dept. of Pediatrics, Huddinge, Sweden.
    Tullus, K.
    Dept. of Pediatrics, Danderyd, Sweden.
    Tuvemo, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wallensteen, M.
    Dept. of Pediatrics, Stockholm, Sweden.
    Westphal, O.
    Dept. of Pediatrics, Göteborg, Sweden.
    Dahlquist, G.
    Dept. of Pediatrics, Umeå, Sweden.
    Åman, J.
    Dept. of Pediatrics, Örebro, Sweden.
    The risk conferred by HLA-DR and DQ for type 1 diabetes in 0-35-year age group are different in different regions of Sweden2008In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1150, p. 106-11Article in journal (Refereed)
    Abstract [en]

    HLA DR4-DQ8 and DR3-DQ2 haplotypes account for 89% of newly diagnosed cases of type 1 diabetes (T1D) in Sweden. The presence of a single copy of DQ6 confers protection. The aim of the present study is to evaluate whether the risk conferred by high risk HLA DR and DQ to T1D is similar in all regions of Sweden and see whether there are any significant regional differences. The subjects comprised 799 consecutively diagnosed T1D patients and 585 age-, sex-, and geography-matched healthy controls in the age group 0-35 years. HLA typing for high-risk haplotypes was previously performed using PCR-SSOP and RFLP. The results showed that HLA DR3-DR4 gave an odds ratio of 8.14 for the whole of Sweden. However, when the study group was divided into six geographical regions, subjects from Stockholm had the highest OR, followed by those from Lund, Linköping, Gothenburg, Umeå, and Uppsala. Absolute protection was conferred by the presence of DQ6 in subjects from the Linköping region, but varied in the other regions. The frequency of DR3 and DQ2, DR4 and DQ8, DR15, and DQ6 in patients showed high linkage for each region, but were different between regions. In conclusion: The risk conferred by high-risk HLA varies in different regions for a homogenous population in Sweden. The results highlight the important role played by the various environmental factors in the precipitation of T1D.

  • 21.
    Schiöth, Helgi B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Haitina, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fridmanis, Davids
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Unusual genomic structure: melanocortin receptors in fugu2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1040, p. 460-463Article in journal (Refereed)
    Abstract [en]

    The melanocortin (MC) receptors are found in five subtypes in mammals and chicken, while recent studies have shown that the Fugu (Takifugu rubripes) genome has only four MC receptors and the zebrafish genome has six subtypes. The MC3 receptor seems to be missing from the two closely related pufferfishes, Fugu and Tetraodon (Tetraodon nigroviridis). The MC2 and MC5 receptors in the pufferfish have introns. Moreover, these two receptors are found in a tandem that is remarkably conserved in several vertebrate species. Here, we speculate about the genomic origin of the MC receptors.

  • 22.
    Sharma, H S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Patnaik, R
    Patnaik, S
    Mohanty, S
    Sharma, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Vannemreddy, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Antibodies to serotonin attenuate closed head injury induced blood brain barrier disruption and brain pathology2007In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1122, p. 295-312Article in journal (Refereed)
    Abstract [en]

    Closed head injury (CHI) often results in profound brain swelling and instant death of the victims due to compression of the vital centers. However, the neurochemical basis of edema formation in CHI is still obscure. Previous studies from our laboratory show that blockade of serotonin synthesis prior to CHI in a rat model attenuates brain edema, indicating a prominent role for serotonin in head injury. Thus, neutralization of endogenous serotonin activity and/or blocking of its receptors will induce neuroprotection in CHI. Since serotonin has more than 14 receptors and selective serotonin antagonists are still not available, we used serotonin antiserum to neutralize its in vivo effects before or after CHI in a rat model. CHI was produced by an impact of 0.224 N on the right parietal skull bone under Equithesin anesthesia by dropping a weight of 114.6 g from a height of 20 cm through a guide tube. This concussive brain injury resulted in blood–brain barrier (BBB) disruption, brain edema formation, and volume swelling at 5 h that were most pronounced in the contralateral cerebral hemisphere. The plasma and brain serotonin levels were increased several-fold at this time. Intracerebroventricular administration of serotonin antiserum (1:20, monoclonal) into the left lateral cerebral ventricle (30 μL in PBS) 30 min before or 30 min (but not 60 min) after CHI significantly attenuated BBB disruption, brain edema formation, volume swelling, and brain pathology. The plasma and brain serotonin levels continued to remain high. These observations are the first to suggest that antiserum to serotonin when administered into the CSF during the early phase of CHI are capable of inducing neuroprotection.

  • 23.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    A combination of tumor necrosis factor-α and neuronal nitric oxide synthase antibodies applied topically over the traumatized spinal cord enhances neuroprotection and functional recovery in the rat2010In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1199, p. 175-185Article in journal (Refereed)
    Abstract [en]

    The possibility that neutralization of nitric oxide synthase and tumor necrosis factor alpha (TNF-alpha) in the cord using their antiserum will induce neuroprotection and improve functional outcome following spinal cord injury (SCI) was examined in a rat model. The SCI was induced in rats by a unilateral incision of the right dorsal horn at the T10-11 segments under equithesin anesthesia. TNF-alpha and/or neuronal nitric oxide synthase (nNOS) antibodies were applied over the traumatized spinal cord at 10-90 minutes after injury and functional recovery and cord pathophysiology were examined at five hours. Topical application of TNF-alpha antiserum at 10 min followed by NOS antiserum at 20 min after SCI significantly improved functional recovery and attenuated blood-spinal cord barrier (BSCB) disturbances, edema formation, and cord pathology. These neuroprotective effects were also seen when the NOS antiserum was applied 10 min after injury followed by TNF-alpha antiserum at 30 min after trauma. However, when TNF-alpha antiserum was applied 1 h after injury and NOS antiserum was given either before or after TNF-alpha antiserum, no neuroprotective effects were observed. Interestingly, neuronal injury was tightly correlated with nNOS expression in the cord in antibody treated groups. These novel observations suggest that early blockade of TNF-alpha and nNOS expression within 20-30 min after SCI is beneficial in nature. This indicates that TNF-alpha. and nitric oxide play synergistic roles in the pathophysiology of SCI and combined antibodies therapy has added neuroprotective values in spinal trauma.

  • 24.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Badgaiyan, Rajendra D.
    Alm, Per
    Mohanty, S.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1053, p. 422-434Article in journal (Refereed)
    Abstract [en]

    The role of nitric oxide (NO) in spinal cord injury (SCI)-induced motor dysfunction, breakdown of the blood-spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L-NAME; an irreversible inhibitor of all isoforms of NOS, L-NMMA; and a long-term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L-NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the T10-11 segments, and the rats were allowed to survive 5 h after injury. Long-term treatment with L-NNA attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L-NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L-NAME. Interestingly, SCI-induced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L-NNA, whereas rats treated with L-NAME or L-NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology.

  • 25.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Muresanu, Dafin
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Zimmermann-Meinzingen, Sibilla
    Cerebrolysin treatment attenuates heat shock protein overexpression in the brain following heat stress: An experimental study using immunohistochemistry at light and electron microscopy in the rat2010In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1199, p. 138-148Article in journal (Refereed)
    Abstract [en]

    The possibility that overexpression of heat shock proteins (HSPs) in the CNS represents a neurodestructive signal following hyperthermia was examined in a rat model using a potent neuroprotective drug, Cerebrolysin (Ebewe Pharma, Austria). Rats subjected to four hours of heat stress in a biological oxygen demand incubator at 38 degrees C developed profound hyperthermia (41.23 +/- 0.14 degrees C) and overexpressed HSP 72 kD in several brain regions: cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus, brain stem, and spinal cord compared to controls. This HSP overexpression closely correlated with the leakage of blood-brain barrier permeability and vasogenic edema formation in these brain areas. HSP positive cells are largely confined in the edematous brain regions showing Evans blue leakage. Pretreatment with Cerebrolysin (5 mL/kg, i.v.) 30 minutes before heat stress markedly attenuated hyperthermia (39.48 +/- 0.23 degrees C, P < 0.01) and the induction of HSP to all the brain regions examined. Leakage of Evans blue albumin and increase in brain water content in these brain areas are also markedly reduced with Cerebrolysin pretreatment. These results are the first to show that Cerebrolysin, if administered before heat stress, attenuates hyperthermia induced stress reaction and HSP 72 kD induction. Taken together, these novel observations suggest that upregulation of HSP 72 kD in brain represents neurodestructive signals and a reduction in cellular stress mechanisms leading to decline in HSP expression is neuroprotective in nature.

  • 26.
    Sharma, Hari Shanker
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Zimmermann-Meinzingen, Sibilla
    Johanson, Conrad E.
    Cerebrolysin reduces blood-cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat2010In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1199, p. 125-137Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injuries (TBIs) induce profound breakdown of the blood-brain and blood-cerebrospinal fluid barriers (BCSFB), brain pathology/edema, and sensory-motor disturbances. Because neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and glial cell-derived neurotrophic factor (GDNF), are neuroprotective in models of brain and spinal cord injuries, we hypothesized that a combination of neurotrophic factors would enhance neuroprotective efficacy. In the present investigation, we examined the effects of Cerebrolysin, a mixture of different neurotrophic factors (Ebewe Neuro Pharma, Austria) on the brain pathology and functional outcome in a rat model of TBI. TBI was produced under Equithesin (3 mL/kg, i.p.) anesthesia by making a longitudinal incision into the right parietal cerebral cortex. Untreated injured rats developed profound disruption of the blood-brain barrier (BBB) to proteins, edema/cell injury, and marked sensory-motor dysfunctions on rota-rod and grid-walking tests at 5 h TBI. Intracerebroventricular administration of Cerebrolysin (10 or 30 mu L) either 5 min or 1 h after TBI significantly reduced leakage of Evans blue and radioiodine tracers across the BBB and BCSFB, and attenuated brain edema formation/neuronal damage in the cortex as well as underlying subcortical regions. Cerebrolysin-treated animals also had improved sensory-motor functions. However, administration of Cerebrolysin 2 h after TBI did not affect these parameters significantly. These observations in TBI demonstrate that early intervention with Cerebrolysin reduces BBB and BCSFB permeability changes, attenuates brain pathology and brain edema, and mitigates functional deficits. Taken together, our observations suggest that Cerebrolysin has potential therapeutic value in TBI.

  • 27.
    Smedby, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Primary care financing in Sweden1978In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 310, p. 247-51Article in journal (Refereed)
  • 28.
    Smedby, B
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Stumbo, G
    Report on Workshop E1978In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 310, p. 42-43Article in journal (Refereed)
  • 29.
    Sundin, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Bergström, Mats
    Uppsala University Petcentre (Imanet).
    Långström, Bengt
    Uppsala University Petcentre (Imanet).
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    PET in the diagnosis of neuroendocrine tumors2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1014, p. 246-257Article in journal (Refereed)
    Abstract [en]

    For general oncological imaging, positron emission tomography (PET) using [18F]fluoro-deoxy-glucose (FDG) has evolved as a powerful functional imaging modality. Unfortunately, FDG-PET has not been as advantageous for imaging gastropancreatic neuroendocrine tumors, and only tumors with high proliferative activity and low differentiation have shown an increased FDG uptake. Therefore, the 11C-labeled amine precursors L-dihydroxyphenylalanine and 5-hydroxy-L-tryptophan (5-HTP) were developed for PET imaging of these tumors. Because of the higher tumor uptake of the latter tracer in a study of patients with endocrine pancreatic tumors, 11C-5-HTP was chosen for further evaluation. In comparative studies of patients with carcinoids and endocrine pancreatic tumors, 5-HTP-PET proved better than CT and somatostatin receptor scintigraphy for tumor visualization, and many small, previously overlooked lesions were diagnosed by 11C-5-HTP-PET. The strong correlation found during medical treatment between the changes in the transport rate constant at repeated PET and those of U-HIAA indicates the possible use of 11C-5-HTP-PET also for therapy monitoring. By premedication of patients with Carbidopa orally before PET examination, in order to block the aromatic amino acid decarboxylase enzyme, the decarboxylation rate of 11C-5-HTP was decreased, leading to a higher tumor uptake and a considerably lower urinary radioactivity concentration.

  • 30.
    Wiklund, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Basu, Samar
    Circulatory arrest as a model for studies of global ischemic injury and neuroprotection2005In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1053, p. 205-219Article in journal (Refereed)
    Abstract [en]

    Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8-12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8-iso-PGF(2alpha)), an indicator of oxidative damage, and prostaglandin F(2alpha) metabolite (15-keto-dihydro-PGF(2alpha)), an indicator of cyclooxygenase-2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S-100beta. Neurological outcome is assessed at >24 h after the incident. Our results show that plasma concentrations of 8-iso-PGF(2alpha) are greater after more extended periods of ischemia. PBN (alpha-phenyl-N-tert-butyl nitrone), a so-called spin-trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8-iso-PGF(2alpha) concentration is decreased during reperfusion. Use of water-soluble sulfonated PBN (S-PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.

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