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  • 101.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Degerstedt, Oliver
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    In vitro evaluation of lipiodol-based emulsions in clinical useManuskript (preprint) (Övrigt vetenskapligt)
  • 102.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Axén, N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A miniaturized in vitro release method for investigating drug-release mechanisms2015Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, nr 1-2, s. 339-349Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

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  • 103.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System2016Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, nr 11, s. 3387-3398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

  • 104.
    Ahnfelt, Nils-Otto
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Gas chromatographic analysis of amines, aminophenols and aminobutyric acids: studies on the derivatization with chloroformate esters1982Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 105. Aho, Leena
    et al.
    Karkola, Kari
    Juusela, Jari
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Heavy alcohol consumption and neuropathological lesions: a post-mortem human study2009Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 87, nr 12, s. 2786-2792Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

  • 106. Aho, Leena
    et al.
    Pikkarainen, Maria
    Hiltunen, Mikko
    Leinonen, Ville
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Immunohistochemical Visualization of Amyloid-β Protein Precursor and Amyloid-β in Extra- and Intracellular Compartments in the Human Brain2010Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, nr 4, s. 1015-1028Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyloid-beta (Abeta) peptide, a cleavage product of the amyloid-beta protein precursor (AbetaPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Abeta are based on the use of immunohistochemistry. In this study, the presence of AbetaPP and Abeta was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages independent of the disease state or existence of extracellular Abeta aggregates with all antibodies directed to AbetaPP, with three Abeta antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Abeta from AbetaPP. These results suggest that it is AbetaPP rather than Abeta that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Abeta was detected with antibodies directed to the C-terminus of Abeta (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Abeta.

  • 107.
    Ahrén, Anna
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Immunhistokemisk undersökning av paraffinbäddade celler från pleuravätska som kompletterande underlag för diagnos av cancermetastaser2005Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats
    Abstract [en]

    Background. Immunohistochemistry is a useful method in the differential diagnosis between pleural mesotheliomas and metastatic adenocarcinomas in the pleura. Cytokeratin 20 and 7 have been used successfully as markers in studies determining primary location of adenocarcinomas from metastases. The current study is a complementary research of archived paraffininbedded material of cases with cancer origin. This study contributes a bigger statistical material that may facilitate the search for unknown primary site of adenocarcinoma by identification of metastatic cells in the pleura.

    Methods. Cells from the pleura taken from fifteen patients with diagnosed cancer of different types and eleven patients with cancer of unknown origin, were stained with antibodies against the tumour markers: Ber EP 4, calretinin, cytokeratin 20 and 7, estrogen receptor α, thyroid transcription factor, prostate-specific antigen and Cdx2.The staining was conducted in an automated immunohistochemical system. The staining of each kind of antibody was confirmed by a control section staining.

    Results. All control staining ended perfect The whole panel of antibodies used on mammary cancer showed the same pattern for every antibody. Of the patients with cancer of unknown origin there were four that gave the same pattern, two men and two women. The women are deceased. To make a more careful evaluation more information and clinic background is needed. The number of samples is too small to draw any statistical conclusions.

    Comment. Although the control staining was perfect the negative result of CK20 in the cases of diagnosed colon cancer was unexpected. This staining should be performed again to confirm the result. In some cases the number of cells were to few for a certain evaluation. The slides and the results of this work will be archived for further research.

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  • 108.
    Aithal, Guruprasad P.
    et al.
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Nicoletti, Paola
    Columbia Univ, New York, NY USA..
    Bjornsson, Einar
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Lucena, M. I.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Andrade, Raul J.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Grove, Jane
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Stephens, C.
    Univ Malaga, E-29071 Malaga, Spain..
    Hallberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Utrecht, Netherlands..
    Martin, Jennifer H.
    Univ Queensland, Brisbane, Qld, Australia.;Princess Alexandra Hosp, Brisbane, Qld, Australia..
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Kiel, Germany..
    Dillon, John F.
    Ninewells Hosp & Med Sch, Dundee, Scotland..
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Larrey, Dominique G.
    Hop St Eloi, Montpellier, France..
    Molokhia, Mariam
    Univ London, Kings Coll London, London SW3 6LX, England..
    Kullak-Ublick, Gerd A.
    Univ Zurich, Zurich, Switzerland..
    Ibanez, Luisa
    Hosp Univ Vall Hebron, Barcelona, Spain..
    Pirmohamed, Munir
    Univ Liverpool, Liverpool L69 3BX, Merseyside, England..
    Qin, Shengying
    Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China..
    Sawle, Ashley
    Columbia Univ, New York, NY USA..
    Bessone, Fernando
    Univ Nacl Rosario, Fac Ciencias Med, RA-2000 Rosario, Argentina..
    Hernandez, Nelia
    Univ Republ, Mentevideo, Uruguay..
    Stolz, Andrew
    Univ So Calif, Los Angeles, CA USA..
    Chalasani, Naga P.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Serrano, Jose
    Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA..
    Barnhart, Huiman X.
    Duke Clin Res Inst, Durham, NC USA..
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Watkins, Paul
    Hamner UNC Inst Drug Safety Sci, Durham, NC USA..
    Urban, Thomas J.
    UNC Eshelman Sch Pharm, Chapel Hill, NC USA..
    Daly, Ann K.
    Newcastle Univ, Newcastle, NSW, Australia..
    HLA-A*33:01 is strongly associated with drug-induced liver injury (DILI) due to terbinafine and several other unrelated compounds2015Ingår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, s. 325A-326AArtikel i tidskrift (Övrigt vetenskapligt)
  • 109.
    Akay, Mervan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    En kartläggning av läkemedelsanvändning och köpbeteende vid köp av receptfria NSAID på apotek2015Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    En kartläggning av läkemedelsanvändning och köpbeteende vid köp av receptfria NSAID på apotek

    Mervan Akay

    Handledare: Pia Frisk, Hälso- och sjukvårdsförvaltningen SLL Institutionen för farmaceutisk biovetenskap, avdelningen för farmakokinetik och läkemedelsterapi Examinator: Margareta Hammarlund-UdenaesFördjupningsprojekt i farmakoterapi D, 30 hp

    Introduktion: NSAID är en av de mest förskrivna läkemedelsgrupperna över hela världen. Efter omregleringen av apoteksmarknaden har tillgängligheten av NSAID-preparat ökat. Syfte: Att kartlägga läkemedelsanvändningen och köpbeteendet avseende receptfria läkemedel med diklofenak, ibuprofen, naproxen och acetylsalicylsyra, hos kunder som köper dessa läkemedel på öppenvårdsapotek. Detta med anledning av att det finns begränsad information om användningen av dessa receptfria substanser. Material och metoder: En prospektiv tvärsnittsstudie som omfattade fyra apotek i Stockholm-Uppsala regionen under tidsperioden 2014-09-15 till 2014-10-21. Data samlades in med hjälp av en enkät som delades ut av en observatör till individer som köpt ett preparat med diklofenak, ibuprofen, naproxen eller acetylsalicylsyra. Resultat: Det var fler kvinnor (148 stycken, 64,1 %) än män som köpte ett receptfritt NSAID-preparat. Den vanligaste åldersgruppen som köpte receptfritt NSAID var 40-49 år (20,8 %) medan det var 11,7 % som tillhörde åldersgruppen 70+. Den mest använda substansen bland NSAID var ibuprofen (46,3 %). De två vanligaste användningsområden för bägge könen var huvudvärk (43,1 %) och muskelvärk (30,4 %). Av samtliga deltagare var det 14 stycken (6,7 %) som kombinerade det köpta läkemedlet med ett annat receptfritt NSAID. Konklusion: Det var fler kvinnor än män som köpte receptfritt NSAID på apotek. Drygt 12 % av deltagarna, som var 70 år och äldre använde sig utav NSAID vilket är en olämplig läkemedelsklass för äldre personer.    

  • 110.
    Akbari Kenari, Sepideh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The role of serotonin and dopamine signalling within the prefrontal cortex and striatum in cognitive function in rats2012Självständigt arbete på grundnivå (kandidatexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 111.
    Akcan, Martina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Smärtstillande läkemedelsbehandling hosäldre i Uppsala län - en retrospektiv studie2014Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Hos äldre är smärta relativt vanligt då det med ökad ålder uppkommerproblem i muskler, leder, senor och skelett, t.ex. artros, osteoporos och sarkopeni.Socialstyrelsen utformade 2004 en mall för god läkemedelsterapi hos äldre, s.k.kvalitetsindikatorer. T.ex. får paracetamol inte överstiga en dygnsdos på 4 g/dygn ochNSAID bör endast användas vid inflammatorisk smärta. När lätta analgetika inte hjälperrekommenderas behandling med starka opioider direkt utan att först använda lättaopioider lätta opioider då dessa anses olämpliga för äldre. Vid perifer neuropatisksmärta rekommenderas i första hand TCA (amitriptylin, nortriptylin) eller gabapentin.Syfte: Det övergripande syftet är att värdera kvaliteten i äldres smärtstillandeläkemedelsbehandling genom att relatera den till rekommenderad behandling för att ökakunskapen om hur behandling med smärtstillande läkemedel ser ut inom äldrevårdenidag. Material och metoder: Läkemedelslistor från 434 patienter från olikaäldreboenden i Uppsala län inkluderas i studien. Insamlade, avidentifierade data fördesin i Excel med information som student-ID, patient-ID, ålder, kön, substansnamn,stående dos, vidbehovsdos och stående + vidbehovsdos. Resultat: Gruppen bestod av299 kvinnor och 135 män med medelåldern 85,4 år. Totalt förskrevs 485 smärtstillandeläkemedel till de 434 patienterna. 75.8 % patienter förskrevs paracetamol, 27,2 %opioider, 3,45 % NSAID, 0,92 % amitriptylin respektive 1,61 % gabapentin.Rekommenderad dygnsdos av paracetamol överskreds hos 13 patienter, av diklofenakhos en patient medan 33 patienter inte hade maximal dygnsdos angiven. Förskrivning avett analgetikum var vanligast och förekom hos 179 patienter. Två analgetika förskrevstill 119 patienter medan två, en man och en kvinna, förskrevs 5 analgetika vardera.Totalt 94 personer, 21,4 %, använde inga smärtstillande läkemedel alls. Konklusion:Studien visar att smärtstillande läkemedelsbehandling hos äldre i Uppsala län inteskiljer sig markant från studier gjorda i övriga Sverige och Europa. Dock var det någrasom, enligt Socialstyrelsen kvalitetsindikatorer, överskred dygnsdosen och stod påläkemedel som anses vara olämpliga för äldre, vilket visar att det fortfarande finnsproblem med äldres läkemedelsterapi.

  • 112. Akeus, Paulina
    et al.
    Langenes, Veronica
    von Mentzer, Astrid
    Yrlid, Ulf
    Sjoling, Asa
    Saksena, Pushpa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Raghavan, Sukanya
    Quiding-Jarbrink, Marianne
    Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice2014Ingår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 63, nr 8, s. 807-819Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tumor progression in the colon moves from aberrant crypt foci to adenomatous polyps to invasive carcinomas. The composition of the tumor-infiltrating leukocyte population affects the ability of the immune system to fight the tumor. T cell infiltration into colorectal adenocarcinomas, particularly T helper 1 (Th1) type T cells as well as increased regulatory T cell (Treg) frequencies, is correlated with improved prognosis. However, whether Th1 cells and Tregs are already present at the adenoma stage is not known. In this study, the APC(Min/+) mouse model of intestinal adenomatous polyposis was used to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas. Compared to unaffected tissue, adenomas accumulated CD4(+)FoxP3(+) putative Treg in parallel with lower frequencies of conventional T cells and B cells. The accumulation of Treg was also observed in human adenomatous polyps. Despite high Treg numbers, the function of conventional T cells present in the APC(Min/+) adenomas was not different from those in the unaffected tissue. Adenomas displayed an altered chemokine balance, with higher CCL17 and lower CXCL11 and CCL25 expression than in the unaffected tissue. In parallel, CXCR3(+) Tregs were largely absent from adenomas. The data indicate that already in early stages of tumor development, the balance of lymphocyte-recruiting chemokines is altered possibly contributing to the observed shift toward higher frequencies of Treg.

  • 113. Akhtar, Malik N.
    et al.
    Southey, Bruce R.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sweedler, Jonathan V.
    Rodriguez-Zas, Sandra L.
    Identification of best indicators of peptide-spectrum match using a permutation resampling approach2014Ingår i: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 12, nr 5, s. 1440001-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Various indicators of observed-theoretical spectrum matches were compared and the resulting statistical significance was characterized using permutation resampling. Novel decoy databases built by resampling the terminal positions of peptide sequences were evaluated to identify the conditions for accurate computation of peptide match significance levels. The methodology was tested on real and manually curated tandem mass spectra from peptides across a wide range of sizes. Spectra match indicators from complementary database search programs were pro filed and optimal indicators were identified. The combination of the optimal indicator and permuted decoy databases improved the calculation of the peptide match significance compared to the approaches currently implemented in the database search programs that rely on distributional assumptions. Permutation tests using p-values obtained from software-dependent matching scores and E-values outperformed permutation tests using all other indicators. The higher overlap in matches between the database search programs when using end permutation compared to existing approaches con firmed the superiority of the end permutation method to identify peptides. The combination of effective match indicators and the end permutation method is recommended for accurate detection of peptides.

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  • 114.
    Akkawi, Ranaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eksborg, Staffan
    Andersson, Asa
    Lundeberg, Stefan
    Bartocci, Marco
    Effect of oral naloxone hydrochloride on gastrointestinal transit in premature infants treated with morphine2009Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, nr 3, s. 442-447Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Opioids are common drugs for pain treatment in preterm newborn infants, in spite of several adverse effects. Constipation is a frequent problem when opioids are used in both adults and neonates. Although several studies indicate that the oral administration of naloxone hydrochloride (NH) improves intestinal motility during opioid therapy, there is still a lack of evidence in newborns. Aim: The aim of this study was to assess the efficacy of NH against reduced intestinal motility during opioid treatment. Methods: A retrospective cohort study was performed. We analysed the medical records of fifteen infants (Group 1) treated with continuous morphine (MO) infusion and fourteen infants (Group 2) treated with both oral NH (3 mu g/kg 4 times daily) and MO. Results: There was no statistically significant difference in the total MO dose. Infants treated both with NH and MO had a tendency to improve their mean stool frequency/day. A statistically significant improvement was observed in the mean total food intake (mL/kg/day) of the infants treated with NH (p = 0.014). No difference in the mean food retention between the two groups was observed. Conclusion: Orally administrated NH seems to improve intestinal motility resulting in increased food intake/day and improved stool frequency/day in premature newborn infants treated with MO. Further studies are needed to corroborate these findings.

  • 115. Akkermann, Kirsti
    et al.
    Nordquist, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Harro, Jaanus
    Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population2010Ingår i: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 34, nr 1, s. 111-114Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Objective: The s-allele of the 5-HTTLPR has been suggested to lead to the development of less efficient and less flexible 5-HT system and has been associated to different forms of psychopathology. It has also been shown that alterations in serotonergic activity contribute to the pathophysiology of binge eating but it is not clear which changes in 5-HT function observed in eating disorder patients represent trait vs state effect. We investigated the association between the 5-HTTLPR and binge eating in a population-representative sample of women, and tested whether the 5-HTTLPR genotype influences the severity of binge eating. Methods: The sample was based on women participating in the third wave of the Estonian Children Personality, Behaviour and Health Study. EDI-2 subscales - drive for thinness and bulimia - were used to assess eating behaviour and attitudes. Barratt Impulsiveness Scale (BIS-11) and State and Trait Anxiety Inventory (STAI) were used to measure impulsivity and anxiety. Participants were genotyped for the 5-HTTLPR. Results: There was no 5-HTTLPR genotype effect on binge eating even after the covarying effect of impulsivity and anxiety was controlled for. However, women prone to binge eating and carrying the s-allele showed significantly higher levels of bulimia scores, and among them, women with s/s genotype had also higher levels of state anxiety and tendency for higher impulsivity. Conclusions: While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.

  • 116. Akopyan, Karen
    et al.
    Edgren, Tomas
    Wang-Edgren, Helen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Rosqvist, Roland
    Fahlgren, Anna
    Wolf-Watz, Hans
    Fallman, Maria
    Translocation of surface-localized effectors in type III secretion2011Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 4, s. 1639-1644Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pathogenic Yersinia species suppress the host immune response by using a plasmid-encoded type III secretion system (T3SS) to trans- locate virulence proteins into the cytosol of the target cells. T3SS- dependent protein translocation is believed to occur in one step from the bacterial cytosol to the target-cell cytoplasm through a conduit created by the T3SS upon target cell contact. Here, we report that T3SS substrates on the surface of Yersinia pseudotuberculosis are translocated into target cells. Upon host cell contact, purified YopH coated on Y. pseudotuberculosis was specifically and rapidly trans- located across the target-cell membrane, which led to a physiological response in the infected cell. In addition, translocation of externally added YopH required a functional T3SS and a specific translocation domain in the effector protein. Efficient, T3SS-dependent transloca- tion of purified YopH added in vitro was also observed when using coated Salmonella typhimurium strains, which implies that T3SS- mediated translocation of extracellular effector proteins is conserved among T3SS-dependent pathogens. Our results demonstrate that polarized T3SS-dependent translocation of proteins can be achieved through an intermediate extracellular step that can be reconstituted in vitro. These results indicate that translocation can occur by a differ- ent mechanism from the assumed single-step conduit model.

    Ladda ner fulltext (pdf)
    PNAS
  • 117.
    Akram, Mehwish
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Punjab, Sch Biol Sci, Quaid E Azam Campus, Lahore 54590, Pakistan.
    Rashid, Naeem
    Univ Punjab, Sch Biol Sci, Quaid E Azam Campus, Lahore 54590, Pakistan.
    Inwardly Rectifying Potassium Channels in Drosophila Regulate the Sleep/Wake Behaviour through PDF-Neurons2019Ingår i: PAKISTAN JOURNAL OF ZOOLOGY, ISSN 0030-9923, Vol. 51, nr 2, s. 709-715Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Potassium channels are important modulators of cell function depending on the cell type of where they are expressed. They are involved in regulation of cell membrane resting potential, potassium homeostasis and control a variety of cellular functions including metabolism. In this study we determined that a regulator of Pigment dispersing factor, PDF-immunoreactive neurons in the Drosophila melanogaster adult brain, is an inwardly rectifying potassium channel, IRK1. Knocking down the potassium channels specifically on PDF expressing neurons using UAS-GAL4 RNA(1) system resulted in altered axonal projections of lateral neurons (LNv) towards the dorsal neurons (DN). Moreover, it was observed that lack of the potassium channels also caused a robust increase in sleep and reduction in the fly's active period during the day. We observed that the normal circadian control of the morning and evening anticipation is also dependant on these potassium channels. The flies deficient in IRK1 channels didn't show an evening anticipation peak. Another interesting disclosure during this study was the inability of PDF- Tri neurons to undergo programmed cell death in the absence of inwardly rectifying potassium channels. Hence, IRK1, though poorly expressed in the Drosophila central nervous system, plays an important role in the normal functioning of PDF expressing neurons. Further studies are needed to elaborate the physiological roles of Drosophila potassium channels which may lead to a better understanding of human Kir channels related to pathological conditions and diseases.

  • 118.
    Akula, Srinivas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Paivandy, Aida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Fu, Zhirong
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Thorpe, Michael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, SE-75007 Uppsala, Sweden.
    Hellman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Quantitative In-Depth Analysis of the Mouse Mast Cell Transcriptome Reveals Organ-Specific Mast Cell Heterogeneity2020Ingår i: CELLS, E-ISSN 2073-4409, Vol. 9, nr 1, artikel-id 211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mast cells (MCs) are primarily resident hematopoietic tissue cells that are localized at external and internal surfaces of the body where they act in the first line of defense. MCs are found in all studied vertebrates and have also been identified in tunicates, an early chordate. To obtain a detailed insight into the biology of MCs, here we analyzed the transcriptome of MCs from different mouse organs by RNA-seq and PCR-based transcriptomics. We show that MCs at different tissue locations differ substantially in their levels of transcripts coding for the most abundant MC granule proteins, even within the connective tissue type, or mucosal MC niches. We also demonstrate that transcript levels for the major granule proteins, including the various MC-restricted proteases and the heparin core protein, can be several orders of magnitude higher than those coding for various surface receptors and enzymes involved in protease activation, as well as enzymes involved in the synthesis of heparin, histamine, leukotrienes, and prostaglandins. Interestingly, our analyses revealed an almost complete absence in MCs of transcripts coding for cytokines at baseline conditions, indicating that cytokines are primarily produced by activated MCs. Bone marrow-derived MCs (BMMCs) are often used as equivalents of tissue MCs. Here, we show that these cells differ substantially from tissue MCs with regard to their transcriptome. Notably, they showed a transcriptome indicative of relatively immature cells, both with respect to the expression of granule proteases and of various enzymes involved in the processing/synthesis of granule compounds, indicating that care should be taken when extrapolating findings from BMMCs to the in vivo function of tissue-resident MCs. Furthermore, the latter finding indicates that the development of fully mature tissue-resident MCs requires a cytokine milieu beyond what is needed for in vitro differentiation of BMMCs. Altogether, this study provides a comprehensive quantitative view of the transcriptome profile of MCs resident at different tissue locations that builds nicely on previous studies of both the mouse and human transcriptome, and form a solid base for future evolutionary studies of the role of MCs in vertebrate immunity.

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    FULLTEXT01
  • 119.
    Akula, Srinivas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Paivandy, Aida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Thorpe, Michael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Pjeler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hellman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    The mouse mast cell transcriptomeManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Mast cells (MCs) are highly specialized tissue resident cells that are often found at the interphase between body and environment such as the skin, lung and intestinal mucosa. To obtain a more detailed picture of the biology of MCs we have analyzed the transcriptome of MCs from different mouse organs by RNA-seq and PCR based transcriptomics.  The results show that MCs at different tissue locations can differ quite substantially in transcript levels of several of the most abundant granule proteins even if they belong to the same basic MC type, i.e connective tissue or mucosal MCs. We can also see that transcript levels for the major granule proteins, like the various proteases and the heparin core protein can be several orders of magnitude higher than the surface receptors.  This also applies for the processing enzymes involved in activation of the proteases and in the synthesis of heparin and histamine. Interestingly also is the almost complete absence of transcripts for cytokines in the MC populations of the various organs, indicating that cytokines only are produced by activated MCs. Bone marrow derived MCs are often used as equivalents of tissue MCs.  We here show that these cells differ substantially in their transcriptome from tissue MCs. They show a transcriptome of relatively immature cells both with respect to the granule components and to the processing enzymes indicating that care should be taken when transferring findings from these cells to the in vivo function of tissue resident MCs.  This latter finding also give clear indication for that additional cytokines are needed, in addition to the stem cell factor (SCF), for the development into fully mature tissue MCs.

  • 120.
    Al Haj, Mahmoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of Dehydration and Blockade of the Renin-Angiotensin System in the One-humped Camel (Camelus dromedarius)2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The one-humped or the dromedarian camel is a pseudo-ruminant mammal, well adapted to the hot and dry climates of the desert. Its ability to withstand torrid heat and extreme desiccation is of paramount importance to its survival. The studies presented in this thesis were designed to investigate and document the effect of dehydration in the presence or absence of angiotensin II (Ang II) AT1 receptor blocker (losartan) on blood constituents, electrolytes, hormones, neurotransmitters as well as liver and kidney enzymes in a subset of dehydrated camels and to compare them with hydrated camels. Additionally, we studied the response of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and revealed for the first time the cardiac storage form of BNP in the camel heart. Dehydration induced significant increments in packed cell volume (PCV), white blood cells (WBC), gamma glutamyl-transferase (GGT), serum sodium, creatinine and urea levels, and a doubling in plasma cortisol and arginine vasopressin (AVP) levels. At the same time dehydration caused significant decrease in body weights, plasma insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3), and a 50% decrement in ANP and BNP levels. Moreover, dehydration with and without losartan resulted in significant changes in stress hormones and anti-oxidants in plasma, liver and kidney homogenates. Losartan on one hand enhanced the effect of dehydration resulting in significant increases in sodium, creatinine and urea levels. In addition losartan raised the  binding affinity of Ang II AT2 receptors in the small intestine with 8-fold and with 16-fold for liver AT1 receptors, indicating that Ang II AT1 and AT2 receptor binding sites were present in camel's small intestine while only AT1 receptor binding sites were found in the camel liver. One the other hand losartan resulted in significant decrease in body weights impaired the rise in anti-diuretic hormone and reduced aldosterone level. Finally, we showed that the proBNP is the storage form of BNP in the camel heart.

    Delarbeten
    1. Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
    Öppna denna publikation i ny flik eller fönster >>Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
    Visa övriga...
    2011 (Engelska)Ingår i: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, nr 2, s. 73-78Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

    Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

    Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

    Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

    Nyckelord
    Blood, camel, dehydration, losartan, and serum
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-207413 (URN)10.2174/1996327001104020073 (DOI)
    Tillgänglig från: 2013-09-13 Skapad: 2013-09-13 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    2. Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Öppna denna publikation i ny flik eller fönster >>Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
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    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 5, s. e37299-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-177622 (URN)10.1371/journal.pone.0037299 (DOI)000305343500092 ()
    Tillgänglig från: 2012-07-18 Skapad: 2012-07-17 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    3. Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
    Öppna denna publikation i ny flik eller fönster >>Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
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    2012 (Engelska)Ingår i: Comparative Clinical Pathology, ISSN 1618-5641, E-ISSN 1618-565X, Vol. 21, nr 6, s. 1745-1749Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In the present study, the effect of 20 days of dehydration in the presence or absence of losartan (angiotensin II AT1 receptor antagonist) on insulin-like growth factor-1(IGF-1) and insulin-like growth factor-binding protein-3(IGFBP-3) in plasma of the one-humped camel was studied. Eighteen male camels, 3-4 years of age, were divided into three equal groups: control, dehydrated, and dehydrated-losartan-treated groups. The control camels were given food and water ad libitum. The two dehydrated groups underwent 20 days of water deprivation but were given food ad libitum. The dehydrated-losartan-treated camels were given losartan injection (Merck, USA), intravenously at a dose of 5 mg/kg body weight daily for 20 days. Our results demonstrated a progressive decrease in the circulating levels of IGF-1 and IGFBP-3 in the dehydrated and dehydrated-losartan-treated animals across dehydration compared to their basal levels and time-matched control. On day 5 of dehydration, the IGF-1 level in the losartan-treated group showed a decrease of 60 % and the dehydrated group showed 45 % decrease from their baseline levels and time-matched control. On day 10 the decrease in the losartan-treated animals reached 74 % and for the dehydrated was 62 %. On day 20 the decrease in the losartan-treated was 89 % and for the dehydrated reached 80 % from their baseline levels and time-matched control. Dehydration in the presence or absence of losartan caused a decrease in the circulating level of IGFBP-3. The decrement reached 26 % on day 10 and 20 for the treated camels, while the decrease for the dehydrated was 22 % on day 10 of dehydration and reached 29 % on day 20 compared to their baseline levels and time-matched control. In conclusion, dehydration alone, or in presence of Angiotensin II AT1 receptor blocker caused significant decrease in the circulating levels of IGF-1 and IGFBP-3 compared to their basal values and to time-matched controls. Losartan enhanced the effect of dehydration mainly in the early phase of dehydration for both parameters; albeit, no significant differences between the two dehydrated groups was observed. Finally, these findings suggest an essential role of IGF-1and IGFBP-3 in the dehydration state of these dromedarian camels.

    Nyckelord
    Camel, Dehydration, IGF-1, IGFBP-3, Losartan
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-193751 (URN)10.1007/s00580-012-1562-y (DOI)
    Tillgänglig från: 2013-02-06 Skapad: 2013-02-06 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    4. ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Öppna denna publikation i ny flik eller fönster >>ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 3, s. e57806-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-200116 (URN)10.1371/journal.pone.0057806 (DOI)000316849200019 ()
    Tillgänglig från: 2013-05-21 Skapad: 2013-05-20 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    5. Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
    Öppna denna publikation i ny flik eller fönster >>Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
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    2013 (Engelska)Ingår i: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, s. 232-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Our objectives were to document and compare plasma levels of Catecholamines, Cortisol,Glutathione and Malondialdehyde in camels after long term dehydration (20 days) in the presenceor absence of angiotensin II AT1 receptor blocker (Losartan) versus levels in non-dehydratedcamels; and to record the effects on glutathione and malondialdehyde activity in liver and kidneyhomogenate in the one-humped camel. Eighteen male camels were used in this study, sixcontrols, six dehydrated and treated with losartan (5mg/kg daily) and six were dehydrated withouttreatment. Our results revealed significant decrease (P<0.05) in plasma epinephrine level in bothtreated and dehydrated camels; while, Plasma norepinephrine showed significant increase in bothdehydrated groups (P< 0.01). Levels of plasma dopamine were also significantly increased (P<0.01) in both dehydrated groups compared to control camels.Plasma levels of cortisol increased significantly across dehydration with or without losartanadministration (P<0.01) compared with time-matched levels in control camels. Losartan had nosignificant modulating effect on the cortisol response to dehydration.Plasma, liver and kidney homogenates revealed significant increase (P<0.05) in glutathione levelsin both dehydrated groups compared to control.Plasma, liver and kidney homogenates for malondialdehyde levels in both treated and dehydratedcamels also showed significant increase (P<0.05 & P<0.01) compared to controls.In conclusion, our study demonstrates that the effect of dehydration with or without losartaninduced oxidative stress in these camels, leading to significant changes in plasma catecholaminesand cortisol levels, together with significant increments in glutathione and malondialdehydeactivities in plasma, liver and kidney homogenate to counter act the damaging effect of the freeradicals in the dehydrated camels.

    Nyckelord
    Camel, Catecholamine, Cortisol, dehydration, Glutathione and Malondialdehyde
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-207417 (URN)10.1186/1746-6148-9-232 (DOI)000329620900001 ()
    Tillgänglig från: 2013-09-13 Skapad: 2013-09-13 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
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    presentationsbild
  • 121.
    Al Haj, Mahmoud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Nagelkerke, Nicolas
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nicholls, Gary M.
    Otago University, Christchurch.
    Adem, Abdu
    United Arab Emirates University.
    Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel2011Ingår i: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, nr 2, s. 73-78Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

    Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

    Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

    Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

  • 122.
    Al Jabri, Nagham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Utvärdering av deltagarnas upplevelse och uppfattning om projektet Hälsoaktiv2018Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 123.
    Al Shemaili, Jasem
    et al.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Parekh, Khatija A.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Newman, Robert A.
    Phoenix Biotechnol Inc, San Antonio, TX 78217 USA..
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Woodward, Carl
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adem, Abdu
    United Arab Emirates Univ, Dept Pharmacol, Fac Med, POB 17666, Al Ain, U Arab Emirates..
    Collin, Peter
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adrian, Thomas E.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer2016Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, nr 6, artikel-id 115Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

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  • 124. Alaerts, Maaike
    et al.
    Ceulemans, Shana
    Forero, Diego
    Moens, Lotte N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    De Zutter, Sonia
    Heyrman, Lien
    Lenaerts, An-Sofie
    Norrback, Karl-Fredrik
    De Rijk, Peter
    Nilsson, Lars-Göran
    Goossens, Dirk
    Adolfsson, Rolf
    Del-Favero, Jurgen
    Support for NRG1 as a susceptibility factor for schizophrenia in a northern Swedish isolated population.2009Ingår i: Archives of General Psychiatry, ISSN 0003-990X, E-ISSN 1538-3636, Vol. 66, nr 8, s. 828-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CONTEXT: Neuregulin 1 (NRG1), a growth factor involved in neurodevelopment, myelination, neurotransmitter receptor expression, and synaptic plasticity, first joined the list of candidate genes for schizophrenia when a 7-marker haplotype at the 5' end of the gene (Hap(ICE)) was shown to be associated with the disorder in the Icelandic population. Since then, more genetic and functional evidence has emerged, which supports a role for NRG1 in the development of schizophrenia.

    OBJECTIVE: To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population.

    DESIGN: Detailed linkage disequilibrium (LD)-based patient-control association study. This is the first study to type and analyze the 7 Hap(ICE) markers and a set of 32 HapMap tagging single-nucleotide polymorphisms (SNPs) that represents variants with a minor allele frequency of at least 1% and fully characterizes the LD structure of the 5' part of NRG1.

    SETTING: Outpatient and inpatient hospitals.

    PARTICIPANTS: A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population.

    MAIN OUTCOME MEASURES: Association between markers and disease.

    RESULTS: Analysis of the Hap(ICE) markers showed the association of a 7-marker and 2-microsatellite haplotype, different from the haplotypes associated in the Icelandic population and overrepresented in northern Swedish control individuals. Subsequently, a more detailed analysis that included all 37 genotyped SNPs was performed by investigating haplotypic association, dependent and independent of LD block structure. We found significant association with 5 SNPs located in the second intron of NRG1 (.007 </= P </= .04). Also, 2-, 3-, and 4-SNP windows that comprise these SNPs were associated (P < 3 x 10(-4)). One protective haplotype (0% vs 1.8%; P <5 x 10(-5)) and 1 disease risk-causing haplotype (40.4% vs 34.9%, P = .02) were defined.

    CONCLUSION: The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.

  • 125.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Alzheimer's disease-related lesions2013Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, nr Suppl 1, s. S173-S179Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The invitation to contribute to "Alzheimer's Disease: Advances for a New Century" gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.

  • 126.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Tau pathology in aging and AD: beyond neurofibrillary tangles (grains, astrocytes, etc.)2014Ingår i: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 24, nr S1, s. 20-21Artikel i tidskrift (Övrigt vetenskapligt)
  • 127.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Aho, L
    Helisalmi, S
    Mannermaa, A
    Soininen, H
    Beta-amyloid deposition in brains of subjects with diabetes2009Ingår i: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 35, nr 1, s. 60-68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM:

    A causative association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been suggested based on clinical and epidemiological studies. One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta). Thus, in diabetics, insulin and Abeta might compete for IDE and this might lead to an increase in Abeta. The objective of this study was to test the hypothesis that hyperinsulinaemia can elevate Abeta levels and thus contribute to AD pathology in humans.

    METHODS:

    Neuropathological examination was carried out employing conventional and immunohistochemical (IHC) methods of the brains obtained post mortem from 701 aged subjects.

    RESULTS:

    The loads of IHC/Abeta, silver stained neuritic plaques (NP) and neurofibrillary tangles (NFT) were significantly higher in subjects carrying the Apolipoprotein E e4 allele. In contrast, the loads of Abeta, NPs and NFT in the brains were not influenced by hyperglycaemia when comparing 134 diabetic with 567 non-diabetic subjects.

    CONCLUSIONS:

    We conclude that the hypothesis that hyperinsulinaemia would significantly elevate the Abeta load and thus increase the extent of AD pathology cannot be supported. Our result challenges the claim that DM is a direct risk factor of developing AD. Thus further studies on pathological lesions in demented diabetics should be conducted.

  • 128.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Parkkinen, Laura
    Staged pathology in Parkinson's disease2014Ingår i: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 20, nr Suppl. 1, s. S57-S61Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There has been a tremendous development since a regional progression of pathology in subjects with Lewy bodies (LB) was initially proposed 30 years ago. The entity of dementia with Lewy bodies has been acknowledged, the main protein constituent of LBs--aggregated α-synuclein (αS)--has been identified and a stepwise progression of the pathology has been reported. Implementation of the staging strategies published provides a common ground for handling a case with a suspected α-synucleinopathy. It is always important to state the staging strategy implemented while assessing a case, as the strategy applied might influence both the reported stage of LB pathology and, ultimately, the final diagnosis of the patient.

  • 129.
    Alafuzoff, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pikkarainen, Maria
    Univ Eastern Finland, Dept Clin Med, Kuopio, Finland.
    Neumann, Manuela
    Univ Tubingen, German Ctr Neurodegenerat Dis, Dept Neuropatol, Tubingen, Germany; DZNE, Tubingen, Germany.
    Arzberger, Thomas
    Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany.
    Al-Sarraj, Safa
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Bodi, Istvan
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Bogdanovic, Nenad
    Univ Oslo, Inst Clin Med, Dept Geriatr, Oslo, Norway.
    Bugiani, Orso
    IRCSS Fdn Ist Neurol Carlo Besta, Div Neuropathol & Neurol 5, Milan, Italy.
    Ferrer, Isidro
    Univ Barcelona, CEBERNED, Bellvitge Univ Hosp, Inst Neuropathol, Barcelona, Spain.
    Gelpi, Ellen
    Biobanc Hosp Clin IDIBAPS, Neurol Tissue Bank, Barcelona, Spain.
    Gentleman, Stephen
    Univ London Imperial Coll Sci Technol & Med, Dept Med, Neuropathol Unit, London, England.
    Giaccone, Giorgio
    IRCSS Fdn Ist Neurol Carlo Besta, Div Neuropathol & Neurol 5, Milan, Italy.
    Graeber, Manuel B.
    Univ Sydney, Fac Med, Sydney, NSW 2006, Australia; Univ Sydney, Fac Hlth Sci, Brain & Mind Res Inst, Sydney, NSW 2006, Australia.
    Hortobagyi, Tibor
    Univ Debrecen, Instutute Pathol, Dept Neuropathol, Debrecen, Hungary.
    Ince, Paul G.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Ironside, James W.
    Univ Edinburgh, Western Gen Hosp, Natl CJD Res & Surveillance Unit, Edinburgh, Midlothian, Scotland.
    Kavantzas, Nikolaos
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    King, Andrew
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Korkolopoulou, Penelope
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    Kovács, Gábor G.
    Med Univ Vienna, Inst Neurol, Vienna, Austria.
    Meyronet, David
    Univ Lyon, Hosp Civils Lyon, Ctr Pathol & Neuropathol Est, Lyon Neurosci Res Ctr, Lyon, France.
    Monoranu, Camelia
    Univ Wurzburg, Abt Neuropathol, Pathol Inst, D-97070 Wurzburg, Germany.
    Nilsson, Tatjana
    Karolinska Inst, Dept Geriatr, Stockholm, Sweden.
    Parchi, Piero
    Univ Bologna, Ist Sci Neurol, Dept Biomed & Neuromotor Sci, IRCCS, Bologna, Italy.
    Patsouris, Efstratios
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    Revesz, Tamas
    UCL Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England.
    Roggendorf, Wolfgang
    Univ Wurzburg, Abt Neuropathol, Pathol Inst, D-97070 Wurzburg, Germany.
    Rozemuller, Annemieke
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands.
    Seilhean, Danielle
    Univ Paris 06, AP HP, Lab Neuropathol Raymond Escourolle, Paris, France; INSERM, Paris, France.
    Streichenberger, Nathalie
    Univ Lyon, Hosp Civils Lyon, Ctr Pathol & Neuropathol Est, Lyon Neurosci Res Ctr, Lyon, France.
    Thal, Dietmar R.
    Univ Ulm, Inst Pathol, Neuropathol Lab, D-89069 Ulm, Germany.
    Wharton, Stephen B.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Kretzschmar, Hans
    Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany.
    Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium2015Ingår i: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 122, nr 7, s. 957-972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

  • 130.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Thal, Dietmar R.
    Arzberger, Thomas
    Bogdanovic, Nenad
    Al-Sarraj, Safa
    Bodi, Istvan
    Boluda, Susan
    Bugiani, Orso
    Duyckaerts, Charles
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Graeber, Manuel
    Hortobagyi, Tibor
    Höftberger, Romana
    Ince, Paul
    Ironside, James W.
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G.
    Meyronet, David
    Monoranu, Camelia
    Nilsson, Tatjana
    Parchi, Piero
    Patsouris, Efstratios
    Pikkarainen, Maria
    Revesz, Tamas
    Rozemuller, Annemieke
    Seilhean, Danielle
    Schulz-Schaeffer, Walter
    Streichenberger, Nathalie
    Wharton, Stephen B.
    Kretzschmar, Hans
    Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium2009Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 117, nr 3, s. 309-320Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer's disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.

  • 131.
    Alaie, Iman
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Marteinsdottir, Ina
    Hartvig, Per
    Tillfors, Maria
    Eriksson, Elias
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Serotonin Synthesis Rate and the Tryptophan Hydroxylase-2 G-703T Polymorphism in Social Anxiety Disorder2014Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 75, nr 9, s. 357S-357SArtikel i tidskrift (Övrigt vetenskapligt)
  • 132.
    Alajlani, M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Karl Franzens Univ Graz, Inst Pharmaceut Sci, Dept Pharmacognosy, Univ Pl 4, A-8010 Graz, Austria..
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Predicting the mechanism of action of antituberculosis agents using chemical global positioning system - natural product2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 133.
    Alamgir, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Uppföljning av PRISS-riktlinjer för antibiotikaprofylax vid elektiv knäprotesoperation på Södersjukhuset2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund och syfte: Södersjukhusets avdelning för vård och omsorg (vo) Ortopedi har inte tidigare i någon större utsträckning undersökt följsamheten till PRISS-riktlinjer som används för att förhindra protesrelaterade infektioner (PJI). Syftet med arbetet var att undersöka följsamheten av PRISS-riktlinjer för antibiotikaprofylax (ABP) vid elektiv knäprotesoperation (KPO) på Södersjukhuset vo Ortopedi. Resultatet från arbetet kommer användas som grund för kvalitetshöjande åtgärder.

    Metod: Journalgranskning utfördes av 273 elektiva KPO som opererats år 2016. Information kring ABP, operationstid, riskfaktorer och så vidare, extraherades ur journalerna och jämfördes sedan mot PRISS-riktlinjer. En annan metod användes för att jämföra icke-infekterade patienter från 2016 med infekterade patienter från år 2016 och år 2017 med hänseende på riskfaktorer. Två patienter som opererats under år 2016 och infekterats exkluderades från den icke infekterade populationen. Med en revisionsriskmodell jämfördes riskfaktorerna för 271 icke-infekterade patienter och fyra infekterade patienter.

    Resultat: Profylax av kloxacillin och klindamycin gavs i adekvat tid till 48,2 % respektive 57,1 % av patienterna. De fyra PJI-fallen hade alla fått ABP-behandling som avvikit från PRISS- riktlinjerna. En patient erhöll fick ingen dos kloxacillin innan operation utan den gavs postoperativt. Medianen för revisionsrisken hos de två grupperna var 2,7 % för icke- infekterade och 2,5 % för infekterade patienter.

    Slutsats: Följsamheten till PRISS- riktlinjerna var låg för både kloxacillin och klindamycin. Klindamycin gavs i stor utsträckning enligt samma doseringsschema som kloxacillin. Ortopediska avdelningens dokument ”ABP vid ortopediska ingrepp”, vilken används som förskrivarstöd för ABP är otydligt översatt från PRISS-riktlinjer. De fyra PJI patienterna fick ABP utanför PRISS- riktlinjer.

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  • 134.
    Alander, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Combination of β-lactam Aztreonam and β-lactamase Inhibitor Avibactam: Differences between Predictions from a Semi-Mechanistic PKPD-Model based on Static Time-Kill Studies and Data from a Hollow Fiber Infection Model (HFIM)2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction: The β-lactam antibiotic aztreonam (ATM) interfere with the cell wall synthesis of Gram-negative bacteria to induce cell death. Bacteria become resistant by producing β-lactamases. Avibactam (AVI), a β-lactamase inhibitor, can protect ATM from degradation due to β-lactamases. An ongoing project at the INSERM Unit of Pharmacology of Antimicrobial Agents in Poitiers, France, aims to investigate the pharmacokinetic and pharmacodynamic (PKPD) features of ATM/AVI on 4 strains of enterobacteria using a semi-mechanistic PKPD model based on static time-kill studies. The intention is to validate the model with a hollow fiber infection model (HFIM). HFIM is a dynamic in vitro model mimicking the drug half-life that can be used to study different posologies to find a suitable dosing regimen. The first HFIM trials show a bacterial killing distinctly faster than predicted  and can not be used as validation.

    Aim: To explain the faster bacterial killing in HFIM. Several theories are examined.

    Methods: Comparing model simulations with static and dynamic HFIM experiments, to find an intrinsic feature of the HFIM system that could explain the differences in bacterial behaviour.

    Results: It seems like a high flow from the central compartment to the cartridge could increase the bacterial killing. This could be due to a high input of nutrients, a high antibiotic exposure and by β-lactamases or bacterial signal substances being “washed” out of the cartridge.

    Conclusion: When using HFIM as a validation method, it is important to be aware of factors that can affect the bacterial behaviour in the model. For bacterial strains producing β-lactamses this is particulary important. Eventhough, the HFIM could still be useful for simulating different posologies.

  • 135.
    Al-Ani, Nadhim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    An experimental study of the complexation between Cu(2+) and some a-amino acids with emphasis on stereoselective effects1984Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 136.
    Alassaad, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Improving the Quality and Safety of Drug Use in Hospitalized Elderly: Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.

    The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.

    Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.

    The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.

    The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization. 

    Delarbeten
    1. Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial
    Öppna denna publikation i ny flik eller fönster >>Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, s. e62401-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. Methods: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. Results: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. Conclusion: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-203295 (URN)10.1371/journal.pone.0062401 (DOI)000319107900008 ()
    Tillgänglig från: 2013-07-08 Skapad: 2013-07-08 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing
    Öppna denna publikation i ny flik eller fönster >>The effects of pharmacist intervention on emergency department visits in patients 80 years and older: subgroup analyses by number of prescribed drugs and appropriate prescribing
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    2014 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, s. e111797-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Clinical pharmacist interventions have been shown to have positive effect on occurrence of drug-related issues as well as on clinical outcomes. However, evidence about which patients benefiting most from the interventions is limited. We aimed to explore whether pharmacist intervention is equally effective in preventing emergency department (ED) visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing. Methods: Patient and outcome data from a randomized controlled trial exploring the clinical effects of a ward-based pharmacist intervention in patients, 80 years and older, were used. The patients were divided into subgroups according to the number of prescribed drugs (< 5 or >= 5 drugs) and the level of inappropriate prescribing [using the Screening Tool Of Older People's potentially inappropriate Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) with a score of >= 2 (STOPP) and >= 1 (START) as cutoff points]. The effect of the intervention on the number of times the different subgroups visited the ED was analyzed. Results: The pharmacist intervention was more effective with respect to the number of subsequent ED visits in patients taking < 5 drugs on admission than in those taking >= 5 drugs. The rate ratio (RR) for a subsequent ED visit was 0.22 [95% confidence interval (CI) 0.09-0.52] for,5 drugs and 0.70 (95% CI 0.47-1.04) for >= 5 drugs (p = 0.02 for the interaction). The effect of intervention did not differ between patients with high or low STOPP or START scores. Conclusion: In this exploratory study, the pharmacist intervention appeared to be more effective in preventing visits to the ED for patients who were taking fewer drugs before the intervention. Our analysis of STOPP and START scores indicated that the level of inappropriate prescribing on admission had no effect on the outcomes of intervention with respect to ED visits.

    Nyckelord
    clinical pharmacy, medication review, inappropriate prescribing, polypharmacy, geriatrics
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:uu:diva-234485 (URN)10.1371/journal.pone.0111797 (DOI)000345558100122 ()25364817 (PubMedID)
    Tillgänglig från: 2014-10-20 Skapad: 2014-10-20 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
    3. A tool for prediction of risk of rehospitalization and mortality in hospitalized elderly
    Öppna denna publikation i ny flik eller fönster >>A tool for prediction of risk of rehospitalization and mortality in hospitalized elderly
    Visa övriga...
    (Engelska)Artikel i tidskrift (Refereegranskat) Submitted
    Abstract [en]

    Importance: Older patients with multiple co-morbidities and multi-drug use are at high risk of revisits to hospital and mortality, which poses an increasing health economic burden.

    Objective: To construct and internally validate a risk score, the “80+ score”, for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person’s Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI).

    Design: Secondary use of data from a randomized controlled trial investigating effects of a comprehensive pharmacist intervention, conducted in 2005-2006.

    Setting: Two acute internal medicine wards at Uppsala University hospital.

    Participants: Data from 368 patients, 80 years and older, admitted to one of the study wards.

    Main outcomes and measures: Time to rehospitalization or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk-estimation was constructed.  The score was internally validated, and the discriminatory ability of the new score and of STOPP, START and MAI was assessed using C-statistics.

    Results: Seven variables were selected for the 80+ score. Impaired renal function, pulmonary disease (chronic obstructive pulmonary disease [COPD or asthma]), malignant disease (past or present), living in nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease was associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+ score), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI).

    Conclusion and Relevance: We developed and internally validated a score for prediction of risk of rehospitalization and mortality in hospitalized older people. The score discriminated risk considerably better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions. 

    Nyckelord
    Geriatrics, drugs, risk-estimation, polypharmacy, pharmacotherapy
    Nationell ämneskategori
    Klinisk medicin
    Identifikatorer
    urn:nbn:se:uu:diva-234487 (URN)
    Tillgänglig från: 2014-10-20 Skapad: 2014-10-20 Senast uppdaterad: 2015-02-03Bibliografiskt granskad
    4. Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study
    Öppna denna publikation i ny flik eller fönster >>Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study
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    2013 (Engelska)Ingår i: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, nr 1, s. 185-191Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

    Nyckelord
    medication error, medication reconciliation, multi-dose dispensed medications, patient safety, prescription error, transition of care
    Nationell ämneskategori
    Samhällsfarmaci och klinisk farmaci
    Forskningsämne
    Farmaceutisk vetenskap; Farmakokinetik och läkemedelsterapi
    Identifikatorer
    urn:nbn:se:uu:diva-167137 (URN)10.1111/j.1365-2753.2011.01798.x (DOI)000314114400026 ()
    Tillgänglig från: 2012-01-22 Skapad: 2012-01-22 Senast uppdaterad: 2018-01-12
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  • 137.
    Alassaad, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Gillespie, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Bertilsson, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Prescription and transcription errors in multidose-dispensed medications on discharge from hospital: an observationaland interventional study2013Ingår i: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 19, nr 1, s. 185-191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background 

    Medication errors frequently occur when patients are transferred between health care settings. The main objective of this study was to investigate the frequency, type and severity of prescribing and transcribing errors for drugs dispensed in multidose plastic packs when patients are discharged from the hospital. The secondary objective was to correct identified errors and suggest measures to promote safe prescribing.

    Methods 

    The drugs on the patients' multidose drug dispensing (MDD) order sheets and the medication administration records were reconciled prior to the MDD orders being sent to the pharmacy for dispensing. Discrepancies were recorded and the prescribing physician was notified and given the opportunity to change the order. Discrepancies categorized as unintentional and related to the discharge process were subject to further analysis.

    Results 

    Seventy-two (25%) of the 290 reviewed MDD orders had at least one discharge error. In total, 120 discharge errors were identified, of which 49 (41%) were assessed as being of moderate and three (3%) of major severity. Orders with a higher number of medications and orders from the orthopaedic wards had a significantly higher error rate.

    Conclusion 

    The main purpose of the MDD system is to increase patient safety by reducing medication errors. However, this study shows that prescribing and transcribing errors frequently occur when patients are hospitalized. Because the population enrolled in the MDD system is an elderly, physically vulnerable group with a high number of prescribed drugs, preventive measures to ensure safe prescribing of MDD drugs are warranted.

  • 138.
    Alavian-Ghavanini, Ali
    et al.
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Lin, Ping-I
    Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Rimfors, Sabina Risen
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lejonklou, Margareta Halin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Dunder, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Tang, Mandy
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lindh, Christian
    Lund Univ, Div Occupat & Environm Med, S-22185 Lund, Sweden.
    Bornehag, Carl-Gustaf
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA;Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Rueegg, Joelle
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 11315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.

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  • 139.
    Alberti, Jean-Christophe
    et al.
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France.;Univ Toulouse, INSA, UPS, INP,LISBP, 135 Ave Rangueil, F-31077 Toulouse, France..
    Mariani, Magali
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    de Caraffa, Virginie Brunini-Bronzini
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    Gambotti, Claude
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    Oliw, Ernst H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Berti, Liliane
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    Maury, Jacques
    Univ Corse, Lab Biochim & Biol Mol Vegetales, CNRS SPE UMR6134, Campus Grimaldi,BP52, F-20250 Corte, France..
    A functional role identified for conserved charged residues at the active site entrance of lipoxygenase with double specificity2016Ingår i: Journal of Molecular Catalysis B: Enzymatic, ISSN 1381-1177, E-ISSN 1873-3158, Vol. 123, s. 167-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Plant lipoxygenases (LOXs) are a class of widespread dioxygenases catalyzing the hydroperoxidation of free polyunsaturated fatty acids, producing 9-hydroperoxides or 13-hydroperoxides from linoleic and alpha-linolenic acids, and are called 9-LOX or 13-LOX, respectively. Some LOXs produce both 9- and 13- hydroperoxides. The models proposed to explain the reaction mechanism specificity fail to explain the "double specificity" character of these LOXs. In this study, we used the olive LOX1 with double specificity to investigate the implication of the charged residues R265, R268, and K283 in the orientation of the substrate into the active site. These residues are present in a conserved pattern around the entrance of the active site. Our results show that these residues are involved in the penetration of the substrate into the active site: this positive patch could capture the carboxylate end of the substrate, and then guide it into the active site. Due to its position on alpha 2 helix, the residue K283 could have a more important role, its interaction with the substrate facilitating the motions of residues constituting the "cork of lipoxygenases" or the alpha 2 helix, by disrupting putative hydrogen and ionic bonds.

  • 140.
    Albertsson, Lovisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effekt och säkerhet av anti-IL-5-behandling vid måttlig till svår eosinofil astma – en systematisk litteraturöversikt2018Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Abstrakt

    Introduktion

    Vid astma är luftrören kroniskt inflammerade och immunförsvarets celler är involverade. En sådan typ av celler är eosinofiler och en typ av astma är eosinofil astma. Eosinofiler aktiveras av interleukin-5 (IL-5) och därmed är IL-5 och dess receptor lämpliga mål för behandling. År 2018 fanns tre läkemedel med tre olika monoklonala antikroppar, mepolizumab, reslizumab och benralizumab, där det första av läkemedlen blev godkänt 2015. Forskningsläget utifrån studier publicerade efter mars 2017 var ej sammanställt.

    Syfte

    Att via systematiska litteratursökningar undersöka om tillägg av anti-IL-5-behandling till standardbehandling vid astma kunde minska antalet exacerbationer, förbättra lungfunktionen och förbättra livskvalitén hos vuxna och barn över 12 år med måttlig till svår eosinofil astma, samt att utvärdera hur vanliga biverkningar var i samband med behandlingen.

    Material och metoder

    Systematiska litteratursökningar genomfördes i databasen PubMed och begränsningar gjordes till artiklar publicerade efter 1 mars 2017. Urval gjordes i tre steg efter titel, abstrakt och artikel i fulltext. Relevans bedömdes utifrån mallar från SBU och de artiklar som ansågs vara relevanta kvalitetsgranskades sedan efter mallar från SBU.

    Resultat

    Fem artiklar inkluderades, tre stycken hade undersökt benralizumab och de resterande två mepolizumab respektive reslizumab. I studien om mepolizumab minskades antalet exacerbationer med statistisk signifikans. I studien om reslizumab kunde statistiska signifikanta förbättringar identifieras med avseende på FEV1 och livskvalité. För benralizumab kunde förbättringar av FEV1, livskvalité och minskningar av antalet exacerbationer identifieras. Studien om mepolizumab var liten och det var oklart om uppföljningen av biverkningar var systematisk. I studien om reslizumab upplevde 9 % av patienterna incidenter som kunde relateras till behandlingen. I studierna om benralizumab var allvarliga incidenter relativt ovanliga. De flesta vanliga biverkningarna var representerade i alla tre studierna och bland dem var de vanligaste nasofaryngit och förvärrad astma.

    Slutsats

    Tendenser fanns till att anti-IL-5-behandling kunde minska antalet exacerbationer, förbättra lungfunktionen och livskvalitén hos vuxna och barn över 12 år med måttlig till svår eosinofil astma och samtidig standardbehandling. Behandlingen föreföll endast i liten grad ge allvarliga biverkningar, men fler och mer långsiktiga studier behövs inom det området.

  • 141.
    Albin, Linn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    En klinisk farmaceuts arbete i primärvården – Uppföljning av läkemedelsgenomgångar2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Den ständigt växande befolkningen med ökad andel äldre medför en högre läkemedelsbörda och en mer komplex medicinsk behandling. Ett föreslaget sätt att hantera den ökande läkemedelskomplexiteten är att inkorporera kliniskt arbetande apotekare i vårdkedjan för utförande av läkemedelsgenomgångar (LMG). Syfte: Huvudsyftet var att utvärdera resultatet av en klinisk apotekares LMG inom primärvården i Bålsta. Utvärderingen gjordes som en del i det pågående arbetet kring att undersöka om implementering av kliniskt arbetande apotekare inom den svenska primärvården kan förbättra patienters läkemedelsanvändning. Metoder: Utvärdering av 110 patienters läkemedelsgenomgångar utförda av apotekare vid två olika vårdcentraler gjordes med hjälp av kvalitetsverktyget ”Medication Appropriateness Index” (MAI). Även Socialstyrelsens publikation ”Indikatorer för god läkemedelsterapi hos äldre” samt interaktionsdatabasen Janusmed användes. Patientunderlag återfanns i det elektroniska journalsystemet Cosmic samt i fysiska dosrecept. Resultat: Förändring från 10,1 (± 8,9) poäng till 4,1 (± 4,7) poäng enligt MAI uppvisades i snitt efter genomförd LMG. Detta innebar en statistiskt signifikant minskning och därmed en ökad behandlingslämplighet. Antal olämpliga läkemedel var 23 före genomgång och 14 efter. Av apotekare framlagda förslag genererade en total genomförandefrekvens á 51%, där muntlig kommunikation medförde högst andel genomförda förslag. Sammanfattning: Utvärderingen visade en förbättring av läkemedelsbehandlingars lämplighet med avseende på MAI och antal förskrivna olämpliga läkemedel. Muntlig kommunikation genererade störst andel genomförda förslag och gynnade samarbetet mellan berörda professioner. Sammantaget verkar implementering av apotekarledda LMG i pirmärvården ha potential att bidra till en förbättrad läkemedelsanvändning.

  • 142.
    Albrecht, Inka
    et al.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wick, Cecilia
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Tjarnlund, Anna
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Nagaraju, Kanneboyina
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Andrade, Felipe
    Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA..
    Thompson, Kathryn
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Coley, William
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Phadke, Aditi
    Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA..
    Diaz-Gallo, Lina-Marcela
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Bottai, Matteo
    Karolinska Inst, Inst Environm Med, Unit Biostat, SE-17176 Stockholm, Sweden..
    Nennesmo, Inger
    Karolinska Inst, Dept Lab Med, SE-17176 Stockholm, Sweden..
    Chemin, Karine
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Johansson, Karin
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Wikberg, Anders
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Ytterberg, A. Jimmy
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Zubarev, Roman A.
    Karolinska Inst, Dept Med Biochem & Biophys, SE-17176 Stockholm, Sweden..
    Danielsson, Olof
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Neurol, Linkoping, Sweden..
    Krystufkova, Olga
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Vencovsky, Jiri
    Charles Univ Prague, Fac Med 1, Inst Rheumatol, Prague, Czech Republic.;Charles Univ Prague, Fac Med 1, Dept Rheumatol, Prague, Czech Republic..
    Landegren, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Dept Med Solna, Expt Rheumatol Unit, SE-17176 Stockholm, Sweden..
    Padyukov, Leonid
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Karolinska Inst, Dept Med Solna, Expt Endocrinol, SE-17176 Stockholm, Sweden..
    Lundberg, Ingrid E.
    Karolinska Inst, Dept Med Solna, Theumatol Unit, SE-17176 Stockholm, Sweden..
    Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies2015Ingår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, nr 12, s. 4612-4624Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

  • 143.
    al-breihi, ayat
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Development of an analytical method for the cyclotide MCoTI-I and assessment of its distribution in the central nervous system2017Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction: The plant derived cyclotide MCoTI-I’s (Momordica cochinchinensis trypsin inhibitor I) distribution in the central nervous system (CNS) was estimated in the project. Cyclotides were cyclic peptides characterized by a stabile chemical structure with extraordinary resistance against physiological degradation. This provided hope in development of MCoTI-I as a scaffold for drugs across the blood brain barrier (BBB).

    Aim: The project aimed for development of a bioanalytical method for MCoTI-I to use in vitro methods for characterization of pharmacokinetic parameters related to the distribution in the CNS, intended for future pharmaceutical development of MCoTI-I.

    Materials and Methods: Liquid Chromatography coupled to Mass Spectrometric system was used for bioanalysis. Equilibrium dialysis and the Brain Slice method was applied to obtain the fraction unbound (fu) in plasma and brain tissue, unbound distribution volume (Vu,brain) in the CNS and the unbound intra-to-extracellular concentration ratio (Kp,uu,cell). Kp,uu,brain  (unbound blood to brain concentration ratio at steady state) was calculated through data of MCoTI-I from a parallel ongoing project.

    Results: An analytical method was successfully developed with linearity R2-values of 0.999 in plasma and 0.988 in brain homogenate. Fu,plasma, fu,brain, Vu,brain, Kp,uu,cell and Kp,uu,brain  was quantified through the methods and equations.

    Conclusions:  MCoTI-I had a high binding to tissue and cellular uptake in the brain parenchyma. However, the cyclotide did not cross the BBB. The pharmacokinetic information could serve for future research on MCoTI-I in other organs and tissues. 

  • 144.
    Alchahin, Adele
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Role of the Dorsal Striatum and 5-HT2A receptor in a mouse model of autism2015Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    BACKGROUND: Some cases of autism spectrum disorder (ASD) are associated with genetic causes. A micro deletion on the human chromosome 16p11.2 is the most common. A mouse model with this deletion demonstrates functional abnormalities in the basal ganglia (BG), mainly the striatum. 5-HT2A receptors are also present in the striatum and may provide substrate for modulating the BG circuitry that possibly has a crucial role in ASD. AIM: To examine neuron activity in the striatum, qualitatively observe the distribution of the 5-HT2A receptor in the striatum and pharmacologically investigate serotonin 5-HT2A involvement in the behavioral abnormalities found in 16p11.2 deletion mice. METHODS: Expression of the gene product of c-fos was measured using immunohistochemistry to provide a measure of neural activity. Autoradiography was used to describe the distribution of the 5-HT2A receptors in the striatum. The effect of risperidone and M100907 on 16p11.2 deletion mice was assayed using the forced swim test. RESULTS: A significant increase in c-fos expression in the dorsal striatum in mutant mice was observed. Both normal and deletion mice exhibited receptor binding to 5-HT2A in the striatum. A significant decrease in mobility in the forced swim test in both mutant and wild type mice was observed only when risperidone was administrated compared to controls and M100907. CONCLUSION: Elevated c-fos expression in the dorsal striatum indicates altered activity in dorsal striatum in this ASD mouse model. 5-HT2A receptor binding in the striatum is qualitatively similar in both genotypes. Risperidone had a greater effect than M100907 in normalizing behavioral response in the swim, yet further dose-response and behavioral studies has to be done for more accurate determinations about the involvement of 5-HT2A as a possible pharmacological target for treatment in autism.

  • 145.
    Al-Darraji, Ahmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Division of Pharmacokinetics and Drug Therapy.
    Building and Validation of a Model to Predict the Unbound Drug Volume of Distribution in the Brain Based on Physicochemical Properties2019Självständigt arbete på grundnivå (högskoleexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion:

    Hjärnan har en skyddsmekanism när det gäller insläpp av ämnen, något som försvårar tillverkning av läkemedel som är avsedda att verka i hjärnan. Då är det viktigt att veta hur väl ett läkemedel distribueras i hjärnan i fri form, då det endast är den fria formen av läkemedlet som har den avsedda effekten. Den obundna distributionsvolymen av läkemedel i hjärnan (Vu,brain) är en parameter som beskriver hur väl läkemedlet binder till och distribueras i hjärnans celler och relaterar det till hjärnans fysiologiska volym. Dessutom tar Vu,brain hänsyn till var läkemedel binder, exempelvis om det binder till det avsedda proteinet eller inte, samt om läkemedlet blir inneslutet i cellen.

    Mål:

    Målet med studien är att använda en matematisk metod som på engelska heter Projection to Latent Structures (PLS) för att bygga en datormodell som förutspår Vu,brain av läkemedel utifrån dess egenskaper.

    Material och metod:

    Detta åstadkoms genom användning av en datamängd föreningar tagna från två publicerade artiklar från Friden et al. och Loryan et al. där datamängden totalt består av 81 föreningar och 158 egenskaper. Datamängden uppdelades så att 53 föreningar användes till modelluppbyggnaden och resterande 28 föreningar användes till att testa modellens prestanda i att förutspå Vu,brain.

    Resultat:

    En PLS-modell byggdes som kräver endast 12 egenskaper för att förutspå Vu,brain för läkemedel. Dessa egenskaper beskriver mestadels hur oljeaktigt läkemedlet är. Modellen lyckades förutspå 23 utav 28 föreningar som användes för testning av modellen.

    Diskussion:

    Modellen är fortfarande under utveckling och det krävs en utifrån inhämtad oberoende datamängd för att testa modellen så att modellen kan bli färdigställd.

  • 146.
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Studies on the importance and characterization of particle fragmentation during tabletting 1985Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 147.
    Alderborn, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Frenning, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mechanical strength of tablets2008Ingår i: Pharmaceutical Dosage Forms: Tablets, Volume 3: Manufacture and Process Control, New York: Informa Healthcare , 2008, 3Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 148.
    Aldi, S.
    et al.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Eriksson, L.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Kronqvist, M.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Lengquist, M.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Folkersen, L.
    Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark..
    Perisic, L.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Grinnemo, K. H.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Li, Jin-Ping
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hedin, U.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Osterholm, C.
    KFC Novum Karolinska Inst Huddinge, Dept Mol Med & Surg, S-14186 Stockholm, Sweden..
    Dual roles of heparanase in vascular calcification associated with human carotid atherosclerosis2017Ingår i: International journal of experimental pathology (Print), ISSN 0959-9673, E-ISSN 1365-2613, Vol. 98, nr 3, s. A5-A5Artikel i tidskrift (Övrigt vetenskapligt)
  • 149.
    Aldi, Silvia
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Eriksson, Linnea
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Kronqvist, Malin
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Lengquist, Mariette
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Löfling, Marie
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Folkersen, Lasse
    Tech Univ Denmark, Ctr Biol Sequence Anal, Copenhagen, Denmark.
    Matic, Ljubica P.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden;Tech Univ Munich, Dept Vasc Surg, D-80333 Munich, Germany.
    Grinnemo, Karl-Henrik
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Li, Jin-Ping
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Österholm, C.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Dual roles of heparanase in human carotid plaque calcification2019Ingår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 283, s. 127-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.

    Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.

    Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.

    Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.

  • 150.
    Aldskogius, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Regenerativ neurobiologi.
    Animal models of spinal cord repair2012Samlingsverk (redaktörskap) (Övrigt vetenskapligt)
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